Comparative basolateral amygdala connectomics reveals dissociable single-neuron projection patterns to frontal cortex in macaques and mice.

Basolateral amygdala (BLA) is a key hub for affect in the brain,1,2,3 and dysfunction within this area contributes to a host of psychiatric disorders.4,5 BLA is extensively and reciprocally interconnected with frontal cortex,6,7,8,9 and some aspects of its function are evolutionarily conserved across rodents, anthropoid primates, and humans.10 Neuron density in BLA is substantially lower in primates compared to murine rodents,11 and frontal cortex (FC) is dramatically expanded in primates, particularly the more anterior granular and dysgranular areas.12,13,14 Yet, how these anatomical differences influence the projection patterns of single BLA neurons to frontal cortex across rodents and primates is unknown. Using a barcoded connectomic approach, we assessed the single BLA neuron connections to frontal cortex in mice and macaques. We found that BLA neurons are more likely to project to multiple distinct parts of FC in mice than in macaques. Further, while single BLA neuron projections to nucleus accumbens were similarly organized in mice and macaques, BLA-FC connections differed substantially. Notably, BLA connections to subcallosal anterior cingulate cortex (scACC) in macaques were least likely to branch to other medial frontal cortex areas compared to perigenual ACC (pgACC). This pattern of connections was reversed in the mouse homologues of these areas, infralimbic and prelimbic cortex (IL and PL), mirroring functional differences between rodents and non-human primates. Taken together, these results indicate that BLA connections to FC are not linearly scaled from mice to macaques and instead the organization of single-neuron BLA connections is distinct between these species.

Accurate genotype imputation from low-coverage whole-genome sequencing data of rainbow trout.

With the rapid and significant cost reduction of next-generation sequencing, low-coverage whole-genome sequencing (lcWGS) followed by genotype imputation is becoming a cost-effective alternative to SNP (single nucleotide polymorphism) array genotyping. The objectives of this study were two-fold: 1) construct a haplotype reference panel for genotype imputation from lcWGS data in rainbow trout (Oncorhynchus mykiss); and 2) evaluate the concordance between imputed genotypes and SNP-array genotypes in two breeding populations. Medium-coverage (12x) whole-genome sequences were obtained from a total of 410 fish representing five breeding populations with various spawning dates. The short-read sequences were mapped to the rainbow trout reference genome, and genetic variants were identified using GATK. After data filtering, 20,434,612 biallelic SNPs were retained. The reference panel was phased with SHAPEIT5, and was used as a reference to impute genotypes from lcWGS data using GLIMPSE2. A total of 90 fish from the Troutlodge November breeding population were sequenced with an average coverage of 1.3x, and these fish were also genotyped with the Axiom 57K rainbow trout SNP array. The concordance between array-based genotypes and imputed genotypes was 99.1%. After downsampling the coverage to 0.5x, 0.2x and 0.1x, the concordance between array-based genotypes and imputed genotypes was 98.7%, 97.8% and 96.7%, respectively. In the USDA odd-year breeding population, the concordance between array-based genotypes and imputed genotypes was 97.8% for 109 fish downsampled to 0.5x coverage. Therefore, the reference haplotype panel reported in this study can be used to accurately impute genotypes from lcWGS data in rainbow trout breeding populations.

Time to Diagnosis and Treatment for Ovarian Cancer and Associations with Outcomes: A Systematic Review.

Background: Ovarian cancer is commonly diagnosed symptomatically at an advanced stage. Better survival for early disease suggests improving diagnostic pathways may increase survival. This study examines literature assessing diagnostic intervals and their association with clinical and psychological outcomes. Methods: Medline, EMBASE, and EmCare databases were searched for studies including quantitative measures of at least one interval, published between January 1, 2000 and August 9, 2022. Interval measures and associations (interval, outcomes, analytic strategy) were synthesized. Risk of bias of association studies was assessed using the Aarhus Checklist and ROBINS-E tool. Results: In total, 65 papers (20 association studies) were included and 26 unique intervals were identified. Interval estimates varied widely and were impacted by summary statistic used (mean or median) and group focused on. Of Aarhus-defined intervals, patient (symptom to presentation, n = 23; range [median]: 7-168 days) and diagnostic (presentation to diagnosis, n = 22; range [median]: 7-270 days) were most common. Nineteen association studies examined survival or stage outcomes with most, including five low risk-of-bias studies, finding no association. Conclusions: Studies reporting intervals for ovarian cancer diagnosis are limited by inconsistent definitions and reporting. Greater utilization of the Aarhus statement to define intervals and appropriate analytic methods is needed to strengthen findings from future studies.

Pre-diagnosis tea and coffee consumption and survival after a diagnosis of ovarian cancer: results from the Ovarian Cancer Association Consortium.

BACKGROUND: Tea and coffee are the most frequently consumed beverages in the world. Green tea in particular contains compounds with potential anti-cancer effects, but its association with survival after ovarian cancer is uncertain. METHODS: We investigated the associations between tea and coffee consumption before diagnosis and survival using data from 10 studies in the Ovarian Cancer Association Consortium. Data on tea (green, black, herbal), coffee and caffeine intake were available for up to 5724 women. We used Cox proportional hazards regression to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI). RESULTS: Compared with women who did not drink any green tea, consumption of one or more cups/day was associated with better overall survival (aHR = 0.84, 95% CI 0.71-1.00, p-trend = 0.04). A similar association was seen for ovarian cancer-specific survival in five studies with this information (aHR = 0.81, 0.66-0.99, p-trend = 0.045). There was no consistent variation between subgroups defined by clinical or lifestyle characteristics and adjustment for other aspects of lifestyle did not appreciably alter the estimates. We found no evidence of an association between coffee, black or herbal tea, or caffeine intake and survival. CONCLUSION: The observed association with green tea consumption before diagnosis raises the possibility that consumption after diagnosis might improve patient outcomes.

Salience Network Segregation Mediates the Effect of Tau Pathology on Mild Behavioral Impairment.

INTRODUCTION: A recently developed mild behavioral impairment (MBI) diagnostic framework standardizes the early characterization of neuropsychiatric symptoms in older adults. However, the links between MBI, brain function, and Alzheimer's disease (AD) biomarkers are unclear. METHODS: Using data from 128 participants with diagnosis of amnestic mild cognitive impairment and mild dementia - Alzheimer's type, we test a novel model assessing direct relationships between AD biomarker status and MBI symptoms, as well as mediated effects through segregation of the salience and default-mode networks. RESULTS: We identified a mediated effect of tau positivity on MBI through functional segregation of the salience network from the other high-level, association networks. There were no direct effects of AD biomarkers status on MBI. DISCUSSION: Our findings suggest an indirect role of tau pathology in MBI through brain network dysfunction and emphasize the role of the salience network in mediating relationships between neuropathological changes and behavioral manifestations.

Update: Protective and risk factors for Parkinson disease.

We review the epidemiologic literature on potential protective and risk factors in Parkinson's Disease (PD). Prior research identified numerous possible protective and risk factors. Potential protective factors include tobacco abuse, physical activity, urate levels, NSAID use, calcium channel blocker use, statin use, and use of some α1-adrenergic antagonists. Some potential protective factors could be products of reverse causation, including increased serum urate, tobacco abuse, and coffee-tea-caffeine consumption. Potential risk factors include traumatic brain injury, pesticide exposure, organic solvent exposure, lead exposure, air pollution, Type 2 Diabetes, some dairy products, cardiovascular disease, and some infections including Hepatitis C, H. pylori, and COVID-19. Potential non-environmental risk factors include bipolar disorder, essential tremor, bullous pemphigoid, and inflammatory bowel disease. There is an inverse relationship with PD and risk of most cancers. Though many potential protective and risk factors for PD were identified, research has not yet led to unique, rigorous prevention trials or successful disease-modifying interventions. While efforts to reduce exposure to some industrial toxicants are well justified, PD incidence might be most effectively reduced by mitigation of risks, such as Type 2 Diabetes, air pollution, traumatic brain injury, or physical inactivity, that are general public health intervention targets.

Genome-wide analysis to assess if heavy alcohol consumption modifies the association between SNPs and pancreatic cancer risk.

BACKGROUND: Pancreatic cancer is a leading cause of cancer-related death globally. Risk factors for pancreatic cancer include common genetic variants and potentially heavy alcohol consumption. We assessed if genetic variants modify the association between heavy alcohol consumption and pancreatic cancer risk. METHODS: We conducted a genome-wide interaction analysis of single nucleotide polymorphisms (SNP) by heavy alcohol consumption (more than 3 drinks per day) for pancreatic cancer in European ancestry populations from genome-wide association studies (GWAS). Our analysis included 3,707 cases and 4,167 controls from case-control studies and 1,098 cases and 1,162 controls from cohort studies. Fixed effect meta-analyses were conducted. RESULTS: A potential novel region of association on 10p11.22, lead SNP rs7898449 (Pinteraction = 5.1 x 10-8 in the meta-analysis, Pinteraction = 2.1x10-9 in the case-control studies, Pinteraction = 0.91 cohort studies) was identified. A SNP correlated with this lead SNP is an eQTL for the NRP1 gene. Of the 17 genomic regions with genome-wide significant evidence of association with pancreatic cancer in prior studies, we observed suggestive evidence that heavy alcohol consumption modified the association for one SNP near LINC00673, rs11655237 on 17q25.1 (Pinteraction = 0.004). CONCLUSIONS: We identified a novel genomic region that may be associated with pancreatic cancer risk in conjunction with heavy alcohol consumption located near an eQTL for the NRP1, a protein that plays an important role in the development and progression of pancreatic cancer Impact: This work can provide insight into the etiology of pancreatic cancer particularly in heavy drinkers.

Genome-wide association analysis of the resistance to infectious hematopoietic necrosis virus in two rainbow trout aquaculture lines confirms oligogenic architecture with several moderate effect quantitative trait loci.

Infectious hematopoietic necrosis (IHN) is a disease of salmonid fish that is caused by the IHN virus (IHNV), which can cause substantial mortality and economic losses in rainbow trout aquaculture and fisheries enhancement hatchery programs. In a previous study on a commercial rainbow trout breeding line that has undergone selection, we found that genetic resistance to IHNV is controlled by the oligogenic inheritance of several moderate and many small effect quantitative trait loci (QTL). Here we used genome wide association analyses in two different commercial aquaculture lines that were naïve to previous exposure to IHNV to determine whether QTL were shared across lines, and to investigate whether there were major effect loci that were still segregating in the naïve lines. A total of 1,859 and 1,768 offspring from two commercial aquaculture strains were phenotyped for resistance to IHNV and genotyped with the rainbow trout Axiom 57K SNP array. Moderate heritability values (0.15-0.25) were estimated. Two statistical methods were used for genome wide association analyses in the two populations. No major QTL were detected despite the naïve status of the two lines. Further, our analyses confirmed an oligogenic architecture for genetic resistance to IHNV in rainbow trout. Overall, 17 QTL with notable effect (≥1.9% of the additive genetic variance) were detected in at least one of the two rainbow trout lines with at least one of the two statistical methods. Five of those QTL were mapped to overlapping or adjacent chromosomal regions in both lines, suggesting that some loci may be shared across commercial lines. Although some of the loci detected in this GWAS merit further investigation to better understand the biological basis of IHNV disease resistance across populations, the overall genetic architecture of IHNV resistance in the two rainbow trout lines suggests that genomic selection may be a more effective strategy for genetic improvement in this trait.

The Application of Next-Generation Sequencing in Preoperative Evaluation for Urologic Stone Surgery.

Introduction: Next-generation sequencing (NGS) is a new molecular technique for identifying microorganisms. Treating bacteriuria in patients undergoing stone removal procedures is important for preventing postoperative urinary tract infection (UTI). The objective of this study is to assess the usefulness of preoperative urine NGS testing by comparing NGS with standard urine culture in predicting postoperative UTI after ureteroscopic lithotripsy (URSL) and percutaneous nephrolithotomy (PCNL). Materials and Methods: This prospective study was conducted from February 16, 2022, to January 11, 2024. Sixty subjects who underwent URSL or PCNL were included. Preoperative voided urine samples were collected for urine culture and tested by MicroGenDX for urine polymerase chain reaction (PCR) and urine NGS. Stone specimens obtained intraoperatively were also sent for stone culture and MicrogenDx. Patients were monitored for 4 weeks post-operation for recording clinical outcomes related to infections and complications. Results: Twenty-six (43.3%) male and 34 (56.7%) female participants were included. Twenty-six (43.3%) patients underwent PCNL (15 standard PCNL and 11 mini PCNL), and 34 (56.7%) underwent URSL. Standard urine culture identified positive results in 26 cases (43.3%), PCR for 17 cases (28.3%), and NGS for 31 cases (51.7%). The overall postoperative UTI rate was 6 (10%). Standard urine culture demonstrated a sensitivity of 50%, specificity of 57.4%, and accuracy of 56.7%. Positive predictive value (PPV) was notably poor at 11.5%. Urine NGS showed a higher sensitivity of 83.3%, specificity of 53.7%, accuracy of 55%, and PPV of 16.7%. Conclusion: Urine NGS significantly improves the sensitivity of detecting microorganisms in preoperative urine compared with standard urine culture. Despite its high sensitivity and capability to identify nonculturable bacteria, using NGS alongside standard urine culture is recommended. This parallel approach harnesses the strengths of both methods. Integrating NGS into standard practice could elevate the quality of care, especially for patients at high risk of UTIs, such as those undergoing invasive stone removal procedures.

Dolutegravir- Versus Efavirenz-Based Treatment in Pregnancy: Impact on Red Blood Cell Folate Concentrations in Pregnant Women and Their Infants.

In IMPAACT 2010/VESTED, pregnant women were randomized to initiate dolutegravir (DTG)+emtricitabine (FTC)/tenofovir alafenamide (TAF), DTG+FTC/tenofovir disoproxil fumarate (TDF), or efavirenz (EFV)/FTC/TDF. We assessed red blood cell folate concentrations (RBC-folate) at maternal study entry and delivery, and infant birth. RBC-folate outcomes were: 1) maternal change entry to delivery (trajectory), 2) infant, 3) ratio of infant-to-maternal delivery. Generalized estimating equation models for each log(folate) outcome were fit to estimate adjusted geometric mean ratio (Adj-GMR)/GMR trajectories (Adj-GMRT) of each arm comparison in 340 mothers and 310 infants. Overall, 90% of mothers received folic acid supplements and 78% lived in Africa. At entry, median maternal age was 25 years, gestational age was 22 weeks, CD4 count was 482 cells/mm3 and log10HIV RNA was 3 copies/mL. Entry RBC-folate was similar across arms. Adj-GMRT of maternal folate was 3% higher in the DTG+FTC/TAF versus EFV/FTC/TDF arm (1.03, 95%CI 1.00, 1.06). The DTG+FTC/TAF arm had an 8% lower infant-maternal folate ratio (0.92, 95%CI 0.78, 1.09) versus EFV/FTC/TDF. Results are consistent with no clinically meaningful differences between arms for all RBC-folate outcomes and they suggest that cellular uptake of folate and folate transport to the infant do not differ in pregnant women starting DTG- vs. EFV-based ART.

Functions and pharmacology of α2ß2 nicotinic acetylcholine receptors; in and out of the shadow of α4ß2 nicotinic acetylcholine receptors.

Although α2 was the first neuronal nicotinic acetylcholine receptor (nAChR) receptor subunit to be cloned, due to its low level of expression in rodent brain, its study has largely been neglected. This study provides a comparison of the α2 and α4 structures and their functional similarities, especially in regard to the existence of low and high sensitivity forms based on subunit stoichiometry. We show that the pharmacological profiles of the low and high sensitivity forms of α2ß2 and α4ß2 receptors are very similar in their responses to nicotine, with high sensitivity receptors showing protracted responses. Sazetidine A, an agonist that is selective for the high sensitivity α4 receptors also selectively activates high sensitivity α2 receptors. Likewise, α2 receptors have similar responses as α4 receptors to the positive allosteric modulators (PAMs) desformylflustrabromine (dFBr) and NS9283. We show that the partial agonists for α4ß2 receptors, cytisine and varenicline are also partial agonists for α2ß2 receptors. Studies have shown that levels of α2 expression may be much higher in the brains of primates than those of rodents, suggesting a potential importance for human therapeutics. High-affinity nAChR have been studied in humans with PET ligands such as flubatine. We show that flubatine has similar activity with α2ß2 and α4ß2 receptors so that α2 receptors will also be detected in PET studies that have previously presumed to selectively detect α4ß2 receptors. Therefore, α2 receptors need more consideration in the development of therapeutics to manage nicotine addiction and declining cholinergic function in age and disease.

Explorations of Agonist Selectivity for the α9* nAChR with Novel Substituted Carbamoyl/Amido/Heteroaryl Dialkylpiperazinium Salts and Their Therapeutic Implications in Pain and Inflammation.

There is an urgent need for nonopioid treatments for chronic and neuropathic pain to provide effective alternatives amid the escalating opioid crisis. This study introduces novel compounds targeting the α9 nicotinic acetylcholine receptor (nAChR) subunit, which is crucial for pain regulation, inflammation, and inner ear functions. Specifically, it identifies novel substituted carbamoyl/amido/heteroaryl dialkylpiperazinium iodides as potent agonists selective for human α9 and α9α10 over α7 nAChRs, particularly compounds 3f, 3h, and 3j. Compound 3h (GAT2711) demonstrated a 230 nM potency as a full agonist at α9 nAChRs, being 340-fold selective over α7. Compound 3c was 10-fold selective for α9α10 over α9 nAChR. Compounds 2, 3f, and 3h inhibited ATP-induced interleukin-1ß release in THP-1 cells. The analgesic activity of 3h was fully retained in α7 knockout mice, suggesting that analgesic effects were potentially mediated through α9* nAChRs. Our findings provide a blueprint for developing α9*-specific therapeutics for pain.

Association of tea and coffee consumption and biliary tract cancer risk: The Biliary Tract Cancers Pooling Project.

BACKGROUND AND AIMS: Tea and coffee are widely consumed beverages worldwide. We evaluated their association with biliary tract cancer (BTC) incidence. APPROACH AND RESULTS: We pooled data from 15 studies in the Biliary Tract Cancers Pooling Project to evaluate associations between tea and coffee consumption and biliary tract cancer development. We categorized participants as nondrinkers (0 cup/day), moderate drinkers (>0 and <3 cups/day), and heavy drinkers (≥3 cups/day). We estimated multivariable HRs and 95% CIs using Cox models. During 29,911,744 person-years of follow-up, 851 gallbladder, 588 intrahepatic bile duct, 753 extrahepatic bile duct, and 458 ampulla of Vater cancer cases were diagnosed. Individuals who drank tea showed a statistically significantly lower incidence rate of gallbladder cancer (GBC) relative to tea nondrinkers (HR=0.77; 95% CI, 0.64-0.91), and intrahepatic bile duct cancer (IHBDC) had an inverse association (HR=0.81; 95% CI, 0.66-1.00). However, no associations were observed for extrahepatic bile duct cancer (EHBDC) or ampulla of Vater cancer (AVC). In contrast, coffee consumption was positively associated with GBC, with a higher incidence rate for individuals consuming more coffee (HR<3 cups/day =1.29; 95% CI, 1.01-1.66; HR≥3 cups/day =1.49; 95% CI, 1.11-1.99, Ptrend=0.01) relative to coffee nondrinkers. However, there was no association between coffee consumption and GBC when restricted to coffee drinkers. There was little evidence of associations between coffee consumption and other biliary tract cancers. CONCLUSIONS: Tea consumption was associated with a lower incidence of GBC and possibly IHBDC. Further research is warranted to replicate the observed positive association between coffee and GBC.

Workflow for the unsupervised clustering of sleep stages identifies light and deep sleep in electrophysiological recordings in mice.

BACKGROUND: Sleep physiology plays a critical role in brain development and aging. Accurate sleep staging, which categorizes different sleep states, is fundamental for sleep physiology studies. Traditional methods for sleep staging rely on manual, rule-based scoring techniques, which limit their accuracy and adaptability. NEW METHOD: We describe, test and challenge a workflow for unsupervised clustering of sleep states (WUCSS) in rodents, which uses accelerometer and electrophysiological data to classify different sleep states. WUCSS utilizes unsupervised clustering to identify sleep states using six features, extracted from 4-second epochs. RESULTS: We gathered high-quality EEG recordings combined with accelerometer data in diverse transgenic mouse lines (male ApoE3 versus ApoE4 knockin; male CNTNAP2 KO versus wildtype littermates). WUCSS showed high recall, precision, and F1-score against manual scoring on awake, NREM, and REM sleep states. Within NREM, WUCSS consistently identified two additional clusters that qualify as deep and light sleep states. COMPARISON WITH EXISTING METHODS: The ability of WUCSS to discriminate between deep and light sleep enhanced the precision and comprehensiveness of the current mouse sleep physiology studies. This differentiation led to the discovery of an additional sleep phenotype, notably in CNTNAP2 KO mice, showcasing the method's superiority over traditional scoring methods. CONCLUSIONS: WUCSS, with its unsupervised approach and classification of deep and light sleep states, provides an unbiased opportunity for researchers to enhance their understanding of sleep physiology. Its high accuracy, adaptability, and ability to save time and resources make it a valuable tool for improving sleep staging in both clinical and preclinical research.

Self-rated health, epigenetic ageing, and long-term mortality in older Australians.

Self-rated health (SRH) is a subjective indicator of overall health based on a single questionnaire item. Previous evidence found that it is a strong predictor of mortality, although the underlying mechanism is poorly understood. Epigenetic age is an objective, emerging biomarker of health, estimated using DNA methylation data at hundreds of sites across the genome. This study aimed to assess the overlap and interaction between SRH and epigenetic ageing in predicting mortality risk. We used DNA methylation data from 1059 participants in the Melbourne Collaborative Cohort Study (mean age: 69 years) to calculate three age-adjusted measures of epigenetic ageing: GrimAge, PhenoAge, and DunedinPACE. SRH was assessed using a five-category questionnaire item ("excellent, very good, good, fair, poor"). Cox models were used to assess the associations of SRH, epigenetic ageing, and their interaction, with all-cause mortality over up to 17 years of follow-up (Ndeaths = 345). The association of SRH with mortality per category increase was HR = 1.29; 95%CI: 1.14-1.46. The association was slightly attenuated after adjusting for all three epigenetic ageing measures (HR = 1.25, 95%CI: 1.10-1.41). A strong gradient was observed in the association of GrimAge (Pinteraction = 0.006) and DunedinPACE (Pinteraction = 0.002) with mortality across worsening SRH strata. For example, the association between DunedinPACE and mortality in participants with "excellent" SRH was HR = 1.02, 95%CI: 0.73-1.43 and for "fair/poor" HR = 1.72, 95%CI: 1.35-2.20. SRH and epigenetic ageing were synergistic risk factors of mortality in our study. These findings suggest that consideration of subjective and objective factors may improve general health assessment, which has implications for the ongoing development of molecular markers of ageing.

Dietary Fiber Intake and Risk of Advanced and Aggressive Forms of Prostate Cancer: A Pooled Analysis of 15 Prospective Cohort Studies.

BACKGROUND: Evidence of an association between dietary fiber intake and risk of advanced and aggressive forms of prostate cancer (PC) and PC mortality is limited. OBJECTIVE: The aim of this study was to examine associations between intakes of dietary fiber overall and by food source and risk of advanced and aggressive forms of PC. DESIGN: The study design was a pooled analysis of the primary data from 15 cohorts in 3 continents. Baseline dietary fiber intake was assessed using a validated food frequency questionnaire or diet history in each study. PARTICIPANTS/SETTING: There were 842 149 men followed for up to 9 to 22 years between 1985 and 2009 across studies. MAIN OUTCOME MEASURES: The primary outcome measures were advanced (stage T4, N1, or M1 or PC mortality), advanced restricted (excluded men with missing stage and those with localized PC who died of PC), and high-grade PC (Gleason score ≥8 or poorly differentiated/undifferentiated) and PC mortality. STATISTICAL ANALYSIS PERFORMED: Study-specific multivariable hazard ratios (MVHR) were calculated using Cox proportional hazards regression and pooled using random effects models. RESULTS: Intake of dietary fiber overall, from fruits, and from vegetables was not associated with risk of advanced (n = 4863), advanced restricted (n = 2978), or high-grade PC (n = 9673) or PC mortality (n = 3097). Dietary fiber intake from grains was inversely associated with advanced PC (comparing the highest vs lowest quintile, MVHR 0.84; 95% CI 0.76-0.93), advanced restricted PC (MVHR 0.85; 95% CI 0.74-0.97), and PC mortality (MVHR 0.78; 95% CI 0.68-0.89); statistically significant trends were noted for each of these associations (P ≤ .03), and a null association was observed for high-grade PC for the same comparison (MVHR 1.00; 95% CI 0.93-1.07). The comparable results were 1.06 (95% CI 1.01-1.10; P value, test for trend = .002) for localized PC (n = 35,199) and 1.05 (95% CI 0.99-1.11; P value, test for trend = .04) for low/intermediate grade PC (n = 34 366). CONCLUSIONS: Weak nonsignificant associations were observed between total dietary fiber intake and risk of advanced forms of PC, high-grade PC, and PC mortality. High dietary fiber intake from grains was associated with a modestly lower risk of advanced forms of PC and PC mortality.