The gut microbiome modifies the associations of short- and long-term physical activity with body weight changes.

BACKGROUND: The gut microbiome regulates host energy balance and adiposity-related metabolic consequences, but it remains unknown how the gut microbiome modulates body weight response to physical activity (PA). METHODS: Nested in the Health Professionals Follow-up Study, a subcohort of 307 healthy men (mean[SD] age, 70[4] years) provided stool and blood samples in 2012-2013. Data from cohort long-term follow-ups and from the accelerometer, doubly labeled water, and plasma biomarker measurements during the time of stool collection were used to assess long-term and short-term associations of PA with adiposity. The gut microbiome was profiled by shotgun metagenomics and metatranscriptomics. A subcohort of 209 healthy women from the Nurses' Health Study II was used for validation. RESULTS: The microbial species Alistipes putredinis was found to modify the association between PA and body weight. Specifically, in individuals with higher abundance of A. putredinis, each 15-MET-hour/week increment in long-term PA was associated with 2.26 kg (95% CI, 1.53-2.98 kg) less weight gain from age 21 to the time of stool collection, whereas those with lower abundance of A. putredinis only had 1.01 kg (95% CI, 0.41-1.61 kg) less weight gain (pinteraction = 0.019). Consistent modification associated with A. putredinis was observed for short-term PA in relation to BMI, fat mass%, plasma HbA1c, and 6-month weight change. This modification effect might be partly attributable to four metabolic pathways encoded by A. putredinis, including folate transformation, fatty acid ß-oxidation, gluconeogenesis, and stearate biosynthesis. CONCLUSIONS: A greater abundance of A. putredinis may strengthen the beneficial association of PA with body weight change, suggesting the potential of gut microbial intervention to improve the efficacy of PA in body weight management. Video Abstract.

Prospective Study of Avocado Consumption and Cancer Risk in U.S. Men and Women.

Avocados contain nutrients and phytochemicals that make it promising for cancer prevention, and chemopreventive properties have been demonstrated in prior studies. Prospective studies on avocado consumption and cancer risk have yet to be conducted. This study included data from 45,289 men in the Health Professionals Follow-Up Study (HPFS, 1986-2016) and 67,039 women in the Nurses' Health Study (NHS, 1986-2014). Avocado consumption was assessed using validated food frequency questionnaires every 4 years. Cox proportional hazards models calculated multivariable HRs and 95% confidence intervals (CI) for associations between avocado consumption and risk of total and site-specific cancers in each cohort. In HPFS, consumption of ≥1 weekly serving of avocados was associated with decreased risk of total (HR, 0.85; 95% CI, 0.80-0.91), colorectal (HR, 0.71; 95% CI, 0.59-0.85), lung (HR, 0.71; 95% CI, 0.57-0.90), and bladder cancer (HR, 0.72; 95% CI, 0.57-0.90). In NHS, avocado consumption was associated with increased risk of breast cancer (HR, 1.21; 95% CI, 1.07-1.37). No associations were observed between avocado consumption and risk of total cancer (HR, 1.06; 95% CI, 0.98-1.14) or other site-specific cancers in NHS. Considering the surprising breast cancer finding, analyses were repeated using data from 93,230 younger women in the parallel NHSII (1991-2017). In NHSII, avocado consumption was not associated with breast cancer risk (HR, 0.93; 95% CI, 0.76-1.13). Overall, avocado consumption may be associated with reduced risk of total and some site-specific cancers in men. The positive association with breast cancer risk in NHS was not seen in the younger NHSII. PREVENTION RELEVANCE: The results of this prospective study suggest that avocado consumption may be associated with decreased risk of total and some site-specific cancers in men. See related Spotlight, p. 187.

Aspirin use and prostate tumor angiogenesis.

PURPOSE: Aspirin use has been shown to be associated with reduced risk of aggressive prostate cancer, although the mechanisms are not fully understood. METHODS: We examined associations between regular aspirin use and prostate tumor angiogenesis among 572 men from the Health Professionals Follow-up Study. Participants reported aspirin use on biennial questionnaires. Prostatectomy tumor blocks were immunostained for CD34 to assess microvessel size and irregularity. Multivariable linear regression was used to calculate percent differences in biomarker measures comparing use vs nonuse, and by duration and tablets per day. RESULTS: Current aspirin users had larger vessel area (14.5%) and diameter (6.5%), and lower vessel irregularity (- 8.1%) compared to non-users, indicating a less angiogenic profile. Duration of use and current tablets per day were also associated with larger vessel diameter. Similar patterns were seen for low- and high-grade prostate cancers. CONCLUSION: Our findings suggest that aspirin use, particularly current use, can lower prostate cancer carcinogenesis through angiogenic mechanisms.

Association of plant-based diet index with prostate cancer risk.

BACKGROUND: Plant-based diets are associated with multiple health benefits and a favorable environmental impact. For prostate cancer, previous studies suggest a beneficial role of specific plant-based foods (e.g., tomatoes) and a potentially harmful role of specific animal-based foods (e.g., meat, dairy). However, less is known about plant-based dietary patterns. OBJECTIVES: We sought to examine the relation between plant-based diet indices and prostate cancer risk, including clinically relevant disease. METHODS: This was a prospective cohort study including 47,239 men in the Health Professionals Follow-Up Study (1986-2014). Overall and healthful plant-based diet indices were calculated from FFQs. Cox proportional hazards models were used to estimate HRs and 95% CIs to examine the risk of incident prostate cancer (total and by clinical category), among men ages <65 and ≥65 y. RESULTS: Of the 47,239 men, 6655 men were diagnosed with prostate cancer over follow-up, including 515 with advanced-stage disease at diagnosis, 956 with lethal disease (metastasis or death), and 806 prostate cancer deaths. Greater overall plant-based consumption was associated with a significantly lower risk of fatal prostate cancer (HR: 0.81; 95% CI: 0.64, 1.01; P-trend = 0.04). In men aged <65, a higher plant-based diet index was associated with a lower risk of advanced, lethal, and fatal prostate cancer. Moreover, greater consumption of a healthful plant-based diet was associated with lower risks of total (HR: 0.84; 95% CI: 0.73, 0.98; P-trend = 0.046) and lethal prostate cancer (HR: 0.56; 95% CI: 0.34, 0.94; P-trend = 0.03) at age <65. There were no associations between overall or healthful plant-based diet indices with prostate cancer among men ≥65 y. Fewer than 1% of participants followed a strict vegetarian or vegan diet. CONCLUSIONS: This prospective study provides supportive evidence that greater consumption of healthful plant-based foods is associated with a lower risk of aggressive forms of prostate cancer, with stronger benefit among men aged <65 y.

Prenatal and Perinatal Factors and Risk of Cancer in Middle and Older Adulthood among Men.

BACKGROUND: Prenatal factors have been associated with risk of cancers later in life, although studies in men have largely been case-control and focused on birth size only. METHODS: We used data from 5,845 men in the Health Professionals Follow-up Study (HPFS) to prospectively examine associations between several prenatal and perinatal factors and incident adult cancer risk. In 1994, mothers of participants reported information on characteristics and behaviors related to their pregnancy with their sons. We used multivariable Cox proportional hazards models to calculate HRs and 95% confidence intervals (CI) of associations between prenatal and perinatal risk factors and cancer risk. RESULTS: During 20 years of follow-up, 1,228 incident cases of overall cancer were documented. Men with a birth weight of ≥4 kg had a 21% increased risk of overall cancer (HR, 1.21; 95% CI, 1.02-1.43) compared with those with a birth weight of 2.5 to 3.9 kg. Greater weight gain during pregnancy (>13.6 kg vs. 6.8-8.6 kg) was also associated with a higher risk of overall cancer (HR, 1.22; 95% CI, 1.02-1.46), and was stronger for men whose mothers had a prepregnancy BMI<21 kg/m2 (HR, 1.30; 95% CI, 1.00-1.67) compared with body mass index (BMI) ≥21 kg/m2 (HR, 1.14; 95% CI, 0.85-1.51). There was no association between maternal age and overall cancer risk. CONCLUSIONS: Higher birth weight and maternal weight gain are associated with increased cancer risk in adult men. IMPACT: Our findings support the hypothesis that the in utero environment plays a role in the etiology of cancer in middle and older adulthood.

Insulinemic and Inflammatory Dietary Patterns and Risk of Prostate Cancer.

BACKGROUND: Hyperinsulinemia and inflammation are inter-related pathways that link diet with the risk of several chronic diseases. Evidence suggests that these pathways may also increase prostate cancer risk. OBJECTIVE: To determine whether hyperinsulinemic diet and inflammatory diet are associated with prostate cancer incidence and mortality. DESIGN, SETTING, AND PARTICIPANTS: We prospectively followed 41 209 men in the Health Professionals Follow-up Study (1986-2014). Scores for two validated dietary patterns were calculated from food frequency questionnaires at baseline and updated every 4 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Total, advanced, and lethal prostate cancer outcomes were assessed. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were determined for associations between two empirical hypothesis-oriented dietary patterns-empirical dietary index for hyperinsulinemia and empirical dietary inflammatory pattern-and prostate cancer risk estimated using Cox proportional hazard regression. RESULTS AND LIMITATIONS: During 28 yr of follow-up, 5929 incident cases of total prostate cancer, including 1019 advanced and 667 fatal, were documented. In multivariable-adjusted models, there was a 7% higher risk of advanced prostate cancer (HR: 1.07; 95% CI: 1.01-1.15) and a 9% higher risk of fatal prostate cancer (HR: 1.09; 95% CI: 1.00-1.18) per standard deviation (SD) increase in the hyperinsulinemic diet. When stratified by age, the hyperinsulinemic diet was associated with only earlier-onset aggressive prostate cancer (men under 65 yr), with per SD HRs of 1.20 (95% CI: 1.06-1.35) for advanced, 1.22 (1.04-1.42) for fatal, and 1.20 (1.04-1.38) for lethal. The inflammatory diet was not associated with prostate cancer risk in the overall study population, but was associated with earlier-onset lethal prostate cancer (per SD increase HR: 1.16; 95% CI: 1.00-1.35). CONCLUSIONS: Hyperinsulinemia and inflammation may be potential mechanisms linking dietary patterns with the risk of aggressive prostate cancer, particularly earlier-onset disease. PATIENT SUMMARY: Avoiding inflammatory and hyperinsulinemic dietary patterns may be beneficial for the prevention of clinically relevant prostate cancer, especially among younger men.

The association of diabetes with risk of prostate cancer defined by clinical and molecular features.

BACKGROUND: To prospectively examine the association between diabetes and risk of prostate cancer defined by clinical and molecular features. METHODS: A total of 49,392 men from the Health Professionals Follow-up Study (HPFS) were followed from 1986 to 2014. Data on self-reported diabetes were collected at baseline and updated biennially. Clinical features of prostate cancer included localised, advanced, lethal, low-grade, intermediate-grade, and high-grade. Molecular features included TMPRSS2: ERG and PTEN subtypes. Cox proportional hazards regression models were used to evaluate the association between diabetes and incidence of subtype-specific prostate cancer. RESULTS: During 28 years of follow-up, we documented 6733 incident prostate cancer cases. Relative to men free from diabetes, men with diabetes had lower risks of total (HR: 0.82, 95% CI: 0.75-0.90), localised (HR: 0.82, 95% CI: 0.74-0.92), low-and intermediate-grade prostate cancer (HR: 0.77, 95% CI: 0.66-0.90; HR: 0.77, 95% CI: 0.65-0.91, respectively). For molecular subtypes, the HRs for ERG-negative and ERG-positive cases were 0.63 (0.42-0.95) and 0.72 (0.46-1.12); and for PTEN-intact and PTEN-loss cases were 0.69 (0.48-0.98) and 0.52 (0.19-1.41), respectively. CONCLUSION: Besides providing advanced evidence for the inverse association between diabetes and prostate cancer, this study is the first to report associations between diabetes and ERG/PTEN defined prostate cancers.

Associations of plasma trimethylamine N-oxide, choline, carnitine, and betaine with inflammatory and cardiometabolic risk biomarkers and the fecal microbiome in the Multiethnic Cohort Adiposity Phenotype Study.

BACKGROUND: Trimethylamine N-oxide (TMAO), a compound derived from diet and metabolism by the gut microbiome, has been associated with several chronic diseases, although the mechanisms of action are not well understood and few human studies have investigated microbes involved in its production. OBJECTIVES: Our study aims were 1) to investigate associations of TMAO and its precursors (choline, carnitine, and betaine) with inflammatory and cardiometabolic risk biomarkers; and 2) to identify fecal microbiome profiles associated with TMAO. METHODS: We conducted a cross-sectional analysis using data collected from 1653 participants (826 men and 827 women, aged 60-77 y) in the Multiethnic Cohort Study. Plasma concentrations of TMAO and its precursors were measured by LC-tandem MS. We also analyzed fasting blood for markers of inflammation, glucose and insulin, cholesterol, and triglycerides (TGs), and further measured blood pressure. Fecal microbiome composition was evaluated by sequencing the 16S ribosomal RNA gene V1-V3 region. Associations of TMAO and its precursors with disease risk biomarkers were assessed by multivariable linear regression, whereas associations between TMAO and the fecal microbiome were assessed by permutational multivariate ANOVA and hurdle regression models using the negative binomial distribution. RESULTS: Median (IQR) concentration of plasma TMAO was 3.05 µmol/L (2.10-4.60 µmol/L). Higher concentrations of TMAO and carnitine, and lower concentrations of betaine, were associated with greater insulin resistance (all P < 0.02). Choline was associated with higher systolic blood pressure, TGs, lipopolysaccharide-binding protein, and lower HDL cholesterol (P ranging from <0.001 to 0.03), reflecting an adverse cardiometabolic risk profile. TMAO was associated with abundance of 13 genera (false discovery rate < 0.05), including Prevotella, Mitsuokella, Fusobacterium, Desulfovibrio, and bacteria belonging to the families Ruminococcaceae and Lachnospiraceae, as well as the methanogen Methanobrevibacter smithii. CONCLUSIONS: Plasma TMAO concentrations were associated with a number of trimethylamine-producing bacterial taxa, and, along with its precursors, may contribute to inflammatory and cardiometabolic risk pathways.

Presenting Complications to a Reconstructive Urologist After Masculinizing Genital Reconstructive Surgery.

OBJECTIVE: To evaluate the presenting complications of patients to reconstructive urologists after masculinizing gender affirming genital reconstructive surgery (GRS) performed elsewhere. METHODS: We identified patients who underwent revision surgery by one of the co-authors for sequelae of masculinizing GRS. We reviewed patient demographics, medical history, details of prior GRS, and complications from GRS. Specific attention was paid to the presence of the following: suprapubic tube dependence, vaginal remnant, urethrocutaneous fistula (UCF) within the fixed urethra (pars fixa), UCF in the phallic urethra, phallic urethral stricture, meatal stenosis, and anastomotic urethral stricture. Statistical analysis was performed using the Fisher's exact test to determine differences in presenting symptoms by GRS. RESULTS: Fifty-five patients who had reconstructive surgery for complications from masculinizing GRS from September 2004 to September 2017 were identified. The median age at surgical correction was 33 years. Fifteen (27%) patients had prior metoidioplasty and 40 (73%) had prior phalloplasty. The median time from date of GRS to presentation to a reconstructive urologist was 4 months. Urethral strictures (n = 47, 86%) were the most common indication for subsequent surgery, followed by urethrocutaneous fistulae (n = 31, 56%) and vaginal remnant (n = 26, 47%). The majority of patients presented with 2 or more simultaneous complications (n = 40, 73%). CONCLUSION: There are several common presenting urologic complications after masculinizing GRS. Patients may present to reconstructive urologists early after GRS performed elsewhere. The long-term outcomes of GRS deserve further study.

Postoperative Imaging Patterns of Pediatric Nephrolithiasis: Opportunities for Improvement.

PURPOSE: Imaging following surgical intervention for nephrolithiasis is important to define operative success and ensure the absence of silent obstruction. We assessed nationwide postoperative imaging patterns in children undergoing ureteroscopy and shock wave lithotripsy. MATERIALS AND METHODS: We reviewed the MarketScan® Commercial Claims and Encounters database from 2007 to 2013 for patients 1 to 18 years old undergoing ureteroscopy or shock wave lithotripsy. We assessed imaging exposure following index procedure within 90 days as a primary analysis and 180 days as a secondary analysis of the index procedure. Univariate and multivariate statistical analyses were performed to assess factors associated with undergoing postoperative imaging. RESULTS: A total of 4,251 children met inclusion criteria, of whom 1,647 had undergone shock wave lithotripsy and 2,604 had undergone ureteroscopy. Postoperative imaging was performed in 57.5% of the cohort, with a higher proportion of children undergong imaging following shock wave lithotripsy compared to ureteroscopy (73% vs 47.8%, p <0.001). Noncomputerized tomographic imaging modalities were most common following ureteroscopy (70.8%) and shock wave lithotripsy (84.6%). Younger children and those with complex medical conditions or complicated postoperative courses were more likely to undergo followup imaging. Computerized tomography was more commonly used in older children and females. At 180-day followup 63% of the cohort had undergone any imaging, again more frequently following shock wave lithotripsy (77.0%) vs ureteroscopy (45.0%). CONCLUSIONS: A large percentage of children with nephrolithiasis do not undergo followup imaging after shock wave lithotripsy, and even fewer undergo imaging after ureteroscopy. Most followup imaging is done within 90 days of surgery. Further work is needed to define appropriate postoperative imaging practices in this population.

Temporal Variability and Stability of the Fecal Microbiome: The Multiethnic Cohort Study.

BACKGROUND: Measurement reliability and biological stability need to be considered when developing sampling protocols for population-based fecal microbiome studies. METHODS: Stool samples were collected biannually over a 2-year period and sequenced for the V1-V3 region of the 16S rRNA gene in 50 participants from the Multiethnic Cohort Study. We evaluated the temporal stability of the fecal microbiome on a community level with permutational multivariate analysis of variance (PERMANOVA), as well as on taxa and diversity measures with intraclass correlation coefficients. RESULTS: Interindividual differences were the predominant source of fecal microbiome variation, and variation within individual was driven more by changing abundances than by the complete loss or introduction of taxa. Phyla and diversity measures were reliable over the 2 years. Most genera were stable over time, although those with low abundances tended to be more dynamic. Reliability was lower among participants who used antibiotics, with the greatest difference seen in samples taken within 1 month of reported use. CONCLUSIONS: The fecal microbiome as a whole is stable over a 2-year period, although certain taxa may exhibit more temporal variability. IMPACT: When designing large epidemiologic studies, a single sample is sufficient to capture the majority of the variation in the fecal microbiome from 16S rRNA gene sequencing, while multiple samples may be needed for rare or less-abundant taxa.

Neonatal Circumcision and Urinary Tract Infections in Infants With Hydronephrosis.

BACKGROUND: Boys with urinary tract abnormalities may derive a greater benefit from newborn circumcision for prevention of urinary tract infection (UTI) than the general population. However, the effect of newborn circumcision on UTI is not well characterized across the etiological spectrum of hydronephrosis. We hypothesized that boys with an early diagnosis of hydronephrosis who undergo newborn circumcision will have reduced rates of UTI. METHODS: The MarketScan data set, an employer-based claims database, was used to identify boys with hydronephrosis or hydronephrosis-related diagnoses within the first 30 days of life. The primary outcome was the rate of UTIs within the first year of life, comparing circumcised boys with uncircumcised boys and adjusting for region, insurance type, year of birth, and infant comorbidity. RESULTS: A total of 5561 boys met inclusion criteria, including 2386 (42.9%) undergoing newborn circumcision and 3175 (57.1%) uncircumcised boys. On multivariate analysis, circumcision was associated with a decreased risk of UTI in both boys with hydronephrosis and healthy cohorts: odds ratio (OR) 0.36 (95% confidence interval [CI] 0.29-0.44) and OR 0.32 (95% CI 0.21-0.48), respectively. To prevent 1 UTI, 10 patients with hydronephrosis would have to undergo circumcision compared with 83 healthy boys. Among specific hydronephrosis diagnoses, circumcision was associated with a reduced risk of UTI for those with isolated hydronephrosis (OR 0.35 [95% CI 0.26-0.46]), vesicoureteral reflux (OR 0.35 [95% CI 0.23-0.54]), and ureteropelvic junction obstruction (OR 0.35 [95% CI 0.20-0.61]). CONCLUSIONS: Newborn circumcision is associated with a significantly lower rate of UTI among infant boys with hydronephrosis.

Follow-up imaging after acute evaluations for pediatric nephrolithiasis: Trends from a National database.

BACKGROUND: Overuse of computed tomography (CT) in the initial evaluation of children with upper urinary tract calculi (UUTC) has been well documented. Follow-up imaging patterns, however, remain undefined. Sequential imaging following an acute episode of UUTC represents additional opportunity for enacting good imaging stewardship, with the optimal goal to reduce unnecessary radiation exposure and cost while ensuring appropriate follow-up. OBJECTIVE: We explored nationwide imaging patterns for children following emergency department (ED) evaluations for UUTC, hypothesizing that initial imaging choice and complicated visits for UUTC increase the risk of follow-up CT scans. STUDY DESIGN: Claims from Marketscan (2007-2013), an employer-based dataset of privately insured patients, were used to assess children aged 1-18 years presenting to the ED an acute UUTC event. The primary outcome was any imaging within 90 days. Using logistic regression, odds for follow-up CT or plain film kidney-ureter-bladder/ultrasound (KUB/US) imaging were calculated adjusting for patient demographics, initial imaging modality, need for admission, and return ED visits. RESULTS: A total of 821 children met the inclusion criteria, of whom 261 (31.8%) received no follow-up imaging. Overall follow-up imaging patterns, including the proportions of children receiving CT scans, KUB/US imaging, or no imaging are shown in the Summary Table. Of the children receiving follow-up imaging, KUB/US was obtained in 363 (65.0%) and CT obtained in 197 (35.0%) children. Risk factors for follow-up CT imaging include hospital admission and return ED visits. Children with ureteral calculi and index US evaluation were more likely to receive KUB/US imaging only at follow-up. For children with ureteral calculi, the median time to first follow-up imaging was 9 days (25th-75th percentiles, 2-26 days). DISCUSSION: One-third of all children with follow-up imaging after an acute presentation for UUTC will receive a CT. Up to 28% of children with a ureteral calculus will not receive any follow-up imaging within 3 months of presentation. These findings suggest imaging strategies for children following acute evaluation for nephrolithiasis are suboptimal in two ways. First, children receive potentially unnecessary additional radiation burden, an alarming finding considering the high rates of CT scan in the index evaluation for these children. Second, many children with ureteral calculi fail to receive follow-up imaging to document stone passage. CONCLUSIONS: Our findings identify follow-up imaging as another area for quality improvement within the care of children with UUTC. Clinical pathways directing imaging strategies for pediatric nephrolithiasis should focus on follow-up imaging practices and initial evaluation, especially with for those children presenting with ureteral calculi.

Variable Resource Utilization in the Prenatal and Postnatal Management of Isolated Hydronephrosis.

OBJECTIVE: To characterize contemporary resource utilization and medical outcomes for infants with antenatal hydronephrosis and their mothers from a national claims database. We hypothesize that management of isolated hydronephrosis (IHN) varies widely, with decreased imaging following the 2010 Society for Fetal Urology Consensus Statement. MATERIALS AND METHODS: Using MarketScan claims from 2007 to 2013, we identified infants 0-12 months of age with hydronephrosis and linked mothers. Those with urologic diagnoses more specific than hydronephrosis, additional urologic comorbidities, or postnatal surgeries were excluded. Resource utilization including prenatal and postnatal imaging, laboratory studies, hospital admissions, and medical outcomes within the first year was captured. Demographics, maternal characteristics, utilization measures, and outcomes were compared across imaging intensity groups based on number of postnatal ultrasounds received using bivariate analysis. RESULTS: Among 801,919 mother-child pairs, 8610 infants (1.1%) had hydronephrosis or a related diagnosis. A total of 5876 (68.2%) met inclusion criteria for IHN. Patients underwent a mean 5.3 ± 3.5 prenatal and 2.1 ± 1.3 postnatal ultrasounds before age 1. Imaging practices were unchanged following the Society for Fetal Urology consensus statement. CONCLUSION: Antenatal hydronephrosis prevalence in an insured population is consistent with published ranges. Prenatal imaging in IHN is variable and potentially excessive. Future study into the efficacy of evidence-based pathways in reducing excess utilization is warranted.

Use of medical expulsive therapy in children: An assessment of nationwide practice patterns and outcomes.

INTRODUCTION: Early data support the use of medical expulsive therapy (MET) in children. However, little is known regarding use or outcomes associated with MET outside of pediatric-specific practices. Using a national administrative dataset, we sought to characterize utilization patterns of MET as well as assess outcomes associated with MET exposure. STUDY DESIGN: We interrogated the MarketScan Commercial Claims and Encounters database to identify children under the age of 18 presenting to the emergency department (ED) with any diagnosis of upper urinary tract calculi (UUTC, including renal and ureteral calculi). MET exposure was defined as having a prescription filled for a MET agent within 1 week of the ED encounter. Characteristics of children receiving MET were defined and outcomes compared between children with and without MET exposure. RESULTS: Of 1325 children included in the study, 13.2% received MET, including 15.4% of children with a diagnosis of "calculus of the ureter." MET use increased significantly throughout the study period (p = 0.004), although only 30.4% of children considered potential MET candidates received MET in the final year of the study (2013). Among all patients, receipt of MET was associated with male gender, presence of comorbidity, provider-type (urologist), and year of diagnosis, although among those with a specific diagnosis of "calculus of the ureter," only year of diagnosis remained a significant factor. Rates of unplanned physician visits and surgical interventions were similar between groups. Children receiving MET were more likely to receive follow-up imaging, although only 46% of children with ureteral calculi had appropriate follow-up imaging within 90 days, regardless of MET exposure. Odds ratios of factors and outcomes associated with MET exposure are shown in the Table. DISCUSSION: Although early data support safety and efficacy MET in children, nationwide use in children is low among potential candidates for MET. For children with ureteral calculi, only year of diagnosis was a significant factor associated with MET use. No difference in unplanned physician visits or surgical interventions was noted. Most notable, however, was the low rate of follow-up imaging within 90 days for children presenting acutely with UUTC. CONCLUSIONS: Use of MET for children with ureteral calculi is increasing, although still fewer than a third of children considered potential candidates receive this treatment. Follow-up imaging is not obtained for many children with ureteral calculi. Future work is needed to standardize management and follow-up protocols for children with acute renal colic.

Characterization of the gut microbiome in epidemiologic studies: the multiethnic cohort experience.

PURPOSE: The development of next-generation sequencing and accompanying bioinformatics tools has revolutionized characterization of microbial communities. As interest grows in the role of the human microbiome in health and disease, so does the need for well-powered, robustly designed epidemiologic studies. Here, we discuss sources of bias that can arise in gut microbiome research. METHODS: Research comparing methods of specimen collection, preservation, processing, and analysis of gut microbiome samples is reviewed. Although selected studies are primarily based on the gut, many of the same principles are applicable to samples derived from other anatomical sites. Methods for participant recruitment and sampling of the gut microbiome implemented in an ongoing population-based study, the Multiethnic Cohort (MEC), are also described. RESULTS: Variation in methodologies can influence the results of human microbiome studies. To help minimize bias, techniques such as sample homogenization, addition of internal standards, and quality filtering should be adopted in protocols. Within the MEC, participant response rates to stool sample collection were comparable to other studies, and in-home stool sample collection yields sufficient high-quality DNA for gut microbiome analysis. CONCLUSIONS: Application of standardized and quality controlled methods in human microbiome studies is necessary to ensure data quality and comparability among studies.

Diet, the gut microbiome, and epigenetics.

Increasingly, the gut microbiome is implicated in the etiology of cancer, not only as an infectious agent but also by altering exposure to dietary compounds that influence disease risk. Whereas the composition and metabolism of the gut microbiome is influenced by diet, the gut microbiome can also modify dietary exposures in ways that are beneficial or detrimental to the human host. The colonic bacteria metabolize macronutrients, either as specialists or in consortia of bacteria, in a variety of diverse metabolic pathways. Microbial metabolites of diet can also be epigenetic activators of gene expression that may influence cancer risk in humans. Epigenetics involves heritable changes in gene expression via post-translational and post-transcriptional modifications. Microbial metabolites can influence epigenetics by altering the pool of compounds used for modification or by directly inhibiting enzymes involved in epigenetic pathways. Colonic epithelium is immediately exposed to these metabolites, although some metabolites are also found in systemic circulation. In this review, we discuss the role of the gut microbiome in dietary metabolism and how microbial metabolites may influence gene expression linked to colon cancer risk.

The influence of anti-infective periodontal treatment on C-reactive protein: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Periodontal infections are hypothesized to increase the risk of adverse systemic outcomes through inflammatory mechanisms. The magnitude of effect, if any, of anti-infective periodontal treatment on systemic inflammation is unknown, as are the patient populations most likely to benefit. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to test the hypothesis that anti-infective periodontal treatment reduces systemic c-reactive protein (CRP). METHODS AND FINDINGS: MEDLINE, EMBASE, CENTRAL and CINAHL databases were searched using sensitivity-enhancing search terms. Eligible RCTs enrolled patients with periodontal infection, compared a clearly defined anti-infective periodontal intervention (experimental group) to an "inactive control" (no periodontal intervention) or to an "active control" (lower treatment intensity than the experimental group). Mean differences in final CRP values at the earliest post-treatment time point (typically 1-3 months) between experimental and control groups were analyzed using random-effects regression. Among 2,753 possible studies 20 were selected, which included 2,561 randomized patients(median=57). Baseline CRP values were >3.0 mg/L in 40% of trials. Among studies with a control group receiving no treatment, the mean difference in CRP final values among experimental treatment vs. control groups was -0.37 mg/L [95%CI=-0.64, -0.11], (P=0.005), favoring experimental treatment. Trials for which the experimental group received antibiotics had stronger effects (P for interaction=0.03) and the mean difference in CRP final values among experimental treatment vs. control was -0.75 mg/L [95%CI=-1.17,-0.33]. No treatment effect was observed among studies using an active treatment comparator. Treatment effects were stronger for studies that included patients with co-morbidities vs. studies that included "systemically healthy" patients, although the interaction was not significant (P=0.48). CONCLUSIONS: Anti-infective periodontal treatment results in short-term modest reductions in systemic CRP.