Mitochondrial sulfide promotes life span and health span through distinct mechanisms in developing versus adult treated Caenorhabditis elegans.

Living longer without simultaneously extending years spent in good health ("health span") is an increasing societal burden, demanding new therapeutic strategies. Hydrogen sulfide (H2S) can correct disease-related mitochondrial metabolic deficiencies, and supraphysiological H2S concentrations can pro health span. However, the efficacy and mechanisms of mitochondrion-targeted sulfide delivery molecules (mtH2S) administered across the adult life course are unknown. Using a Caenorhabditis elegans aging model, we compared untargeted H2S (NaGYY4137, 100 µM and 100 nM) and mtH2S (AP39, 100 nM) donor effects on life span, neuromuscular health span, and mitochondrial integrity. H2S donors were administered from birth or in young/middle-aged animals (day 0, 2, or 4 postadulthood). RNAi pharmacogenetic interventions and transcriptomics/network analysis explored molecular events governing mtH2S donor-mediated health span. Developmentally administered mtH2S (100 nM) improved life/health span vs. equivalent untargeted H2S doses. mtH2S preserved aging mitochondrial structure, content (citrate synthase activity) and neuromuscular strength. Knockdown of H2S metabolism enzymes and FoxO/daf-16 prevented the positive health span effects of mtH2S, whereas DCAF11/wdr-23 - Nrf2/skn-1 oxidative stress protection pathways were dispensable. Health span, but not life span, increased with all adult-onset mtH2S treatments. Adult mtH2S treatment also rejuvenated aging transcriptomes by minimizing expression declines of mitochondria and cytoskeletal components, and peroxisome metabolism hub components, under mechanistic control by the elt-6/elt-3 transcription factor circuit. H2S health span extension likely acts at the mitochondrial level, the mechanisms of which dissociate from life span across adult vs. developmental treatment timings. The small mtH2S doses required for health span extension, combined with efficacy in adult animals, suggest mtH2S is a potential healthy aging therapeutic.

Aerobically trained older adults show impaired resting, but preserved exercise-induced circulating progenitor cell count, which was not improved by sprint interval training.

Older adults exhibit a reduced number and function of CD34 + circulating progenitor cells (CPC), a known risk factor for cardiovascular disease. Exercise promotes the mobilisation of CPCs from bone marrow, so whether ageing per se or physical inactivity in older age reduces CPCs is unknown. Thus, this study examined the effect of age on resting and exercise-induced changes in CPCs in aerobically trained adults and the effect of 8 weeks of sprint interval training (SIT) on resting and exercise-induced CPCs in older adults. Twelve young (22-34 years) and nine older (63-70 years) adults participated in the study. Blood was sampled pre and immediately post a graded exercise test to exhaustion in both groups. Older participants repeated the process after 8 weeks of SIT (3 × 20 s 'all-out' sprints, 2 × a week). Total CPCs (CD34+) and endothelial progenitor cells (EPCs: CD34+KDR+) were determined by flow cytometry. Older adults exhibited lower basal total CD34+ CPCs (828 ± 314 vs. 1186 ± 272 cells·mL-1, p = 0.0149) and CD34+KDR+ EPCs (177 ± 128 vs. 335 ± 92 cells·mL-1, p = 0.007) than younger adults. The maximal exercise test increased CPCs in young (CD34+: p = 0.004; CD34+KDR+: p = 0.017) and older adults (CD34+: p < 0.001; CD34+KDR+: p = 0.008), without difference between groups (p = 0.211). SIT did not alter resting or exercise-induced changes in CPCs in the older cohort (p > 0.232). This study suggests age per se does not impair exercise-induced CPC counts, but does lower resting CPC counts.

The oncologic risk of magnetic resonance imaging-targeted and systematic cores in patients treated with radical prostatectomy.

BACKGROUND: Magnetic resonance imaging (MRI)-targeted prostate biopsy (MRI-biopsy) detects high-Grade Group (GG) prostate cancers not identified by systematic biopsy (S-biopsy). However, questions have been raised whether cancers detected by MRI-biopsy and S-biopsy, grade-for-grade, are of equivalent oncologic risk. The authors evaluated the relative oncologic risk of GG diagnosed by S-biopsy and MRI-biopsy. METHODS: This was a retrospective analysis of all patients who had both MRI-biopsy and S-biopsy and underwent with prostatectomy (2014-2022) at Memorial Sloan Kettering Cancer Center. Three logistic regression models were used with adverse pathology as the primary outcome (primary pattern 4, any pattern 5, seminal vesicle invasion, or lymph node involvement). The first model included the presurgery prostate-specific antigen level, the number of positive and negative S-biopsy cores, S-biopsy GG, and MRI-biopsy GG. The second model excluded MRI-biopsy GG to obtain the average risk based on S-biopsy GG. The third model excluded S-biopsy GG to obtain the risk based on MRI-biopsy GG. A secondary analysis using Cox regression evaluated the 12-month risk of biochemical recurrence. RESULTS: In total, 991 patients were identified, including 359 (36%) who had adverse pathology. MRI-biopsy GG influenced oncologic risk compared with S-biopsy GG alone (p < .001). However, if grade was discordant between biopsies, then the risk was intermediate between grades. For example, the average risk of advanced pathology for patients who had GG2 and GG3 on S-biopsy was 19% and 66%, respectively, but the average risk was 47% for patients who had GG2 on S-biopsy and patients who had GG3 on MRI-biopsy. The equivalent estimates for 12-month biochemical recurrence were 5.8%, 15%, and 10%, respectively. CONCLUSIONS: The current findings cast doubt on the practice of defining risk group based on the highest GG. Because treatment algorithms depend fundamentally on GG, further research is urgently required to assess the oncologic risk of prostate tumors depending on detection technique. PLAIN LANGUAGE SUMMARY: Using magnetic resonance imaging (MRI) to help diagnose prostate cancer can help identify more high-grade cancers than using a systematic template biopsy alone. However, we do not know if high-grade cancers diagnosed with the help of an MRI are as dangerous to the patient as high-grade cancers diagnosed with a systematic biopsy. We examined all of our patients who had an MRI biopsy and a systematic biopsy and then had their prostates removed to find out if these patients had risk factors and signs of aggressive cancer (cancer that spread outside the prostate or was very high grade). We found that, if there was a difference in grade between the systematic biopsy and the MRI-targeted biopsy, the risk of aggressive cancer was between the two grades.

A randomized comparison of two-stage versus traditional one-stage consent for a low-stakes randomized trial.

BACKGROUND/AIMS: It has been proposed that informed consent for randomized trials should be split into two stages, with the purported advantage of decreased information overload and patient anxiety. We compared patient understanding, anxiety and decisional quality between two-stage and traditional one-stage consent. METHODS: We approached patients at an academic cancer center for a low-stakes trial of a mind-body intervention for procedural distress during prostate biopsy. Patients were randomized to hear about the trial by either one- or two-stage consent (n = 66 vs n = 59). Patient-reported outcomes included Quality of Informed Consent (0-100); general and consent-specific anxiety and decisional conflict, burden, and regret. RESULTS: Quality of Informed Consent scores were non-significantly superior for two-stage consent, by 0.9 points (95% confidence interval = -2.3, 4.2, p = 0.6) for objective and 1.1 points (95% CI = -4.8, 7.0, p = 0.7) for subjective understanding. Differences between groups for anxiety and decisional outcomes were similarly small. In a post hoc analysis, consent-related anxiety was lower among two-stage control patients, likely because scores were measured close to the time of biopsy in the two-stage patients receiving the experimental intervention. CONCLUSION: Two-stage consent maintains patient understanding of randomized trials, with some evidence of lowered patient anxiety. Further research is warranted on two-stage consent in higher-stakes settings.

The effect of the enhanced recovery programme on long-term survival following liver resection for colorectal liver metastases.

BACKGROUND: Enhanced recovery programmes are associated with improved short-term outcomes following liver surgery. The impact of enhanced recovery programmes on medium- and long-term outcomes is incompletely understood. This study aimed to assess the impact of an enhanced recovery programme on long-term survival in patients undergoing surgery for colorectal liver metastases. METHODS: At a tertiary hepatobiliary centre, we analysed short-, medium- and long-term outcomes in consecutive patients undergoing liver resection for colorectal liver metastases. A five-year retrospective review was carried out comparing the enhanced recovery programme to standard care. RESULTS: A total of 172 patients were included in the analysis: 87 on standard care and 85 on an enhanced recovery programme. Open surgery was performed in 122 patients: 74 (85.1%) and 48 (56.5%) patients in the standard care and enhanced recovery programme, respectively (p < 0.001). There was a significant reduction in the median (IQR) length of hospital stay in the enhanced recovery programme compared with standard care (7 (5) days vs. 8 (3) days, p = 0.0009). There was no significant difference in survival between standard care and the Enhanced Recovery Programme at one (p = 0.818), three (p = 0.203), and five years (p = 0.247). CONCLUSION: An enhanced recovery programme was associated with a reduced length of hospital stay. There was no effect on the one-, three- and five-year survival.

Comparative Analysis of Muscle Atrophy During Spaceflight, Nutritional Deficiency and Disuse in the Nematode Caenorhabditis elegans.

While spaceflight is becoming more common than before, the hazards spaceflight and space microgravity pose to the human body remain relatively unexplored. Astronauts experience muscle atrophy after spaceflight, but the exact reasons for this and solutions are unknown. Here, we take advantage of the nematode C. elegans to understand the effects of space microgravity on worm body wall muscle. We found that space microgravity induces muscle atrophy in C. elegans from two independent spaceflight missions. As a comparison to spaceflight-induced muscle atrophy, we assessed the effects of acute nutritional deprivation and muscle disuse on C. elegans muscle cells. We found that these two factors also induce muscle atrophy in the nematode. Finally, we identified clp-4, which encodes a calpain protease that promotes muscle atrophy. Mutants of clp-4 suppress starvation-induced muscle atrophy. Such comparative analyses of different factors causing muscle atrophy in C. elegans could provide a way to identify novel genetic factors regulating space microgravity-induced muscle atrophy.

Weighted vests in CrossFit increase physiological stress during walking and running without changes in spatiotemporal gait parameters.

This study quantified the physiological and biomechanical effects of the 20 lb (9.07 kg, males) and 14 lb (6.35 kg, females) weighted vest used in CrossFit, and whether they were predisposed to injury. Twenty subjects (10 males, 10 females) undertook walking (0%, 5% and 10% gradient) and running trials in two randomised study visits (weighted vest/no weighted vest). Physiological demand during walking was increased with the vest at 10% but not 5% or 0% with no change in gait variables. In the running trial, the weighted vest increased oxygen uptake (males; females) (+0.22L/min, p < 0.01; +0.07 L/min, p < 0.05), heart rate (+11bpm, p < 0.01; +11bpm, p < 0.05), carbohydrate oxidation (+0.6 g/min, p < 0.001; +0.2 g/min, p < 0.01), and energy expenditure (+3.8 kJ/min, p < 0.001; +1.5 kJ/min, p < 0.05) whilst blood lactate was increased only in males (+0.6 mmol/L, p < 0.05). There was no change in stride length or frequency. Weighted vest training increases physiological stress and carbohydrate oxidation without affecting measured gait parameters. Practitioner summary: We examined the effect of weighted vest training prescribed in CrossFit (20 lb/9.07 kg, males and 14 lb/6.35 kg, females) in a randomised controlled trial. We found that physiological stress is increased in both sexes, although three-fold greater in males, but with no change in biomechanical gait that predisposes to lower-limb injury.

The Impact of Prehabilitation on Patient Outcomes in Hepatobiliary, Colorectal, and Upper Gastrointestinal Cancer Surgery: A PRISMA-Accordant Meta-analysis.

OBJECTIVE: To determine the impact of prehabilitation on hospital length of stay, functional capacity, complications, and mortality after surgery in patients with hepatobiliary, colorectal, and upper gastrointestinal cancer. BACKGROUND: "Prehabilitation" encompasses exercise, nutrition, and psychosocial interventions to optimize health before surgery. The benefits of prehabilitation are ill-defined. METHODS: Medline, Embase and Cochrane Databases were searched systematically for the terms "prehabilitation AND exercise," "perioperative care AND cancer surgery," and "colorectal AND hepatobiliary AND hepatopancreatobiliary AND esophagogastric AND recovery AND outcomes." Primary outcomes analyzed were hospital length of stay, functional capacity, significant postoperative complications (Clavien Dindo ≥ III), and mortality. A meta-analysis was conducted on the effect of all-modality prehabilitation for patients with colorectal, hepatopancreatobiliary and upper gastrointestinal cancer surgery using the raw mean difference, risk difference, and a random-effects model. RESULTS: Three hundred and seventy seven original titles were identified. Fifteen studies (randomized controlled trials; n = 9 and uncontrolled trials; n = 6) were included in the meta-analysis. Prehabilitation reduced hospital length of stay by 1.78 days versus standard care (95% CI: -3.36, -0.20, P < 0.05). There was no significant difference in functional capacity with prehabilitation determined using the 6-minute walk test (P = 0.816) and no significant reduction in postoperative complications (P = 0.378) or mortality rates (P = 0.114). CONCLUSIONS: Prehabilitation was associated with reduced hospital length of stay but had no effect on functional capacity, postoperative complications, or mortality rates. Thus, prehabilitation should be recommended to accelerate recovery from cancer surgery, demonstrated by reduced hospital length of stay.

Adoption, Safety, and Retreatment Rates of Prostatic Urethral Lift for Benign Prostatic Enlargement.

PURPOSE: Novel minimally invasive therapies like the prostatic urethral lift are among the many endoscopic options for the treatment of benign prostatic enlargement and lower urinary tract symptoms (BPE/LUTS). To further understand the relative uptake, complications and retreatment rates of contemporary endoscopic procedures for BPE/LUTS across diverse practice types, we performed a retrospective study of inpatient and ambulatory surgery encounters in the Premier Healthcare database. MATERIALS AND METHODS: We included men who underwent endoscopic procedures for BPE/LUTS between 2000 and 2018. We determined the utilization of endoscopic therapies for BPE/LUTS, 30-day and 90-day readmission rates, and retreatment rate. Multivariable logistic regression was used to assess the association of procedure type with outcomes for the 3 most commonly performed procedures. RESULTS: We identified 175,150 men treated with endoscopic surgery for BPE/LUTS. The annual percent utilization of the prostatic urethral lift increased from <1% in 2014 to 10.4% in 2018. Compared to transurethral resection of the prostate and prostate photovaporization, prostatic urethral lift was associated with a lower odds of readmission at 30 (OR 0.58, p <0.01) and 90 (OR 0.55, p <0.01) days and a higher odds of retreatment within 2 years of followup (OR 1.78, p <0.01). CONCLUSIONS: Providers have rapidly adopted prostatic urethral lift which accounted for more than 1 in 10 endoscopic procedures captured for BPE/LUTS in 2018. Men treated with prostatic urethral lift are readmitted less within 30 and 90 days but are more likely to be retreated within 2 years of their index procedure as compared to men treated with transurethral resection of the prostate or prostate photovaporization.

Immune Deficiency Does Not Increase Inflatable Penile Prosthesis Reoperation Rates.

INTRODUCTION: Immunocompromised patients are postulated to have higher rates of post-operative infection. We sought to determine if inflatable penile prosthesis (IPP) reoperation rates (due to infection, erosion, device malfunction or patient dissatisfaction) are higher among immunocompromised men. METHODS: We analyzed men who underwent initial IPP insertion from 2000 to 2016 in the New York Statewide Planning and Research Cooperative System database. Immunocompromised patients were propensity-score matched in a 1:3 fashion with immunocompetent patients. We estimated and compared reoperation rates (including removal, reoperation due to infection, revision, or replacement of an IPP after an index procedure) at 30 days, 90 days, 1 year and 3 years of follow up between immunocompromised men and controls by performing a Kaplan Meier analysis and Log-rank tests. Cox proportional hazards models were built to examine the overall association between immune deficient status and the risk of reoperation. MAIN OUTCOME MEASURE: Reoperation rate and time to reoperation after index IPP placement. RESULTS: A total of 245 immunocompromised patients who received an initial IPP between 2000 and 2016 were identified. After propensity score matching, we analyzed 235 immunocompromised men and 705 controls. There was no difference in overall reoperation rates between immunocompromised men and controls within any time period assessed (30 days, 90 days, 1 year, or 3 years). In our Cox proportional hazards model, the hazards of overall reoperation, removal, or revision/replacement (HR 1.11 [95% CI 0.74-1.67], HR 1.58 [95% CI 0.90-2.79)], and HR 0.83 [95% CI 0.47-1.45], respectively) were not significant different between immunocompromised men and controls. Reoperation due to infection was also not significantly different between immunocompromised and immunocompetent men (HR 2.06 [95% CI 0.97-4.40]). STRENGTHS & LIMITATIONS: This study is strengthened by its size as the largest cohort of immunocompromised men treated with IPP to date in the literature, but is limited by the retrospective nature of the database which may introduce selection bias and by the low event rate for IPP reoperation. CONCLUSIONS: Reoperation rates, including those due to infection, are not significantly different between immunocompromised men and immunocompetent controls. Therefore, immune status in appropriately selected candidates does not appear to place patients at substantially higher risk of explant or revision. Gaffney CD, Fainberg J, Aboukhshaba A, et al. Immune Deficiency Does Not Increase Inflatable Penile Prosthesis Reoperation Rates. J Sex Med 2021;18:1427-1433.

Symptomatic Improvement of Lower Urinary Tract Symptoms of Benign Prostatic Hyperplasia: A Comparative Systematic Review and Meta-Analysis of 4 Different Minimally Invasive Therapies.

PURPOSE: To review and compare the outcomes of prostatic artery embolization (PAE) with 3 other minimally invasive surgical treatments for benign prostatic hyperplasia, including photoselective vaporization (PVP), prostatic urethral lift (PUL), and water vapor thermal therapy (WV). METHODS: A literature review was used to identify 35 publications, which included 2,653 patients (studies, patients): PVP (13, 949), PUL (9, 577), WV (3, 330), and PAE (10, 728). The international prostate symptom score (IPSS) and the international index of erectile function (IIEF-5) and quality of life (QOL) scores were recorded at baseline, 6 months, and 12 months. Meta-analyses, pooling the standardized mean difference between scores recorded before and after treatment, were conducted for each modality and time point to assess the magnitude of a therapy's effect to yield pooled effect sizes. A negative score indicates IPSS and QOL improvement. A positive score indicates IIEF-5 improvement. RESULTS: At 6 and 12 months, the IPSS and QOL were most improved after PVP, followed by that after PAE, PUL, and, lastly, WV (measured only at 12 months). Between 6 and 12 months, the IPSS and QOL improved with PAE and worsened with PVP and PUL. Only PAE demonstrated statistical improvement in the IIEF-5, which improved from 6 to 12 months. CONCLUSIONS: PVP and PAE resulted in the largest improvements in the IPSS and QOL. Only PAE resulted in improvement of the IIEF-5.

Increasing Utilization of MRI Before Prostate Biopsy in Black and Non-Black Men: An Analysis of the SEER-Medicare Cohort.

OBJECTIVE. The potential for significant disparities exists in the setting of increased adoption of prostate MRI. We sought to assess temporal trends in the utilization of MRI before prostate biopsy in a nationally representative sample. MATERIALS AND METHODS. Using the SEER-Medicare linked database, we identified men undergoing prostate biopsy who had an MRI within 6 months of diagnosis of prostate cancer. Men were stratified according to whether they were biopsy naive or had undergone a prior negative prostate biopsy. RESULTS. We identified 82,483 men undergoing prostate biopsy in SEER-Medicare from 2008 to 2015 of whom 78,253 were biopsy naive and 4230 had a known prior negative biopsy. We found that the percentage of patients who received an MRI before biopsy has increased from 2008 to 2015 in biopsy-naive men (0.5-8.2%; p < .001), men with a prior negative biopsy (1.4-25.5%; p < .001), and overall (0.5-9.2%; p < .001). On multivariable modeling, the odds ratio (OR) of a patient undergoing an MRI before biopsy for Black men (OR, 0.4; 95% CI, 0.3-0.5; p < .001) was half that of White men, and the OR of MRI before biopsy in men from the Northeast (OR, 3.4; 95% CI, 2.8-4.3; p < .001) was more than three times that of men from the West. CONCLUSION. The steady overall increase in the utilization of MRI before prostate biopsy since 2008 has been associated with significant racial and regional disparities in utilization.

Sprint interval training (SIT) reduces serum epidermal growth factor (EGF), but not other inflammatory cytokines in trained older men.

PURPOSE: The present study aimed to investigate the effect of age on circulating pro- and anti-inflammatory cytokines and growth factors. A secondary aim was to investigate whether a novel sprint interval training (SIT) intervention (3 × 20 s 'all out' static sprints, twice a week for 8 weeks) would affect inflammatory markers in older men. METHODS: Nine older men [68 (1) years] and eleven younger men [28 (2) years] comprised the younger group. Aerobic fitness and inflammatory markers were taken at baseline for both groups and following the SIT intervention for the older group. RESULTS: Interleukin (IL)-8, vascular endothelial growth factor (VEGF), and monocyte chemoattractant protein-1 (MCP-1) were unchanged for the older and younger groups at baseline (IL-8, p = 0.819; MCP-1, p = 0.248; VEGF, p = 0.264). Epidermal growth factor (EGF) was greater in the older group compared to the younger group at baseline [142 (20) pg mL-1 and 60 (12) pg mL-1, respectively, p = 0.001, Cohen's d = 1.64]. Following SIT, older men decreased EGF to 100 (12) pg mL-1 which was similar to that of young men who did not undergo training (p = 0.113, Cohen's d = 1.07). CONCLUSION: Older aerobically trained men have greater serum EGF than younger aerobically trained men. A novel SIT intervention in older men can shift circulating EGF towards trained younger concentrations. As lower EGF has previously been associated with longevity in C. elegans, the manipulative effect of SIT on EGF in healthy ageing in the human may be of further interest.

Predictors of varicocele-associated pain and its impact on semen parameters following microsurgical repair.

Our study aimed to assess for predictors of varicocele-associated pain and whether it predicts semen parameters after microsurgical varicocelectomy. We assessed all men diagnosed with a varicocele by two surgeons from 2017 to 2020, excluding those who did not undergo surgical treatment. Patients were stratified based on the presence of pain at clinical assessment, and these groups were compared. Logistic regression models were utilised to assess for predictors of pain. A total of 313 men were included, with relatively similar proportions completed by both surgeons (48.2% and 51.8%). A total of 98 (31.3%) had typical varicocele-associated pain at the time of assessment. The pain group was younger than the no pain group (30.5 versus. 35.0, respectively, p < .01), and those with pain had greater varicocele grades (p = .008). Although not statistically different, there was a greater portion of left-sided only varicoceles in the pain group (p = .09). No significant differences were demonstrated between sperm concentration, motility, volume or morphology pre-operatively, or post-operatively between groups. Younger age and varicocele grade were predictive of varicocele-associated pain. In conclusion, almost 1/3 of men presented with varicocele-associated pain. Pain does not predict response to varicocelectomy, but these men tend to be younger, and have higher grade varicoceles.

Practice patterns of vasal reconstruction in a large United States cohort.

We aimed to characterise diverse practice patterns for vasal reconstruction and to determine whether surgeon volume is associated with vasoepididymostomy performance at the time of reconstruction. We identified adult men who underwent vasal reconstruction from 2000 to 2020 in Premier Healthcare Database and determined patient, surgeon, cost and hospital characteristics for each procedure. We identified 3,494 men who underwent either vasovasostomy-alone (N = 2,595, 74.3%) or any-vasoepididymostomy (N = 899, 25.7%). The majority of providers (N = 487, 88.1%) performed only-vasovasostomy, 10 (1.8%) providers performed only-vasoepididymostomy and 56 (10.1%) providers performed both. Median total hospital charge of vasoepididymostomy was significantly higher than vasovasostomy ($39,163, interquartile range [IQR]$11,854-53,614 and $17,201, IQR$10,904-29,986, respectively). On multivariable regression, men who underwent procedures at nonacademic centres (OR 2.71, 95% CI 2.12-3.49) with higher volume surgeons (OR 11.60, 95% CI 8.65-16.00) were more likely to undergo vasoepididymostomy. Furthermore, men who underwent vasoepididymostomy were more likely to self-pay (OR 2.35, 95% CI 1.83-3.04, p < .001) and more likely had procedures in the Midwest or West region (OR 2.22, 95% CI 1.66-2.96 and OR 2.11, 95% CI 1.61-2.76, respectively; p < .001). High-volume providers have increased odds of performing vasoepididymostomy at the time of reconstruction but at a significantly higher cost. These data suggest possibly centralising reconstructive procedures among high-volume providers.

Effect of acute and short-term dietary fat ingestion on postprandial skeletal muscle protein synthesis rates in middle-aged, overweight, and obese men.

Muscle anabolic resistance to dietary protein is associated with obesity and insulin resistance. However, the contribution of excess consumption of fat to anabolic resistance is not well studied. The aim of these studies was to test the hypothesis that acute and short-term dietary fat overload will impair the skeletal muscle protein synthetic response to dietary protein ingestion. Eight overweight/obese men [46.4 ± 1.4 yr, body mass index (BMI) 32.3 ± 5.4 kg/m2] participated in the acute feeding study, which consisted of two randomized crossover trials. On each occasion, subjects ingested an oral meal (with and without fat emulsion), 4 h before the coingestion of milk protein, intrinsically labeled with [1-13C]phenylalanine, and dextrose. Nine overweight/obese men (44.0 ± 1.7 yr, BMI 30.1 ± 1.1 kg/m2) participated in the chronic study, which consisted of a baseline, 1-wk isocaloric diet, followed by a 2-wk high-fat diet (+25% energy excess). Acutely, incorporation of dietary amino acids into the skeletal muscle was twofold higher (P < 0.05) in the lipid trial compared with control. There was no effect of prior lipid ingestion on indices of insulin sensitivity (muscle glucose uptake, pyruvate dehydrogenase complex activity, and Akt phosphorylation) in response to the protein/dextrose drink. Fat overfeeding had no effect on muscle protein synthesis or glucose disposal in response to whey protein ingestion, despite increased muscle diacylglycerol C16:0 (P = 0.06) and ceramide C16:0 (P < 0.01) levels. Neither acute nor short-term dietary fat overload has a detrimental effect on the skeletal muscle protein synthetic response to dietary protein ingestion in overweight/obese men, suggesting that dietary-induced accumulation of intramuscular lipids per se is not associated with anabolic resistance.

Impact of prebiopsy magnetic resonance imaging on biopsy and radical prostatectomy grade concordance.

BACKGROUND: Adoption of prostate magnetic resonance imaging (MRI) before biopsy is based on evidence demonstrating superior detection of clinically significant prostate cancer on biopsy. Whether this is due to the detection of otherwise occult higher grade cancers or preferential sampling of higher grade areas within an otherwise low-grade cancer is unknown. METHODS: To distinguish these two possibilities, this study examined the effect of prebiopsy MRI on the rate of pathologic upgrading and downgrading at prostatectomy in Surveillance, Epidemiology, and End Results-Medicare linked data from 2010 to 2015. Logistic regression was performed to assess the effect of MRI use on the Gleason grade change between biopsy and prostatectomy. RESULTS: Among biopsy-naive men, those who underwent prebiopsy MRI had higher odds of downgrading at prostatectomy (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.05-1.66). In contrast, the odds of upgrading were significantly lower for men who underwent prebiopsy MRI (OR, 0.78; 95% CI, 0.61-0.99). Limitations included a low overall rate of MRI-utilization prior to biopsy and an inability to distinguish between template, software-assisted and cognitive fusion biopsy. CONCLUSIONS: Prebiopsy MRI is associated with both oversampling of higher grade areas, which results in downgrading at prostatectomy, and the detection of otherwise occult higher grade lesions, which results in less upgrading at prostatectomy.

The Clinical Utility of the Genomic Prostate Score in Men with Very Low to Intermediate Risk Prostate Cancer.

PURPOSE: We retrospectively investigated the Genomic Prostate Score® assay in clinical practice at an urban tertiary care academic center. MATERIALS AND METHODS: We reviewed all Genomic Prostate Score results acquired during a 3-year period. Changes in patient NCCN® (National Comprehensive Cancer Network®) risk group, including very low, low, intermediate or high risk, and ultimate management decisions were recorded. RESULTS: Genomic Prostate Score risk stratification was performed in 134 men. According to the NCCN Guidelines®, 31 of the 134 men (23.1%) were at very low risk, 45 (33.6%) were at low risk and 58 (43.3%) were at intermediate risk. After adding the score the risk group changed in 32 of 134 patients (23.9%). The risk group did not change in the 31 men at very low risk. However, in the low risk group the risk changed in 19 of the 45 men (42.2%), including in 15 to very low and in 4 to intermediate risk. Also, in the intermediate risk group the risk changed in 13 of the 58 men (22.4%), including to low in 12 and to high risk in 1. Nine of the 15 men (60%) in whom risk changed from low to very low elected active surveillance. Nine of the 12 patients (75%) at intermediate risk in whom risk changed to low risk elected active surveillance, 2 (16.7%) elected definitive therapy and in 1 (8.3%) the choice was unknown. Of the 45 men at intermediate risk in whom risk was unchanged 28 (62.2%) elected definitive therapy, 12 (26.0%) elected active surveillance and in 5 (11.1%) the choice was unknown. Of the 4 men upgraded from low to intermediate risk after adding the genomic prostate score 2 elected definitive therapy and 2 chose active surveillance. CONCLUSIONS: The Genomic Prostate Score has limited clinical usefulness in patients at very low risk since the NCCN risk group did not change. While it may be more useful for men at low and intermediate risk, for 32 (31%) of whose risk group was reclassified, clinical management decisions did not always appear to reflect these changes.

Magnetic resonance and computed tomography imaging features of epithelioid sarcoma in children and young adults with pathological and clinical correlation: a report from Children's Oncology Group study ARST0332.

OBJECTIVE: To correlate imaging features of epithelioid sarcoma in children and young adults enrolled in Children's Oncology Group study ARST0332 with clinical and pathological findings. MATERIALS AND METHODS: Fifteen patients (6 males; median age 16.1 years, range 6.5-24.8 years) with epithelioid sarcoma enrolled in ARST0332 had preoperative imaging (MRI, n=10; CT, n=5) that was reviewed by two radiologists who recorded numerous features including presence and percentage of tumor necrosis, presence of surrounding edema, and lymph node involvement. Discrepancies between reviewers were adjudicated by concurrent re-review. We correlated imaging findings with histological assessment of percentage tumor necrosis, proximal- vs. classic-type histology, lymph node involvement and recurrence. RESULTS: Eleven patients (11/15, 73%) had proximal-type histology tumors. Ten of 14 tumors (71%) had imaging evidence of necrosis. Among the nine tumors with imaging and histological estimates of percentage necrosis, agreement was within 30% (in six tumors there was ≤10% difference between pathology and imaging). All 10 tumors imaged with MRI had surrounding edema. Four patients had biopsy-proven nodal involvement; all had necrotic nodes on imaging. There were four false-positives for nodal involvment by imaging. Twelve patients (12/15, 80%) had recurrences (local only, n=1; local and distant, n=1; distant only, n=10). CONCLUSION: Proximal-type histology was prevalent in this young cohort with preoperative imaging. Necrosis is common in primary tumors and involved nodes. There is good agreement between histological and imaging estimates of primary tumor necrosis. Surrounding tumor edema is common in this tumor, which is known to spread along fascial planes.