Association between expedited review designations and the US or global burden of disease for drugs approved by the US Food and Drug Administration, 2010-2019: a cross-sectional analysis.

OBJECTIVES: Pharmaceutical innovation can contribute to reducing the burden of disease in human populations. This research asks whether products approved by the US Food and Drug Administration (FDA) from 2010 to 2019 and expedited review programmes incentivising development of products for serious disease were aligned with the US or global burden of disease. DESIGN: Cross-sectional study. OUTCOME MEASURES: Association of FDA product approvals (2010-2019), first approved indications, designations for expedited review with the burden of disease (disability-adjusted life years (DALYs)), years of life lost (YLL) and years of life lived with disability (YLD) for 122 WHO Global Health Estimates (GHE) conditions in US and global (ex-US) populations. RESULTS: The FDA approved 387 drugs in 2010-2019 with lead indications associated with 59/122 GHE conditions. Conditions with at least one new drug had greater US DALYs (p=0.001), US YLL (p<0.001), global DALYs (p=0.030) and global YLL (p=0.004) but not US YLD (p=0.158) or global YLD (p=0.676). Most approvals were for conditions in the top quartile of US DALYs or YLL, but <27% were for conditions in the top quartile of global DALYs or YLL. The likelihood of a drug having one or more designations for expedited review programmes was negatively associated (OR<1) with US DALYs, US YLD and global YLD. There was a weak negative association with global DALYs and a weak positive association (OR>1) with US and global YLL. CONCLUSIONS: FDA drug approvals from 2010 to 2019 were more strongly aligned with US than global disease burden. Designations for expedited review were not aligned with either the US or global burdens of disease and may inadvertently disincentivise development of products addressing global disease burdens. These results may inform policies to better align pharmaceutical innovation with the burdens of disease.

Spending on Phased Clinical Development of Approved Drugs by the US National Institutes of Health Compared With Industry.

Importance: The launch of the Advanced Research Projects Agency for Health to advance new cures and address public concern regarding drug prices has raised questions about the roles of government and industry in drug development. Objectives: To compare National Institutes of Health (NIH) spending on phased clinical development of approved drugs with that by industry. Design: This cross-sectional study examined NIH funding for published research reporting the results of phased clinical trials of drugs approved between 2010 and 2019 and compared the findings with reported industry spending estimates. Data analysis was performed between May 2021 and August 2022 using PubMed data from January 1999 through October 2021 and NIH Research Portfolio Online Reporting Tools Expenditures and Results data from January 1999 through December 2020. Exposures: Drugs approved between 2010 and 2019. Main Outcome and Measures: National Institutes of Health funding for published research describing applied research on approved drugs, basic research on their biological targets, and phased clinical trials related to drugs approved between 2010 and 2019 were evaluated using Mann-Whitney U tests. All costs were inflation adjusted to 2018. Results: National Institutes of Health funding for basic or applied research related to 386 of 387 drugs approved between 2010 and 2019 totaled $247.3 billion. Of this amount, $8.1 billion (3.3%) was related to phased clinical development. This funding contributed to 12 340 publications on phased clinical trial results involving 240 of 387 (62.0%) drugs. Average NIH spending was $33.8 million per drug, including $13.9 million per drug for phase 1, $22.2 million per drug for phase 2, and $12.9 million per drug for phase 3 trials. Spending by NIH on phased development represented 9.8% to 10.7% of estimated industry spending, including 24.6% to 25.3% of estimated phase 1, 21.4% to 23.2% of phase 2, and 3.7% to 4.3% of phase 3 costs. Considering 60 products for which estimated industry costs were publicly available, NIH spending on clinical trials was significantly lower than estimated industry spending (sum of averages, $54.9 million per drug; mean difference, $326.0 million; 95% CI, $235.6-$416.4 million; 2-tailed paired t test P < .001). More than 90% of NIH funding came through cooperative agreements or program projects and centers, while 3.3% of NIH funding came through investigator-initiated research projects. Conclusions and Relevance: In this cross-sectional study, NIH funding for phased clinical development of drugs approved between 2010 and 2019 represented a small fraction of NIH spending on pharmaceutical innovation. This spending focused primarily on early-phase clinical trials and research capacity and was significantly less than estimated industry spending on clinical development. These results may inform the efficient allocation of government funding to advance pharmaceutical innovation.

Comparison of Research Spending on New Drug Approvals by the National Institutes of Health vs the Pharmaceutical Industry, 2010-2019.

Importance: Government and the pharmaceutical industry make substantive contributions to pharmaceutical innovation. This study compared the investments by the National Institutes of Health (NIH) and industry and estimated the cost basis for assessing the balance of social and private returns. Objectives: To compare NIH and industry investments in recent drug approvals. Design, Setting, and Participants: This cross-sectional study of NIH funding associated with drugs approved by the FDA from 2010 to 2019 was conducted from May 2020 to July 2022 and accounted for basic and applied research, failed clinical candidates, and discount rates for government spending compared with analogous estimates of industry investment. Main Outcomes and Measures: Costs from the NIH for research associated with drug approvals. Results: Funding from the NIH was contributed to 354 of 356 drugs (99.4%) approved from 2010 to 2019 totaling $187 billion, with a mean (SD) $1344.6 ($1433.1) million per target for basic research on drug targets and $51.8 ($96.8) million per drug for applied research on products. Including costs for failed clinical candidates, mean (SD) NIH costs were $1441.5 ($1372.0) million per approval or $1730.3 ($1657.6) million per approval, estimated with a 3% discount rate. The mean (SD) NIH spending was $2956.0 ($3106.3) million per approval with a 10.5% cost of capital, which estimates the cost savings to industry from NIH spending. Spending and approval by NIH for 81 first-to-target drugs was greater than reported industry spending on 63 drugs approved from 2010 to 2019 (difference, -$1998.4 million; 95% CI, -$3302.1 million to -$694.6 million; P = .003). Spending from the NIH was not less than industry spending considering clinical failures, a 3% discount rate for NIH spending, and a 10.5% cost of capital for the industry (difference, -$1435.3 million; 95% CI, -$3114.6 million to $244.0 million; P = .09) or when industry spending included prehuman research (difference, -$1394.8 million; 95% CI, -$3774.8 million to $985.2 million; P = .25). Accounting for spillovers of NIH-funded basic research on drug targets to multiple products, NIH costs were $711.3 million with a 3% discount rate, which was less than the range of reported industry costs with 10.5% cost of capital. Conclusions and Relevance: The results of this cross-sectional study found that NIH investment in drugs approved from 2010 to 2019 was not less than investment by the pharmaceutical industry, with comparable accounting for basic and applied research, failed clinical trials, and cost of capital or discount rates. The relative scale of NIH and industry investment may provide a cost basis for calibrating the balance of social and private returns from investments in pharmaceutical innovation.

Kynurenines in polycystic kidney disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a common hereditary disorder, characterized by kidney cyst formation. A major pathological feature of ADPKD is the development of interstitial inflammation. Due to its role in inflammation and oxidative stress, tryptophan metabolism and related kynurenines may have relevance in ADPKD. METHODS: Data were collected from a well-characterized longitudinal cohort of pediatric and adult patients with ADPKD and compared to age-matched healthy subjects. To evaluate the role of kynurenines in ADPKD severity and progression, we investigated their association with height-corrected total kidney volume (HtTKV) and kidney function (estimated glomerular filtration rate (eGFR)). Key tryptophan metabolites were measured in plasma using a validated liquid chromatography-mass spectrometry assay. RESULTS: There was a significant accumulation of kynurenine and kynurenic acid (KYNA) in children and adults with ADPKD as compared to healthy subjects. Downstream kynurenines continued to accumulate in adults with ADPKD concurrent with the increase of inflammatory markers IL-6 and MCP-1. Both markers remained unchanged in ADPKD as compared to healthy children, suggesting alternate pathways responsible for the observed rise in kynurenine and KYNA. KYNA and kynurenine/tryptophan positively associated with disease severity (HtTKV or eGFR) in patients with ADPKD. After Bonferroni adjustment, baseline kynurenines did not associate with disease progression (yearly %change in HtTKV or yearly change in eGFR) in this limited number of patients with ADPKD. CONCLUSION: Kynurenine metabolism seems dysregulated in ADPKD as compared to healthy subjects. Inhibition of kynurenine production by inhibition of main pathway enzymes could present a novel way to reduce the progression of ADPKD.

Endocannabinoid System in Polycystic Kidney Disease.

INTRODUCTION: Autosomal dominant polycystic kidney disease (ADPKD) is a commonly inherited disorder characterized by renal cyst formation. A major pathological feature of ADPKD is the development of interstitial inflammation. The endocannabinoid (EC) system is present in the kidney and has recently emerged as an important player in inflammation and the pathogenesis of progressive kidney disease. METHODS: Data on ECs were collected using a validated mass spectrometry assay from a well-characterized cohort of 102 ADPKD patients (at baseline and after 2- and 4 years on standard vs. rigorous blood-pressure control) and compared to 100 healthy subjects. RESULTS: Compared to healthy individuals, we found higher interleukins-6 and -1b as well as reduced plasma levels of anandamide (AEA), 2-arachidonoyl-glycerol (2-AG), and their congeners in ADPKD patients. Baseline AEA concentration negatively associated with the progression of ADPKD as expressed by the yearly percent change in height-corrected total kidney volume and positively with the yearly change in renal function (measured as estimated glomerular filtration rate, ΔeGFR). AEA analog palmitoylethanolamide (PEA) is also associated positively with the yearly change in eGFR. DISCUSSION AND CONCLUSION: The results of the present study suggest that ADPKD patients present with lower levels of ECs and that reestablishing the normality of the renal EC system via augmentation of AEA, PEA, and 2-AG levels, either through the increase of their synthesis or through a reduction of their degradation, could be beneficial and may present a promising therapeutic target in said patients.

NIH funding for vaccine readiness before the COVID-19 pandemic.

Rapid development of vaccines for COVID-19 has relied on the application of existing vaccine technologies. This work examines the maturity of ten technologies employed in candidate vaccines (as of July 2020) and NIH funding for published research on these technologies from 2000-2019. These technologies vary from established platforms, which have been used successfully in approved products, to emerging technologies with no prior clinical validation. A robust body of published research on vaccine technologies was supported by 16,358 fiscal years of NIH funding totaling $17.2 billion from 2000-2019. During this period, NIH funding for published vaccine research against specific pandemic threats such as coronavirus, Zika, Ebola, and dengue was not sustained. NIH funding contributed substantially to the advance of technologies available for rapid development of COVID-19 vaccines, suggesting the importance of sustained public sector funding for foundational technologies in the rapid response to emerging public health threats.

The Musculoskeletal Health Benefits of Tennis.

BACKGROUND: The prevalence of musculoskeletal (MSK) conditions is increasing, and although current guidelines for physical activity attempt to combat this, many fail to achieve the recommended targets. The present study sought to investigate whether regular tennis participation is more effective at enhancing MSK function than meeting the current international physical activity guidelines. HYPOTHESIS: Tennis players will display significantly enhanced MSK function when compared with age-matched healthy active nonplayers. STUDY DESIGN: Cross-sectional study. LEVEL OF EVIDENCE: Level 3. METHODS: Ninety participants (age range, 18-65 years) took part in this study; there were 43 tennis players (18 men, 25 women) and 47 nonplayers (26 men, 21 women). MSK function was assessed by cluster analysis of 3 factors: (1) electromyographic fatigability of prime movers during handgrip, knee extension, and knee flexion; (2) isometric strength in the aforementioned movements; and (3) body composition measured by bioelectrical impedance analysis. Maximal oxygen uptake was also assessed to characterize cardiorespiratory fitness. RESULTS: Tennis players displayed significantly greater upper body MSK function than nonplayers when cluster scores of body fat percentage, handgrip strength, and flexor carpi radialis fatigue were compared by analysis of covariance, using age as a covariate (tennis players, 0.33 ± 1.93 vs nonplayers, -0.26 ± 1.66; P < 0.05). Similarly, tennis players also demonstrated greater lower extremity function in a cluster of body fat percentage, knee extension strength, and rectus femoris fatigue (tennis players, 0.17 ± 1.76 vs nonplayers, -0.16 ± 1.70; P < 0.05). CONCLUSION: The present study offers support for improved MSK functionality in tennis players when compared with age-matched healthy active nonplayers. This may be due to the hybrid high-intensity interval training nature of tennis. CLINICAL RELEVANCE: The findings suggest tennis is an excellent activity mode to promote MSK health and should therefore be more frequently recommended as a viable alternative to existing physical activity guidelines.

Characterization of Supersaturated Danazol Solutions - Impact of Polymers on Solution Properties and Phase Transitions.

PURPOSE: Excipients are essential for solubility enhancing formulations. Hence it is important to understand how additives impact key solution properties, particularly when supersaturated solutions are generated by dissolution of the solubility enhancing formulation. Herein, the impact of different concentrations of dissolved polymers on the thermodynamic and kinetic properties of supersaturated solutions of danazol were investigated. METHODS: A variety of experimental techniques was used, including nanoparticle tracking analysis, fluorescence and ultraviolet spectroscopy and flux measurements to characterize the solution phase behavior. RESULTS: Neither the crystalline nor amorphous solubility of danazol was impacted by common amorphous solid dispersion polymers, polyvinylpyrrolidone, hydroxypropylmethyl cellulose (HPMC) or HPMC-acetate succinate. Consequently, the maximum membrane transport rate was limited only by the amorphous solubility, and not by the presence of the polymers. The polymers were able to inhibit crystallization to some extent at concentrations as low as 1 µg/mL, with the maximum effectiveness being reached at 10 µg/mL. Aqueous danazol solutions formed a drug-rich phase with a mean size of 250 nm when the concentration exceeded the amorphous solubility, and the polymers modified the surface properties of this drug-rich phase. CONCLUSIONS: The phase behavior of supersaturated solutions is complex and the kinetics of phase transformations can be substantially modified by polymeric additives present at low concentrations. However, fortunately, these additives do not appear to impact the bulk thermodynamic properties of the solution, thus enabling supersaturated solutions, which provide enhanced membrane transport relative to saturated solutions to be generated.

Intermittent self-dilatation for urethral stricture disease in males: A systematic review and meta-analysis.

BACKGROUND: Intermittent self-dilatation (ISD) may be recommended to reduce the risk of recurrent urethral stricture. Level one evidence to support the use of this intervention is lacking. OBJECTIVES: Determine the clinical and cost-effectiveness of ISD for the management of urethral stricture disease in males. SEARCH METHODS: The strategy developed for the Cochrane Incontinence Review Group as a whole (last searched May 7, 2014). SELECTION CRITERIA: Randomised trials where one arm was a programme of ISD for urethral stricture. DATA COLLECTION AND ANALYSIS: At least two independent review authors carried out trial assessment, selection, and data abstraction. RESULTS: Data from six trials that were pooled and collectively rated very low quality per the GRADE approach, indicated that recurrent urethral stricture was less likely in men who performed ISD than those who did not (RR 0.70, 95% CI 0.48-1.00). Two trials compared programmes of ISD but the data were not combined and neither were sufficiently robust to draw firm conclusions. Three trials compared devices for performing ISD, results from one of which were too uncertain to determine the effects of a low friction hydrophilic catheter versus a polyvinyl chloride catheter on risk of recurrent urethral stricture (RR 0.32, 95% CI 0.07 to 1.40); another did not find evidence of a difference between 1% triamcinolone gel for lubricating the ISD catheter versus water-based gel on risk of recurrent urethral stricture (RR 0.68, 95% CI 0.35 to 1.32). No trials gave cost-effectiveness or validated PRO data. CONCLUSIONS: ISD may decrease the risk of recurrent urethral stricture. A well-designed RCT is required to determine whether that benefit alone is sufficient to make this intervention worthwhile and in whom. Neurourol. Urodynam. 35:759-763, 2016. © 2015 Wiley Periodicals, Inc.

Dissolution of Danazol Amorphous Solid Dispersions: Supersaturation and Phase Behavior as a Function of Drug Loading and Polymer Type.

Amorphous solid dispersions (ASDs) are of great interest as enabling formulations because of their ability to increase the bioavailability of poorly soluble drugs. However, the dissolution of these formulations under nonsink dissolution conditions results in highly supersaturated drug solutions that can undergo different types of phase transitions. The purpose of this study was to characterize the phase behavior of solutions resulting from the dissolution of model ASDs as well as the degree of supersaturation attained. Danazol was chosen as a poorly water-soluble model drug, and three polymers were used to form the dispersions: polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC), and hydroxypropylmethyl cellulose acetate succinate (HPMCAS). Dissolution studies were carried out under nonsink conditions, and solution phase behavior was characterized using several orthogonal techniques. It was found that liquid-liquid phase separation (LLPS) occurred following dissolution and prior to crystallization for most of the dispersions. Using flux measurements, it was further observed that the maximum attainable supersaturation following dissolution was equivalent to the amorphous solubility. The dissolution of the ASDs led to sustained supersaturation, the duration of which varied depending on the drug loading and the type of polymer used in the formulation. The overall supersaturation profile observed thus depended on a complex interplay between dissolution rate, polymer type, drug loading, and the kinetics of crystallization.

Quality and length of life, money and urethral stricture disease.

PURPOSE OF REVIEW: This article walks through some of the ideas behind patient-reported outcome measurement and quality of life research against the backdrop of urethral stricture disease and conditions of the lower urinary tract more generally, why measurement matters at all, future areas for research and development and potential opportunities for misuse and manipulation. RECENT FINDINGS: It is the authors' opinion that only one published study has substantially advanced our understanding of the way men with urethral stricture disease manage this condition in the real world, and, in turn, the outcomes those men seek when they consent to surgery and its associated risks. There is, however, almost certainly greater acceptance now by reconstructive urologists of the utility of patient-reported outcome measures in audit; surgical performance evaluation; clinical research; and fair, logical and transparent healthcare resource allocation at a population level. This is evidenced by the recent proliferation of studies incorporating patient-reported outcomes, which appear today to be on parity at least with those that surgeons historically gave priority to. SUMMARY: The next frontier in urethral stricture disease outcomes research is a better understanding of the impact of this condition on men's daily lives. That level of insight is likely to be gained through a mixture of qualitative and quantitative research methods applied to collaborative research ventures with men with the condition who, as those that have the most to gain and lose, must be majority stakeholders in this process.

Intermittent self-dilatation for urethral stricture disease in males.

BACKGROUND: Intermittent urethral self-dilatation is sometimes recommended to reduce the risk of recurrent urethral stricture. There is no consensus as to whether it is a clinically effective or cost-effective intervention in the management of this disease. OBJECTIVES: The purpose of this review is to evaluate the clinical effectiveness and cost-effectiveness of intermittent self-dilatation after urethral stricture surgery in males compared to no intervention. We also compared different programmes of, and devices for, intermittent self-dilatation. . SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Register (searched 7 May 2014), CENTRAL (2014, Issue 4), MEDLINE (1 January 1946 to Week 3 April 2014), PREMEDLINE (covering 29 April 2014), EMBASE (1 January 1947 to Week 17 2014), CINAHL (31 December 1981 to 30 April 2014) OpenGrey (searched 6 May 2014), ClinicalTrials.gov (6 May 2014), WHO International Clinical Trials Registry Platform (6 May 2014), Current Controlled Trials (6 May 2014) and the reference lists of relevant articles. SELECTION CRITERIA: Randomised and quasi-randomised trials where one arm was a programme of intermittent self-dilatation for urethral stricture were identified. Studies were excluded if they were not randomised or quasi-randomised trials, or if they pertained to clean intermittent self-catheterisation for bladder emptying. DATA COLLECTION AND ANALYSIS: Two authors screened the records for relevance and methodological quality. Data extraction was performed according to predetermined criteria using data extraction forms. Analyses were carried out in Cochrane Review Manager (RevMan 5). The primary outcomes were patient-reported symptoms and health-related quality of life, and risk of recurrence; secondary outcomes were adverse events, acceptability of the intervention to patients and cost-effectiveness. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: Eleven trials were selected for inclusion in the review, including a total of 776 men. They were generally small; all were of poor quality and all were deemed to have high risk of bias. Performing intermittent self-dilatation versus not performing intermittent self-dilatation The data from six trials were heterogeneous, imprecise and had a high risk of bias, but indicated that recurrent urethral stricture was less likely in men who performed intermittent self-dilatation than men who did not perform intermittent self-dilatation (RR 0.70, 95% CI 0.48 to 1.00; very low quality evidence). Adverse events were generally poorly reported: two trials did not report adverse events and two trials reported adverse events only for the intervention group. Meta-analysis of the remaining two trials found no evidence of a difference between performing intermittent self-dilatation and not performing it (RR 0.60, 95% CI 0.11 to 3.26). No trials formally assessed acceptability, and no trials reported on patient-reported lower urinary tract symptoms, patient-reported health-related quality of life, or cost-effectiveness. One programme of intermittent self-dilatation versus another We identified two trials that compared different durations of intermittent self-dilatation, but data were not combined. One study could not draw robust conclusions owing to cross-over, protocol deviation, administrative error, post-hoc analysis and incomplete outcome reporting. The other study found no evidence of a difference between intermittent self-dilatation for six months versus for 12 months after optical urethrotomy (RR 0.67, 95% CI 0.12 to 3.64), although again the evidence is limited by the small sample size and risk of bias in the included study. Adverse events were reported narratively and were not stratified by group. No trials formally assessed acceptability, and no trials reported on patient-reported lower urinary tract symptoms, patient-reported health-related quality of life, or cost-effectiveness. One device for performing intermittent self-dilatation versus another Three trials compared one device for performing intermittent self-dilatation with another. Results from one trial at a high risk of bias were too uncertain to determine the effects of a low friction hydrophilic catheter and a standard polyvinyl chloride catheter on the risk of recurrent urethral stricture (RR 0.32, 95% CI 0.07 to 1.40). Similarly one study did not find evidence of a difference between one percent triamcinolone gel for lubricating the intermittent self-dilatation catheter versus water-based gel on risk of recurrent urethral stricture (RR 0.68, 95% CI 0.35 to 1.32). Two trials reported adverse events, but one did not provide sufficient detail for analysis. The other small study reported fewer instances of prostatitis, urethral bleeding or bacteriuria with a low friction hydrophilic catheter compared with a standard polyvinyl chloride catheter (RR 0.13, 95% CI 0.02 to 0.98). 'Happiness with the intervention' was assessed using a non-validated scale in one study, but no trials formally assessed patient-reported health-related quality of life or acceptability. No trials reported on patient-reported lower urinary tract symptoms or cost-effectiveness. GRADE quality assessment The evidence that intermittent self-dilatation reduces the risk of recurrent urethral stricture after surgical intervention was downgraded to 'very low' on the basis that the studies comprising the meta-analysis were deemed to have high risk of bias, and the data was imprecise and inconsistent. Insufficient evidence No trials provided cost-effectiveness data or used a validated patient-reported outcome measure, and adverse events were not reported rigorously. Acceptability of the intervention to patients has not been assessed quantitatively or qualitatively. AUTHORS' CONCLUSIONS: Performing intermittent self-dilatation may confer a reduced risk of recurrent urethral stricture after endoscopic treatment. We have very little confidence in the estimate of the effect owing to the very low quality of the evidence. Evidence for other comparisons and outcomes is limited. Further research is required to determine whether the apparent benefit is sufficient to make the intervention worthwhile, and in whom.

Impact of polymers on the precipitation behavior of highly supersaturated aqueous danazol solutions.

The phase behavior of supersaturated solutions of a relatively hydrophobic drug, danazol, was studied in the absence and presence of polymeric additives. To differentiate between phase separation to a noncrystalline phase and phase separation to a crystalline phase, an environmentally sensitive fluorescent probe was employed. Induction times for crystallization in the presence and absence of polymeric additives were studied using a combination of ultraviolet and fluorescence spectroscopy. It was found that, when danazol was added to aqueous media at concentrations above the amorphous solubility, liquid-liquid phase separation was briefly observed prior to crystallization, resulting in a short-lived, drug-rich noncrystalline danazol phase with an initial size of around 500 nm. The addition of polymers was found to greatly extend the lifetime of the supersaturated two phase system, delaying the onset of crystallization from a few minutes to a few hours. Below a certain threshold danazol concentration, found to represent the amorphous solubility, only crystallization was observed. Thus, although the addition of polymers was unable to prevent danazol from precipitating once a threshold concentration was exceeded, they did inhibit crystallization, leading to a solution with prolonged supersaturation. This observation highlights the need to determine the structure of the precipitating phase, since it is linked to the resultant solution concentration time profile.

A prospective patient-centred evaluation of urethroplasty for anterior urethral stricture using a validated patient-reported outcome measure.

BACKGROUND: Studies of interventions for urethral stricture have inferred patient benefit from clinician-driven outcomes or questionnaires lacking scientifically robust evidence of their measurement properties for men with this disease. OBJECTIVE: To evaluate urethral reconstruction from the patients' perspective using a validated patient-reported outcome measure (PROM). DESIGN, SETTING, AND PARTICIPANTS: Forty-six men with anterior urethral stricture at four UK urology centres completed the PROM before (baseline) and 2 yr after urethroplasty. INTERVENTION: A psychometrically robust PROM for men with urethral stricture disease. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Lower urinary tract symptoms (LUTS), health status, and treatment satisfaction were measured, and paired t and Wilcoxon matched-pairs tests were used for comparative analysis. RESULTS AND LIMITATIONS: Thirty-eight men underwent urethroplasty for bulbar stricture and eight for penile stricture. The median (range) follow-up was 25 (20-30) mo. Total LUTS scores (0 = least symptomatic, 24 = most symptomatic) improved from a median of 12 at baseline to 4 at 2 yr (mean [95% confidence interval (CI)] of differences 6.6 [4.2-9.1], p < 0.0001). A total of 33 men (72%) felt their urinary symptoms interfered less with their overall quality of life, 8 (17%) reported no change, and 5 (11%) were worse 2 yr after urethroplasty. Overall, 40 men (87%) remained "satisfied" or "very satisfied" with the outcome of their operation. Health status visual analogue scale scores (100 = best imaginable health, 0 = worst) 2 yr after urethroplasty improved from a mean of 69 at baseline to 79 (mean [95% CI] of differences 10 [2-18], p = 0.018). Health state index scores (1 = full health, 0 = dead) improved from 0.79 at baseline to 0.89 at 2 yr (mean [95% CI] of differences 0.10 [0.02-0.18), p = 0.012]). CONCLUSIONS: This is the first study to prospectively evaluate urethral reconstruction using a validated PROM. Men reported continued relief from symptoms with related improvements in overall health status 2 yr after urethroplasty. These data can be used as a provisional reference point against which urethral surgeons can benchmark their performance.

Adaptive metabolic response to 4 weeks of sugar-sweetened beverage consumption in healthy, lightly active individuals and chronic high glucose availability in primary human myotubes.

PURPOSE: Chronic sugar-sweetened beverage (SSB) consumption is associated with obesity and type 2 diabetes mellitus (T2DM). Hyperglycaemia contributes to metabolic alterations observed in T2DM, such as reduced oxidative capacity and elevated glycolytic and lipogenic enzyme expressions in skeletal muscle tissue. We aimed to investigate the metabolic alterations induced by SSB supplementation in healthy individuals and to compare these with the effects of chronic hyperglycaemia on primary muscle cell cultures. METHODS: Lightly active, healthy, lean subjects (n = 11) with sporadic soft drink consumption underwent a 4-week SSB supplementation (140 ± 15 g/day, ~2 g glucose/kg body weight/day, glucose syrup). Before and after the intervention, body composition, respiratory exchange ratio (RER), insulin sensitivity, muscle metabolic gene and protein expression were assessed. Adaptive responses to hyperglycaemia (7 days, 15 mM) were tested in primary human myotubes. RESULTS: SSB supplementation increased fat mass (+1.0 kg, P < 0.05), fasting RER (+0.12, P < 0.05), fasting glucose (+0.3 mmol/L, P < 0.05) and muscle GAPDH mRNA expressions (+0.94 AU, P < 0.05). PGC1α mRNA was reduced (-0.20 AU, P < 0.05). Trends were found for insulin resistance (+0.16 mU/L, P = 0.09), and MondoA protein levels (+1.58 AU, P = 0.08). Primary myotubes showed elevations in GAPDH, ACC, MondoA and TXNIP protein expressions (P < 0.05). CONCLUSION: Four weeks of SSB supplementation in healthy individuals shifted substrate metabolism towards carbohydrates, increasing glycolytic and lipogenic gene expression and reducing mitochondrial markers. Glucose-sensing protein MondoA might contribute to this shift, although further in vivo evidence is needed to corroborate this.

Taste perception and implicit attitude toward sweet related to body mass index and soft drink supplementation.

These studies examined the differences in sweet taste perception and implicit attitude toward sweet between normal-weight and overweight/obese adults; and tested the effects of soft drink consumption on sweet taste, explicit preference and implicit attitude toward sweet in normal-weight subjects. In study 1, normal-weight (n = 22) and overweight/obese (n = 11) adults were assessed for sweet taste intensity and pleasantness. Implicit attitude toward sweet was assessed by implicit association test (IAT). In study 2, normal-weight, lightly active adults (n = 12) underwent one month soft drink supplementation (≈760 ml/day). This increased their daily carbohydrate intake by 2.1 ± 0.2g/kg body weight. Sweet taste perception, explicit preference and implicit attitudes to sweet were assessed. In both studies salty taste was also assessed as a contrasting perception. Overweight/obese subjects perceived sweet and salty tastes as less intense (-23% and -19%, respectively) and reported higher IAT scores for sweet than normal-weight controls (2.1-fold). The supplementation changed sweet intensity/pleasantness ratings and it increased explicit preference (2.3-fold) for sweet in a subgroup of initial sucrose-dislikers. In conclusion, overweight/obese individuals are more implicitly attracted to sweet. One month of soft drink supplementation changed sweet taste perception of normal-weight subjects.

Defining a patient-reported outcome measure for urethral stricture surgery.

BACKGROUND: A systematic literature review did not identify a formally validated patient-reported outcome measure (PROM) for urethral stricture surgery. OBJECTIVE: Devise a PROM for urethral stricture surgery and evaluate its psychometric properties in a pilot study to determine suitability for wider implementation. DESIGN, SETTING, AND PARTICIPANTS: Constructs were identified from existing condition-specific and health-related quality of life (HRQoL) instruments. Men scheduled for urethroplasty were prospectively enrolled at five centres. INTERVENTION: Participants self-completed the draft PROM before and 6 mo after surgery. MEASUREMENTS: Question sets underwent psychometric assessment targeting criterion and content validity, test-retest reliability, internal consistency, acceptability, and responsiveness. RESULTS AND LIMITATIONS: A total of 85 men completed the preoperative PROM, with 49 also completing the postoperative PROM at a median of 146 d; and 31 the preoperative PROM twice at a median interval of 22 d for test-retest analysis. Expert opinion and patient feedback supported content validity. Excellent correlation between voiding symptom scores and maximum flow rate (r = -0.75), supported by parallel improvements in EQ-5D visual analogue and time trade-off scores, established criterion validity. Test-retest intraclass correlation coefficients ranged from 0.83 to 0.91 for the total voiding score and 0.93 for the construct overall; Cronbach's α was 0.80, ranging from 0.76 to 0.80 with any one item deleted. Item-total correlations ranged from 0.44 to 0.63. These values surpassed our predefined thresholds for item inclusion. Significant improvements in condition-specific and HRQoL components following urethroplasty demonstrated responsiveness to change (p < 0.0001). Wider implementation and review of the PROM will be required to establish generalisability across different disease states and for more complex interventions. CONCLUSIONS: This pilot study has defined a succinct, practical, and psychometrically robust PROM designed specifically to quantify changes in voiding symptoms and HRQoL following urethral stricture surgery.

Twenty-nine Leydig cell tumors: histological features, outcomes and implications for management.

Leydig cell tumors are the most common interstitial neoplasm of the testes. Metastatic progression is historically quoted at over 10%, fuelling uncertainty as to the safety of testis sparing surgery. Between June 1998 and March 2009, 29 patients underwent surgery for Leydig cell tumor of the testis in our cancer network. We reviewed their histological features and clinical outcomes. Four patients with sub-5 millimetre lesions underwent testis sparing surgery and 25 were treated with radical orchidectomy. Histopathological characteristics that have been linked with risk of malignant progression were seen infrequently in our cohort: diameter greater than 50 mm, 0%; nuclear atypia, 14%; >3 mitoses per 10 high-power fields, 3%; infiltrative borders, 10%; necrosis, 3%; and vascular invasion 0%. No patient developed local or distant recurrent disease over a median follow up of 49 months, including seven and four patients disease-free at 5 and 10 years, respectively. The rate of metastatic progression is likely to be significantly less than 10%. Our data suggest that, in the absence of high-risk histopathological features, this tumor can be safely regarded as benign, pending a longer-term follow-up evaluation.

The importance of patient-reported outcome measures in reconstructive urology.

PURPOSE OF REVIEW: Patient-reported outcome measures (PROMs) are now recognised as the most appropriate instruments to assess the effectiveness of healthcare interventions from the patient's perspective. The purpose of this review was to identify recent publications describing the use of PROMs following reconstructive urological surgery. RECENT FINDINGS: A wide systematic search identified only three original articles published in the last 2 years that prospectively assessed effectiveness using a patient-completed condition-specific or generic health-related quality of life (HRQoL) instrument. These publications illustrate the need to administer PROMs at a postoperative interval relevant to the anticipated recovery phase of individual procedures. They also highlight the difference in responsiveness of generic HRQoL instruments to symptomatic improvement between straightforward conditions such as pelviureteric junction obstruction and complex multidimensional conditions such as meningomyelocele. SUMMARY: PROMs uptake and awareness is increasing in reconstructive urology but more work is required to demonstrate the effectiveness of surgical procedures for patients and healthcare funders alike. Healthcare policy-makers now rely on these measures to determine whether specific treatments are worth financing and to compare outcomes between institutions.