68Ga-RM2 PET-MRI versus MRI alone for evaluation of patients with biochemical recurrence of prostate cancer: a single-centre, single-arm, phase 2/3 imaging trial.

BACKGROUND: National Comprehensive Cancer Network guidelines include prostate-specific membrane antigen (PSMA)-targeted PET for detection of biochemical recurrence of prostate cancer. However, targeting a single tumour characteristic might not be sufficient to reflect the full extent of disease. Gastrin releasing peptide receptors (GRPR) have been shown to be overexpressed in prostate cancer. In this study, we aimed to evaluate the diagnostic performance of the GRPR-targeting radiopharmaceutical 68Ga-RM2 in patients with biochemical recurrence of prostate cancer. METHODS: This single-centre, single-arm, phase 2/3 trial was done at Stanford University (USA). Adult patients (aged ≥18 years) with biochemical recurrence of prostate cancer, a Karnofsky performance status of 50 or higher, increasing prostate-specific antigen concentration 0·2 ng/mL or more after prostatectomy or 2 ng/mL or more above nadir after radiotherapy, and non-contributory conventional imaging (negative CT or MRI, and bone scan) were eligible. All participants underwent 68Ga-RM2 PET-MRI. The primary outcome was the proportion of patients with PET-positive findings on 68Ga-RM2 PET-MRI compared with MRI alone after initial therapy, at a per-patient and per-lesion level. The primary outcome would be considered met if at least 30% of patients had one or more lesions detected by 68Ga-RM2 PET-MRI and the detection by 68Ga-RM2 PET-MRI was significantly greater than for MRI. Each PET scan was interpreted by three independent masked readers using a standardised evaluation criteria. This study is registered with ClinicalTrials.gov, NCT02624518, and is complete. FINDINGS: Between Dec 12, 2015, and July 27, 2021, 209 men were screened for eligibility, of whom 100 were included in analyses. Median follow-up was 49·3 months (IQR 36·7-59·2). The primary endpoint was met; 68Ga-RM2 PET-MRI was positive in 69 (69%) patients and MRI alone was positive in 40 (40%) patients (p<0·0001). In the per-lesion analysis 68Ga-RM2 PET-MRI showed significantly higher detection rates than MRI alone (143 vs 96 lesions; p<0·0001). No grade 1 or worse events were reported. INTERPRETATION: 68Ga-RM2 PET-MRI showed better diagnostic performance than MRI alone in patients with biochemical recurrence of prostate cancer. Further prospective comparative studies with PSMA-targeted PET are needed to gain a better understanding of GRPR and PSMA expression patterns in these patients. FUNDING: The US Department of Defense.

Endospores associated with deep seabed geofluid features in the eastern Gulf of Mexico.

Recent studies have reported up to 1.9 × 1029 bacterial endospores in the upper kilometre of deep subseafloor marine sediments, however, little is understood about their origin and dispersal. In cold ocean environments, the presence of thermospores (endospores produced by thermophilic bacteria) suggests that distribution is governed by passive migration from warm anoxic sources possibly facilitated by geofluid flow, such as advective hydrocarbon seepage sourced from petroleum deposits deeper in the subsurface. This study assesses this hypothesis by measuring endospore abundance and distribution across 60 sites in Eastern Gulf of Mexico (EGM) sediments using a combination of the endospore biomarker 2,6-pyridine dicarboxylic acid or 'dipicolinic acid' (DPA), sequencing 16S rRNA genes of thermospores germinated in 50°C sediment incubations, petroleum geochemistry in the sediments and acoustic seabed data from sub-bottom profiling. High endospore abundance is associated with geologically active conduit features (mud volcanoes, pockmarks, escarpments and fault systems), consistent with subsurface fluid flow dispersing endospores from deep warm sources up into the cold ocean. Thermospores identified at conduit sites were most closely related to bacteria associated with the deep biosphere habitats including hydrocarbon systems. The high endospore abundance at geological seep features demonstrated here suggests that recalcitrant endospores and their chemical components (such as DPA) can be used in concert with geochemical and geophysical analyses to locate discharging seafloor features. This multiproxy approach can be used to better understand patterns of advective fluid flow in regions with complex geology like the EGM basin.

Diverse patient trajectories during cytotoxic chemotherapy: Capturing longitudinal patient-reported outcomes.

BACKGROUND: High-value cancer care balances effective treatment with preservation of quality of life. Chemotherapy is known to affect patients' physical and psychological well-being negatively. Patient-reported outcomes (PROs) provide a means to monitor declines in a patients' well-being during treatment. METHODS: We identified 741 oncology patients undergoing chemotherapy in our electronic health record (EHR) system who completed Patient-Reported Outcomes Measurement Information System (PROMIS) surveys during treatment at a comprehensive cancer center, 2013-2018. PROMIS surveys were collected before, during, and after chemotherapy treatment. Linear mixed-effects models were performed to identify predictors of physical and mental health scores over time. A k-mean cluster analysis was used to group patient PROMIS score trajectories. RESULTS: Mean global physical health (GPH) scores were 48.7 (SD 9.3), 47.7 (8.8), and 48.6 (8.9) and global mental health (GMH) scores were 50.4 (8.6), 49.5 (8.8), and 50.6 (9.1) before, during, and after chemotherapy, respectively. Asian race, Hispanic ethnicity, public insurance, anxiety/depression, stage III cancer, and palliative care were predictors of GPH and GMH decline. The treatment time period was also a predictor of both GPH and GMH decline relative to pre-treatment. Trajectory clustering identified four distinct PRO clusters associated with chemotherapy treatment. CONCLUSIONS: Patient-reported outcomes are increasingly used to help monitor cancer treatment and are now a part of care reimbursement. This study leveraged routinely collected PROMIS surveys linked to EHRs to identify novel patient trajectories of physical and mental well-being in oncology patients undergoing chemotherapy and potential predictors. Supportive care interventions in high-risk populations identified by our study may optimize resource deployment. NOVELTY AND IMPACT: This study leveraged routinely collected patient-reported outcome (PROMIS) surveys linked to electronic health records to characterize oncology patients' quality of life during chemotherapy. Important clinical and demographic predictors of declines in quality of life were identified and four novel trajectories to guide personalized interventions and support. This work highlights the utility of monitoring patient-reported outcomes not only before and after, but during chemotherapy to help advert adverse patient outcomes and improve treatment adherence.

Assessment of a Clinical Trial-Derived Survival Model in Patients With Metastatic Castration-Resistant Prostate Cancer.

Importance: Randomized clinical trials (RCTs) are considered the criterion standard for clinical evidence. Despite their many benefits, RCTs have limitations, such as costliness, that may reduce the generalizability of their findings among diverse populations and routine care settings. Objective: To assess the performance of an RCT-derived prognostic model that predicts survival among patients with metastatic castration-resistant prostate cancer (CRPC) when the model is applied to real-world data from electronic health records (EHRs). Design, Setting, and Participants: The RCT-trained model and patient data from the RCTs were obtained from the Dialogue for Reverse Engineering Assessments and Methods (DREAM) challenge for prostate cancer, which occurred from March 16 to July 27, 2015. This challenge included 4 phase 3 clinical trials of patients with metastatic CRPC. Real-world data were obtained from the EHRs of a tertiary care academic medical center that includes a comprehensive cancer center. In this study, the DREAM challenge RCT-trained model was applied to real-world data from January 1, 2008, to December 31, 2019; the model was then retrained using EHR data with optimized feature selection. Patients with metastatic CRPC were divided into RCT and EHR cohorts based on data source. Data were analyzed from March 23, 2018, to October 22, 2020. Exposures: Patients who received treatment for metastatic CRPC. Main Outcomes and Measures: The primary outcome was the performance of an RCT-derived prognostic model that predicts survival among patients with metastatic CRPC when the model is applied to real-world data. Model performance was compared using 10-fold cross-validation according to time-dependent integrated area under the curve (iAUC) statistics. Results: Among 2113 participants with metastatic CRPC, 1600 participants were included in the RCT cohort, and 513 participants were included in the EHR cohort. The RCT cohort comprised a larger proportion of White participants (1390 patients [86.9%] vs 337 patients [65.7%]) and a smaller proportion of Hispanic participants (14 patients [0.9%] vs 42 patients [8.2%]), Asian participants (41 patients [2.6%] vs 88 patients [17.2%]), and participants older than 75 years (388 patients [24.3%] vs 191 patients [37.2%]) compared with the EHR cohort. Participants in the RCT cohort also had fewer comorbidities (mean [SD], 1.6 [1.8] comorbidities vs 2.5 [2.6] comorbidities, respectively) compared with those in the EHR cohort. Of the 101 variables used in the RCT-derived model, 10 were not available in the EHR data set, 3 of which were among the top 10 features in the DREAM challenge RCT model. The best-performing EHR-trained model included only 25 of the 101 variables included in the RCT-trained model. The performance of the RCT-trained and EHR-trained models was adequate in the EHR cohort (mean [SD] iAUC, 0.722 [0.118] and 0.762 [0.106], respectively); model optimization was associated with improved performance of the best-performing EHR model (mean [SD] iAUC, 0.792 [0.097]). The EHR-trained model classified 256 patients as having a high risk of mortality and 256 patients as having a low risk of mortality (hazard ratio, 2.7; 95% CI, 2.0-3.7; log-rank P < .001). Conclusions and Relevance: In this study, although the RCT-trained models did not perform well when applied to real-world EHR data, retraining the models using real-world EHR data and optimizing variable selection was beneficial for model performance. As clinical evidence evolves to include more real-world data, both industry and academia will likely search for ways to balance model optimization with generalizability. This study provides a pragmatic approach to applying RCT-trained models to real-world data.

Hydrocarbon seepage in the deep seabed links subsurface and seafloor biospheres.

Marine cold seeps transmit fluids between the subseafloor and seafloor biospheres through upward migration of hydrocarbons that originate in deep sediment layers. It remains unclear how geofluids influence the composition of the seabed microbiome and if they transport deep subsurface life up to the surface. Here we analyzed 172 marine surficial sediments from the deep-water Eastern Gulf of Mexico to assess whether hydrocarbon fluid migration is a mechanism for upward microbial dispersal. While 132 of these sediments contained migrated liquid hydrocarbons, evidence of continuous advective transport of thermogenic alkane gases was observed in 11 sediments. Gas seeps harbored distinct microbial communities featuring bacteria and archaea that are well-known inhabitants of deep biosphere sediments. Specifically, 25 distinct sequence variants within the uncultivated bacterial phyla Atribacteria and Aminicenantes and the archaeal order Thermoprofundales occurred in significantly greater relative sequence abundance along with well-known seep-colonizing members of the bacterial genus Sulfurovum, in the gas-positive sediments. Metabolic predictions guided by metagenome-assembled genomes suggested these organisms are anaerobic heterotrophs capable of nonrespiratory breakdown of organic matter, likely enabling them to inhabit energy-limited deep subseafloor ecosystems. These results point to petroleum geofluids as a vector for the advection-assisted upward dispersal of deep biosphere microbes from subsurface to surface environments, shaping the microbiome of cold seep sediments and providing a general mechanism for the maintenance of microbial diversity in the deep sea.

The Urine Albumin-to-Creatinine Ratio and Kidney Function after Nephrectomy.

PURPOSE: Patients with kidney cancer are at risk for chronic kidney disease after radical and partial nephrectomy. We determined if the urine albumin-to-creatinine ratio is independently associated with progressive chronic kidney disease after nephrectomy. MATERIALS AND METHODS: We performed a cohort study based within a large, integrated health care system. We identified patients who underwent radical or partial nephrectomy from 2004 to 2014 with urine albumin-to-creatinine ratio measured in the 12 months before surgery. We fit multivariable models to determine if the urine albumin-to-creatinine ratio was associated with the time to chronic kidney disease progression (defined as reaching stage 4 or 5 chronic kidney disease, estimated glomerular filtration rate less than 30 ml/minute/1.73 m2). We performed a parallel analysis measuring the time to stage 3b, 4 or 5 chronic kidney disease (estimated glomerular filtration rate less than 45 ml/minute/1.73 m2) among patients with normal or near normal preoperative kidney function (estimated glomerular filtration rate 60 ml/minute/1.73 m2 or greater). We also examined the association between urine albumin-to-creatinine ratio and survival. RESULTS: A total of 1,930 patients underwent radical or partial nephrectomy and had preoperative urine albumin-to-creatinine ratio and preoperative and postoperative estimated glomerular filtration rate. Of these patients 658 (34%) and 157 (8%) had moderate (urine albumin-to-creatinine ratio 30 to 300 mg/gm) or severe albuminuria (urine albumin-to-creatinine ratio greater than 300 mg/gm), respectively. Albuminuria severity was independently associated with progressive chronic kidney disease after radical (moderate albuminuria HR 1.7, 95% CI 1.4-2.2; severe albuminuria HR 2.3, 95% CI 1.7-3.1) and partial nephrectomy (moderate albuminuria HR 1.8, 95% CI 1.2-2.7; severe albuminuria HR 4.3, 95% CI 2.7-7.0). Albuminuria was also associated with survival following radical and partial nephrectomy. CONCLUSIONS: In patients undergoing radical or partial nephrectomy the severity of albuminuria can stratify risk of progressive chronic kidney disease.

Metabolic potential of uncultured bacteria and archaea associated with petroleum seepage in deep-sea sediments.

The lack of microbial genomes and isolates from the deep seabed means that very little is known about the ecology of this vast habitat. Here, we investigate energy and carbon acquisition strategies of microbial communities from three deep seabed petroleum seeps (3 km water depth) in the Eastern Gulf of Mexico. Shotgun metagenomic analysis reveals that each sediment harbors diverse communities of chemoheterotrophs and chemolithotrophs. We recovered 82 metagenome-assembled genomes affiliated with 21 different archaeal and bacterial phyla. Multiple genomes encode enzymes for anaerobic oxidation of aliphatic and aromatic compounds, including those of candidate phyla Aerophobetes, Aminicenantes, TA06 and Bathyarchaeota. Microbial interactions are predicted to be driven by acetate and molecular hydrogen. These findings are supported by sediment geochemistry, metabolomics, and thermodynamic modelling. Overall, we infer that deep-sea sediments experiencing thermogenic hydrocarbon inputs harbor phylogenetically and functionally diverse communities potentially sustained through anaerobic hydrocarbon, acetate and hydrogen metabolism.

Thermophilic endospores associated with migrated thermogenic hydrocarbons in deep Gulf of Mexico marine sediments.

Dormant endospores of thermophilic bacteria (thermospores) can be detected in cold marine sediments following high-temperature incubation. Thermospores in the cold seabed may be explained by a dispersal history originating in deep biosphere oil reservoir habitats where upward migration of petroleum fluids at hydrocarbon seeps transports viable cells into the overlying ocean. We assessed this deep-to-shallow dispersal hypothesis through geochemical and microbiological analyses of 111 marine sediments from the deep water Eastern Gulf of Mexico. GC-MS and fluorescence confirmed the unambiguous presence of thermogenic hydrocarbons in 71 of these locations, indicating seepage from deeply sourced petroleum in the subsurface. Heating each sediment to 50 °C followed by 16S rRNA gene sequencing revealed several thermospores with a cosmopolitan distribution throughout the study area, as well as thermospores that were more geographically restricted. Among the thermospores having a more limited distribution, 12 OTUs from eight different lineages were repeatedly detected in sediments containing thermogenic hydrocarbons. A subset of these were significantly correlated with hydrocarbons (p < 0.05) and most closely related to Clostridiales previously detected in oil reservoirs from around the world. This provides evidence of bacteria in the ocean being dispersed out of oil reservoirs, and suggests that specific thermospores may be used as model organisms for studying warm-to-cold transmigration in the deep sea.

Contemporary Use of Partial Nephrectomy: Are Older Patients With Impaired Kidney Function Being Left Behind?

OBJECTIVE: To assess whether patient factors, such as age and preoperative kidney function, were associated with receipt of partial nephrectomy in a national integrated healthcare system. MATERIALS AND METHODS: We identified patients treated with a radical or partial nephrectomy from 2002 to 2014 in the Veterans Health Administration. We examined associations among patient age, sex, race or ethnicity, multimorbidity, baseline kidney function, tumor characteristics, and receipt of partial nephrectomy. We estimated the odds of receiving a partial nephrectomy and assessed interactions between covariates and the year of surgery to explore whether patient factors associated with partial nephrectomy changed over time. RESULTS: In our cohort of 14,186 patients, 4508 (31.2%) received a partial nephrectomy. Use of partial nephrectomy increased from 17% in 2002 to 32% in 2008 and to 38% in 2014. Patient race or ethnicity, age, tumor stage, and year of surgery were independently associated with receipt of partial nephrectomy. Black veterans had significantly increased odds of receipt of partial nephrectomy, whereas older patients had significantly reduced odds. Partial nephrectomy utilization increased for all groups over time, but older patients and patients with worse baseline kidney function showed the least increase in odds of partial nephrectomy. CONCLUSION: Although the utilization of partial nephrectomy increased for all groups, the greatest increase occurred in the youngest patients and those with the highest baseline kidney function. These trends warrant further investigation to ensure that patients at the highest risk of impaired kidney function are considered for partial nephrectomy whenever possible.

Safety and performance benefits of arginine supplements for military personnel: a systematic review.

CONTEXT: Dietary supplements are widely used by military personnel and civilians for promotion of health. OBJECTIVE: The objective of this evidence-based review was to examine whether supplementation with l-arginine, in combination with caffeine and/or creatine, is safe and whether it enhances athletic performance or improves recovery from exhaustion for military personnel. DATA SOURCES: Information from clinical trials and adverse event reports were collected from 17 databases and 5 adverse event report portals. STUDY SELECTION: Studies and reports were included if they evaluated the safety and the putative outcomes of enhanced performance or improved recovery from exhaustion associated with the intake of arginine alone or in combination with caffeine and/or creatine in healthy adults aged 19 to 50 years. DATA EXTRACTION: Information related to population, intervention, comparator, and outcomes was abstracted. Of the 2687 articles screened, 62 articles meeting the inclusion criteria were analyzed. Strength of evidence was assessed in terms of risk of bias, consistency, directness, and precision. RESULTS: Most studies had few participants and suggested risk of bias that could negatively affect the results. l-Arginine supplementation provided little enhancement of athletic performance or improvements in recovery. Short-term supplementation with arginine may result in adverse gastrointestinal and cardiovascular effects. No information about the effects of arginine on the performance of military personnel was available. CONCLUSIONS: The available information does not support the use of l-arginine, either alone or in combination with caffeine, creatine, or both, to enhance athletic performance or improve recovery from exhaustion. Given the information gaps, an evidence-based review to assess the safety or effectiveness of multi-ingredient dietary supplements was not feasible, and therefore the development of a computational model-based approach to predict the safety of multi-ingredient dietary supplements is recommended.

Unconventional Magnetic and Resistive Hysteresis in an Iodine-Bonded Molecular Conductor.

Simultaneous manipulation of both spin and charge is a crucial issue in magnetic conductors. We report on a strong correlation between magnetism and conductivity in the iodine-bonded molecular conductor (DIETSe)2 FeBr2 Cl2 [DIETSe=diiodo(ethylenedithio)tetraselenafulvalene], which is the first molecular conductor showing a large hysteresis in both magnetic moment and magnetoresistance associated with a spin-flop transition. Utilizing a mixed-anion approach and iodine bonding interactions, we tailored a molecular conductor with random exchange interactions exhibiting unforeseen physical properties.

Comparison of prevalence of inadequate nutrient intake based on body weight status of adults in the United States: an analysis of NHANES 2001-2008.

OBJECTIVE: To compare micronutrient intake status of those overweight and those obese with normal weight adults. METHODS: Using total nutrient intake (from foods and supplements) from the National Health and Nutrition Examination Survey (NHANES) 2001-2008, we determined usual intakes for micronutrients using the National Cancer Institute methodology in adults (n = 18,177). Only subjects with reliable dietary records were included and pregnant and lactating females were excluded. Subjects were categorized by body weight status as either normal weight (body mass index [BMI] < 25), overweight (BMI ≥ 25 to < 30), or obese (BMI ≥ 30). RESULTS: A substantial proportion of the adult population (over 40%) had inadequate intakes of vitamin A, vitamin C, vitamin D, vitamin E, calcium, and magnesium. Compared to normal weight adults, obese adults had about 5% to 12% lower (p < 0.05) intakes of micronutrients and higher (p < 0.01) prevalence of nutrient inadequacy. CONCLUSION: We conclude that obese adults compared to normal weight adults have lower micronutrient intake and higher prevalence of micronutrient inadequacy.

U.S. adults are not meeting recommended levels for fish and omega-3 fatty acid intake: results of an analysis using observational data from NHANES 2003-2008.

BACKGROUND: The American Heart Association's Strategic Impact Goal Through 2020 and Beyond recommends ≥ two 3.5-oz fish servings per week (preferably oily fish) partly to increase intake of omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). We examined the intake of total fish, fish high in omega-3 fatty acids, α-linolenic acid, EPA, and DHA in U.S. adults (19 + years) using data from the National Health and Nutrition Examination Survey, 2003-2008. METHODS: Usual intakes from foods alone and from foods plus dietary supplements were determined using the methods from the National Cancer Institute. RESULTS: Mean usual intake of total fish and fish high in omega-3 fatty acids was 0.61 ± 0.03 and 0.15 ± 0.03 oz/day, 0.43 and 0.07 respectively. Total fish and fish high in omega-3 fatty acids median intake was 0.43 and 0.07 oz/day, respectively. Intake from foods alone for ALA, EPA and DHA was 1.5 ± 0.01 g/d, 23 ± 7 mg/d and 63 ± 2 mg/d, respectively. ALA, EPA and DHA from food only median intakes were 1.4 g/d, 18 mg/d and 50 mg/d, respectively. Intake of ALA, EPA and DHA from foods and dietary supplements was 1.6 ± 0.04 g/d, 41 ± 4 mg/d and 72 ± 4 mg/d, respectively. While intakes of fish high in omega-3 fatty acids were higher in older adults (0.13 ± 0.01 oz/d for those 19-50 yrs and 0.19 ± 0.02 oz/d for those 51+ year; p < 0.01) and in males as compared to females (0.18 ± 0.02 vs 0.13 ± 0.01 oz/d, respectively; p < 0.05), few consumed recommended levels. Males also had higher (p < 0.05) intake of EPA and DHA from foods and dietary supplements relative to females (44 ± 6 vs 39 ± 4 and 90 ± 7 vs 59 ± 4 mg/d, respectively) and older adults had higher intakes of EPA, but not DHA compared to younger adults (EPA: 34 ± 3 vs 58 ± 9, p < 0.05; DHA: 68 ± 4 vs 81 ± 6, p < 0.05). CONCLUSIONS: As omega-3 fatty acids are deemed important from authoritative bodies, supplementation in addition to food sources may need to be considered to help U.S. adults meet recommendations.

A softgel dietary supplement containing esterified plant sterols and stanols improves the blood lipid profile of adults with primary hypercholesterolemia: a randomized, double-blind, placebo-controlled replication study.

A well-controlled clinical trial previously demonstrated the efficacy of a novel softgel dietary supplement providing 1.8 g/day esterified plant sterols and stanols, as part of the National Cholesterol Education Program Therapeutic Lifestyle Changes diet, to improve the fasting lipid profile of men and women with primary hypercholesterolemia (fasting low-density lipoprotein [LDL] cholesterol ≥ 130 and <220 mg/dL [≥ 3.37 and <5.70 mmol/L]). The purpose of this randomized, double blind, placebo-controlled crossover study (conducted July 2011 to January 2012) was to support these previous findings in a similar, but independent, sample with a different lead investigator and research site. Repeated measures analysis of covariance was used to compare outcomes for sterol/stanol and placebo treatment conditions using the baseline value as a covariate. Forty-nine subjects were screened and 30 (8 men and 22 women) were randomized to treatment (all completed the trial). Baseline (mean ± standard error of the mean) plasma lipid concentrations were: total cholesterol 236.6 ± 4.2 mg/dL (6.11 ± 0.11 mmol/L), high-density lipoprotein (HDL) cholesterol 56.8 ± 3.0 mg/dL (1.47 ± 0.08 mmol/L), LDL cholesterol 151.6 ± 3.3 mg/dL (3.92 ± 0.09 mmol/L), non-HDL cholesterol 179.7 ± 4.6 mg/dL (4.64 ± 0.12 mmol/L), and triglycerides 144.5 ± 14.3 mg/dL (1.63 ± 0.16 mmol/L). Mean placebo-adjusted reductions in plasma lipid levels were significant (P<0.01) for LDL cholesterol (-4.3%), non-HDL cholesterol (-4.1%), and total cholesterol (-3.5%), but not for triglycerides or HDL cholesterol. These results support the efficacy of 1.8 g/day esterified plant sterols/stanols in softgel capsules, administered as an adjunct to the National Cholesterol Education Program Therapeutic Lifestyle Changes diet, to augment reductions in atherogenic lipid levels in individuals with hypercholesterolemia.

An industry perspective: dietary supplements and mortality rates in older women.

This special article seeks to provide balance and clarity to the confusion brought about by the conclusions resulting from a recent study published in Archives of Internal Medicine by Mursu et al. (2011). An examination of three key limitations of the study provides context to why additional research is needed: (a) Nonusers were poorly defined; (b) supplement users were healthier than nonusers; and (c) the number of supplement users increased throughout the study. Although the literature is limited, other similar observational studies have also shown positive effects on the risk mortality for both multivitamins and single-nutrient supplements. Observational trials are an essential component of evidence-based nutrition but do not offer certainty because other data, such as the one generated from randomized controlled trials, are equally important in regard to the totality of evidence. The Senior Scientific Advisory Committee for the Council for Responsible Nutrition, an industry trade group, feels that the conclusions of the study by Mursu et al. (2011) are overstated and suggests that researchers analyze cohort(s) designed to specifically examine vitamin and mineral supplements free of confounding from factors, such as hormone replacement therapy, to better assess their benefits to the general population.

Lipid effects of a dietary supplement softgel capsule containing plant sterols/stanols in primary hypercholesterolemia.

OBJECTIVE: This randomized, placebo-controlled, crossover trial assessed the lipid-altering efficacy of a softgel capsule dietary supplement, providing esterified plant sterols/stanols 1.8 g/d, in 28 participants (≈ 75% women) with primary hypercholesterolemia (fasting low-density lipoprotein cholesterol [LDL-C] levels ≥ 130 and <220 mg/dL), a mean age of 58.4 y, and a mean body mass index of 27.9 kg/m(2). METHODS: After a 5-wk National Cholesterol Education Program (NCEP) Therapeutic Lifestyle Changes (TLC) diet and a single-blinded placebo lead-in, subjects received double-blinded placebo or sterol/stanol softgel capsules for 6 wk and then crossed over to the opposite product for 6 wk while continuing the TLC diet. Fasting lipids were assessed in duplicate at the end of the diet lead-in (baseline) and the end of each treatment. RESULTS: The mean baseline lipid concentrations (milligrams per deciliter) were 223 for total cholesterol (TC), 179 for non-high-density lipoprotein cholesterol (non-HDL-C), 154 for low-density lipoprotein cholesterol, 44 for HDL-C, 125 for triacylglycerols, and 5.2 for TC/HDL-C. Differences from the control responses (plant sterol/stanol minus control) in the per-protocol sample were significant (P < 0.05) for LDL-C (-9.2%), non-HDL-C (-9.0%), TC (-7.4%), TC/HDL-C (-5.4%), and triacylglycerols (-9.1%). The HDL-C responses were not significantly different between treatments. CONCLUSION: The incorporation of softgel capsules providing esterified plant sterols/stanols 1.8 g/d into the NCEP TLC diet produced favorable changes in atherogenic lipoprotein cholesterol levels in these subjects with hypercholesterolemia.

Absorption of folic acid from a softgel capsule compared to a standard tablet.

Consumption of 400 µg folic acid per day from fortified foods and/or supplements, plus food folate from a varied diet is recommended for women of childbearing potential to reduce the risk for neural tube defects during fetal development. This randomized crossover study was designed to evaluate the bioavailability of folic acid from a multivitamin softgel capsule vs a folic acid tablet in 16 premenopausal women (18 to 45 years of age). Participants were randomly assigned to receive a single dose of ∼1,000 µg folic acid in two tablets or ∼1,000 µg folic acid in a multivitamin softgel capsule, and then crossed over to receive the other study product ∼1 week later. Products were administered with a low-folate breakfast. Blood samples were collected predose (0 hour) and 1, 2, 3, 4, 6, and 8 hours post-dose for serum folate analysis. Repeated measures analysis of variance was used to compare responses between treatments. Data from the two sequence groups (n=8 per sequence) were pooled. Mean serum folate total and net incremental areas under the curve (AUC(0-8 hours)) were not significantly different between tablets and softgel capsule (AUC(0-8 hours) 214.9±11.2 hours×ng/mL [487±25.4 hours×nmol/L] and 191.6±13.3 hours×ng/mL [434.2±30.1 hours×nmol/L]; net incremental AUC(0-8 hours) 117.3±8.5 hours×ng/mL [265.8±19.3 hours×nmol/L] and 105.8±12.5 hours×ng/mL [239.7±28.3 hours×nmol/L], respectively), nor was maximum folate concentration (45.1±2.5 ng/mL [102.2±5.7 nmol/L] and 42.5±3.8 ng/mL [96.3±8.6 nmol/L], respectively). Time to peak folate concentration was significantly (P<0.001) delayed for the softgel capsule vs tablet (3.9±0.3 vs 1.7±0.2 hours, respectively). In conclusion, apparent bioavailability of folic acid was similar for the folic acid tablets and a multivitamin softgel capsule.

Lipid-altering effects of a dietary supplement tablet containing free plant sterols and stanols in men and women with primary hypercholesterolaemia: a randomized, placebo-controlled crossover trial.

This randomized, placebo-controlled, crossover trial assessed the lipid-altering efficacy of a dietary supplement (tablet form) providing 1.8 g/day free (non-esterified) plant sterols and stanols versus placebo for 6 weeks as part of a therapeutic lifestyle changes (TLC) diet in 32 men and women with primary hypercholesterolaemia. Mean ± SE baseline (end of a 5-week TLC diet lead-in) lipid concentrations (mmol/l) were total cholesterol (TC), 5.88 ± 0.08; non-high-density lipoprotein cholesterol (non-HDL-C), 4.71 ± 0.09; low-density lipoprotein cholesterol (LDL-C), 4.02 ± 0.08; HDL-C, 1.17 ± 0.06 and triglycerides (TGs), 1.51 ± 0.12. Differences from control in responses (plant sterol/stanol - control) were significant (p < 0.05) for LDL-C ( - 4.9%), non-HDL-C ( - 3.6%) and TC ( - 2.8%). HDL-C and TG responses were not significantly different between treatment conditions. These results indicate that 1.8 g/day free plant sterols/stanols administered in a tablet produced favourable lipoprotein lipid changes in men and women with hypercholesterolaemia.

Prostatic soy isoflavone concentrations exceed serum levels after dietary supplementation.

BACKGROUND: The effects of soy isoflavones on prostate cancer may be concentration-dependent. The impact of soy supplementation on isoflavone concentrations in prostate tissues and serum remain unclear. OBJECTIVE: To assess and compare concentrations of soy isoflavones in prostate tissue and serum among 19 men with prostate cancer who had elected to undergo radical prostatectomy. METHODS: Participants were randomized to receive either daily soy supplements (82 mg/day aglycone equivalents) or placebos for 2 weeks (14 days) prior to surgery. Serum samples were obtained at the time of the surgery. Isoflavone concentrations were measured by HPLC/ESI-MS-MS. RESULTS: The median (25th, 75th percentile) total isoflavone concentration in the isoflavone-supplemented group was 2.3 micromol/L (1.2, 6.9) in the prostate tissue and 0.7 micromol/L (0.2, 1.2) in the serum. Total isoflavone concentrations in this group were an average of approximately 6-fold higher in prostate tissue compared to serum; the tissue versus serum ratio was significantly lower for genistein than daidzein, 4-fold versus 10-fold, P = 0.003. Tissue and serum levels of isoflavones among the placebo group were negligible with a few exceptions. CONCLUSIONS: The findings from the present study suggest that prostate tissue may have the ability to concentrate dietary soy isoflavones to potentially anti-carcinogenic levels.

Inhibition of prostaglandin synthesis and actions by genistein in human prostate cancer cells and by soy isoflavones in prostate cancer patients.

Soy and its constituent isoflavone genistein inhibit the development and progression of prostate cancer (PCa). Our study in both cultured cells and PCa patients reveals a novel pathway for the actions of genistein, namely the inhibition of the synthesis and biological actions of prostaglandins (PGs), known stimulators of PCa growth. In the cell culture experiments, genistein decreased cyclooxygenase-2 (COX-2) mRNA and protein expression in both human PCa cell lines (LNCaP and PC-3) and primary prostate epithelial cells and increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) mRNA levels in primary prostate cells. As a result genistein significantly reduced the secretion of PGE(2) by these cells. EP4 and FP PG receptor mRNA were also reduced by genistein, providing an additional mechanism for the suppression of PG biological effects. Further, the growth stimulatory effects of both exogenous PGs and endogenous PGs derived from precursor arachidonic acid were attenuated by genistein. We also performed a pilot randomised double blind clinical study in which placebo or soy isoflavone supplements were given to PCa patients in the neo-adjuvant setting for 2 weeks before prostatectomy. Gene expression changes were measured in the prostatectomy specimens. In PCa patients ingesting isoflavones, we observed significant decreases in prostate COX-2 mRNA and increases in p21 mRNA. There were significant correlations between COX-2 mRNA suppression, p21 mRNA stimulation and serum isoflavone levels. We propose that the inhibition of the PG pathway contributes to the beneficial effect of soy isoflavones in PCa chemoprevention and/or treatment.