Prostate cancer risk stratification via eNose urine odor analysis: a preliminary report.

Introduction: Prostate cancer (PCa) is known for its highly diverse clinical behavior, ranging from low-risk, slow-growing tumors to aggressive and life-threatening forms. To avoid over-treatment of low-risk PCa patients, it would be very important prior to any therapeutic intervention to appropriately classify subjects based on tumor aggressiveness. Unfortunately, there is currently no reliable test available for this purpose. The aim of the present study was to evaluate the ability of risk stratification of PCa subjects using an electronic nose (eNose) detecting PCa-specific volatile organic compounds (VOCs) in urine samples. Methods: The study involved 120 participants who underwent diagnostic prostate biopsy followed by robot assisted radical prostatectomy (RARP). PCa risk was categorized as low, intermediate, or high based on the D'Amico risk classification and the pathological grade (PG) assessed after RARP. The eNose's ability to categorize subjects for PCa risk stratification was evaluated based on accuracy and recall metrics. Results: The study population comprised 120 participants. When comparing eNose predictions with PG an accuracy of 79.2% (95%CI 70.8 - 86%) was found, while an accuracy of 74.2% (95%CI 65.4 - 81.7%) was found when compared to D'Amico risk classification system. Additionally, if compared low- versus -intermediate-/high-risk PCa, the eNose achieved an accuracy of 87.5% (95%CI 80.2-92.8%) based on PG or 90.8% (95%CI 84.2-95.3%) based on D'Amico risk classification. However, when using low-/-intermediate versus -high-risk PCa for PG, the accuracy was found to be 91.7% (95%CI 85.2-95.9%). Finally, an accuracy of 80.8% (95%CI72.6-87.4%) was found when compared with D'Amico risk classification. Discussion: The findings of this study indicate that eNose may represent a valid alternative not only for early and non-invasive diagnosis of PCa, but also to categorize patients based on tumor aggressiveness. Further studies including a wider sample population will be necessary to confirm the potential clinical impact of this new technology.

Prostate Cancer Microvascular Routes: Exploration and Measurement Strategies.

Angiogenesis is acknowledged as a pivotal feature in the pathology of human cancer. Despite the absence of universally accepted markers for gauging the comprehensive angiogenic activity in prostate cancer (PCa) that could steer the formulation of focused anti-angiogenic treatments, the scrutiny of diverse facets of tumoral blood vessel development may furnish significant understanding of angiogenic processes. Malignant neoplasms, encompassing PCa, deploy a myriad of strategies to secure an adequate blood supply. These modalities range from sprouting angiogenesis and vasculogenesis to intussusceptive angiogenesis, vascular co-option, the formation of mosaic vessels, vasculogenic mimicry, the conversion of cancer stem-like cells into tumor endothelial cells, and vascular pruning. Here we provide a thorough review of these angiogenic mechanisms as they relate to PCa, discuss their prospective relevance for predictive and prognostic evaluations, and outline the prevailing obstacles in quantitatively evaluating neovascularization via histopathological examinations.

Off-clamp robotic-assisted partial nephrectomy: surgical experience from a single centre.

Introduction: Robot-assisted partial nephrectomy (RAPN) is a minimally invasive treatment for localized renal tumours, which can sometimes result in extended warm ischaemic time and serious complications. This study reports on surgical outcomes including feasibility, positive margins, and complications during and after surgery. Material and methods: From January 2011 to November 2022, a single centre performed off-clamp sutureless RAPN on 287 patients. The study recorded preoperative patient characteristics, estimated glomerular filtration rate, and tumour features according to the preoperative aspects and dimensions used for an anatomical (PADUA) classification, and utilized the RENAL nephrometry scoring system. Intraoperative details and complications were documented. Postoperative complications within 30 days were classified according to the Clavien-Dindo system. Follow-up appointments were scheduled at 1, 3, and 6 months in the first year, followed by subsequent appointments every 6 months, and then annually. Results: The study included 145 males and 142 females, with a mean age of 58.9 years and a mean body mass index of 26.7 kg/m2. The mean PADUA score was 8.3, the average console time was 83 minutes, and the estimated blood loss was 280 mL. The average hospital stay was 3 days, and no intraoperative complications were observed. However, 4 patients (1.4%) experienced post-operative haemorrhage that required laparotomy (Clavien-Dindo stage IIIB), and 4 patients (1.4%) had positive surgical margins. Conclusions: Off-clamp selective arterial clamping during minimally invasive partial nephrectomy is a safe and feasible approach for small renal tumours. Further randomized prospective studies are required to confirm if RAPN without clamping offers any renal functional benefits and reduces perioperative bleeding complications.

Systematic review of ablative therapy for the treatment of renal allograft neoplasms.

BACKGROUND: To date, there are no guidelines on the treatment of solid neoplasms in the transplanted kidney. Historically, allograft nephrectomy has been considered the only reasonable option. More recently, nephron-sparing surgery (NSS) and ablative therapy (AT) have been proposed as alternative procedures in selected cases. AIM: To review outcomes of AT for the treatment of renal allograft tumours. METHODS: We conducted a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2009 Checklist. PubMed was searched in March 2019 without time restrictions for all papers reporting on radiofrequency ablation (RFA), cryoablation (CA), microwave ablation (MWA), high-intensity focused ultrasound (HIFU), and irreversible electroporation (IRE) of solid tumours of the kidney allograft. Only original manuscripts describing actual cases and edited in English were considered. All relevant articles were accessed in full text. Additional searches included all pertinent references. Selected studies were also assessed for methodological quality using a tool based on a modification of the Newcastle Ottawa scale. Data on recipient characteristics, transplant characteristics, disease characteristics, treatment protocols, and treatment outcomes were extracted and analysed. Given the nature and the quality of the studies available (mostly retrospective case reports and small retrospective uncontrolled case series), a descriptive summary was provided. RESULTS: Twenty-eight relevant studies were selected describing a total of 100 AT procedures in 92 patients. Recipient age at diagnosis ranged from 21 to 71 years whereas time from transplant to diagnosis ranged from 0.1 to 312 mo. Most of the neoplasms were asymptomatic and diagnosed incidentally during imaging carried out for screening purposes or for other clinical reasons. Preferred diagnostic modality was Doppler-ultrasound scan followed by computed tomography scan, and magnetic resonance imaging. Main tumour types were: papillary renal cell carcinoma (RCC) and clear cell RCC. Maximal tumour diameter ranged from 5 to 55 mm. The vast majority of neoplasms were T1a N0 M0 with only 2 lesions staged T1b N0 M0. Neoplasms were managed by RFA (n = 78), CA (n = 15), MWA (n = 3), HIFU (n = 3), and IRE (n = 1). Overall, 3 episodes of primary treatment failure were reported. A single case of recurrence was identified. Follow-up ranged from 1 to 81 mo. No cancer-related deaths were observed. Complication rate was extremely low (mostly < 10%). Graft function remained stable in the majority of recipients. Due to the limited sample size, no clear benefit of a single procedure over the other ones could be demonstrated. CONCLUSION: AT for renal allograft neoplasms represents a promising alternative to radical nephrectomy and NSS in carefully selected patients. Properly designed clinical trials are needed to validate this therapeutic approach.

Safety and feasibility of thullium laser transurethral resection of prostate for the treatment of benign prostatic enlargement in overweight patients.

OBJECTIVE: We aimed to determine safety and feasibility of thulium laser transurethral vapoenucleation of prostate (ThuVEP) for treatment of obese patients affected by benign prostatic hyperplasia (BPH). METHODS: We retrospectively analysed data of 452 patients with BPH who underwent ThuVEP from February 2012 to March 2016 in a single center. Patients were divided into three groups according to body mass index (BMI, kg/m2): Normal weight (18.5 ≤ BMI < 25; Group A), overweight (25 ≤ BMI < 30; Group B) and obese (BMI ≥ 30; Group C), for a total of 412 patients evaluable for this study. Preoperative total serum prostate-specific antigen (PSA), digital rectal examination of the prostate, transrectal ultrasound (TRUS), renal ultrasound, urine culture, uroflowmetry, International Prostate Symptoms Score (IPSS), and Quality of Life (QoL) score were analyzed. Post-operative complications, hospital stay and days of catheterization, questionnaires and uroflowmetry at 1 and 3 months after surgery were evaluated. Preoperative data, surgical outcomes, complication rate and clinical outcomes were compared between groups. RESULTS: The median age of patients was 69 years (Interquartile Range [IQR 10]). The preoperative median IPSS among groups was 19 (IQR 8.75), 20 (IQR 10), and 18 (IQR 10) respectively. At 1 and 3 months of follow-up, this value was 8 (IQR 7), 8 (IQR 4), 7 (IQR 5) and 5 (IQR 6.25), 5 (IQR 6), 6 (IQR 5), respectively (all p between groups > 0.05). There was no statistically significant difference among three groups as for hospital stay and days of catheterization (p > 0.05). CONCLUSION: Our results showed that ThuVEP was safe and feasible even in overweight patients with substantially enlarged prostate.

Postoperative paralytic ileus after major oncological procedures in the enhanced recovery after surgery era: A population based analysis.

BACKGROUND: Enhanced recovery after surgery (ERAS) protocols have been developed and implemented as of 2001 and may have significantly reduced several complication types including paralytic ileus. However, no formal analyses targeted paralytic ileus rates after contemporary major surgical oncology procedures. We examined temporal trends of paralytic ileus following ten major oncological surgical procedures. The effect of paralytic ileus on length of stay (LOS) and total hospital charges was examined. Univariable and multivariable linear and logistic regression analyses were used. METHODS: Between 2003 and 2013, we retrospectively identified patients, who underwent prostatectomy, colectomy, cystectomy, mastectomy, gastrectomy, hysterectomy, nephrectomy, oophorectomy, lung resection or pancreatectomy within the Nationwide Inpatient Sample. A total of 3 431 602 patients were included in our analyses. Annual paralytic ileus rate differences after major oncological surgical procedures were evaluated using linear regression. Multivariable logistic regression analyses were used to test for paralytic ileus rates determinants, as well as on the effect of paralytic ileus rates on LOS and hospital charges. RESULTS: Paralytic ileus rates ranged from 0.1% (mastectomy) to 23.2% (cystectomy) after ten examined major oncological surgical procedures. Overall annual paralytic ileus rates did not change [estimated annual percentage change (EAPC)+0.1%, p = 0.7]. Multivariable logistic regression derived predicted probabilities (PP) of paralytic ileus were highest for cystectomy (PP: 26.1%) and colectomy (PP: 17.15%) and were lowest for lung resection (PP: 2.22%) and mastectomy (PP: 0.16%). In analyses predicting LOS above the 75th percentile, paralytic ileus effect after mastectomy (OR: 14.66) and prostatectomy (OR: 13.21) ranked, as highest and second highest respectively. In analyses predicting hospital charges above the 75th percentile, paralytic ileus effect after mastectomy (OR: 2.21) and oophorectomy (OR: 1.99) ranked as highest and second highest respectively. CONCLUSIONS: Despite implementation of ERAS protocols paralytic ileus rates have not decreased over time. Gastrointestinal procedures are among the highest contributors of paralytic ileus. Moreover, procedures with short LOS represent the strongest relative contributors to LOS increases and increases in hospitalization costs.

Awareness and knowledge of human papillomavirus-related diseases are still dramatically insufficient in the era of high-coverage vaccination programs.

PURPOSE: Assess knowledge and awareness concerning human papillomavirus (HPV) infection, HPV-associated diseases, and the existence of a specific vaccine among non-HPV-screened Caucasian-European adults after the market introduction of HPV vaccines. METHODS: A cohort of 934 consecutive patients seeking their first medical help for uroandrologic purposes anonymously completed a 17-item questionnaire related to HPV. Data were compared with those of an age-comparable cohort of nurses (controls; n = 172). RESULTS: Knowledge and awareness of HPV infection were reported in 564 (51%) and 735 (66.5%) participants, respectively. Overall, 51.3% participants were informed that HPV is sexually transmitted, but most reported not being aware that HPV infection can be associated with anogenital warts (61.7%), female genitalia (46.6%), penile (58.5%), and oropharyngeal cancer (79.7%). Only 36.5% of the participants were informed regarding the existence of a specific vaccine. HPV knowledge was retrieved through the media and/or the Internet, at school, doctors, and relatives or friends in 395 (35.7%), 155 (14%), 97 (8.8%), and 88 (8.0%) participants, respectively. Multivariable analyses showed that female gender [odds ratio (OR) 3.08; p < 0.001; 95% confidence interval 2.18-4.35] and educational status [high school diploma versus primary-secondary (OR 1.61; p = 0.03; 1.04-2.51); university degree versus primary-secondary (OR 2.89; p < 0.001; 1.83-4.57)] were significantly associated with awareness of HPV. CONCLUSIONS: Only approximately half of the participants reported knowing what HPV infection is, even after the approval and market introduction of the HPV vaccine. Awareness about the existence and availability of a HPV vaccine was even lower.

Secondary provoked vestibulodynia in sexually active women with uncomplicated recurrent urinary tract infections.

INTRODUCTION: Uncomplicated recurrent urinary tract infections (rUTIs) associated with uropathogenic Escherichia coli (UPEC) are common among healthy, reproductive-aged women. Provoked vestibulodynia (PVD) is a major reason of sexual pain in premenopausal women. AIM: The aim of this paper is to assess prevalence and predictors of secondary PVD in a cohort of Caucasian-European, heterosexual, sexually active, reproductive-aged women seeking medical help for rUTIs as their primary complaint. METHODS: Clinical and psychometric variables for 60 consecutive patients with rUTIs were considered. Patients were assessed with a thorough medical and sexual history, a number of psychometric instruments, and a specific physical examination. Urinalysis and self-collected urine cultures from the previous 12 months were also examined. MAIN OUTCOME MEASURE: Descriptive statistics and logistic regression models were used to test the associations between secondary PVD and sociodemographic and clinical variables. RESULTS: Mean age was 34.2 years (median 33 years; range 21-42). Secondary PVD was found in 36 of 60 patients (60%). Women with PVD had a higher prevalence of urinary tract infections (UTIs) over the previous 12 months (χ(2) : 4.54; P = 0.03) and suffered more frequently from UPEC-related rUTIs (χ(2) : 5.92; P = 0.01) than those without PVD. Moreover, women with PVD showed significantly lower scores on Female Sexual Function Index domains (all P ≤ 0.01), as compared with PVD-negative women. UPEC-related rUTIs (odds ratio [OR]: 3.1; P = 0.01), six or more UTIs over the previous 12 months (OR: 2.8; P = 0.01), and treatment with three or more antibiotics throughout the same period (OR: 2.1; P = 0.04) emerged as independent predictors of PVD. CONCLUSIONS: Three of five Caucasian-European, heterosexual, sexually active women of reproductive age complaining of rUTIs as their primary disorder also suffer from secondary PVD. Uncomplicated UPEC-related rUTIs are more frequently associated with secondary PVD than are UTIs caused by different uropathogens.

One patient out of four with newly diagnosed erectile dysfunction is a young man--worrisome picture from the everyday clinical practice.

INTRODUCTION: Erectile dysfunction (ED) is a common complaint in men over 40 years of age, and prevalence rates increase throughout the aging period. Prevalence and risk factors of ED among young men have been scantly analyzed. AIM: Assessing sociodemographic and clinical characteristics of young men (defined as ≤ 40 years) seeking first medical help for new onset ED as their primary sexual disorder. METHODS: Complete sociodemographic and clinical data from 439 consecutive patients were analyzed. Health-significant comorbidities were scored with the Charlson Comorbidity Index (CCI). Patients completed the International Index of Erectile Function (IIEF). MAIN OUTCOME MEASURE: Descriptive statistics tested sociodemographic and clinical differences between ED patients ≤ 40 years and >40 years. RESULTS: New onset ED as the primary disorder was found in 114 (26%) men ≤ 40 years (mean [standard deviation [SD]] age: 32.4 [6.0]; range: 17-40 years). Patients ≤ 40 years had a lower rate of comorbid conditions (CCI = 0 in 90.4% vs. 58.3%; χ(2) , 39.12; P < 0.001), a lower mean body mass index value (P = 0.005), and a higher mean circulating total testosterone level (P = 0.005) as compared with those >40 years. Younger ED patients more frequently showed habit of cigarette smoking and use of illicit drug, as compared with older men (all P ≤ 0.02). Premature ejaculation was more comorbid in younger men, whereas Peyronie's disease was prevalent in the older group (all P = 0.03). At IIEF, severe ED rates were found in 48.8% younger men and 40% older men, respectively (P > 0.05). Similarly, rates of mild, mild-to-moderate, and moderate ED were not significantly different between the two groups. CONCLUSIONS: This exploratory analysis showed that one in four patients seeking first medical help for new onset ED was younger than 40 years. Almost half of the young men suffered from severe ED, with comparable rates in older patients. Overall, younger men differed from older individuals in terms of both clinical and sociodemographic parameters.

Sperm banking is of key importance in patients with prostate cancer.

OBJECTIVE: To assess the need for sperm banking among patients with prostate cancer (PCa) who are candidates for radical prostatectomy (RP). DESIGN: Cross-sectional study. SETTING: Urologic department. PATIENT(S): Cohort of 510 Caucasian-European candidates for RP. INTERVENTION(S): A 10-item self-administered questionnaire to assess opinions on sperm banking before RP, to which descriptive statistics and logistic regression models were applied. MAIN OUTCOME MEASURE(S): PCa patients' wishes for preoperative sperm banking. RESULT(S): Data collection was completed for 495 patients (97.1%). Ninety-nine (20%) expressed a wish for preoperative sperm banking. Men who wanted to bank sperm were younger (mean 62.2 vs. 65.1 years), were more frequently childless (21.2% vs. 8.8%), and more frequently had a more intense desire for fatherhood (64.7% vs. 9.3%) than the patients not interested in banking sperm. Willingness to bank sperm was not affected by the patient's educational or relationship status. Moreover, the interest for sperm banking was maintained regardless of cost issues. Overall, 84% of the patients considered it necessary to have a dedicated service of preoperative sperm cryopreservation. CONCLUSION(S): One out of five PCa patients would bank sperm before RP. Most patients considered it necessary to establish a dedicated service for preoperative sperm cryopreservation, regardless of their own motivation to bank sperm.

Circulating sex steroids and prostate cancer: introducing the time-dependency theory.

PURPOSE: We sought whether serum total testosterone (tT), estradiol (E2), tT/E2 ratio, and sex hormone-binding globulin (SHBG) significantly fluctuate throughout time in men with prostate cancer (PCa). METHODS: Circulating hormones were measured in a cohort of 631 candidates for radical prostatectomy. Hormone levels were analyzed according to either patient age, stratified into quartiles, or body mass index (BMI). Linear regression analyses tested the association between sex steroids and continuously coded patient age and BMI values. RESULTS: No significant differences were found among age quartiles regarding serum tT levels and tT/E2 ratio. Conversely, E2 and SHBG levels significantly increased throughout time (all, p ≤ 0.001). Total T did not linearly change according to continuously coded patient age; in contrast, E2 and SHBG linearly increased (all, p ≤ 0.001), whereas tT/E2 decreased (p = 0.016) with aging. Rate of hypogonadism significantly increased with aging (p = 0.04). Total T, T/E2 ratio, and SHBG linearly decreased along with BMI increases (all p ≤ 0.02), whereas serum E2 did not significantly change. Rate of hypogonadism significantly increased with BMI increases (p < 0.001). CONCLUSIONS: In contrast with longitudinal studies in the general male population, these data indirectly suggest that serum tT levels could be stable over time in PCa patients. This finding led to formulation of a "time-dependency theory", which postulates that the endocrine biology of prostate tissue is dependent on the exposure time at a given concentration of sex steroid, which, in turn, fluctuates throughout the lifespan of the individual.

Is erectile dysfunction a reliable indicator of general health status in men?

INTRODUCTION: Erectile dysfunction (ED) is a common risk factor in men and its incidence increases with age. Ageing and older men frequently have comorbidities such as cardiovascular diseases (CVD), diabetes mellitus (DM), hypertension, chronic obstructive pulmonary disease and dyslipidaemia; likewise, they concurrently refer to a clinician for impairments in sexual function, mostly for ED. The association of ED and other organic, multi-organic or even systemic diseases is widely described, with a specific emphasis on the fact that they often share common pathophysiological factors and mechanisms. Thus we reviewed previous reports assessing the role of ED as a sentinel marker of overall men's health. DISCUSSION: ED is considered an important sentinel marker for CVD. Numerous studies have highlighted the predictive role of ED for subsequent CV events in patients with a silent history of coronary artery disease. Indeed, ED might be considered as a clinical manifestation of a generalised vascular disease, and it should provoke clinicians to check for CVDs in those patients complaining of impaired erectile function. This concept appears to be even more important for men with DM, where ED has already been shown to have a significant predictive ability for major vascular complications. Moreover, data from large population-based studies showed that ED is a significant predictor of all-cause mortality, in addition to CV outcomes. The severity of erectile function is assessed with the International Index of Erectile Function-Erectile Function domain score, and this has emerged as a proxy for men's general health status, as assessed with the Charlson Comorbidity Index score. CONCLUSIONS: Patients complaining of ED should be evaluated with a comprehensive medical and sexual history, and a thorough physical examination, regardless of their age, considering ED as an opportunity to screen for the presence of health-threatening concomitant comorbidities.

Preoperative sex steroids are significant predictors of early biochemical recurrence after radical prostatectomy.

PURPOSE: We sought the association of preoperative serum total testosterone (tT), hypogonadism, 17ß estradiol (E2), and sex hormone-binding globulin (SHBG) with early biochemical recurrence (BCR) after radical prostatectomy (RP). METHODS: Sex steroids were assessed the day before surgery (7-11 a.m.) in a cohort of 605 patients with a median follow-up of 24 months following RP. Cox regression models tested the association between predictors [including age, body mass index (BMI), prostate-specific antigen (PSA), clinical stage, biopsy Gleason scores, tT, hypogonadism, E2, and SHBG] and early BCR (defined as a PSA ≥ 0.1 ng/ml that occurred within 24 months after RP). RESULTS: Early BCR was found in 34 (5.6 %) patients. Patients with BCR did not differ in terms of age, BMI, serum PSA, tT, E2, and SHBG levels, rate of hypogonadism, and clinical stage as compared with those without BCR (all p ≥ 0.05). Conversely, patients with BCR showed a greater prevalence of biopsy Gleason scores ≥4 + 3 (all p ≤ 0.001). At multivariable Cox regression analysis, tT [hazard ratio (HR): 1.43; p = 0.03] E2 (HR: 1.05; p = 0.04), SHBG (HR: 1.29; p = 0.02), and biopsy Gleason scores equal to 4 + 3 (HR: 3.37; p = 0.04) and ≥8 (HR: 20.06; p < 0.001) achieved independent predictor status for early BCR. Conversely, no significant associations were found for all the other predictors. CONCLUSIONS: Current findings show that preoperative serum sex steroids are independent predictors of early BCR in a homogeneous, large cohort of nonscreened patients treated with RP.

Delay in seeking medical help in patients with new-onset erectile dysfunction remained high over and despite the PDE5 era--an ecological study.

INTRODUCTION: It is common knowledge among researchers that erectile dysfunction (ED) is an important sentinel marker of cardiovascular and overall men's health. AIM: Determine whether the delay of time between ED onset and seeking medical help (DSH), considered as a proxy of awareness of the importance of ED for overall men's health, has shortened during the phosphodiesterase type 5 inhibitors (PDE5) era. METHODS: Complete data from 619 patients seeking first medical help for new-onset ED as their primary disorder between July 2000 and July 2010 were analyzed (i.e., DSH, ED severity as defined by the International Index of Erectile Function-erectile function [IIEF-EF] domain score, patient's awareness of any PDE5, and Charlson Comorbidity Index [CCI]). Analysis of variance tested DSH throughout the 10-year time frame. Cox regression models tested the association between predictors and DSH. MAIN OUTCOME MEASURES: Assess if DSH has shortened throughout PDE5 era. Evaluate potential predictors of DSH. RESULTS: Overall, mean DSH was 30.2 months (median 12.0; range 5-300 months). DSH shortened throughout the analyzed 10-year period (F = 1.918; P = 0.047), with a significant drop only from year 2009 (DSH up to year 2008 vs. from year 2009: 31.0 months [12.0] vs. 7.5 months [6.0], respectively; P < 0.001). Age, CCI, educational status, and ED severity did not significantly change over time. As a whole, 560 patients (90.5%) were aware of PDE5 at the time of their first office visit. PDE5 awareness emerged as an univarible and multivariable predictor of a shortened DSH. Conversely, DSH was not clearly associated with age, CCI, educational status, or ED severity. CONCLUSIONS: Delay in seeking medical help in new-onset ED patients remained high over the PDE5 era, with a significant drop only from the year 2009. PDE5 awareness emerged as an independent predictor of shortening of this delay.