[Minimally invasive treatment of benign prostatic hyperplasia : The German S2e guideline 2023-part 4]. / Minimalinvasive Therapien des benignen Prostatasyndroms : Die deutsche S2e-Leitlinie 2023 ­ Teil 4/4.

BACKGROUND: Lower urinary tract symptoms suggestive for benign prostatic obstruction (LUTS/BPO) are one of the most frequent diseases in men and can have a significant impact on quality of life. Instrumental therapies are common, and many patients seek minimally invasive treatment options. OBJECTIVE: Presentation and evidence-based evaluation of the minimally invasive therapy for benign prostatic syndrome. MATERIALS AND METHODS: Summary and overview of chapters 11-13 on minimally invasive therapies for LUTS/BPO of the current long version of the German S2e guideline. RESULTS: In case of absolute indication for surgery or after unsatisfactory or undesired medical therapy, minimally invasive treatments such as UroLift® (Neotract Inc., Pleasanton, CA, USA), Rezá¿¡m™ (Boston Scientific, Malborough, MA, USA), iTIND™ (Olympus America Inc., Westborough, MA, USA), and prostatic artery embolization (PAE) can be considered. These indirect/delayed ablative therapies offer lower morbidity and the possibility of performing them under local anesthesia, but they are inferior to direct ablative/resective techniques in terms of effectiveness and sustainability. CONCLUSIONS: The updated German S2e guideline summarizes evidence-based recommendations for new minimally invasive therapies for LUTS/BPO, which present alternative treatment options for selected patients.

Real-World Evidence of Triplet Therapy in Metastatic Hormone-Sensitive Prostate Cancer: An Austrian Multicenter Study.

INTRODUCTION: Two randomized trials demonstrated a survival benefit of triplet therapy (androgen deprivation therapy [ADT]) plus androgen receptor pathway inhibitor [ARPI] plus docetaxel) over doublet therapy (ADT plus docetaxel), thus changing treatment strategies in metastatic hormonesensitive prostate cancer (mHSPC). PATIENTS AND METHODS: We conducted the first real-world analysis comprising 97 mHSPC patients from 16 Austrian medical centers, among them 79.4% of patients received abiraterone and 17.5% darolutamide treatment. Baseline characteristics and clinical parameters during triplet therapy were documented. Mann-Whitney U test for continuous or X²-test for categorical variables was used. Variables on progression were tested using logistic regression analysis and tabulated as hazard ratios (HR), 95% confidence interval (CI). RESULTS: Of 83.5% patients with synchronous and 16.5% with metachronous disease were included. 83.5% had high-volume disease diagnosed by conventional imaging (48.9%) or PSMA PET-CT (51.1%). While docetaxel and ARPI were administered consistent with pivotal trials, prednisolone, prophylactic gCSF and osteoprotective agents were not applied guideline conform in 32.5%, 37%, and 24.3% of patients, respectively. Importantly, a nonsimultaneous onset of chemotherapy and ARPI, performed in 44.3% of patients, was associated with significantly worse treatment response (P = .015, HR 0.245). Starting ARPI before chemotherapy was associated with significantly higher probability for progression (P = .023, HR 15.781) than vice versa. Strikingly, 15.6% (abiraterone) and 25.5% (darolutamide) low-volume patients as well as 14.4% (abiraterone) and 17.6% (darolutamide) metachronous patients received triplet therapy. Adverse events (AE) occurred in 61.9% with grade 3 to 5 in 15% of patient without age-related differences. All patients achieved a PSA decline of 99% and imaging response was confirmed in 88% of abiraterone and 75% of darolutamide patients. CONCLUSIONS: Triplet therapy arrived in clinical practice primarily for synchronous high-volume mHSPC. Regardless of selected therapy regimen, treatment is highly effective and tolerable. Preferably therapy should be administered simultaneously, however if not possible, chemotherapy should be started first.

Knowledge on the male reproductive tract and testicular cancer among adolescents in Austria.

PURPOSE: Testicular cancer is the most frequent malignant tumour among young adults. Therefore, regular self-examination for early detection is recommended by all guidelines. The fact that the knowledge of young adults living in Austria on this important topic is unknown, prompted the current investigation. MATERIALS AND METHODS: To evaluate the knowledge on anatomy and function of the male reproductive tract and of testicular cancer in particular a German questionnaire recently developed by Anheuser et al. (Urologe 2019;58:1331-1337) was applied. This 4-page questionnaire contains mainly multiple-choice questions. This questionnaire was distributed in three different schools to male and female students in the 11th and 12th school level. RESULTS: A total of 337 students (mean age: 17.3 years; male: n = 183; female: n = 154) completed the questionnaire. In a simple pictogramm, 63% were able to correctly identify the prostate, 87% the testis and 64% the epididymis. Half of the students (49.3%) could describe the function of the testis. The question regarding the age peak of testicular cancer was correctly answered by 81%, yet 18% believed that testicular cancer is caused by the sexual contact. The purpose of the testicular self-examination was correctly answered by only 54.9% with a higher rate for women (67.5% vs. 44.3%, p = 0.001). With a theoretical maximal score of 15, the students reached a mean overall of 10.4 with no sex difference (p > 0.05). Differences were noted for the school type: the highest score was present in the Gymnasium (11.2), followed by the Realgymnasium (10.8) and the HTL (9.8; p = 0.001). CONCLUSIONS: This survey demonstrates relevant knowledge deficits of young adults regarding the male reproductive tract, testicular cancer and self-examination.

[Surgical treatment options of lower urinary tract symptoms due to benign prostatic obstruction : The German S2e guideline 2023-part 3]. / Operative Therapie des benignen Prostatasyndroms ­ klassische Desobstruktion : Die deutsche S2e-Leitlinie 2023 ­ Teil 3.

BACKGROUND: Lower urinary tract symptoms (LUTS) due to benign prostatic obstruction (BPO) are one of the most common diagnoses in clinical practice. Bothersome LUTS impact considerably quality of life of men and may cause severe complications without treatment. According to the diagnostic assessment every patient should be treated with an adequate therapy. Management comprises a conservative approach, medication, novel minimally invasive options, and surgical procedures with the aim to remove the obstructing adenoma. The German guideline panel has updated the German guidelines on diagnostic evaluation and management of LUTS due to BPO. OBJECTIVES: Evidence-based recommendations of surgical treatment options of LUTS due to BPO are evaluated. MATERIALS AND METHODS: Chapters 11.1.1 and 11.2 of the updated German S2e guideline on the management of LUTS due to BPO are summarized as a review article. RESULTS: A treatment algorithm based on current evidence has been proposed. It is considered to provide guidance for the selection of the best procedure according to the needs of the patient. Anatomic features of the prostate, the patients' morbidity, and the preservation of ejaculatory function are taken into account for the choice of the best procedures. These surgical options can be divided into techniques with direct, delayed or no removal of the adenoma, procedures with suprapubic access, and embolizing approaches. CONCLUSIONS: The updated German S2e guideline on the management of LUTS due to BPO provides evidence-based recommendations for the selection of the best procedure according to the needs of the individual patient.

[Conservative and pharmacological treatment of benign prostatic hyperplasia : The German S2e-guideline 2023-part2]. / Konservative und medikamentöse Therapie des benignen Prostatasyndroms : Die deutsche S2e-Leitlinie 2023 ­ Teil 2.

BACKGROUND: Lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH, in German guidelines: benign prostatic syndrome [BPS]) is considered the most common disease of the lower urinary tract in men and can have a tremendous impact on the quality-of-life of affected patients. Conservative and pharmacological therapy of this disease are of great importance, both in improving LUTS and reducing progression-related complications. OBJECTIVES: Presentation of the conservative and pharmacological treatment options according to the current German S2e guideline on BPS. MATERIALS AND METHODS: Summary and overview of chapters 9 and 10 of the current German S2e guideline on BPS. RESULTS: In addition to a controlled watchful waiting for BPS patients without an absolute indication for prostate surgery, a variety of phytopharmacological formulations and synthetic drugs according to the symptomatology and clinical progress are available. Phytotherapy should, due to inconsistent study data, only be considered for mild to moderate symptoms. Synthetic drugs include alpha-blockers, 5α-reductase inhibitors, phosphodiesterase inhibitors, antimuscarinics and, more recently, the ß3-agonist mirabegron in the current guideline. In addition, various combination therapies are listed and evaluated according to their indications, effects and side effects. CONCLUSIONS: The current German S2e guideline on the diagnosis and treatment of BPS provides an evidence-based foundation for finding the best possible and most effective medication.

Medical Treatment Incidence and Persistence After Surgical Relief of Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Obstruction: A Critical Analysis of the Literature.

CONTEXT: The incidence and risk factors for persisting pharmacotherapy following surgical treatment of benign prostatic obstruction (BPO) remain unclear. OBJECTIVE: To evaluate the evidence on persisting pharmacotherapy of lower urinary tract symptoms (LUTS) following surgical treatment of BPO. EVIDENCE ACQUISITION: A systematic review of the literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses checklist (PROSPERO ID CRD42022310598). PubMed and EMBASE databases were searched in February 2022, with an updated search in October 2022. Studies evaluating pharmacotherapy in men aged >18 yr following surgical treatment of BPO were included. EVIDENCE SYNTHESIS: Overall, ten nonrandomized studies and one post hoc analysis of two randomized controlled trials were included. The incidence of persisting medical treatment or medical retreatment varied strongly between time points and investigated surgical techniques. Among the investigated techniques, most data were available for transurethral resection of the prostate (TURP). Persistence of pharmacotherapy after TURP at 6 mo ranged from 8.7% to 57% for the use of alpha-blockers. The use of 5-alpha reductase inhibitors after TURP ranged from 5.5% at 6 mo to 19% at 6-24 mo, whereas the use of antimuscarinics ranged from 3.4% to 28.1% at 6 mo. Data on initiation of pharmacotherapy after TURP also differed between study and type of medication. At 12 yr, the use of alpha-blockers after TURP ranged from 12% to 38%. The risk factors associated with medication after BPO surgery were age, history of diabetes mellitus, history of cerebrovascular accident, preoperative medication use, as well as surgical techniques other than laser enucleation of the prostate. CONCLUSIONS: Pharmacotherapy for LUTS is common after BPO surgery. The outcomes following different surgical techniques are heterogeneous, with limited data from randomized controlled trials. Future studies on surgical treatment of BPO should include the use of LUTS-related pharmacotherapy after BPO surgery as a secondary endpoint. PATIENT SUMMARY: In the present systematic review, we investigated the risk of ongoing or novel therapy with drugs following surgery for benign prostate enlargement. We found that a non-negligible proportion of men will need to take drug therapy after surgery. Certain risk factors can be identified, which are associated with a higher risk of drug therapy after surgery.

Urinary Incontinence, Quality of Life, and Risk Factors in a Geriatric Cohort.

INTRODUCTION: The aim of the study was to evaluate the prevalence of urinary incontinence (UI) and its subtypes, associated clinical factors, and impact on quality of life (QoL) in a geriatric population aged 80 years or older. METHODS: Male and female residents (inclusion criterion: 80 years or older) of three Viennese senior citizen homes were personally interviewed with the aid of a structured questionnaire based on the Bristol Female Lower Urinary Tract Symptom Questionnaire within a 12-month period. UI was defined as any involuntary loss of urine during the past 4 weeks. Several demographic parameters were obtained additionally. RESULTS: 434 participants with a mean age of 86.8 years (women: 87.6 years; men: 86.1 years) were included. UI was present in 52.5% (57% female vs. 23% male, p < 0.001), stress UI affected 36% (41% female vs. 5% male, p < 0.001), urge UI 38% (40.5% female vs. 23% male, p < 0.01), and mixed UI 28% (24% female vs. 5.0% male, p < 0.01). While the overall prevalence of UI remained rather stable in the four age cohorts (80-84 years, 85-89 years, 90-94 years, >94 years), there was a constant decline of SUI paralleled by an increase of UI and - to a lesser extent - of MUI with age. 36.5% (33% female vs. 57% male) participants did not report any negative impact on QoL, while a severe reduction of QoL was present in 31% of cases (35% female vs. 10.0% male). Risk factors for UI and its subtypes included female sex, reduced/no mobility, hysterectomy, and number of births. CONCLUSION: This study provides data on the high prevalence of UI in a low-morbid geriatric cohort and evaluates gender-specific differences in UI prevalence, associated risk factors, and QoL.

[Diagnostic work-up of benign prostatic hyperplasia : The German S2e-guideline 2023 part 1]. / Diagnostik des benignen Prostatasyndroms : Die deutsche S2e-Leitlinie 2023 Teil 1.

BACKGROUND: Lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH; in German guidelines: benign prostatic syndrome [BPS]) is the most frequent urological disease in men and can result in a considerable deterioration of quality-of-life. BPS can be associated with LUTS, benign prostatic enlargement (BPE), and bladder outlet obstruction (BOO) or benign prostatic obstruction (BPO), respectively. The expert group on BPS of the German Society of Urology has re-evaluated the tests for the assessment of BPH and provides evidence-based recommendations. OBJECTIVES: Presentation and evidence-based rating of tests for the assessment of patients with BPS. MATERIALS AND METHODS: Summary and overview of chapters 5, 6, and 8 of the latest long version of the German S2e guideline on BPS. RESULTS: The diagnostic work-up should clarify (1) whether the complaints of the patient are caused by BPS, (2) how relevant the complaints are and whether treatment is necessary, (3) whether complications of the lower or upper urinary tract already exist, and (4) which treatment will be most suitable. Baseline assessment should be done in all BPS patients and include history, measurement of LUTS and quality-of-life, urinalysis, serum prostate-specific antigen, post-void residual, ultrasound of the lower urinary tract, including measurements of prostate volume, intravesical prostatic protrusion and detrusor wall thickness, and ultrasound of the upper urinary tract. Additional tests can follow when questions remain unanswered after baseline assessment. These optional tests include bladder diaries, uroflowmetry, serum creatinine, urethrocystoscopy, other noninvasive tests for the determination of BOO/BPO such as penile cuff test, condom catheter method and near-infrared spectroscopy, and other imagining tests such as X­ray and MRI investigations. CONCLUSIONS: The updated German S2e guideline summarizes evidence-based recommendations on the diagnostic work-up, including the assessment of the BPS components BPE, LUTS, and BOO/BPO.

Resource use in the last year of life of prostate cancer patients-A register-based analysis.

BACKGROUND: Given the paucity of data on the end of life (EOL) of prostate-cancer (PC) patients, we investigated medication prescription patterns and hospitalizations during their final year of life. METHODS: The data base of the Österreichische Gesundheitskasse Vienna (ÖGK-W) was used to identify all men who died with the diagnosis PC between 1.1.2015 and 31.12.2021 and who were under androgen deprivation and/or new hormonal therapies. Patient age, prescription patterns and hospitalizations during the last year of life were recorded, odds ratios for age groups were analyzed. RESULTS: A total of 1.109 patients were included. ADT was given in 86.7% (n = 962) and NHT in 62.8% (n = 696). Overall, prescription of analgesics increased from 41% (n = 455) during the first to 65.1% (n = 722) in the last quarter of the final year of life. Prescription of NSAIDs was almost consistent (18-20%) whereas the number of patients receiving other non-opioids (paracetamol, metamizole) more than doubled (18 to 39%). Older men had lower prescription rates for NSAID (OR: 0.47, 95% CI: 0.35-0.64), non-opioids (OR: 0.43, 95% CI: 0.32-0.57), opioids (OR: 0.45, 95% CI: 0.34-0.6) and adjuvant analgesics (OR: 0.42, 95% CI: 0.28-0.65). Approximately 2/3 of patients (n = 733) died in the hospital with a median of four hospitalizations in the final year of life. The overall cumulative length of admission was less than 50d in 61.9%, 51-100d in 30.6% and >100d in 7.6%. Younger patients (<70 yrs) were more likely to die in the hospital (OR: 1.66, 95% CI: 1.15-2.39), had a higher median rate of hospitalizations (n = 6) and longer cumulative duration of admissions. CONCLUSIONS: Resource use increased during the last year life of PC patients with highest rates in younger men. Hospitalization rates were high and 2/3 died in the hospital, both showed clear age dependency with higher rates, duration and death in the hospital for younger men.

Rezum water vapor thermal therapy for treatment of lower urinary tract symptoms: A retrospective single-centre analysis from a German high-volume centre.

OBJECTIVE: Rezum is a minimal invasive surgical treatment for patients with lower urinary tract symptoms (LUTS) related to benign prostatic enlargement (BPE). The aim of our study was to assess safety and efficacy of the Rezum procedure in a consecutive series of patients. MATERIAL AND METHODS: A retrospective study was performed in a single tertiary care hospital in patients undergoing Rezum procedure between 2018 and 2020. All patients that underwent intervention because of drug-refractory moderate to severe LUTS were assessed. Descriptive outcomes such as symptoms scores (IPSS, IPSS-QoL), peak flow in uroflowmetry (Qmax), post-micturition residual urine volume (PVR) and prostate volume (PVol) were analysed. RESULTS: In total, 92 Rezum procedures were performed in the observational period. All interventions were competed without device- or procedure relates adverse events. Patients achieved a significant symptom relief as measured in IPSS (50% reduction, p<0.001, n = 35) and IPSS-QoL score (53% reduction, p<0.001, n = 35). Qmax improved by 7.3 ml/s from 10.6 ± 4.2 ml/s to 17.9 ± 9.3 ml/s (p = 0.003, n = 20) were as mean PVR significantly decreased by 136 ml from 175 ± 194.1 to 39 ± 62 ml (p = 0.007, n = 20). PVol significantly decreased by 40.3% from 73.9 ± 41.2 to 44.9 ± 29 ccm (p = 0.024, n = 17). All pre-interventional catheter-depending patients (28.3% of all patient) were catheter independent after six weeks. CONCLUSION: Rezum therapy is safe and effective and can be considered a viable treatment option for BPH related LUTS.

Transurethral resection of the prostate in 85+ patients: a retrospective, multicentre study.

PURPOSE: To determine the safety and efficacy of transurethral resection of the prostate (TUR-P) in patients 85 years or older. METHODS: In this retrospective, multicentre study, patients equal or older than 85 years at the time of surgery (2015-2020) were included. Several pre-, peri- and postoperative parameters were collected. The main outcome criterion was spontaneous voiding with a post-void residual (PVR) volume < 100 ml at dismission and at 12 months after surgery. RESULTS: One hundred sixty-eight patients (median age: 87 years, interquartile range [IQR]: 86-89) were recruited. The patients took on average 5.2 permanent medications (3-8), 107 (64%) were anticoagulated preoperatively and neurological co-morbidities were present in 29 (17%). The indication for surgery was recurrent urinary retention in 66.3% (n = 110) with a mean retention volume of 849 ml. The mean PVR volume of the remaining 35% was 146 ml. Surgery was successfully completed in all patients. A perioperative surgical revision had to be performed in 3% and 13 patients (7.7%) required blood transfusion. After catheter removal, 85% of patients were able to void spontaneously with a PVR < 100 ml, and 14.3% were dismissed with a catheter. Twelve months data were available for 93 patients (55%). Of this cohort, 78 (83.9%) were able to void spontaneously with a PVR < 100 ml, 12 (12.9%) were on permanent catheterization. One patient (0.6%) died perioperatively. The only significant factor associated with an unsuccessful outcome was the number of permanent medications (6.8 vs. 5.0, p = 0.005). CONCLUSION: This retrospective multicentre study documents the safety and efficacy of TURP (monopolar and bipolar) in the old-old cohort.

[Medical treatment of male lower urinary tract symptoms: what's new?] / Medikamentöse Behandlung des benignen Prostatasyndroms: Was gibt's Neues?

Decades after the introduction of 5α-reductase inhibitors and α1-adrenoceptor antagonists, new data of practical relevance related to their desired and adverse effects continues to emerge. Some of these novel findings are to be taken seriously but are insufficiently established, for instance associations between drug use and depression or dementia. Multiple combination treatments have been tested. While combination treatment was often statistically superior to monotherapy, the difference was mostly in the range of 1 IPSS point, which raises doubts on the clinical relevance of the findings at the group level. The new evidence enables further personalisation of the treatment of male lower urinary tract dysfunction, but also makes individual risk-benefit considerations more complex.

Seasonal Variations in the Diagnosis of Testicular Germ Cell Tumors: A National Cancer Registry Study in Austria.

We conducted a retrospective National Cancer Registry study in Austria to assess a possible seasonal variation in the clinical diagnosis of testicular germ cell tumors (TGCT). In total, 3615 testicular cancer diagnoses were identified during an 11-year period from 2008 to 2018. Rate ratios for the monthly number of TGCT diagnoses, as well as of seasons and half-years, were assessed using a quasi-Poisson model. We identified, for the first time, a statistically significant seasonal trend (p < 0.001) in the frequency of monthly newly diagnosed cases of TGCT. In detail, clear seasonal variations with a reduction in the tumor incidence during the summer months (Apr-Sep) and an increase during the winter months (Oct-Mar) were observed (p < 0.001). Focusing on seasonality, the incidence during the months of Oct-Dec (p = 0.008) and Jan-Mar (p < 0.001) was significantly higher compared to the months of Jul-Sep, respectively. Regarding histopathological features, there is a predominating incidence in the winter months compared to summer months, mainly concerning pure seminomas (p < 0.001), but not the non-seminoma or mixed TGCT groups. In conclusion, the incidence of TGCT diagnoses in Austria has a strong seasonal pattern, with the highest rate during the winter months. These findings may be explained by a delay of self-referral during the summer months. However, the hypothetical influence of vitamin D3 in testicular carcinogenesis underlying seasonal changes in TGCT diagnosis should be the focus of further research.

Testicular Tumor Markers in the Spermatic Vein - Correlation to Pathology, Stage and Outcome.

OBJECTIVE: To report our findings in patients with determination of testicular tumor markers from the vena spermatica during inguinal orchiectomy. METHODS: In a retrospective setting, data of patients who underwent inguinal orchiectomy between January 2004 and December 2014 were analyzed. Cubital and testicular vein tumor markers were assessed and correlated to histology, clinical stage and outcome. RESULTS: A total of 90 patients (seminomatous: n = 53, non-seminomatous: n = 37) with a median age of 37 years were included. The mean follow-up was 109 months. Overall, 60% (n = 54) of patients had one or more positive tumor marker level in the cubital vein vs 88.9% (n = 80) in the testicular vein. Median tumor marker levels of hCGß in cubital and testicular vein were 1.9 U/l and 30.8U/l; the respective values for AFP were 2.9ng/ml and 2.4ng/ml and for hPLAP 49.9 mU/l and 418.9 mU/l. Differences in cubital vs testicular vein positivity were stage dependant and highest for pT1. Patients with seminomatous tumors had peripheral positivity of 59.3% vs 88.9% in the testicular vein (P = 0.003); in non-seminomatous patients the respective values were 61.1% and 88.9% (P = 0.02). All recurrent cancer patients under active surveillance (n = 5) were positive in the testicular vein. CONCLUSION: Virtually all testicular cancers shed tumor markers in the circulation. Differences in marker positivity (testicular vs testicular vein) were stage dependent (greatest in pT1), largely independent of histology and highest for hCGß. The prognostic value of testicular vein sampling remains speculative.

The future of urology: nonagenarians admitted to a urological ward.

PURPOSE: To analyze the outcome of nonagenarians with urological conditions. As demographic changes will lead to a substantial rise of geriatric patients in need of health care services and as little is known on the outcome of these patients, we retrospectively analyzed a consecutive series of nonagenarians admitted to our urological ward. MATERIALS AND METHODS: In a retrospective study we analyzed all nonagenarians admitted to our urological ward between 2014 and 2018. Patients were followed for 12 months and predictors for mortality were calculated. RESULTS: A total of 152 patients with a mean age of 92 years entered this study. The most frequent indications for admission were macrohematuria, bladder dysfunction, urinary tract infection, hydronephrosis and urinary retention. A history of bladder cancer was present in 18% and of renal cell cancer in 5% of patients. Prostate cancer was present in 21%. The most frequent invasive interventions were the insertion of an irrigation catheter, cystoscopy, bladder tumor resection and insertion of a DJ-catheter. The mean length of hospitalization was 6.5 days. In-house mortality was 9% and the 12 months mortality rate 45%. The strongest predictor for a 12 months mortality was the CSHA-Frailty Scale. CONCLUSION: Urogerontology is one of the biggest challenges in our field. The cohort of nonagenarians studied herein demonstrates a high rate of invasive interventions, an acceptable length of hospitalization and an in-house mortality in the range of 9%. The 12 months mortality rate is almost 50% and predictors thereof, as elaborated, might aid in the disease management of this ever-increasing cohort.