Prevalence of integrase inhibitor resistance mutations in Austrian patients recently diagnosed with HIV from 2008 to 2013.

PURPOSE: Treatment guidelines often do not advocate testing for integrase inhibitor resistance associated mutations (IRAM) before initiation of first line ART given the extremely low prevalence of mutations found in older surveillance studies. We aimed to describe the prevalence of IRAM in Austrian patients recently diagnosed with HIV in the 5 years following introduction of integrase inhibitors and to analyse trends and factors associated with their detection. METHODS: Samples of antiretroviral treatment (ART) naïve patients recently diagnosed with HIV in Austria between 2008 and 2013 were analysed for the existence of IRAM and drug penalty scores were calculated to estimate response to drugs. Demographic and virological data were extracted from a database. Descriptive and comparative statistics were used. RESULTS: A total of 303 samples were analysed. 78 % were male and mean age was 38 years. Overall prevalence of IRAM was 2.3 %. Six percent had at least potentially low-level resistance to raltegravir or elvitegravir, versus 1 % for dolutegravir. One primary mutation was observed (F121Y) in a patient sample from 2012 leading to 5-10-fold reduced susceptibility to raltegravir and elvitegravir. Two patients carried the accessory mutations E138K and G140A, respectively, where both lie on the Q148 pathway. No temporal trend of IRAM prevalence was observed (p = 0.16). DISCUSSION: Primary IRAM are still rarely found despite the increasing use of INSTI in Austria, but there is a potential for reduced susceptibility to these drugs in selected patients. Routine resistance testing seems prudent to avoid the consequences including accumulation of further mutations and therapeutic failure.

Risk factors for lower urinary tract symptoms in elderly men. For the Prostate Study Group of the Austrian Society of Urology.

OBJECTIVE: The aim of this study was to confirm previous studies with respect to risk factors for lower urinary tract symptoms (LUTS) as assessed by the International Prostate Symptom Score (IPSS) as well as, for the first time, specifically for storage and voiding symptoms in elderly men. MATERIAL AND METHODS: During a health survey organised in the area of Vienna in 1996, the following parameters were obtained: (1) IPSS including the quality of life question; (2) a detailed medical history; (3) assessment of all concurrent medical therapies; (4) physical examination with assessment of age, weight, height, body mass index, heart rate and blood pressure; (5) sociodemographic parameters, and (6) a blood laboratory study including kidney and liver function tests, low- and high-density lipoproteins, cholesterol and glucose. Only men aged 40 years or older without previous surgery to the prostate and without concurrent medication for LUTS were analysed. The IPSS, its irritative (storage symptoms) and obstructive (voiding symptoms) components were correlated to these parameters by partial correlation analysis which was controlled for age. RESULTS: The data of 1,557 men (mean age: 51.3 years; range: 40-96 years) were analysed. The most important risk factor for the development of LUTS was age, as the IPSS (correlation coefficient r = 0.294), its obstructive (r = 0.248) and irritative (r = 0.261) components all correlated significantly (p<0.0001) with patient age. In all life decades there was no significant difference of the IPSS, its obstructive and irritative components in current smokers and non-smokers. The irritative score, however, correlated significantly (p = 0.001; r = 0.158) with the number of cigarettes smoked per day. In men aged 40-49 years, regular alcohol consumption resulted in a higher total IPSS (p = 0.01) and irritative (p = 0.002) score. This difference was not demonstrable in older age groups. Patient weight and body mass index did not correlate with the IPSS, yet there was a trend for a higher IPSS in men with elevated blood pressure and larger waist size. CONCLUSIONS: This large-scale cross-sectional study underlines the importance of age for the development of LUTS. Few avoidable risk factors for the development of LUTS have been identified, such as obesity, cigarette smoking, elevated blood pressure and alcohol consumption. The subcategorization of LUTS into irritative/obstructive symptoms might provide new insights into the assessment of risk factors for LUTS.

Endocrine status in elderly men with lower urinary tract symptoms: correlation of age, hormonal status, and lower urinary tract function. The Prostate Study Group of the Austrian Society of Urology.

OBJECTIVES: To correlate endocrine parameters in elderly men with lower urinary tract symptoms (LUTS) to patient age and clinical parameters such as prostate volume, prostate-specific antigen (PSA) levels, and uroflowmetry and to compare the clinical and endocrinologic parameters in men with or without hypogonadism. METHODS: Men (40 years old or older) with untreated LUTS as defined by an International Prostate Symptom Score (IPSS) of 7 or greater due to benign prostatic hyperplasia were included in this study and underwent the following investigations: IPSS, free uroflow study, postvoid residual volume, transrectal ultrasound for assessment of prostate volume, serum PSA determination, and an endocrine study, including testosterone, human luteinizing hormone, human follicle-stimulating hormone, prolactin, dehydroepiandrostendione-sulphate (DHEA-S), and prolactin. RESULTS: Three hundred twelve men (mean age 62.8 +/- 10.6 years, range 40 to 91) were analyzed. The serum levels of estradiol (correlation coefficient [r] = 0.19), human luteinizing hormone (r = 0.32), human follicle-stimulating hormone (r = 0.19), and DHEA-S (r = -0.39) correlated (P <0.05) with age; no such correlation was seen for testosterone (r = 0.04; P0.05) or prolactin (r = 0.09; P0.05). Estradiol (but not testosterone) correlated (r = 0.17, P = 0.01) with prostate volume. The peak flow rate and PSA did not correlate with any endocrinologic parameter. Hypogonadism (serum testosterone less than 3.0 ng/mL) was detected in 22.1% of patients and had no impact on clinical (IPSS, peak flow rate, prostate volume, and PSA level) or endocrine (human luteinizing hormone, human follicle-stimulating hormone, estradiol, prolactin, and DHEA-S) parameters. CONCLUSIONS: A number of age-related endocrine changes are seen in elderly men with LUTS. Hypogonadism is seen in approximately one fifth of elderly men with LUTS, but in our study it had no impact on symptom status, PSA level, prostate volume, uroflowmetry, or endocrine parameters.

Randomized double-blind placebo-controlled multicenter evaluation of efficacy and dose finding of midodrine hydrochloride in women with mild to moderate stress urinary incontinence: a phase II study.

Midodrine is a potent and selective alpha1-receptor agonist and its potential to increase urethral closure pressure could be useful in the treatment of female stress incontinence. The aim of this randomized double-blind placebo-controlled multicenter study was to evaluate the efficacy and safety of midodrine for the treatment of stress urinary incontinence. The primary criterion of efficacy was the maximum urethral closure pressure at rest. Voiding diaries, symptom and incontinence questionnaires and patient/investigator global assessment were also used to evaluate its efficacy. After 4 weeks of treatment no significant changes in MUCP were found. The global assessment by the patient and investigator did indicate that patients on active treatment had a more positive assessment than the placebo group. In conclusion, midodrine did not cause significant improvements in urodynamic parameters, but there were subjective improvements in some of the patients in the treated groups. Furthermore midodrine was well tolerated.

Prevalence of lower urinary tract symptoms in Austria as assessed by an open survey of 2,096 men.

OBJECTIVE: The lack of knowledge on the prevalence of lower urinary tract symptoms (LUTS) in German-speaking countries prompted us to assess this issue in Austria by means of a large open-scale study. METHODS: A community sample of 2,096 men equal to or older than 20 years, who participated in a health survey in Vienna, completed the recently validated German translation of the International Prostate Symptom Score (IPSS). In addition, a detailed urological history and a physical evaluation (including digital rectal examination) were obtained. RESULTS: The mean age in the study population was 47 +/- 14 (range 20-96) years. The mean IPSS increased from 2.1 (20-29 years, n = 128) to 2.6 (30-39, n = 322), 3.0 (40-49, n = 902), 5.8 (50-59, n = 325), 5.7 (60-69, n = 219), 6.4 (70-79, n = 158), and 6.1 (>/=80 years, n = 42). The proportion of patients with moderate/severe LUTS defined by an IPSS >7 increased from 6.3% (20-29 years) to 8.4 (30-39), 11.1 (40-49), 27.1 (50-59), 28.3 (60-69), 36 (70-79), and 35.7% (>/=80 years). Overall, 7.8% of the men aged >/=50 years previously underwent transurethral resection of the prostate. In men aged 50-59 years, this proportion was 1.3%, and it increased to 4.2, 20.9, and 27.5% in those aged 60-69, 70-79, and >/=80 years, respectively. 7% of the men had previously consulted an urologist for micturition problems. In all life decades, these patients had higher IPSS levels than those with no previous urological visit. CONCLUSIONS: Based on the data generated, it is estimated that at present in Austria 26.9% (n = 291,761) of the men aged >/=50 years have moderate and further 2.8% (n = 30,815) severe LUTS. 7.8% of the men aged >/=50 years (n = 84,256) had a previous transurethral resection of the prostate. These data confirm the high prevalence of this condition in Austria.

Morbidity of the evaluation of the lower urinary tract with transurethral multichannel pressure-flow studies.

PURPOSE: The aim of this prospective study was to determine morbidity and complication rate of invasive urodynamic evaluation of the lower urinary tract after transurethral multichannel pressure-flow studies. MATERIALS AND METHODS: The study included 63 men with the clinical diagnosis of benign prostatic hyperplasia and 56 women with stress urinary incontinence. All patients underwent routine pressure-flow study as part of the urodynamic evaluation. A week later the patients returned for followup which also included a detailed interview on post-evaluation morbidity. RESULTS: The overall complication rate, including urinary retention, gross hematuria, urinary tract infection and fever, was 19.0% (12 of 63) for men and 1.8% (1 of 56) for women. In men there was no statistically significant correlation between post-void residual urine or age and complication rate (p > 0.05). Of the men 4.8% experienced post-investigational urinary retention and all of them had significant bladder outflow obstruction. In addition, obstructed men reported a higher incidence of dysuria and pain (76.2%, 32 of 42) compared to those without obstruction (57.1%, 12 of 21), whereas only 53.6% of women reported these complaints. Of the 63 men 4 (6.2%) had significant urinary tract infections, while only 1 woman (1.8%) had infections. CONCLUSIONS: Invasive urodynamic investigation is associated with a considerable rate of complications and morbidity, particularly in men with infravesical obstruction. These facts must be considered and discussed with the patient before urodynamic testing.

Is obstruction predictable by clinical evaluation in patients with lower urinary tract symptoms?

OBJECTIVE: To determine whether it is possible to predict the presence of bladder outlet obstruction (BOO) by non-invasive clinical variables in patients with lower urinary tract symptoms (LUTS) suggestive of BOO. PATIENTS AND METHODS: Patients with LUTS suggestive of BOO were entered into a prospective protocol evaluating the International Prostate Symptom Score (IPSS), prostate size, non-invasive uroflow, post-void residual urine volume (PVR) and a pressure flow study. Only patients with a maximum flow rate (Qmax) of < or = 15 mL/s and an IPSS > or = 7 were included. The study comprised 253 patients; the degree of obstruction was correlated to several non-invasive clinical variables. Subsequently nomograms were developed by multiple logistic regression analysis to obtain the probability of BOO in patients with LUTS. RESULTS: Prostate volume, Qmax, PVR and voided volume correlated significantly with the degree of BOO rated according to the linear passive urethral resistance relation (linPURR). In contrast, there was no such correlation for the IPSS and the quality-of-life question of the IPSS. The percentage of patients with BOO defined by a linPURR of 3-6 decreased from 85% in those with a Qmax of 0-5 mL/s to 60% (Qmax 6-10 mL/s) and 44% (Qmax 11-15 mL/s). In parallel, the percentage of patients with BOO increased from 53% of those with a prostate volume of < or = 50 mL, to 79% of those with prostates of 51-100 mL and 75% of those > 100 mL. Based on Qmax, PVR and prostate volume, nomograms were established by multiple logistic regression analysis for the probability of BOO in patients with LUTS. CONCLUSION: The nomograms presented herein should help the clinician to identify patients with LUTS who should undergo pressure flow studies before surgical intervention to detect the presence of obstruction and in whom these studies can be safely spared.

Age related urodynamic changes in patients with benign prostatic hyperplasia.

PURPOSE: We determined age related urodynamic changes in patients with untreated symptomatic benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: A total of 222 patients (mean age 67.3 years, range 45 to 90) with the clinical diagnosis of symptomatic BPH was entered into a prospective protocol evaluating the international prostate symptom score (I-PSS), prostate volume, noninvasive uroflowmetry, residual volume and a pressure-flow study. To obtain a homogeneous study population only patients with a noninvasive maximum flow rate of 15 ml. per second or less and an I-PSS of 7 or more were eligible. RESULTS: There was no correlation between age and I-PSS (p > 0.05) but there was a statistically significant decrease in maximum flow rate (p = 0.045) and voided volume (p = 0.0013) with age. Prostate volume increased constantly from 31.3 to 64.4 ml. in patients 45 to 50 and older than 80 years, respectively (p < 0.0001). Pressure-flow studies revealed an age related decrease in cystometric bladder capacity (p = 0.0003) and invasive maximum flow rate (p = 0.0057) but no changes in detrusor pressure at maximum flow rate (p > 0.05), maximum detrusor pressure (p > 0.05) and linear passive urethral resistance relation (p > 0.05). The incidence of urodynamically proved bladder instability increased from 20 to 47% in men 45 to 50 and older than 80 years, respectively. CONCLUSIONS: The well established age related decrease in maximum flow rate and voided volume in patients with prostatism cannot be attributed to an increase in bladder outflow obstruction or impaired detrusor function. Because 60% of all men older than 80 years did not have urodynamic obstruction despite a decreased maximum flow rate of 10 to 15 ml. per second, all patients meeting these criteria and having symptoms bothersome enough to justify surgery should undergo pressure-flow studies before surgical intervention.

Impact of different sized catheters on pressure-flow studies in patients with benign prostatic hyperplasia.

The importance of pressure-flow studies for the diagnostic work-up of patients suffering from benign prostatic hyperplasia (BPH) has recently been recognized more widely. For these studies, several different types and sizes of catheters have been used. According to our experience, the degree of obstruction seems to be dependent on the catheter size applied. To evaluate the impact of catheter size on urodynamic results, 64 male patients underwent pressure-flow studies; 41 had the clinical diagnosis BPH; 23 were a nonobstructed control group. The 41 BPH-patients were randomized into two groups: group BPH 1 (n = 20) had a 5F catheter and group BPH 2 (n = 21) had a 10F filling catheter in addition to the 5F pressure transmission catheter in the urethra. All patients underwent three filling and pressure-flow studies. The filling catheter was removed for the third pressure-flow study. Peak flow rates (Qmax; ml/s), the corresponding detrusor pressure at maximum uroflow (PdetQmax; cm H2O) and the degree of obstruction, rated according to the linear passive urethral resistance relation (linear-PURR), were assessed. The removal of the 5F (group BPH 1) or 10F (group BPH 2) filling catheter resulted in a 21.1% and 55.7% increase of maximum uroflow rate respectively. In parallel, we observed a 9.9% and 18.8% decrease of detrusor pressure at maximum flow. The degree of obstruction classified according to linear-PURR decreased by 14.6% and 21.1% respectively. Furthermore, it became evident that five patients (21.7%) of the unobstructed control group could have been wrongly interpreted as being obstructed if measured with the filling (10F) and the pressure measurement (5F) catheter in situ. In conclusion, the degree of obstruction is dependent on the cross-sectional diameter of the used catheters. Consequently, standardization with regard to catheter size is mandatory if data from different institutions are to be compared.

[Current drug therapy of benign prostatic hyperplasia]. / Aktuelle medikamentöse Therapie der benignen Prostatahyperplasie.

Almost 60% of elderly men suffer from symptoms of BPH, which have significant impact on their daily lives. Transurethral resection of the prostate (TURP) is currently the most effective therapy for relieve of obstruction and obstructive symptoms. Morbidity of TURP and disappointing results in patients with mild or moderate symptoms make surgery not suitable for all patients. 2 groups of drugs were currently developed, and showed efficacy in double-blinded placebo-controlled studies: alpha-blocking agents and 5 alpha-reductase inhibitors. Inhibition of alpha-adrenoreceptors significantly increases urinary flow rates and improves symptoms of BPH. Long-acting drugs, who selectively block alpha 1-adrenoreceptors (terazosin, doxazosin, tamsulosin) have the advantage, when compared with non-selective-alpha-blockers, that they have generally less adrenergic side effects. After intake alpha-adrenorceptor antagonists develop almost immediate action. 5 alpha-reductase inhibitors (finasteride) reduce prostatic size by 27%, they increase urinary flow rates and improve prostatic symptom scores, whilst adverse effects are extremely low. Full medical action is after 4 to 6 weeks. Both, alpha-Blockers and 5 alpha-reductase inhibitors need permanent administration for maintenance of action. Yet, synergistic effects, using their different modes of action have not been demonstrated after application of both drugs. Herbal products have not proved efficacious inspite of singular surprising results in clinical trials, their efficacy to treat BPH related symptoms was classified as placebo alike. Prior to therapy urological diagnosis and exclusion of prostate cancer is mandatory. Pharmacotherapy with alpha 1-adrenoreceptor antagonists and 5 alpha-reductase inhibitors have a place in the management of BPH patients with mild to moderate disease, who are bothered by their symptoms, or for those awaiting or wishing to delay surgery.

The urodynamic impact of transrectal high-intensity focused ultrasound on bladder outflow obstruction.

OBJECTIVES: The aim of this study was to determine the urodynamic impact of transrectal high-intensity focused ultrasound (HIFU), which is presently evaluated as a minimally invasive treatment option for benign prostatic hyperplasia (BPH), on bladder outflow obstruction by means of pressure flow analyses. METHODS: A total number of 30 patients suffering from symptomatic BPH underwent pressure flow studies before and after transrectal HIFU (mean time interval: 4.5 months; range: 3-6 months). In parallel, the international prostate symptom score (IPSS), free flow and postvoid residual volume were determined at regular time intervals postoperatively. RESULTS: The IPSS decreased from preoperatively 15.8 +/- 5.9 (n = 30; mean +/- SD) to 6.9 +/- 4.4 at 3 months (n = 30) and 7.2 +/- 5 at 6 months (n = 30). Within the same time period the maximum uroflow (Qmax; ml/s) increased from 8.8 +/- 2.2 to 11.3 +/- 3.4 (3 months) and 12.1 +/- 3.6 (6 months) and the postvoid residual volume (ml) declined from 100 +/- 47 to 44 +/- 33 and 55 +/- 50, respectively. Pressure flow studies revealed a reduction of the minimal voiding pressure (cm H2O) from preoperatively 70 +/- 23 (mean +/- SD) to 51 +/- 22 (p < 0.005) postoperatively and a decline of the detrusor pressure at maximum flow (cm H2O) from 74.2 +/- 24 to 57 +/- 15 (p < 0.005). The linear passive urethral resistance relations (linear PURR) dropped from 3.7 +/- 1.1 to 2.2 +/- 1.2 (p < 0.005). According to the Abrams-Griffiths nomogram, 24 (80%) patients were classified preoperatively as obstructed, the remaining 20% as being in equivocal zone. Postoperatively, 13% were obstructed, 50% in the equivocal zone and 37% of patients were rated as obstructed. CONCLUSION: Transrectal HIFU is capable of improving objective and subjective BPH parameters as well as of decreasing the degree of bladder outflow obstruction.

[Vaginal estriol administration in treatment of postmenopausal urinary incontinence]. / Vaginale Ostriolapplikation zur Behandlung der postmenopausalen Harninkontinenz.

In an open, prospective, multicenter, controlled study, 629 female subjects suffering from stress and urgency urinary incontinence were treated with vaginally administered estriol at a dose of 0.01 g daily for 3 weeks, and 0.01 g bi-weekly for a further 3 weeks. All data of 552 patients were available at follow-up after 6 weeks of treatment. The subjective improvement in symptoms of stress urinary incontinence (SUI) was 82% for grade 1, 77% for grade 2, and 69% for grade 3. Voluntary urinary control and symptoms of urgency were improved in more than 80% of patients. Frequency was reduced in almost 50%. Compared with conditions at the outset of the study, after 6 weeks, vaginal lubrication is normal in 77%, and intercourse is no longer painful for 88%. Objective parameters were: no change in existing descent of the anterior vaginal wall, and normal cytoscopic findings in 66% of the patients in whom these were previously pathologic. Vaginal atrophy improved in approximately 40% of cases. A quality of life score revealed improvement in 72%, no change in 20% and worsening in 9% of patients compared with conditions at the start of therapy. During therapy, symptoms worsened in 1%; 2% of patients suffered from the adverse effects, with vaginal itching and burning sensations. Our results confirm the value of topical estrogen application as a cornerstone of efficient treatment of stress and/or urge incontinence in the postmenopausal patient.

[Surgical treatment possibilities of severe urinary incontinence in women]. / Chirurgische Behandlungsmöglichkeiten schwerster Harninkontinenz bei Frauen.

Severe female urinary incontinence type 3 is a most difficult challenge to a urologic surgeon. In 40 of more than 800 patients evaluated for stress incontinence, type 3 urinary incontinence was diagnosed by clinical, urodynamic, and radiographic examination. The etiology was neurogenic or non-neurogenic. The first step of treatment in all patients was a modified pubovaginal sling to increase urethral resistance; this procedure was successful in 65%. Severely damaged periurethral tissues resulting from earlier multiple pelvic surgery (111 operations in 28 patients with non-neurogenic etiology), radiation, or prior local infections were responsible for failures. Patients whose incontinence was not corrected by this initial treatment required further surgical procedures, such as suburothelial Teflon injection, urethral reconstruction, and continent urinary diversion. This additional surgery resulted in an overall 92% success rate after a minimum follow-up of 18 months. In view of the severe nature of the incontinence of these individually problematic patients, this is a satisfactory results.

The impact of detubularization on ileal reservoirs.

For many years, parts of the large or small bowel have been used for bladder augmentation and substitution. Recent controversy over the advantages and disadvantages of continent urinary diversion using detubularized ileum (the Kock pouch) and tubular ileum (the Camey procedure) focussed on how a highly compliant urinary reservoir should be formed. We compared the compliance of isolated intact ileal segments and ileal pouches constructed after transection of the antimesenteric border. Hydrodynamic data was obtained at four different points in time: acute (immediately after pouch construction), and after two, six and twelve weeks. Over the first six weeks the reservoirs were connected to the bladder for drainage. At six weeks, subtotal cystectomy and separate anastomosis of the tubular ileal loop and the detubularized ileal pouch to the trigone was performed to study the influence of cyclic reservoir distention. Statistical analysis of the pressure-volume curves revealed significantly better compliance of the detubularized ileal pouch as compared to the intact ileal segments. The area under the pressure curve values (AUC) were p less than 0.025, p less than 0.02, p less than 0.005 and p less than 0.02 for the acute experiment, after two weeks, after six weeks, and after 12 weeks respectively. Our findings suggest that transection of the circular intestinal wall is an important step in the creation of a good-compliant urinary reservoir.

[Sonography of the scrotal contents]. / Sonographie des Skrotalinhaltes.

In 394 patients with various urological symptoms, the content of the scrotum was examined sonographically. 71 testicular lesions were found, 194 extratesticular pathologies were diagnosed. In 69% the enlargement of the testicle was due to a tumor, in 4 patients due to acute orchitis and in 3 patients due to acute torsion. An unilateral smaller sized testicle was found in chronic inflammation [5], cryptorchism [9], hypoplastic testicle [2] and after corticoid medication [1] and radiation therapy [1]. In normal sized testicles 8 tumors, 19 fibromas of the tunica albuginea, 2 scars after trauma and 1 haematoma were found sonographically. In 91% of patients with epididymitis the epididymis was enlarged. The echo structure was altered in 74%, in 13% abscesses were found. Sonography was useful in evaluation of scrotal herniation, especially when combined with hydroceles. Varicoceles were better detected and graduated by sonography than by clinical examination.

[Occult and clinically suspected testicular tumor. Assessment using real-time sonography]. / Der okkulte und der klinisch verdächtige Hodentumor. Abklärung mittels Realtime-Sonographie.

The diagnostic value of real-time-sonography was evaluated in 62 patients with suspected and occult testicular tumors. In 28 patients intratesticular tumors were identified on real-time-sonograms. In addition 7 clinically occult tumors were diagnosed by real-time-sonography. It was not possible to differentiate between orchitis and tumors on sonograms (3 cases). There was correlation only between the morphologic appearance of tumors on sonograms and the corresponding histology. Using high frequency transducers sonography proved to be an useful diagnostic modality to identify or to rule out occult intratesticular tumors.

Surgical treatment for female geriatric incontinence.

Surgery may be the most effective treatment for incontinence in the elderly female patient. Today, most of these incontinent patients are cured with surgery using the transvaginal approach, an access at low risk (especially for the geriatric female population). Surgery for stress urinary incontinence of all grades is established; however, surgical treatment for urge incontinence due to bladder instability is still controversial.