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Dose-limiting toxicities remain a major barrier to drug development and therapy, revealing the limited predictive power of human genetics. Herein, we demonstrate the utility of a more comprehensive approach to studying drug toxicity through longitudinal study of the human gut microbiome during colorectal cancer (CRC) treatment (NCT04054908) coupled to cell culture and mouse experiments. 16S rRNA gene sequencing revealed significant shifts in gut microbial community structure during oral fluoropyrimidine treatment across multiple patient cohorts, in mouse small and large intestinal contents, and in patient-derived ex vivo communities. Metagenomic sequencing revealed marked shifts in pyrimidine-related gene abundance during oral fluoropyrimidine treatment, including enrichment of the preTA operon, which is sufficient for the inactivation of active metabolite 5-fluorouracil (5-FU). preTA + bacteria depleted 5-FU in gut microbiota grown ex vivo and the mouse distal gut. Germ-free and antibiotic-treated mice experienced increased fluoropyrimidine toxicity, which was rescued by colonization with the mouse gut microbiota, preTA + E. coli , or preTA -high CRC patient stool. Finally, preTA abundance was negatively associated with fluoropyrimidine toxicity in patients. Together, these data support a causal, clinically relevant interaction between a human gut bacterial operon and the dose-limiting side effects of cancer treatment. Our approach is generalizable to other drugs, including cancer immunotherapies, and provides valuable insights into host-microbiome interactions in the context of disease., Competing Interests: Competing interests: W.A.K. has received research funding (institution) from Pfizer; there is no direct overlap with the current study. P.J.T. is on the scientific advisory boards of Pendulum, Seed and SNIPRbiome; there is no direct overlap between the current study and these consulting duties. C.E.A served on the scientific advisory board of Pionyr Immunotherapeutics and has received research funding (institution) from Bristol Meyer Squibb, Erasca, Gossamer Bio, Guardant Health, Kura Oncology, Merck and Novartis; there is no direct overlap with the current study. E.V.B. is on the medical advisory board for Fight CRC; there is no direct overlap with the current study. All other authors declare no competing interests.

Objectives: Visceral adipose tissue (VAT) is highly associated with metabolic syndrome (MetS), which is rapidly increasing in young adults. However, accessible VAT measurement methods are limited, restricting the use of VAT in early detection. This cross-sectional study sought to determine if near-infrared reactance spectroscopy (NIRS)-derived VAT (VAT NIRS ) was associated with MetS in a multi-ethnic sample of young adults., Methods: A total of 107 male and female (F:62, M:45) participants (age: 23.0 ± 4.3y; BMI: 27.1 ± 6.6 kg/m 2 ) completed measurements of fasting blood pressure, blood glucose (FBG), blood lipids, and anthropometric assessments including waist circumference and VAT NIRS . MetS severity (MetS index ) was calculated from the aforementioned risk factors using sex and race-specific equations., Results: VAT NIRS was higher in participants with, and at risk for, MetS compared to those with lower risks (all p < .001). VAT NIRS was positively associated with MetS index for all groups (all p < .001). VAT NIRS showed positive associations with systolic (SBP), diastolic (DBP), and mean arterial pressure (MAP), LDL-C and LDL-C-related biomarkers, and FBG; and negative associations with HDL-C and HDL-C-to-total cholesterol ratio (all p < .050). Associations between VAT NIRS and blood pressure for females, and LDL-C and LDL-C-related biomarkers for males, were nonsignificant (all p > .050). VAT NIRS was positively associated with DBP in African-American participants, and SBP in White participants, resulting in positive associations with MAP for both groups (all p < .050)., Conclusions: VAT NIRS is associated with MetS and individual MetS risks factors in a multi-ethnic sample of young adults; providing a noninvasive, cost-effective, portable, and accessible method that may assist in the early detection of MetS and other cardiometabolic abnormalities., (© 2024 Wiley Periodicals LLC.)

Background: The incidence of breast and colorectal cancer (CRC) in younger-than-average-age patients is rising and poorly understood. This is the largest study on patients with both cancers who are less than 60 years old and aims to characterize demographic, clinicopathologic, and genetic features and describe therapeutic dilemmas and management strategies., Materials and Methods: This is a retrospective medical records review of patients at the University of California San Francisco with both primary breast and CRC before age 60., Results: Fifty-one patients were identified; 41 had detailed medical records. Median age of diagnosis with breast cancer was 43 (range 27-59) and CRC was 50 (28-59). Most were Caucasian (38, 74.5%) and never smokers (23, 56.1%); about half were current alcohol consumers (20, 48.8%) and about one-third had sedentary jobs (14, 34.1%). Average BMI was 25.8 (range: 14-49), and 30% were overweight or obese. Breast was the first cancer diagnosed in 36 patients (70.6%) and 44 (86.3%) had a metachronous CRC diagnosis. Breast cancer was early stage (0-2) in 32 (78.0%) patients whereas CRC was split between early stage (1-2) in 14 (34.1%) and later stage (3-4) in 19 (46.2%). Ten patients (24.3%) had a known germline mutation, although 23 (56.1%) had a family history of cancer in a first-degree relative., Conclusion: Younger patients with both breast and CRC are a unique cohort, often without known risk factors. Alcohol consumption and sedentary jobs were the most common risk factors, and about one-quarter had a known genetic predisposition. Comanagement of both cancers requires individualized, multidisciplinary care., (© The Author(s) 2024. Published by Oxford University Press.)

Purpose: Persistent gastrointestinal (GI) symptoms are frequently experienced by colon cancer survivors and may help identify patients with higher utilization of healthcare services. To assess the relationship between GI symptoms and specialty care utilization among colon cancer survivors., Methods: A prospective longitudinal cohort study at an academic medical center of 126 adults surgically treated for stage I-IV colon cancer between February 2017 and June 2022. Participants reported GI symptoms through the EORTC QLQ-C30 and QLQ-CR29 at enrollment and as frequently as every 6 months for 5 years. Main outcome measures were visits, telephone encounters, and secure messages with a medical provider within specialty oncology clinics within 6 months after each survey completion. Generalized linear mixed regression model for repeated measurements with random trajectory for each participant was performed to estimate the associations between symptoms and healthcare use. Models were adjusted for demographics, clinical and surgical factors, and timing in relation to onset of the COVID-19 pandemic., Results: In the 6 months after each survey time point, patients averaged 1.2 visits, 0.5 telephone encounters, and 3.2 patient-initiated messages. In adjusted models, those with any abdominal pain (RR 1.45; p = 0.002), buttock pain (RR 1.30; p = 0.050), or increased stool frequency (RR 1.26; p = 0.046) had more clinic visits in the following 6 months than those without these symptoms. Including these three symptoms in one model revealed that only abdominal pain was statistically significantly associated with increased clinic visits (RR 1.36; p = 0.016). Patients with any blood or mucus in stool (RR 2.46; p = 0.009) had significantly more telephone encounters, and those with any abdominal pain (RR 1.65; p = 0.002) had significantly more patient-initiated messages than those without these symptoms., Conclusions: Our findings identify GI symptoms associated with increased use of oncologic specialty care among colon cancer survivors, with abdominal pain as an important predictor of utilization., Implications for Cancer Survivors: Early identification and anticipatory management of colon cancer survivors experiencing abdominal pain may decrease healthcare utilization., (© 2024. The Author(s).)

Metabolic syndrome (MetS), a precursor to cardiovascular disease and type II diabetes, is rapidly increasing in young adults. Accordingly, earlier interventions aimed at combating the onset of MetS in young adults are required. However, current behavioral interventions have failed to consider the eating behaviors that precede disease development, likely contributing to the consistently high failure rates of these interventions. The purpose of this cross-sectional study was to evaluate the associations between eating behaviors and MetS severity (MetS index ) in a sample of young adults. A sample of 104 (non-Hispanic White: 45; non-Hispanic Black: 49; Hispanic White: 5; Asian: 5) young adult (age: 23.1 ± 4.4) males and females (F:61, M:43) completed anthropometric, blood pressure, blood glucose, and blood lipid assessments; each of which were used to calculate a continuous MetS index score. Participants also completed the revised version of the 18-item Three-factor Eating Questionnaire to measure emotional eating (EmE), uncontrolled eating (UE), and cognitive restraint (CR). EmE was positively associated with MetS index for young adult females (p = 0.033) and non-Hispanic Black participants (p = 0.050), but not male (p = 0.506) or non-Hispanic White participants (p = 0.558). Additionally, MetS index was greater in the highest EmE tertile compared to the lowest EmE tertile for the total sample (p = 0.037) and young adult females (p = 0.015). UE and CR were not associated with MetS index . These data suggest a potential link between EmE and MetS severity in young adults, and that behavioral interventions aimed at MetS prevention should focus on treating the underlying EmE behaviors common in young adults, particularly for young female and Black adults at the greatest risk., Competing Interests: Declaration of competing interest None., (Published by Elsevier Ltd.)

Background: Colorectal cancer (CRC) is more prevalent among some racial and ethnic minority and low socioeconomic status populations. Although the gut microbiota is a risk factor for CRC and varies with race and ethnicity, its role in CRC disparities remains poorly understood., Methods: We examined the feasibility of recruiting sociodemographically diverse CRC patients for a microbiome study involving a home stool collection. We also explored whether race and ethnicity were associated with gut microbiome composition. We recruited Black/African American, Hispanic/Latino, and non-Hispanic White patients who were receiving care for active CRC to complete a comprehensive dietary and lifestyle survey, self-collect a stool sample, and complete an exit interview. Gut microbial diversity and composition were analyzed using 16S rRNA gene sequencing., Results: 30 individuals consented (of 35 who were eligible and contacted) with 5 (17%) Black/African American, 11 (37%) Hispanic/Latino, and 14 (46%) non-Hispanic White. A total of 22 (73%) completed the dietary and lifestyle survey; 18 (63%) returned a stool sample. Even after controlling for socioeconomic, dietary, or treatment-related covariates, microbiome composition was associated with race and ethnicity. Fusobacteriota (a phylum associated with the development and progression of CRC) was significantly higher in the Black/African American group compared to others, and microbial diversity was higher in samples from non-Hispanic White individuals compared to Hispanic/Latino individuals., Conclusion: Our study shows that it is feasible to recruit and collect stool samples from diverse individuals with CRC and found significant associations in gut microbial structure with race and ethnicity.

Background: Adherence to the American Cancer Society (ACS) guidelines of avoiding obesity, maintaining physical activity, and consuming a diet rich in fruits, vegetables, and whole grains is associated with longer survival in colorectal cancer (CRC) survivors. Dietary components of the ACS guidelines may act in part by changing the microbiome, which is implicated in CRC outcomes., Objectives: We conducted a pilot cross-sectional study to explore associations between ACS guidelines and the gut microbiome., Methods: Stool samples and questionnaires were collected from 28 CRC survivors at the University of California, San Francisco from 2019 to 2020. ACS scores were calculated based on validated questionnaires. Gut microbial community structure from 16S amplicons and gene/pathway abundances from metagenomics were tested for associations with the ACS score and its components using ANOVA and general linear models., Results: The overall ACS score was not significantly associated with variations in the fecal microbiota. However, fruit and vegetable intake and alcohol intake accounted for 19% (P = 0.005) and 13% (P = 0.01) of variation in the microbiota, respectively. Fruit/vegetable consumption was associated with increased microbial diversity, increased Firmicutes, decreased Bacteroidota, and changes to multiple genes and metabolic pathways, including enriched pathways for amino acid and short-chain fatty acid biosynthesis and plant-associated sugar degradation. In contrast, alcohol consumption was positively associated with overall microbial diversity, negatively associated with Bacteroidota abundance, and associated with changes to multiple genes and metabolic pathways. The other components of the ACS score were not statistically significantly associated with the fecal microbiota in our sample., Conclusions: These results guide future studies examining the impact of changes in the intake of fruits, vegetables, and alcoholic drinks on the gut microbiome of CRC survivors., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Prior studies report conflicting evidence regarding exercise pressor and metaboreflex responses in individuals with metabolic syndrome (MetS). Purpose: To test the hypotheses that 1) exercise pressor and metaboreflex responses are exaggerated in MetS and 2) these differences may be explained by elevated resting blood pressure. Methods: Blood pressure and heart rate (HR) were evaluated in 26 participants (13 MetS) during 2 min of handgrip exercise followed by 3 min of post-exercise circulatory occlusion (PECO). Systolic (SBP), diastolic (DBP), and mean arterial pressure (MAP), along with HR and a cumulative blood pressure index (BPI), were compared between groups using independent samples t -tests, and analyses of covariance were used to adjust for differences in resting blood pressure, fasting blood glucose (FBG), and waist circumference (WC). Results: ΔSBP (∼78% and ∼54%), ΔMAP (∼67% and ∼55%), and BPI (∼16% and ∼20%) responses were significantly exaggerated in individuals with MetS during handgrip and PECO, respectively (all p ≤ 0.04). ΔDBP, ΔMAP, and BPI responses during handgrip remained significantly different between groups after independently covarying for resting blood pressure ( p < 0.01), and after simultaneously covarying for resting blood pressure, FBG, and WC ( p ≤ 0.03). Likewise, peak SBP, DBP, MAP, and BPI responses during PECO remained significantly different between groups after adjusting for resting blood pressure ( p ≤ 0.03), with peak SBP, MAP, and BPI response remaining different between groups after adjusting for all three covariates simultaneously ( p ≤ 0.04). Conclusion: These data suggest that exercise pressor and metaboreflex responses are significantly exaggerated in MetS independent of differences in resting blood pressure, FBG, or WC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Stavres, Aultman, Brandner, Newsome, Vallecillo-Bustos, Wise, Henderson, Stanfield, Mannozzi and Graybeal.)

Purpose: We sought to determine whether adherence to the American Cancer Society (ACS) Nutrition and Physical Activity Guidelines was associated with better bowel function among colon cancer survivors., Methods: This prospective cohort study included patients surgically treated for stage I-IV colon cancer enrolled in the Lifestyle and Outcomes after Gastrointestinal Cancer (LOGIC) study between February 2017 and May 2021. Participants were assigned an ACS score (0-6 points) at enrollment. Stool frequency (SF) was assessed every 6 months using the EORTC QLQ-CR29. Higher SF is an indication of bowel function impairment. ACS score at enrollment was examined in relation to SF at enrollment and over a 3-year period. Secondarily, we examined associations between the ACS score components (body mass index, dietary factors, and physical activity) and SF. Multivariable models were adjusted for demographic and surgical characteristics., Results: A total of 112 people with colon cancer (59% women, mean age 59.5 years) were included. Cross-sectionally, for every point increase in ACS score at enrollment, the odds of having frequent stools at enrollment decreased by 43% (CI 0.42-0.79; p < 0.01). Findings were similar when we examined SF as an ordinal variable and change in SF over a 3-year period. Lower consumption of red/processed meats and consuming a higher number of unique fruits and vegetables were associated with lower SF (better bowel function) at enrollment., Conclusions: Colon cancer survivors who more closely followed the ACS nutrition and physical activity guidelines had lower SF, an indication of better bowel function., Implications for Cancer Survivors: Our findings highlight the value of interventions that support health behavior modification as part of survivorship care for long-term colon cancer survivors., (© 2022. The Author(s).)

Background: Women diagnosed with colorectal cancer (CRC) or anal squamous cell carcinoma (ASCC) are at high risk of sexual dysfunction after treatment, yet little is known about recovery and risk factors for chronic dysfunction., Aim: We aimed to describe sexual function and sexual activity among women who underwent definitive treatment for CRC or ASCC, examine relationships between time since treatment completion and sexual function, and explore factors associated with desire and changes in sexual desire over time., Methods: As part of a prospective cohort study of patients with gastrointestinal cancer at the University of California San Francisco, female-identifying participants who finished definitive treatment for CRC or ASCC completed the Female Sexual Function Index (FSFI) at 6- to 12-month intervals. We used multivariable linear mixed models to explore factors associated with the FSFI desire subscale., Outcomes: Outcomes were rates of sexual activity, proportion at risk for sexual dysfunction (FSFI score <26.55), total FSFI score, and FSFI desire subscale., Results: Among the 97 cancer survivors who completed at least 1 FSFI, the median age was 59 years, the median time since treatment end was 14 months, and 87% were menopausal. Fifty-five women (57%) had a history of colon cancer; 21 (22%), rectal cancer; and 21 (22%), ASCC. An additional 13 (13%) had a current ostomy. Approximately half the women were sexually active (n = 48, 49%). Among these 48 sexually active women, 34 (71%) had FSFI scores indicating risk for sexual dysfunction. Among the 10 sexually active women who completed a FSFI ≥2 years since end of treatment, the median total score was 22.6 (IQR, 15.6-27.3). None of the evaluated characteristics were associated with desire (age, tumor site, treatment, menopause status, or ostomy status)., Clinical Implications: Consistent with prior studies, we found low desire scores after treatment for CRC or ASCC, with little recovery over time, suggesting that patients should not expect an eventual rebound of sexual function., Strengths and Limitations: Strengths of our study include longitudinal data and use of the validated FSFI. Women with ASCC composed 22% of our cohort, allowing for insight into this rare disease group. Limitations of this study include the small sample size, particularly for longitudinal analyses, and the enrollment of patients at variable times since treatment end., Conclusion: We observed a high prevalence of sexual health concerns, including low desire, after the treatment of CRC and ASCC that persisted for years after treatment was completed., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society of Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aims: Liver transplantation (LT) in alcohol-associated hepatitis (AH) remains controversial, in part because spontaneous recovery (SR) can occur. There is a paucity of data on SR in patients with severe AH who undergo LT evaluation. The purpose of this study was to determine factors associated with SR and survival in patients with severe AH who undergo LT evaluation., Approach and Results: This is a retrospective study of ALD patients with Model for End-Stage Liver Disease (MELD) >25 and <90 days abstinence who underwent LT evaluation at a single center between 2012 and 2018. One hundred forty-four patients (median age, 45.5 years; 68.1% male) were included. Forty-nine (34%) underwent LT and 95 (66%) patients did not undergo LT, and of those, 34 (23.6%) experienced SR. Factors associated with recovery were younger age (OR, 0.92; p = 0.004), lower index international normalized ratio (INR; 0.31; p = 0.03), and lower peak MELD (OR, 0.83; p = 0.02). Only 7 patients (20.6%) achieved a compensated state with a MELD <15 and absence of therapy for ascites or HE. Survival was improved in patients who underwent early LT when compared to SR. Survival was impaired in SR following relapse to alcohol use when compared to SR patients who abstained and LT recipients. Among all 6-month survivors of AH, alcohol use trended toward an association with mortality (HR, 2.05; p = 0.17), but only LT was associated with decreased mortality risk (HR, 0.20; p = 0.005)., Conclusions: SR from AH after LT evaluation is associated with age, index INR, and lower peak MELD. Most recovered patients continue to experience end-stage complications. LT is the only factor associated with lower mortality., (© 2021 by the American Association for the Study of Liver Diseases.)

Background: Injury to the ipsilateral graft used for reconstruction of the anterior cruciate ligament (ACL) or a new injury to the contralateral ACL are disastrous outcomes after successful ACL reconstruction (ACLR), rehabilitation, and return to activity. Studies reporting ACL reinjury rates in younger active populations are emerging in the literature, but these data have not yet been comprehensively synthesized., Purpose: To provide a current review of the literature to evaluate age and activity level as the primary risk factors in reinjury after ACLR., Study Design: Systematic review and meta-analysis., Methods: A systematic review of the literature was conducted via searches in PubMed (1966 to July 2015) and EBSCO host (CINAHL, Medline, SPORTDiscus [1987 to July 2015]). After the search and consultation with experts and rating of study quality, 19 articles met inclusion for review and aggregation. Population demographic data and total reinjury (ipsilateral and contralateral) rate data were recorded from each individual study and combined using random-effects meta-analyses. Separate meta-analyses were conducted for the total population data as well as the following subsets: young age, return to sport, and young age + return to sport., Results: Overall, the total second ACL reinjury rate was 15%, with an ipsilateral reinjury rate of 7% and contralateral injury rate of 8%. The secondary ACL injury rate (ipsilateral + contralateral) for patients younger than 25 years was 21%. The secondary ACL injury rate for athletes who return to a sport was also 20%. Combining these risk factors, athletes younger than 25 years who return to sport have a secondary ACL injury rate of 23%., Conclusion: This systematic review and meta-analysis demonstrates that younger age and a return to high level of activity are salient factors associated with secondary ACL injury. These combined data indicate that nearly 1 in 4 young athletic patients who sustain an ACL injury and return to high-risk sport will go on to sustain another ACL injury at some point in their career, and they will likely sustain it early in the return-to-play period. The high rate of secondary injury in young athletes who return to sport after ACLR equates to a 30 to 40 times greater risk of an ACL injury compared with uninjured adolescents. These data indicate that activity modification, improved rehabilitation and return-to-play guidelines, and the use of integrative neuromuscular training may help athletes more safely reintegrate into sport and reduce second injury in this at-risk population., (© 2016 The Author(s).)

Background: Hip and knee strength abnormalities have been implicated in patellofemoral pain (PFP) in multiple studies. However, the relationship is unclear, as many of these studies have been retrospective., Purpose: To compare prospective hip and knee isokinetic strength in young female athletes who subsequently went on to develop PFP relative to their uninjured, healthy peers., Study Design: Descriptive epidemiology study., Methods: Adolescent female athletes (N = 329) were tested for isokinetic strength of the knee (flexion and extension) and hip (abduction) and screened for the prevalence of PFP before their basketball seasons. After exclusion based on current PFP symptoms, 255 participants were prospectively enrolled in the study. A 1-way analysis of variance was used to determine between-group differences in incident PFP and the referent (no incident PFP) participants., Results: The cumulative incidence rate for the development of PFP was 0.97 per 1000 athlete-exposures. Female athletes who developed PFP demonstrated increased normalized hip abduction strength (normalized torque, 0.013 ± 0.003) relative to the referent control group (normalized torque, 0.011 ± 0.003) (P < .05). Unlike hip strength, normalized knee extension and knee flexion strength were not different between the 2 groups (P > .05)., Conclusion: The findings in this study indicate that young female athletes with greater hip abduction strength may be at an increased risk for the development of PFP. Previous studies that have looked at biomechanics indicated that those with PFP have greater hip adduction dynamic mechanics., Clinical Relevance: Combining the study data with previous literature, we theorize that greater hip abduction strength may be a resultant symptom of increased eccentric loading of the hip abductors associated with increased dynamic valgus biomechanics, demonstrated to underlie increased PFP incidence. Further research is needed to verify the proposed mechanistic link to the incidence of PFP., (© 2015 The Author(s).)

Purpose: In an effort to identify risk factors for anterior cruciate ligament (ACL) injury, many potential risk factors have been proposed, including familial predisposition. However, no study has evaluated familial predisposition in male or females separately. The purpose of this study was to determine whether a familial predisposition to ACL injury exists in both males and females., Methods: One hundred and twenty (78 males and 42 females) patients who had undergone surgical ACL reconstruction were recruited as the ACL group, and 107 patients (67 males and 40 females) that had undergone arthroscopic partial menisectomy, with no previous history of ACL injury, were recruited as the referent control group. A familial ACL injury and subject particulars questionnaire was completed., Results: When all subjects were combined, the ACL group (20.0 %, 24 of 120) did not demonstrate a higher familial (first-degree relative) prevalence (n.s.) of ACL injury compared to the referent control group (15.0 %; 16 of 107 patients). When the data were stratified by sex, the male ACL group (19.2 %, 15 of 78) demonstrated a significantly higher familial (first-degree relative) prevalence (P = 0.02) of ACL injury compared to the male referent control group (7.5 %; 5 of 67 patients). There were no differences among the females (n.s.)., Discussion: The results of this study show that male patients with ACL tears are more likely to have a first-degree relative with an ACL tear compared to male referent control subjects. Future research is warranted to better delineate sex-specific risk factors for ACL injuries could help guide intervention programs aimed at preventative treatment strategies, especially in high-risk families.

The development of posterior capsule opacification secondary to extracapsular cataract extraction is a common occurrence. The patient complains of decreased visual acuity, glare, and sensitivity to light. The YAG laser posterior capsulotomy has become standard treatment for this anomaly: an opening is created in the opacified posterior capsule, which immediately improves visual acuity. This review describes the indications, preparation, procedure, follow-up, and complications associated with using a yttrium-aluminum-garnet (YAG) laser to perform capsulotomy.