IntroductionFunctional dyspepsia (FD) is a prevalent functional gastrointestinal disorder associated with oxidative stress (OS) and dysbiosis. Chaihushugan powder (CHSGP) demonstrates efficacy in treating FD; however, the underlying therapeutic mechanism is not yet elucidated. This study aims to investigate the effects of CHSGP on OS and gut microbiota (GM) in FD rats, with a particular emphasis on the role of GM as a potential target for the antioxidant properties of CHSGP.MethodsThe FD rat model was established with a modified tail-clamp stimulation and the administration of the CHSGP decoction at a dosage of 9.6 g/kg via gavage for a duration of 4 weeks. The GM was depleted by the administration of a cocktail of metronidazole (200 mg/kg), ampicillin (200 mg/kg), neomycin sulfate (200 mg/kg), and vancomycin (100 mg/kg). Fecal microbiota transplantation (FMT) was performed with CHSGP-treated fecal supernatant at a dosage of 10 mL/kg. The gastrointestinal motility was measured using the rates of gastric emptying and small intestine propulsion. Hematoxylin and eosin staining was employed to elucidate the pathological changes, while the transmission electron microscope was used to examine the microstructures of the interstitial cells of Cajal (ICC). Chemiluminescence, colorimetric assay, immunofluorescence co-staining, and western blot assay were employed to identify the OS-related markers (ROS, SOD, NOX4, PRDX1, and TRX2). Sequencing of fecal microbiota was performed utilizing 16S rDNA.ResultsThe CHSGP decoction promoted gastrointestinal motility, protected the microstructure of ICC, and reduced OS in FD rats. The GM composition was also regulated by CHSGP. However, these effects disappeared after microbiota depletion. Fortunately, the FMT therapy reinstated them.ConclusionChaihushugan powder decoction might regulate the GM to alleviate mitochondrial OS in the gastric tissues of FD rats.

Fecal incontinence (FI) is a common condition associated with aging. Asthma and chronic obstructive pulmonary disease (COPD) are obstructive lung diseases associated with both urinary incontinence and increased intraabdominal pressures. We sought to evaluate whether these obstructive lung diseases increase the risk of developing FI. We prospectively examined the association between asthma, COPD and asthma/COPD overlap and risk of FI among women from the Nurses’ Health Study (NHS). We defined incident FI as ≥ 1 liquid or solid FI episode/month during four years of follow-up using self-administered, biennial questionnaires (2008–2012). Validated self-report of asthma and COPD were used from 1988 to 2008. We used Cox proportional hazards models to calculate multivariable-adjusted hazard ratios (aHRs) and 95

INTRODUCTION:Few studies have evaluated multitarget stool DNA (mt-sDNA) in clinical practice. We analyzed mt-sDNA utilization at the University of Pittsburgh Medical Center. METHODS:We assessed mt-sDNA orders between January 1, 2017, and December 31, 2021. Data collection included electronic capture of mt-sDNA orders, completed stool submissions, and test results. Multivariable models were used to assess associations between mt-sDNA completion and results and age, sex, and race. RESULTS:There were 91,664 mt-sDNA orders in 73,704 patients. A total of 54.7% (40,337/73,704) completed an mt-sDNA test, and 7,424 (18.6%) tested positive. Completion rates increased by age <50-59 years (N = 12,818; 48.2%), 60-69 years (14,982; 56.3%), and ≥70 years (N = 9,850; 55.6%) ( P < 0.0001). The completion rate for males (52.7%; 15,297/29,025) did not differ significantly from females (53.3%; 22,353/41,901) ( P = 0.09). By race, the completion rates of White patients (54.1%; 34,874/64,512) and Asian patients (56.9%; 493/867) were higher than those of Black patients (38.8%; 1,699/4,376) ( P < 0.0001). Test completion declined with repeat mt-sDNA orders, with ≤32% completion rate after ≥3 orders. In a multivariable model, older age was associated with greater likelihood of a positive test (odds ratio 1.22, 95% confidence interval 1.20-1.24, P < 0.0001), and Black patients had lower odds of a positive test (odds ratio 0.65, 95% confidence interval 0.56-0.76, P < 0.0001). DISCUSSION:Only 54.7% of patients completed their mt-sDNA test order. Older individuals were more likely to complete testing and test positive. Black patients were less likely to complete testing and, unexpectedly, less likely to test positive. Further exploration of mt-sDNA utilization including better understanding of the determinants of uptake, appropriateness, and evaluation of outcomes at colonoscopy is needed.

BACKGROUND:Irritable bowel syndrome (IBS) is common among individuals with eating disorders. The relationship between these conditions is likely bidirectional. However, data on the risk of IBS among those with prior eating disorders is largely limited to cross-sectional studies. AIM:To prospectively evaluate the association between maladaptive weight control/eating behaviours in females during adolescence/young adulthood with subsequent IBS using the Growing Up Today Study (GUTS). METHODS:Starting in 1996 (age: 9-14) and during follow-up, participants reported frequency of maladaptive eating/weight control behaviours during the past year to lose weight: self-induced vomiting (n = 5740), laxative use (n = 5438), and fasting (n = 5522) in addition to reporting binge eating (n = 4459). Starting in 2001 and during follow-up, participants reported if they had ever been diagnosed with an eating disorder (n = 5316). Incident IBS cases were identified from four questionnaire cycles (2013, 2014, 2016, 2019), with participants specifying the year of diagnosis if occurring before the questionnaire date. Multivariable logistic regressions adjusting for age, body mass index, and depressive symptoms estimated the associations of interest. RESULTS:Maladaptive weight control/eating behaviours were associated with increased IBS risk [ORs (95% CIs) for laxatives to lose weight = 3.67 (2.52-5.35), vomiting to lose weight = 1.83 (1.29-2.60), fasting to lose weight = 2.62 (1.86-3.70), and bingeing = 2.25 (1.54-3.28)] as was history of eating disorder diagnosis [OR (95% CI) = 3.42 (2.38-4.90)]. The magnitude of IBS risk increased with the frequency of maladaptive behaviours. CONCLUSIONS:There is evidence for the potential role of early maladaptive weight control/eating behaviours in the development of adult IBS among females.

BACKGROUND & AIMS: Prior studies have suggested that proton pump inhibitor (PPI) use is associated with increased risk of dementia; however, these have been limited by incomplete assessment of medication use and failure to account for confounders. Furthermore, prior studies have relied on claims-based diagnoses for dementia, which can lead to misclassification. We investigated the associations of PPI and histamine-2 receptor antagonist (H2RA) use with dementia and cognitive decline. METHODS: We conducted a post hoc analysis of ASPirin in Reducing Events in the Elderly (ASPREE), a randomized trial of aspirin in the United States and Australia, including 18,934 community-based adults >65 years of all races/ethnicities. Baseline and recent PPI and H2RA use were determined according to review of medications during annual in-person study visits. Incident dementia was defined according to Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, criteria. Secondaryendpoints include cognitive impairment, no dementia (CIND) and changes in cognition. Associations of medication use with dementia and CIND outcomes were examined using Cox proportional hazards models. Changes in cognitive test scores were examined using linear mixed-effects models.RESULTS: Baseline PPI use vs nonuse was not associated with incident dementia (multivariable hazard ratio, 0.88; 95% confidence interval, 0.72-1.08), CIND (multivariable hazard ratio, 1.00; 95% confidence interval, 0.92-1.09), or with changes in overall cognitive test scores over time (multivariable B, -0.002; standard error, 0.01; P 1/4 .85). Similarly, no associations were observed between H2RA use and all cognitive endpoints.CONCLUSIONS: In adults >65 years of age, PPI and H2RA use were not associated with incident dementia, CIND, or decline in cognition over time. These data provide reassurance about the safety of long-term use of PPIs among older adults.

Mitochondria are key cytoplasmic organelles in eukaryotic cells that generate adenosine triphosphate (ATP) through the electron transport chain and oxidative phosphorylation. Mitochondrial DNA (mtDNA) copy number (mtDNAcn) is considered a biomarker for both mitochondrial quantity and function as well as cellular oxidative stress level. Previous epidemiologic findings revealed that weight gain, higher body mass index (BMI), smoking, and high insulinemic potential of lifestyle were associated with lower leukocyte mtDNAcn. Carnitines are a group of compounds that play a critical role in energy production. We quantified the associations of plasma L-carnitine levels with leukocyte mtDNAcn. We then examined the association between mtDNAcn and L-carnitine (HMDB0000062) in 538 U.S. men without cancers, diabetes, or cardiovascular disease at blood collection from the Health Professionals Follow-Up Study (HPFS). We found a significant inverse association between L-carnitine and mtDNAcn (ρ = −0.1, P = 0.02). This implies that the carnitine metabolic pathway may be associated with mitochondrial function and oxidative stress.

BACKGROUND:Preclinical studies have suggested potential beneficial effects of newer glucose-lowering drugs (GLDs) including dipeptidyl peptidase (DPP)-4 inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and sodium glucose co-transporter-2 (SGLT2) inhibitors, in protecting humans against cognitive decline and dementia. However, population studies aiming to demonstrate such cognitive benefits from newer GLDs have produced mixed findings. This meta-analysis aimed to evaluate the association between newer GLDs and risk of dementia in adults with type 2 diabetes (T2D). METHODS:Electronic databases were searched up to March 11, 2022 to include observational studies that examined the association between DPP-4 inhibitors, GLP-1RAs, and SGLT2 inhibitors and risk of dementia (including all-cause dementia, Alzheimer's disease [AD], and vascular dementia [VD]) in people with T2D. We conducted a random-effects meta-analysis to calculate the relative risk (RR) with 95% confidence interval (CI) for each class of newer GLD. RESULTS:Ten studies (from nine articles) involving 819,511 individuals with T2D were included. Three studies found that SGLT2 inhibitor users had a lower risk of all-cause dementia than non-SGLT2 inhibitor users (RR, 0.62; 95% CI, 0.39-0.97). Five studies found that users versus nonusers of GLP-1RAs were associated with a significant reduction in the risk of all-cause dementia (RR, 0.72; 95% CI, 0.54-0.97). However, a meta-analysis for AD and VD was unavailable for SGLT2 inhibitors and GLP-1RAs because only one study was included for each drug. In seven studies, users vs. nonusers of DPP-4 inhibitors were significantly associated with a decreased risk of all-cause dementia (RR, 0.84; 95% CI, 0.74-0.94) and VD (RR, 0.59; 95% CI, 0.47-0.75) but not AD (RR, 0.82; 95% CI, 0.63-1.08). CONCLUSION:Newer GLDs were associated with a decreased risk of all-cause dementia in people with T2D. Because of the observational nature and significant heterogeneity between studies, the results should be interpreted with caution. Further research is warranted to confirm our findings.

Fecal incontinence (FI) is a debilitating gastrointestinal disorder with a devastating impact on quality of life,1,2 particularly on older women, partly because of unique risk factors including parity and menopause.2,3 Therefore, identifying modifiable factors, such as diet, are crucial for developing effective prevention strategies for FI among those at risk. We previously found higher dietary fiber intake was associated with lower FI risk,4 providing the first population-based data to connect diet and FI prevention. However, prospective evidence on other dietary factors and FI risk has been limited. Dietary patterns may be associated with gut microbiome characteristics, which may influence inflammatory responses in the gastrointestinal tract5 and drive neurosensory disturbances.6 Moreover, chronic inflammation may drive reduced muscle mass and function,7 and pelvic floor dysfunction is an established FI risk factor.1,2 We hypothesized that a proinflammatory dietary pattern may be associated with increased FI risk and tested this hypothesis in the Nurses' Health Study.

Legends for Supplementary Figure and Table

Introduction We examined the associations of baseline telomere length (TL) and TL change with cognitive function over time in older US adults, as well as differences by sex and race. Methods A total of 1820 cognitively healthy individuals (median baseline age: 63 years) were included. Telomere length was measured using qPCR-based method at baseline and among 614 participants in the follow-up examination 10 years later. Cognitive function was assessed by a four-test battery every 2 years. Results In multivariable-adjusted linear mixed models, longer baseline TL and smaller attrition/lengthening of TL over time were associated with better Animal Fluency Test score. Longer baseline TL was also linearly associated with better Letter Fluency Test score. The observed associations were consistently more pronounced in women than men and in Black compared to White participants. Discussion Telomere length may be a biomarker that predicts long-term verbal fluency and executive function, particularly in women and Black Americans.

To the Editor: The metabolism of glutamine and glutamate, 2 important amino acids synthesized in the human body, may have an etiologic role in melanoma, an aggressive skin malignancy.1Shah R. Singh S.J. Eddy K. Filipp F.V. Chen S. Concurrent targeting of glutaminolysis and metabotropic glutamate receptor 1 (grm1) reduces glutamate bioavailability in grm1(+) melanoma.Cancer Res. 2019; 79: 1799-1809Crossref PubMed Scopus (16) Google Scholar,2Le M.N. Chan J.L. Rosenberg S.A. et al.The glutamate release inhibitor riluzole decreases migration, invasion, and proliferation of melanoma cells.J Invest Dermatol. 2010; 130: 2240-2249Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar Preclinical experiments and clinical trials have found that metabotropic glutamate receptor 1 blocker and glutamate release inhibitor (eg, Riluzole) can suppress melanoma cell migration, invasion, and proliferation.2Le M.N. Chan J.L. Rosenberg S.A. et al.The glutamate release inhibitor riluzole decreases migration, invasion, and proliferation of melanoma cells.J Invest Dermatol. 2010; 130: 2240-2249Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar Additionally, inhibiting glutaminase, the enzyme that converts glutamine to glutamate, further reduced glutamate bioavailability and suppressed tumor progression.1Shah R. Singh S.J. Eddy K. Filipp F.V. Chen S. Concurrent targeting of glutaminolysis and metabotropic glutamate receptor 1 (grm1) reduces glutamate bioavailability in grm1(+) melanoma.Cancer Res. 2019; 79: 1799-1809Crossref PubMed Scopus (16) Google Scholar Susceptibility to sunburn, a pigmentary trait, is a well-known risk factor for melanoma.3Wu S. Han J. Laden F. Qureshi A.A. Long-term ultraviolet flux, other potential risk factors, and skin cancer risk: a cohort study.Cancer Epidemiol Biomarkers Prev. 2014; 23: 1080-1089Crossref PubMed Scopus (93) Google Scholar However, it is unclear whether plasma glutamate and glutamine are affected by this host factor even before cancer onset. We hypothesized plasma glutamate/glutamine levels may differ by individuals' sunburn susceptibilities. To test this hypothesis, we examined the association among 9129 women from previous case-control studies nested within the Nurses' Health Study (NHS) I (n = 5981) and II (n = 3148).4Bao Y. Bertoia M.L. Lenart E.B. et al.Origin, methods, and evolution of the three nurses' health studies.Am J Pub Health. 2016; 106: 1573-1581Crossref PubMed Scopus (195) Google Scholar Nonwhites and participants with a history of skin cancer or any other malignancy prior to blood collection were excluded. Information on skin reaction after 2 or more hours' sun exposure as a child/adolescent was collected and grouped into 4 categories (ie, none/some redness only, burn, painful burn, painful burn with blisters). Plasma glutamate and glutamine concentrations were obtained using liquid chromatography-tandem mass spectrometry at the Broad Institute of MIT and Harvard University. Details of metabolite profiling methods have been published previously.5Mayers J.R. Wu C. Clish C.B. et al.Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development.Nat Med. 2014; 20: 1193-1198Crossref PubMed Scopus (366) Google Scholar Age and multivariable-adjusted linear regressions were performed, and percentage differences in levels of glutamate, glutamine, and glutamate/glutamine ratio between sunburn susceptibility groups were calculated using the following equation: [exp (β-coefficient) − 1] × 100%. All analyses were performed using SAS (Unix 9.4). Characteristics of participants by quintiles of glutamate/glutamine ratio are presented in Table I. We found a significant decreasing trend of glutamine (painful burn with blisters vs reference, –9.2% [–16.9%, –0.7%]; P trend = .005) and significant increasing trends of glutamate (painful burn with blisters vs reference, 19.9% [10.0%, 30.7%]; P trend < .0001) as well as glutamate/glutamine ratio (painful burn with blisters vs reference, 22.8% [12.6%, 33.8%]; P trend < .0001) across sunburn susceptibility groups (Table II). The association patterns were consistent and significant in the sensitivity analysis of controls-only samples (n = 4,672; painful burn with blisters vs reference: 13.4% [0.6%, 27.8%] for glutamate, –11.8% [–22.1%, –0.2%] for glutamine, 15.6% [2.6%, 30.2%] for glutamate/glutamine ratio). We did not find significant interactions of sunburn susceptibility and selected covariates (ie, age, smoking, body mass index, physical activity, alcohol consumption, Alternate Healthy Eating Index and personal history of diabetes, cardiovascular diseases, or hypercholesterolemia in relation to plasma glutamate/glutamine ratio (all P interaction > .05/7) (Supplementary Table I; available at https://doi.org/10.17632/h95pksd5jz.1).Table ICharacteristics of 9129 cancer-free participants from NHS I and II by quintiles of plasma glutamate/glutamine ratio∗Information presented was collected at the time of blood collection or at the questionnaire cycle closest to blood collection (NHS I: 1989-1990, NHS II: 1996-1999) except for otherwise noted. Values are means (SD) for continuous variables, percentages for categorical variables and are standardized to the age distribution of the study population except for age.CharacteristicsQuintile 1Quintile 2Quintile 3Quintile 4Quintile 5Number of participants18251826182618261826Age at blood collection, y51.5 (8.0)52.0 (8.3)52.7 (8.7)53.5 (8.6)53.1 (8.5)Plasma glutamate level, z-score–1.1 (0.5)–0.5 (0.5)–0.1 (0.5)0.4 (0.5)1.3 (0.8)Plasma glutamine level, z-score0.5 (0.9)0.2 (0.9)0.1 (0.9)–0.2 (0.9)–0.6 (1.0)Plasma glutamate/glutamine ratio, z-score–1.3 (0.3)–0.6 (0.1)–0.1 (0.1)0.5 (0.2)1.5 (0.6)Painful burn or blistering after ≥2h sun exposure, %13.515.118.220.221.3Red or blonde hair, %†Natural color of hair at 21 and 18 was asked in NHS I and II, respectively.14.816.115.617.817.7≥6 moles on the extremity, %‡Total number of moles greater than 3 mm diameter was asked for the left arm in NHS I, for both lower legs in NHS II.8.811.612.813.010.8Average July noontime erythemal UV, mW/m2188.7 (29.4)190.1 (29.2)189.8 (28.9)192.6 (30.5)191.4 (30.2)Body mass index, kg/m223.7 (3.5)24.6 (4.2)25.8 (4.7)26.8 (5.3)27.8 (6.1)Physical activity, metabolic equivalents, h/wk17.1 (18.8)17.5 (25.7)15.7 (19.1)17.0 (25.8)15.2 (18)Cigarette smoking Never smoker, %58.155.652.551.046.7 Past smoker, %31.533.435.335.940.3 Current smoker, %10.410.912.213.113.0Alcohol intake, g/d4.6 (7.8)5 (9.0)5.2 (9.3)5.6 (10.2)5.2 (9.4)Alternate healthy eating index46.6 (10.0)46.4 (10.0)46.4 (9.6)46.3 (9.9)46.5 (9.7)History of cardiovascular diseases0.80.91.10.91.6History of diabetes0.20.41.02.25.5History of hypercholesterolemia30.034.532.837.737.8∗ Information presented was collected at the time of blood collection or at the questionnaire cycle closest to blood collection (NHS I: 1989-1990, NHS II: 1996-1999) except for otherwise noted. Values are means (SD) for continuous variables, percentages for categorical variables and are standardized to the age distribution of the study population except for age.† Natural color of hair at 21 and 18 was asked in NHS I and II, respectively.‡ Total number of moles greater than 3 mm diameter was asked for the left arm in NHS I, for both lower legs in NHS II. Open table in a new tab Table IIPercentage differences (95% confidence intervals) in plasma levels of glutamate, glutamine, and glutamate/glutamine ratio according to sunburn susceptibility among 9129 cancer-free participants from NHS I and II∗Covariates adjusted in multivariable-adjusted model include continuous age, body mass index, physical activity, alcohol consumption, alternate healthy eating index, smoking status (never, past, current), fasting status, case-control status in previous nested case-control studies, history of diabetes, cardiovascular diseases or hypercholesterolemia, hair color (black/dark brown, light brown, blonde, red), mole counts (none, 1-2, 3-5, 6+), and cohort.None or some redness onlyBurnPainful burnPainful burn with blistersP for trendNumber of participants544520421106536Glutamate Age-adjusted model0 (ref)4.1% (–1.1%, 9.5%)15.2% (8.0%, 22.9%)34.7% (23.3%, 47.1%)<.0001 Multivariable-adjusted model0 (ref)1.7% (–3.1%, 6.8%)7.0% (0.5%, 13.9%)19.9% (10.0%, 30.7%)<.0001Glutamine Age-adjusted model0 (ref)–0.3% (−5.2%, 4.8%)–8.4% (–14.1%, –2.4%)–10.1% (–17.7%, –1.9%).002 Multivariable-adjusted model0 (ref)–0.4% (–5.4%, 4.7%)–8.0% (–13.8%, –1.8%)-9.2% (−16.9%, −0.7%).005Glutamate/glutamine ratio Age-adjusted model0 (ref)4.3% (–0.8%, 9.7%)17.7% (10.4%, 25.6%)37.6% (26.0%, 50.3%)<.0001 Multivariable-adjusted model0 (ref)2.0% (–2.9%, 7.1%)9.6% (2.9%, 16.7%)22.8% (12.6%, 33.8%)<.0001∗ Covariates adjusted in multivariable-adjusted model include continuous age, body mass index, physical activity, alcohol consumption, alternate healthy eating index, smoking status (never, past, current), fasting status, case-control status in previous nested case-control studies, history of diabetes, cardiovascular diseases or hypercholesterolemia, hair color (black/dark brown, light brown, blonde, red), mole counts (none, 1-2, 3-5, 6+), and cohort. Open table in a new tab Overall, our study found that being susceptible to sunburn, especially painful burn with blisters, was associated with higher glutamate and lower glutamine in plasma among cancer-free participants. Although several limitations are acknowledged, such as the women-only and cross-sectional study design, this is the first study that found a potential association between sunburn susceptibility (a highly heritable trait and melanoma risk factor) and plasma glutamate/glutamine (a target of antimelanoma therapy). Additionally, our epidemiologic findings provide evidence for future investigations in terms of whether glutamatergic signaling is a potential underlying pathway by which sunburn susceptibility alters melanoma risk. Further studies are needed to replicate our findings. None disclosed. We thank the participants and staff of the Nurses' Health Study (NHS) I and II for their valuable contributions.

BACKGROUND & AIMS:Interval colorectal cancers (CRCs), cancers diagnosed after a screening/surveillance examination in which no cancer is detected, and before the date of next recommended examination, reflect an unprecedented challenge in CRC detection and prevention. To better understand this poorly characterized CRC variant, we examined the clinical and mutational characteristics of interval CRCs in comparison with screen detected CRCs.METHODS:We included 1175 CRCs documented in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial and 3661 CRCs in the Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS). Multivariable Cox models were performed to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of death risk. Whole exome sequencing was conducted in 147 PLCO cases and 796 NHS/HPFS cases.RESULTS:A total of 619 deaths (312 CRC-specific) and 2404 deaths (1904 CRC-specific) were confirmed during follow-up of PLCO and NHS/HPFS, respectively. Compared with screen detected CRCs, interval CRCs had a multivariate-adjusted HR (95% CI) of 1.47 (1.21-1.78) for CRC-specific mortality and 1.27 (1.09-1.47) for overall mortality (meta-analysis combining all 3 cohorts). However, we did not observe significant differences in mutational features between interval and screen detected CRCs (false discovery rate adjusted P > .05).CONCLUSION:Interval CRCs had a significantly increased risk of death compared with screen detected CRCs that were not explained by established clinical prognostic factors, including stage at diagnosis. The survival disadvantage of interval CRCs did not appear to be explained by differences in the genomic landscape of tumors characterized by whole exome sequencing.

Background: Progressive telomere shortening may be related to genomic instability and carcinogenesis. Prospective evidence relating telomere length (TL) with colorectal cancer (CRC) risk has been limited and inconsistent. Methods: We examined the association between pre-diagnostic peripheral blood leukocyte TL and CRC risk in two matched case-control studies nested within the Nurses' Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS). Relative leukocyte TL was measured using qPCR among 356 incident CRC cases and 801 controls (NHS: 186/465, HPFS: 170/336). Results: We did not find a significant association between pre-diagnostic TL and CRC risk [in all participants, multivariable-adjusted odds ratio (OR) (95% CI) for TL Quartile 1 (shortest) vs. Quartile 4 (longest) = 1.36 (0.85, 2.17), P-trend = 0.27; OR (95% CI) per 1 SD decrease in TL = 1.12 (0.92, 1.36)]. Conclusions: Our prospective analysis did not support a significant association between pre-diagnostic leukocyte TL and CRC risk.