Safety and efficacy of beta-3 adrenergic agonists in treating neurogenic lower urinary tract dysfunction: A systematic review and meta-analysis.

PURPOSE: To evaluate efficacy and safety of beta-3 adrenergic agonists in adults with neurogenic lower urinary tract dysfunction. MATERIALS AND METHODS: According to a protocol (CRD42022350079), we searched multiple data sources for published and unpublished randomized controlled trials (RCTs) up to 2nd August 2022. Two review authors independently screened studies and abstracted data from the included studies. We performed statistical analyses by using a random-effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. We used GRADE guidance to rate the certainty of evidence (CoE). RESULTS: We found data to inform two comparisons: beta-3 adrenergic agonists versus placebo (4 RCTs) and anticholinergics (2 RCTs). Only mirabegron was used for intervention in all included studies. Compared to placebo, beta-3 adrenergic agonists may have a clinically unimportant effect on urinary symptoms score (mean difference [MD] -2.50, 95% confidence interval [CI] -4.78 to -0.22; I²=92%; 2 RCTs; 192 participants; low CoE) based on minimal clinically important difference of 3. We are very uncertain of the effects of beta-3 adrenergic agonists on quality of life (MD 10.86, 95% CI 1.21 to 20.50; I²=41%; 2 RCTs; 98 participants; very low CoE). Beta-3 adrenergic agonists may result in little to no difference in major adverse events (cardiovascular adverse events) (risk ratio 0.57, 95% CI 0.14 to 2.37; I²=0%; 4 RCTs; 310 participants; low CoE). Compared to anticholinergics, no study reported urinary symptom scores and quality of life. There were no major adverse events (cardiovascular adverse events) in either study group (1 study; 60 participants; very low CoE). CONCLUSIONS: Compared to placebo, beta-3 adrenergic agonists may have similar effects on urinary symptom scores and major adverse events. There were uncertainties about their effects on quality of life. Compared to anticholinergics, we are either very uncertain or have no evidence about urinary symptom scores, quality of life, and major adverse events.

Testosterone replacement in men with sexual dysfunction.

BACKGROUND: Clinical practice guidelines recommend testosterone replacement therapy (TRT) for men with sexual dysfunction and testosterone deficiency. However, TRT is commonly promoted in men without testosterone deficiency and existing trials often do not clearly report participants' testosterone levels or testosterone-related symptoms. This review assesses the potential benefits and harms of TRT in men presenting with complaints of sexual dysfunction. OBJECTIVES: To assess the effects of testosterone replacement therapy compared to placebo or other medical treatments in men with sexual dysfunction. SEARCH METHODS: We performed a comprehensive search of CENTRAL (the Cochrane Library), MEDLINE, EMBASE, and the trials registries ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform, with no restrictions on language of publication or publication status, up to 29 August 2023. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in men (40 years or over) with sexual dysfunction. We excluded men with primary or secondary hypogonadism. We compared testosterone or testosterone with phosphodiesterase-5 inhibitors (PDEI5I) to placebo or PDE5I alone. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the literature, assessed the risk of bias, extracted data, and rated the certainty of evidence (CoE) according to GRADE using a minimally contextualized approach. We performed statistical analyses using a random-effects model and interpreted them according to standard Cochrane methodology. Predefined primary outcomes were self-reported erectile dysfunction assessed by a validated instrument, sexual quality of life assessed by a validated instrument, and cardiovascular mortality. Secondary outcomes were treatment withdrawal due to adverse events, prostate-related events, and lower urinary tract symptoms (LUTS). We distinguished between short-term (up to 12 months) and long-term (> 12 months) outcomes. MAIN RESULTS: We identified 43 studies with 11,419 randomized participants across three comparisons: testosterone versus placebo, testosterone versus PDE5I, and testosterone with PDE5I versus PDE5I alone. This abstract focuses on the most relevant comparison of testosterone versus placebo. Testosterone versus placebo (up to 12 months) Based on a predefined sensitivity analysis of studies at low risk of bias, and an analysis combing data from the similar International Index of Erectile Function (IIEF-EF) and IIEF-5 instruments, TRT likely results in little to no difference in erectile function assessed with the IIEF-EF (mean difference (MD) 2.37, 95% confidence interval (CI) 1.67 to 3.08; I² = 0%; 6 RCTs, 2016 participants; moderate CoE) on a scale from 6 to 30 with larger values reflecting better erectile function. We assumed a minimal clinically important difference (MCID) of greater than or equal to 4. TRT likely results in little to no change in sexual quality of life assessed with the Aging Males' Symptoms scale (MD -2.31, 95% CI -3.63 to -1.00; I² = 0%; 5 RCTs, 1030 participants; moderate CoE) on a scale from 17 to 85 with larger values reflecting worse sexual quality of life. We assumed a MCID of greater than or equal to 10. TRT also likely results in little to no difference in cardiovascular mortality (risk ratio (RR) 0.83, 95% CI 0.21 to 3.26; I² = 0%; 10 RCTs, 3525 participants; moderate CoE). Based on two cardiovascular deaths in the placebo group and an assumed MCID of 3%, this would correspond to no additional deaths per 1000 men (95% CI 1 fewer to 4 more). TRT also likely results in little to no difference in treatment withdrawal due to adverse events, prostate-related events, or LUTS. Testosterone versus placebo (later than 12 months) We are very uncertain about the longer-term effects of TRT on erectile dysfunction assessed with the IIEF-EF (MD 4.20, 95% CI -2.03 to 10.43; 1 study, 42 participants; very low CoE). We did not find studies reporting on sexual quality of life or cardiovascular mortality. We are very uncertain about the effect of testosterone on treatment withdrawal due to adverse events. We found no studies reporting on prostate-related events or LUTS. AUTHORS' CONCLUSIONS: In the short term, TRT probably has little to no effect on erectile function, sexual quality of life, or cardiovascular mortality compared to a placebo. It likely results in little to no difference in treatment withdrawals due to adverse events, prostate-related events, or LUTS. In the long term, we are very uncertain about the effects of TRT on erectile function when compared to placebo; we did not find data on its effects on sexual quality of life or cardiovascular mortality. The certainty of evidence ranged from moderate (signaling that we are confident that the reported effect size is likely to be close to the true effect) to very low (indicating that the true effect is likely to be substantially different). The findings of this review should help to inform future guidelines and clinical decision-making at the point of care.

Serenoa repens for the Treatment of Lower Urinary Tract Symptoms Due to Benign Prostatic Enlargement: An Updated Cochrane Review.

PURPOSE: To assess the effects of Serenoa repens in the treatment of men with lower urinary tract symptoms (LUTS) consistent with benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: We performed a comprehensive search using multiple databases up to September 2022 with no language or publication status restrictions. We included parallel-group randomized controlled trials of participants with BPH who were treated with Serenoa repens or placebo/no treatment. We used standard Cochrane methods, including a GRADE assessment of the certainty of the evidence (CoE). RESULTS: We included 27 studies involving a total of 4,656 participants. Serenoa repens results in little to no difference in urologic symptoms at short-term follow-up (International Prostate Symptom Score [IPSS]: mean difference [MD] -0.90, 95% confidence interval [CI] -1.74 to -0.07; I²=68%; 9 studies, 1,681 participants; high CoE). Serenoa repens results in little to no difference in the quality of life at short-term follow-up (high CoE). Serenoa repens probably results in little to no difference in adverse events (moderate CoE). Different phytotherapeutic agents that include Serenoa repens may result in little to no difference in urologic symptoms compared to placebo at short-term follow-up (IPSS: MD -2.41, 95% CI -4.54 to -0.29; I²=67%; 4 studies, 460 participants; low CoE). We are very uncertain about the effects of these agents on quality of life (very low CoE). These agents may result in little to no difference in the occurrence of adverse events (low CoE). CONCLUSIONS: Serenoa repens alone provides little to no benefits for men with LUTS due to benign prostatic enlargement. There is more uncertainty about the role of Serenoa repens in combination with other phytotherapeutic agents.

2023 Korean Association of Urogenital Tract Infection and Inflammation guidelines for gonococcal infection.

The incidence of gonorrhea has increased significantly in recent years in the United States, especially among sexually active twenty-year-olds. Although the incidence of gonorrhea has decreased in Korea since the early 2000s, it is still common among people in their twenties. Nucleic acid amplification test (NAAT) is the most sensitive diagnostic test for detecting gonococcal infection. Gram-staining is a simple and useful laboratory test for diagnosing symptomatic male gonococcal urethritis. Although bacterial culture can be used to detect antimicrobial susceptibility, its sensitivity is lower than that of NAAT. Treatment for uncomplicated gonorrhea infection is a single intramuscular injection of ceftriaxone 500 mg. Doxycycline (100 mg twice daily for 7 days) is added if there is a possibility of co-infection with chlamydia. If ceftriaxone is difficult to use, spectinomycin 2 g can be injected intramuscularly in Korea. Patients with gonorrhea should have repeated examinations within three months at the exposure site because of a high risk of re-infection. A person diagnosed with gonorrhea should discuss the nature of the infection, the importance of informing partners, when sexual activity can resume, and how to reduce the risk of sexually transmitted infections.

Population attributable fractions of modifiable cancer risk factors in Korea: A systematic review.

OBJECTIVES: The population attributable fraction (PAF), an epidemiologic measure of exposures and health outcomes, can provide information on the public health impacts of exposures in populations. This study aimed to systematically summarize the PAF estimates of modifiable cancer risk factors in Korea. METHODS: This review included studies that determined PAFs of modifiable risk factors for cancer in Korea. We performed systematic searches in EMBASE, MEDLINE, Cochrane library, and Korean databases for studies published up to July 2021. Two reviewers independently screened studies for eligibility, extracted data, and performed quality assessments of the included studies. Due to high variability among the data acquisition methods and PAF estimates, we presented the results qualitatively and did not perform quantitative data synthesis. RESULTS: We reviewed 16 studies that reported the PAFs of risk factors for cancer, including smoking, alcohol consumption, obesity, and various cancer sites. We found considerable variability in the PAF estimates across exposure and cancer pairs. However, PAF estimates for smoking and respiratory cancer were consistently high in men. PAF estimates were higher in men than in women for smoking and alcohol consumption but higher in women for obesity. We found limited evidence for other exposures and cancers. CONCLUSION: Our findings may be used to prioritize and plan strategies to reduce cancer burden. We encourage further and updated assessments of cancer risk factors, including those not addressed in the studies included in this review, and their potential contributions to cancer burden to better inform strategies for cancer control.

Forsythia velutina Nakai extract: A promising therapeutic option for atopic dermatitis through multiple cell type modulation.

BACKGROUND: Atopic dermatitis (AD) is a complex condition characterized by impaired epithelial barriers and dysregulated immune cells. In this study, we demonstrated Forsythia velutina Nakai extract (FVE) simultaneously inhibits basophils, macrophages, keratinocytes, and T cells that are closely interrelated in AD development. METHODS: We analyzed the effect of FVE on nitric oxide and reactive oxygen species (ROS) production in macrophages, basophil degranulation, T cell activation, and tight junctions in damaged keratinocytes. Expression of cell-type-specific inflammatory mediators was analyzed, and the underlying signaling pathways for anti-inflammatory effects of FVE were investigated. The anti-inflammatory effects of FVE were validated using a DNCB-induced mouse model of AD. Anti-inflammatory activity of compounds isolated from FVE was validated in each immune cell type. RESULTS: FVE downregulated the expression of inflammatory mediators and ROS production in macrophages through TLR4 and NRF2 pathways modulation. It significantly reduced basophil degranulation and expression of type 2 (T2) and pro-inflammatory cytokines by perturbing FcεRI signaling. Forsythia velutina Nakai extract also robustly inhibited the expression of T2 cytokines in activated T cells. Furthermore, FVE upregulated the expression of tight junction molecules in damaged keratinocytes and downregulated leukocyte attractants, as well as IL-33, an inducer of T2 inflammation. In the AD mouse model, FVE showed superior improvement in inflammatory cell infiltration and skin structure integrity compared to dexamethasone. Dimatairesinol, a lignan dimer, was identified as the most potent anti-inflammatory FVE compound. CONCLUSION: Forsythia velutina Nakai extract and its constituent compounds demonstrate promising efficacy as a therapeutic option for prolonged AD treatment by independently inhibiting various cell types associated with AD and disrupting the deleterious link between them.

Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT.

Gastrointestinal stromal tumors (GISTs) frequently show KIT mutations, accompanied by overexpression and aberrant localization of mutant KIT (MT-KIT). As previously established by multiple studies, including ours, we confirmed that MT-KIT initiates downstream signaling in the Golgi complex. Basic leucine zipper nuclear factor 1 (BLZF1) was identified as a novel MT-KIT-binding partner that tethers MT-KIT to the Golgi complex. Sustained activation of activated transcription factor 6 (ATF6), which belongs to the unfolded protein response (UPR) family, alleviates endoplasmic reticulum (ER) stress by upregulating chaperone expression, including heat shock protein 90 (HSP90), which assists in MT-KIT folding. BLZF1 knockdown and ATF6 inhibition suppressed both imatinib-sensitive and -resistant GIST in vitro. ATF6 inhibitors further showed potent antitumor effects in GIST xenografts, and the effect was enhanced with ER stress-inducing drugs. ATF6 activation was frequently observed in 67% of patients with GIST (n = 42), and was significantly associated with poorer relapse-free survival (P = 0.033). Overall, GIST bypasses ER quality control (QC) and ER stress-mediated cell death via UPR activation and uses the QC-free Golgi to initiate signaling.

Prognostic factors of mortality in patients with cancer infected with COVID-19: a systematic review protocol.

INTRODUCTION: The COVID-19 pandemic has resulted in many cases of infection and deaths worldwide. Patients with cancer are a high-risk group for COVID-19-related death. However, a systematic summary of the prognostic factors related to mortality in these patients is limited. We systematically summarise the evidence on the prognostic factors of mortality in patients with pre-existing cancer, infected with COVID-19. METHODS AND ANALYSIS: We will address the prognostic factors for mortality, including cohort studies of adult patients with cancer infected with COVID-19. We will search MEDLINE, Embase and Cochrane Central Libraries for data from December 2019 to the present day. The prognostic factors for mortality include general, cancer-related and clinical characteristics. We will not limit the COVID-19 severity, cancer type and follow-up period of the included studies. Two reviewers will independently and in duplicate conduct reference screening, data abstraction and risk of bias assessment. We will perform a random-effect meta-analysis to calculate the pooled relative effect estimates for each prognostic factor of mortality. We will assess the risk of bias for each included study and rate the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. This study will provide information about high-risk groups for mortality in patients with cancer infected with COVID-19. ETHICS AND DISSEMINATION: This study will use only the published references and would not need to obtain ethical approval. We will disseminate our study findings through a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42023390905.

Non-surgical therapies for Peyronie's disease.

BACKGROUND: Peyronie's disease is a condition that results in the development of penile plaques that can lead to penile curvature, pain, and erectile dysfunction, making sexual activity difficult. A number of non-surgical interventions exist to improve this condition, which include topical and injection agents as well as mechanical methods; however, their effectiveness remains uncertain. We performed this review to determine the effects of these non-surgical treatments. OBJECTIVES: To assess the effects of non-surgical therapies compared to placebo or no treatment in individuals with Peyronie's disease. SEARCH METHODS: We performed a comprehensive search using multiple databases (the Cochrane Library, MEDLINE, Embase, Scopus, Google Scholar, and Web of Science), trials registries, other sources of grey literature, and conference proceedings, up to 23 September 2022. We applied no restrictions on publication language or status. SELECTION CRITERIA: We included trials in which men with Peyronie's disease were randomized to undergo non-surgical therapies versus placebo or no treatment for penile curvature and sexual function. DATA COLLECTION AND ANALYSIS: Two of four review authors, working in pairs, independently classified studies and abstracted data from the included studies. Primary outcomes were: patient-reported ability to have intercourse, quality of life, and treatment-related adverse effects. Secondary outcomes were: degree of penile curvature, discontinuation from treatment (for any reason), subjective patient-reported change in penile curvature, and improvement in penile pain. We performed statistical analyses using a random-effects model. We rated the certainty of evidence (CoE) according to the GRADE approach. MAIN RESULTS: Our search identified 1288 relevant references of which we included 18 records corresponding to 14 unique randomized controlled trials (RCTs) with 1810 men. These informed 10 distinct comparisons with relevant outcome data that were mostly extracted from single trials. In this abstract, we focus only on the most clinically relevant comparisons for the three primary outcomes and also include the outcome of degree penile curvature. Injectional collagenase (short-term): We found no short-term evidence on injectional collagenase for patients' self-reported ability to have intercourse and treatment-related adverse effects compared to placebo injection. Injectional collagenase may result in little to no difference in quality of life (scale 0 to 20 with lower scores indicating better quality of life; mean difference (MD) 1.8 lower, 95% confidence interval (CI) -3.58 to -0.02; 1 study, 134 participants; low CoE) and there may be little to no effect on the degree of penile curvature (MD 10.90 degrees less, 95% CI -16.24 to -5.56; 1 study, 136 participants; low CoE). Injectional collagenase (long-term): We also found no long-term evidence on injectional collagenase for patients' self-reported ability to have intercourse compared to placebo injection. It likely results in little to no effect on quality of life (MD 1.00 lower, 95% CI -1.60 to -0.40; 1 study, 612 participants; moderate CoE). Treatment-related adverse effects are likely increased (risk ratio (RR) 2.32, 95% CI 1.98 to 2.72; 1 study, 832 participants; moderate CoE). Injectional collagenase likely results in little to no change in the degree of penile curvature (MD 6.90 degrees less, 95% CI -9.64 to -4.14; 1 study, 612 participants; moderate CoE). Injectional verapamil (short-term): We are very uncertain how injectional verapamil may affect patients' self-reported ability to have intercourse compared to placebo injection short-term (RR 7.00, 95% CI 0.43 to 114.70; 1 study, 14 participants; very low CoE). We found no evidence for the outcome of quality of life. We are very uncertain how injectional verapamil may affect treatment-related adverse effects (RR not estimable; 1 study, 14 participants; very low CoE). Similarly, we are very uncertain how injectional verapamil may affect degree of penile curvature (MD -1.86, 95% CI -10.39 to 6.67; 1 study, 14 participants; very low CoE). We found no long-term data for any outcome. Extracorporeal shock wave treatment (ESWT) (short-term): We are very uncertain how ESWT affects patients' self-reported ability to have intercourse short-term (RR 1.60, 95% CI 0.71 to 3.60; 1 study, 26 participants; very low CoE). ESWT may result in little to no difference in quality of life (MD 3.10, 95% CI 1.57 to 4.64; 2 studies, 130 participants; low CoE). We are very uncertain if ESWT has an effect on treatment-related adverse effects (RR 2.73, 95% CI 0.74 to 10.14; 3 studies, 166 participants; very low CoE). ESWT may result in little to no difference in the degree of penile curvature compared to placebo (RR -2.84, 95% -7.35 to 1.67; 3 studies, 166 participants; low CoE). We found no long-term data for any outcome. Penile traction therapy (short-term): We found no evidence for whether penile traction compared to no treatment affects patients' self-reported ability to have intercourse. We are very uncertain how traction therapy may affect quality of life (MD 1.50 lower, 95% CI -3.42 to 0.42; 1 study, 90 participants; very low CoE). We are also very uncertain how traction therapy may affect treatment-related adverse effects (RR not estimable; 1 study, 90 participants; very low CoE) and how it affects the degree of curvature (MD 7.40 degrees less, 95% CI -11.18 to -3.62; 1 study, 89 participants; very low CoE). We found no long-term data for any outcome. AUTHORS' CONCLUSIONS: There is little evidence supporting the effectiveness of most non-surgical treatments for Peyronie's disease. Existing trials are mostly of poor methodological quality and/or fail to address patient-centered outcomes. Injectional collagenase appears to have some effectiveness; however, many individuals may not experience the improvement as clinically relevant, and this comes with the risk of increased adverse events. There is a critical need for better non-surgical treatment options for men with Peyronie's disease.

ANTECEDENTES: La enfermedad de Peyronie es una afección que da lugar al desarrollo de placas en el pene que pueden provocar curvatura peneana, dolor y disfunción eréctil, dificultando la actividad sexual. Existen varias intervenciones no quirúrgicas para mejorar esta afección, que incluyen agentes tópicos e inyectables, así como métodos mecánicos; sin embargo, su eficacia aún es incierta. Esta revisión se realizó para determinar los efectos de estos tratamientos no quirúrgicos. OBJETIVOS: Evaluar los efectos de los tratamientos no quirúrgicos en comparación con placebo o ningún tratamiento en individuos con enfermedad de Peyronie. MÉTODOS DE BÚSQUEDA: Se realizó una búsqueda exhaustiva en múltiples bases de datos (la Biblioteca Cochrane, MEDLINE, Embase, Scopus, Google Scholar y Web of Science), en registros de ensayos, otras fuentes de literatura gris y resúmenes de congresos, hasta el 23 de septiembre de 2022. No se impusieron restricciones respecto al idioma ni el estado de publicación. CRITERIOS DE SELECCIÓN: Se incluyeron ensayos en los que se asignó al azar a hombres con enfermedad de Peyronie a someterse a tratamientos no quirúrgicos versus placebo o ningún tratamiento para la curvatura del pene y la función sexual. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos de los cuatro autores de la revisión, trabajando en pareja, clasificaron de forma independiente los estudios y resumieron los datos de los estudios incluidos. Los desenlaces principales fueron: capacidad para mantener relaciones sexuales autoinformada por el paciente, calidad de vida y efectos adversos relacionados con el tratamiento. Los desenlaces secundarios fueron: grado de curvatura del pene, interrupción del tratamiento (por cualquier motivo), cambio subjetivo de la curvatura del pene autoinformado por el paciente y mejoría del dolor del pene. Se realizaron análisis estadísticos con un modelo de efectos aleatorios. La certeza de la evidencia se calificó según el método GRADE. RESULTADOS PRINCIPALES: La búsqueda identificó 1288 referencias pertinentes, de las cuales se incluyeron 18 registros correspondientes a 14 ensayos controlados aleatorizados (ECA) individuales con 1810 hombres. Éstos informaron 10 comparaciones distintas con datos de desenlaces relevantes que se extrajeron en su mayoría de ensayos individuales. Este resumen se centra solo en las comparaciones clínicamente más relevantes para los tres desenlaces principales y también se incluye el desenlace de grado de curvatura peneana. Colagenasa inyectable (a corto plazo): No se encontró evidencia a corto plazo de la colagenasa inyectable, en comparación con la inyección placebo, en la capacidad autoinformada por los pacientes de tener relaciones sexuales ni en los efectos adversos relacionados con el tratamiento. La colagenasa inyectable podría dar lugar a poca o ninguna diferencia en la calidad de vida (escala de 0 a 20 con puntuaciones más bajas que indican mejor calidad de vida; diferencia de medias [DM] 1,8 menor; intervalo de confianza [IC] del 95%: ­3,58 a ­0,02; un estudio, 134 participantes; evidencia de certeza baja) y podría haber poco o ningún efecto en el grado de curvatura del pene (DM 10,90 grados menos; IC del 95%: ­16,24 a ­5,56; un estudio, 136 participantes; evidencia de certeza baja). Colagenasa inyectable (a largo plazo): Tampoco se encontró evidencia a largo plazo sobre la colagenasa inyectable en la capacidad autoinformada por los pacientes de tener relaciones sexuales en comparación con la inyección placebo. Es probable que tenga un efecto escaso o nulo sobre la calidad de vida (DM 1,00 inferior; IC del 95%: ­1,60 a ­0,40; un estudio, 612 participantes; evidencia de certeza moderada). Es probable que aumenten los efectos adversos relacionados con el tratamiento (razón de riesgos [RR] 2,32; IC del 95%: 1,98 a 2,72; un estudio, 832 participantes; evidencia de certeza moderada). La colagenasa inyectable probablemente provoca poco o ningún cambio en el grado de curvatura del pene (DM 6,90 grados menos; IC del 95%: ­9,64 a ­4,14; un estudio, 612 participantes; evidencia de certeza moderada). Verapamilo inyectable (a corto plazo): No está muy claro cómo el verapamilo inyectable podría afectar la capacidad autoinformada por los pacientes de tener relaciones sexuales en comparación con la inyección placebo a corto plazo (RR 7,00; IC del 95%: 0,43 a 114,70; un estudio, 14 participantes; evidencia de certeza muy baja). No se encontró evidencia del desenlace de calidad de vida. No se sabe con certeza cómo podría afectar el verapamilo inyectable los efectos adversos relacionados con el tratamiento (RR no estimable; un estudio, 14 participantes; evidencia de certeza muy baja). Del mismo modo, es muy incierto cómo el verapamilo inyectable podría afectar el grado de curvatura peneana (DM ­1,86; IC del 95%: ­10,39 a 6,67; un estudio, 14 participantes; evidencia de certeza muy baja). No se encontraron datos a largo plazo para ningún desenlace. Tratamiento con ondas de choque extracorpóreas (OCE) (a corto plazo): No está muy claro cómo el tratamiento con OCE afecta la capacidad autoinformada por los pacientes de mantener relaciones sexuales a corto plazo (RR 1,60; IC del 95%: 0,71 a 3,60; un estudio, 26 participantes; evidencia de certeza muy baja). El tratamiento con OCE podría dar lugar a poca o ninguna diferencia en la calidad de vida (DM 3,10; IC del 95%: 1,57 a 4,64; dos estudios, 130 participantes; evidencia de certeza baja). No está muy claro si el tratamiento con OCE influye en los efectos adversos relacionados con el tratamiento (RR 2,73; IC del 95%: 0,74 a 10,14; tres estudios, 166 participantes; evidencia de certeza muy baja). El tratamiento con OCE podría dar lugar a poca o ninguna diferencia en el grado de curvatura peneana en comparación con el placebo (RR ­2,84; 95%: ­7,35 a 1,67; tres estudios, 166 participantes; evidencia de certeza baja). No se encontraron datos a largo plazo para ningún desenlace. Terapia de tracción peneana (a corto plazo): No se encontró evidencia de si la tracción peneana comparada con ningún tratamiento afecta la capacidad autoinformada por los pacientes de tener relaciones sexuales. No se sabe con certeza cómo podría afectar la terapia de tracción la calidad de vida (DM 1,50 inferior; IC del 95%: ­3,42 a 0,42; un estudio, 90 participantes; evidencia de certeza muy baja). Tampoco se sabe con certeza cómo podría afectar la terapia de tracción los efectos adversos relacionados con el tratamiento (RR no estimable; un estudio, 90 participantes; evidencia de certeza muy baja) ni cómo afecta el grado de curvatura (DM 7,40 grados menos; IC del 95%: ­11,18 a ­3,62; un estudio, 89 participantes; evidencia de certeza muy baja). No se encontraron datos a largo plazo para ningún desenlace. CONCLUSIONES DE LOS AUTORES: Existe poca evidencia que respalde la eficacia de la mayoría de los tratamientos no quirúrgicos para la enfermedad de Peyronie. Los ensayos existentes son en su mayoría de baja calidad metodológica y no abordan los desenlaces centrados en el paciente. La colagenasa inyectable parece tener cierta eficacia; sin embargo, es posible que muchas personas no experimenten una mejoría clínicamente relevante, lo que conlleva el riesgo de un aumento de los eventos adversos. Existe una necesidad imperiosa de mejores opciones terapéuticas no quirúrgicas para los hombres con enfermedad de Peyronie.

Risk of uterine cervical cancer in inflammatory bowel disease: a systematic review and meta-analysis.

BACKGROUND AND AIMS: There are limited data on the association between uterine cervical cancer (UCC) and inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC). METHODS: This systematic review and meta-analysis assessed the risk of UCC in patients with IBD. We searched MEDLINE, Embase, Cochrane Library, Scopus, Web of Science, ClinicalTrials.gov, gray literature and conference proceedings for studies published before 21 January 2022. Two reviewers independently screened studies, extracted data and assessed quality using the Newcastle-Ottawa Scale. Subgroup analyses were based on IBD type, biologic era, immunosuppression status, study location and design, and publication status. Fifteen studies were included. RESULTS: The pooled relative risk (RR) of UCC in IBD was 1.34 (95% confidence interval [CI], 1.07-1.69; I2 = 53.4%). In subgroup analyses, the pooled RRs of UCC in CD and UC were 1.18 (95% CI, 0.97-1.42) and 1.50 (95% CI, 1.01-12.21), respectively. The pooled RRs of UCC in pre-biologic and biologic eras were 1.36 (95% CI, 0.83-2.23) and 1.99 (95% CI, 1.03-3.86), respectively. The pooled RR of UCC in immunomodulator users was 2.18 (95% CI, 0.81-5.87). The pooled RRs of UCC in Asia, Europe and North America were 5.65 (95% CI, 2.65-12.07), 1.13 (95% CI, 0.96-1.34) and 1.38 (95% CI, 1.10-1.73), respectively. CONCLUSIONS: The risk of UCC was significantly increased in IBD, particularly in UC but not in CD, suggesting that women with IBD should undergo regular UCC screening and consider vaccination.

Serenoa repens for the treatment of lower urinary tract symptoms due to benign prostatic enlargement.

BACKGROUND: Benign prostatic hyperplasia (BPH) is a non-malignant enlargement of the prostate, which can lead to obstructive and irritative lower urinary tract symptoms (LUTS). The pharmacologic use of plants and herbs (phytotherapy) for the treatment of LUTS associated with BPH is common. The extract of the berry of the American saw palmetto or dwarf palm plant, Serenoa repens (SR), which is also known by its botanical name of Sabal serrulatum, is one of several phytotherapeutic agents available for the treatment of BPH. OBJECTIVES: To assess the effects of Serenoa repens in the treatment of men with LUTS consistent with BPH. SEARCH METHODS: We performed a comprehensive search of multiple databases (the Cochrane Library, MEDLINE, Embase, Scopus, Web of Science, and LILACS), trials registries, other sources of grey literature, and conference proceedings published up to 16 September 2022, with no restrictions on language or publication status. SELECTION CRITERIA: We included randomized controlled trials of participants with BPH who were treated with Serenoa repens or placebo/no treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion at each stage and undertook data extraction and risk of bias assessment and GRADE assessment of the certainty of the evidence. We considered review outcomes measured up to 12 months after randomization as short term, and beyond 12 months as long term. Our main outcomes included urologic symptom scores, quality of life, and adverse events. MAIN RESULTS: For this update, we narrowed the review question to only comparisons with placebo. We included 27 studies (of which 9 were new) involving a total of 4656 participants, 19 studies comparing Serenoa repens with placebo, and 8 studies comparing Serenoa repens in combination with other phytotherapeutic agents versus placebo. Most studies included men aged > 50 (mean age range 52 to 68) with moderate urologic symptoms (International Prostate Symptom Score [IPSS] range 8 to 19). Ten studies were funded by the pharmaceutical industry; two studies were funded by government agencies; and the remaining studies did not specify funding sources. Serenoa repens versus placebo or no intervention Results for this comparison are based on predefined sensitivity analyses limited to studies at low risk of bias. Serenoa repens results in little to no difference in urologic symptoms at short-term follow-up (3 to 6 months; IPSS score range 0 to 35, higher scores indicate worse symptoms; mean difference (MD) -0.90, 95% confidence interval (CI) -1.74 to -0.07; I2 = 68%; 9 studies, 1681 participants; high-certainty evidence). Serenoa repens results in little to no difference in the quality of life at short-term follow-up (3 to 6 months; IPSS quality of life domain range 0 to 6, higher scores indicate worse quality of life; MD -0.20, 95% CI -0.40 to -0.00; I2 = 39%; 5 studies, 1001 participants; high-certainty evidence). Serenoa repens probably results in little to no difference in adverse events (1 to 17 months; risk ratio (RR) 1.01, 95% CI 0.77 to 1.31; I2 = 18%; 12 studies, 2399 participants; moderate-certainty evidence). Based on 164 cases per 1000 men in the placebo group, this corresponds to 2 more (38 fewer to 51 more) per 1000 men in the Serenoa repens group. Serenoa repens results in little to no difference in urologic symptoms at long-term follow-up (12 to 17 months, IPSS score, MD 0.07, 95% CI -0.75 to 0.88; I2 = 34%; 3 studies, 898 participants; high-certainty evidence). Serenoa repens results in little to no difference in quality of life at long-term follow-up (12 to 17 months, IPSS quality of life, MD -0.11, 95% CI -0.41 to 0.19; I2 = 65%; 3 studies, 882 participants; high-certainty evidence). There were no data on long-term adverse events for this comparison. Serenoa repens in combination with other phytotherapy versus placebo or no intervention Different phytotherapeutic agents that include Serenoa repens may result in little to no difference in urologic symptoms compared to placebo at short-term follow-up (12 to 24 weeks, IPSS score, MD -2.41, 95% CI -4.54 to -0.29; I2 = 67%; 4 studies, 460 participants; low-certainty evidence). We are very uncertain about the effects of these agents on quality of life (very low-certainty evidence). These agents may result in little to no difference in the occurrence of adverse events; however, the CIs included substantial benefits and harms (12 to 48 weeks, RR 0.91, 95% CI 0.58 to 1.41; I2 = 0%; 4 studies, 481 participants; low-certainty evidence). Based on 132 cases per 1000 men in the placebo group, this corresponds to 12 fewer (55 fewer to 54 more) per 1000 men in the combined phytotherapeutic agents with Serenoa repens group. AUTHORS' CONCLUSIONS: Serenoa repens alone provides little to no benefits for men with lower urinary tract symptoms due to benign prostatic enlargement. There is more uncertainty about the role of Serenoa repens in combination with other phytotherapeutic agents.

GRADE Reporting in Systematic Reviews Published in the Urological Literature (2009-2021).

PURPOSE: We evaluate the reporting of the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to rating the certainty of evidence in systematic reviews published in the urological literature. MATERIALS AND METHODS: Based on a predefined protocol, we identified all systematic reviews published in 5 major urological journals from 1998 to 2021 that reported the use of GRADE. Two authors performed study selection and data abstraction independently to assess reporting in accordance with established criteria for applying GRADE. RESULTS: We included 68 of 522 (13.0%) systematic reviews that reported the use of GRADE; the first was published in 2009. Approximately half were published between 2009-2018 (n=36) and the other half between 2019-2021 (n=32). Oncology (24; 35.3%) was the most common clinical topic, and the authors were mostly based in Europe (34; 50%). In their abstract, less than half of all systematic reviews (32; 47.1%) provided any certainty of evidence rating. Only 41 (60.3%) included a tabular result summary in the format of a summary of findings table (24; 35.3%) or evidence profile (17; 25.0%). Few (35.3%) addressed the GRADE certainty of evidence rating in the discussion section. Reporting did not improve over time when comparing the 2 time periods. CONCLUSIONS: Whereas GRADE is increasingly being applied for rating the certainty of evidence, systematic reviews published in the urological literature frequently have not followed established criteria for applying or using GRADE. There is a need for better training of authors and editors, as well as for a GRADE reporting checklist for systematic review authors.

Fosfomycin for Antibiotic Prophylaxis in Men Undergoing a Transrectal Prostate Biopsy: A Systematic Review and Meta-Analysis.

Background and Objectives: To assess the effects of fosfomycin compared with other antibiotics as a prophylaxis for urinary tract infections (UTIs) in men undergoing transrectal prostate biopsies. Materials and Methods: We searched multiple databases and trial registries without publication language or status restrictions until 4 January 2022. Parallel-group randomized controlled trials (RCTs) and non-randomized studies (NRS) were included. The primary outcomes were febrile UTI, afebrile UTI, and overall UTI. We used GRADE guidance to rate the certainty of evidence of RCTs and NRSs. The protocol was registered with PROSPERO (CRD42022302743). Results: We found data on five comparisons; however, this abstract focuses on the primary outcomes of the two most clinically relevant comparisons. Regarding fosfomycin versus fluoroquinolone, five RCTs and four NRSs with a one-month follow-up were included. Based on the RCT evidence, fosfomycin likely resulted in little to no difference in febrile UTIs compared with fluoroquinolone. This difference corresponded to four fewer febrile UTIs per 1000 patients. Fosfomycin likely resulted in little to no difference in afebrile UTIs compared with fluoroquinolone. This difference corresponded to 29 fewer afebrile UTIs per 1000 patients. Fosfomycin likely resulted in little to no difference in overall UTIs compared with fluoroquinolone. This difference corresponded to 35 fewer overall UTIs per 1000 patients. Regarding fosfomycin and fluoroquinolone combined versus fluoroquinolone, two NRSs with a one- to three-month follow-up were included. Based on the NRS evidence, fosfomycin and fluoroquinolone combined may result in little to no difference in febrile UTIs compared with fluoroquinolone. This difference corresponded to 16 fewer febrile UTIs per 1000 patients. Conclusions: Compared with fluoroquinolone, fosfomycin or fosfomycin and fluoroquinolone combined may have a similar prophylactic effect on UTIs after a transrectal prostate biopsy. Given the increasing fluoroquinolone resistance and its ease to use, fosfomycin may be a good option for antibiotic prophylaxis.

Update on the management of benign prostatic hyperplasia and the role of minimally invasive procedures.

Lower urinary tract symptoms due to benign prostatic hyperplasia constitute a substantial burden, affecting the quality of life of those affected by this condition. While watchful waiting and medical management using a wide array of pharmaceuticals can be effective, surgery has been one of the most definite solutions for those highly affected by this condition. Transurethral resection of the prostate (TURP) is the gold standard surgical procedure, but other alternatives using laser (HoLEP and ThuLEP) and robotic water jets (Aquablation) are emerging treatments aimed at reducing postoperative morbidity. Minimally invasive procedures conducted in outpatient settings and under local anesthesia or sedation are increasingly being used, especially in those patients with high surgical risk due to comorbidities. These procedures include prostatic arterial embolization, water vapor thermal therapy (Rezum), prostatic urethral lift (Urolift), temporary implantable nitinol device (TIND/iTIND), and transurethral microwave thermotherapy (TUMT). The evidence supporting these treatments is growing, but some uncertainties remain as to what is the magnitude of their advantages and disadvantages compared to TURP. Innovations in the technologies involved in these new procedures may improve their profile for effectiveness and safety. Moreover, new devices are being investigated for marketing approval. Issues around costs and patients' preferences are also yet to be elucidated, thus their evolving role needs to be weighed against the aforementioned considerations.

Prevalence and methodological quality of systematic reviews in Korean medical journals.

This study aimed to assess and evaluate the prevalence and methodological quality of systematic reviews (SRs) published in major Korean medical journals (KMJs). The top 15 journals with the highest Korean Medical Citation Index, published between 2018 to 2021, were selected. We assessed the methodological quality of SRs using A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2). In total, 126 SRs were included, with an average of 32 SRs being reported annually. The overall prevalence of SRs in KMJs was 2.8%, with an increase from 2.6% in 2018 to 3.4% in 2021. Overall, the methodological quality of SRs was low (9.5% low, 90.5% critically low). More than 80% of the studies adhered to critical domain items such as a comprehensive literature search and risk of bias assessment, but for items such as protocol registration and listing excluded studies and the justification for exclusion, the adherence rate was less than 15%. While the number of SRs in KMJs steadily increased, the overall confidence in the methodological quality was low to critically low. Therefore, in order to provide the best evidence for decision-making in clinical and public health areas, editors, reviewers, and authors need to pay more attention to improving the quality of SRs.

Prostatic arterial embolisation for men with benign prostatic hyperplasia: a Cochrane review.

OBJECTIVES: To assess the effects of prostatic arterial embolisation (PAE) compared to other procedures for treatment of lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH). METHODS: We included randomised controlled trials (RCTs), as well as non-randomised studies (NRSs) enrolling men with BPH undergoing PAE vs other surgical interventions via a comprehensive search up until 8 November 2021. Two independent reviewers screened the literature, extracted data, assessed risk of bias, performed statistical analyses by using a random-effects model, and rated the certainty of evidence (CoE) of RCTs and NRSs. RESULTS: We found data to inform two comparisons: PAE vs transurethral resection of prostate (TURP; six RCTs and two NRSs), and PAE vs sham (one RCT). This abstract focuses on the primary outcomes in a comparison of PAE vs TURP. Short-term follow-up: based on RCT evidence, there may be little to no difference in urological symptom score improvement (mean difference [MD] 1.72, 95% confidence interval [CI] -0.37 to 3.81; low CoE) and quality of life (QoL; MD 0.28, 95% CI -0.28 to 0.84; low CoE) measured by International Prostatic Symptom Score. We are very uncertain about the effects of PAE on major adverse events (risk ratio [RR] 0.75, 95% CI 0.19-2.97; very low CoE). Long-term follow-up: based on RCT evidence, PAE may result in little to no difference in urological symptom scores (MD 2.58, 95% CI -1.54 to 6.71; low CoE) and QoL (MD 0.50, 95% CI -0.03 to 1.04; low CoE). We are very uncertain about major adverse events (RR 0.91, 95% CI 0.20-4.05; very low CoE). CONCLUSION: Compared to TURP, the impact on urological symptoms and QoL improvement as perceived by patients appears to be similar. This review did reveal major uncertainty as to how major adverse events compare.

A systematic review and meta-analysis of clinical signs, symptoms, and imaging findings in patients with suspected renal colic.

Study Objective: The objective of this study was to conduct a systematic review and meta-analysis of the diagnostic accuracy of the clinical signs, symptoms, laboratory investigations, and imaging modalities commonly used in patients with clinically suspected renal colic. Methods: We conducted this systematic review and meta-analysis according to an a priori, registered protocol (PROSPERO CRD42017055153). A literature search was performed using MEDLINE and EMBASE from inception to July 2, 2020. We assessed the risk of bias using Quality Assessment of Diagnostic Accuracy Studies-2, calculated likelihood ratios (LRs), and applied a random-effects model for meta-analysis. Results: Among 7641 references screened, 76 were included in the systematic review and 53 were included in the meta-analyis. The overall pooled prevalence for ureteral stones was 63% (95% confidence interval [CI], 58%-67%). No individual demographic feature, symptom, or sign when present had an LR+ ≥2.0 for identifying ureterolithiasis. A (Sex, Timing and Origin of pain, race, presence or absence of Nausea, and Erythrocytes) STONE score ≥10 increased (sensitivity 0.49, specificity 0.91, LR 5.3 [95% CI, 4.1-6.7]) and a STONE score <6 reduced the likelihood of ureteral stones (sensitivity 0.94, specificity 0.43, LR 0.15 [95% CI, 0.10-0.22]). Standard-dose (sensitivity 0.96, specificity 0.94, LR+ 16 [95% CI, 11-23], LR- 0.05 [95% CI, 0.03-0.07]) and low-dose computed tomography (CT) scanning (sensitivity 0.93, specificity 0.94, LR+ 17 [95% CI, 8.8-31], LR- 0.08 [95% CI, 0.03-0.19]) were the most useful imaging techniques for identifying patients with or without ureteral stones. Conclusions: Individual signs, symptoms, or the presence of microscopic hematuria do not substantially impact the likelihood of ureteral stones in patients with clinically suspected renal colic. The STONE score at high and low thresholds and a modified STONE score at a high threshold may sufficiently guide physicians' decisions to obtain imaging. Low-dose, non-contrast CT imaging provides superior diagnostic accuracy compared with all other imaging index tests that are comparable with standard CT imaging. Limitations of the evidence include methodological shortcomings and considerable heterogeneity of the included studies.

Perioperative Probiotics Application for Preventing Postoperative Complications in Patients with Colorectal Cancer: A Systematic Review and Meta-Analysis.

Background and Objectives: Perioperative probiotic administration in patients who undergo gastrointestinal surgery can reduce postoperative infectious complications. This systematic review and meta-analysis aimed to evaluate the effect of probiotics on postoperative outcomes in patients who underwent colorectal cancer surgery. Materials and Methods: For this study, we followed the protocol published by PROSPERO (registration number: CRD42021247277). We included studies on patients undergoing open, laparoscopic, or robotic colorectal cancer surgery for curative intent. We conducted a comprehensive search with online databases (trial registries and ClinicalTrials.gov), other literature sources, and conference proceedings, with no language restriction, up until 12 August 2022. We assessed risk of bias, extracted data, and conducted statistical analyses by using a random-effects model and interpreted the results based on the Cochrane Handbook for Systematic Reviews of Interventions. We rated the certainty of evidence (CoR) according to the GRADE approach. Results: We identified 20 published full-text studies. The use of probiotics probably results in little to no difference in perioperative mortality (risk ratio (RR): 0.17, 95% CI: 0.02 to 1.38; I2 = 0%; moderate CoE) and may result in reducing the overall postoperative infectious complications (RR: 0.45, 95% CI: 0.27 to 0.76; I2 = 38%; low CoE) after colorectal cancer surgery. Probiotics may result in little to no difference in probiotics-related adverse events (RR: 0.73, 95% CI: 0.45 to 1.19; I2 = 0%; low CoE). While probiotics may result in reducing the overall postoperative complications (RR: 0.47, 95% CI: 0.30 to 0.74; I2 = 8%; low CoE), it may result in little to no difference in hospital length of stay (LOS) (MD: -1.06, 95% CI: -1.64 to -0.47; I2 = 8%; low CoE) and postoperative quality of life (QOL) (MD: +5.64, 95% CI: 0.98 to 10.3; low CoE). Conclusions: Perioperative probiotic administration may reduce complications, including overall infectious complications, in patients undergoing colorectal cancer surgery without any additional adverse effects. In addition, probiotics may have similar effects on perioperative mortality; procedure-related complications such as anastomotic leakage, and hospital LOS; or improve the QOL. Thus, probiotics may be considered a beneficial supplement to routine perioperative care for colorectal cancer surgery.

The status quo of systematic reviews published in high-impact journals in Korea: a study focused on protocol registration and GRADE use.

OBJECTIVES: This study investigated the status quo of systematic reviews published in major journals in Korea from the perspective of protocol registration and adopting the grading of recommendation, assessment, development and evaluation (GRADE) system. METHODS: We examined systematic reviews published in Korea's top 15 medical journals from 2018 to 2021. Teams of 2 reviewers assessed the studies' eligibility criteria and extracted data independently and in duplicate. We collected information on study characteristics, protocol registration, and GRADE use of the included reviews, and reviewed the "Instructions for Authors" of the selected journals to assess any guidance related to systematic reviews. RESULTS: Out of the 126 identified reviews, 18 (14.3%) reported that they registered or published their protocol. Only 5 (4.0%) rated the certainty of evidence; and all 5 used the GRADE system. Only 6 of 15 journals mentioned systematic reviews in their "Instructions for Authors." Six journals endorsed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework for systematic review reporting (2 mandatory, 3 recommended, and 1 unclear). None of the journals included mentioned protocol registration or certainty of evidence in their authors' guidelines. CONCLUSIONS: Overall, the proportion of systematic reviews that had prior protocol registration or used the GRADE approach to rate the certainty of evidence was very low. Our study highlights the need for adherence to systematic review standards in medical journals in Korea, including prior protocol registration and certainty of evidence assessment. Our review will help improve the quality of systematic reviews in Korea.

Korean guideline of desmopressin for the treatment of nocturia in men.

PURPOSE: Nocturia is the most bothersome of lower urinary tract symptoms in men. Desmopressin, a synthetic analog of the human hormone vasopressin, has been used for the treatment of nocturia. However, the guidelines include varying recommendations for the use of desmopressin for the management of nocturia in men. Therefore, the Korean Urological Association (KUA) developed recommendations for desmopressin for the treatment of nocturia in men. MATERIALS AND METHODS: A rigorous systematic review was performed and Grading of Recommendations, Assessment, Development, and Evaluation methodology was used to rate the certainty of evidence for patient outcomes and to develop the evidence into recommendations. The steering group, guidelines development group, systematic review team, and external review group consisted of members of the Korean Continence Society, Korean Society of Geriatric Urological Care, and KUA, respectively, who were involved in the guidelines development process. RESULTS: The guidelines address the benefits, harms, patients' values and preferences, costs, and resources related to desmopressin by using a single clinical question: What is the effectiveness of desmopressin compared to that of placebo, behavior modification, or other pharmacological therapies? CONCLUSIONS: The guidelines development panel suggests desmopressin for men with nocturia instead of placebo, behavior modification, or alpha-blocker monotherapy (low certainty of evidence, weak recommendation). Additionally, the panel suggests desmopressin combination therapy with alpha-blockers for men with nocturia instead of alpha-blocker monotherapy or alpha-blocker combination therapy with anticholinergic agents (low certainty of evidence, weak recommendation).