1.Impact of Varicocele Repair on Assisted Reproductive Technique Outcomes in Infertile Men: A Systematic Review and Meta-Analysis
Ayad PALANI ; Rossella CANNARELLA ; Ramadan SALEH ; Gianmaria SALVIO ; Ahmed M. HARRAZ ; Andrea CRAFA ; Fahmi BAHAR ; Kadir BOCU ; Naveen KUMAR ; Priyank KOTHARI ; Germar-Michael PINGGERA ; Selahittin CAYAN ; Giovanni M. COLPI ; Widi ATMOKO ; Rupin SHAH ; Ashok AGARWAL
The World Journal of Men's Health 2025;43(2):344-348
Purpose:
In this systematic review and meta-analysis, we investigated assisted reproductive technology (ART) success in infertile men with clinical varicocele and abnormal semen parameters who underwent varicocele repair (VR) before the ART procedure as compared to those who did not.
Materials and Methods:
A comprehensive search of the Scopus, PubMed, Embase, and Cochrane Library databases was conducted using a specific query string to identify studies examining the impact of VR on ART outcomes, including fertilization rate, clinical pregnancy, pregnancy loss, and live-birth rate, until October 2023. Outcomes were analyzed based on the type of ART. Studies on VR in infertile men with non-obstructive azoospermia and those who underwent ART only due to female factor infertility were excluded from the study.
Results:
Out of 1,554 articles reviewed, only 9 met the inclusion criteria for the study. All the included articles were observational studies. The variability in study quality in the included literature resulted in a moderate overall risk of bias. Data analysis showed that for intrauterine insemination, there was no difference in the clinical pregnancy rate (odds ratio [OR] 1.01, 95% confidence interval [CI]: 0.42, 2.45; p=0.97). However, for intracytoplasmic sperm injection (ICSI), men with VR showed a significant improvement in fertilization rate (mean difference 10.9, 95% CI: 5.94, 15.89; p<0.01), clinical pregnancy rate (OR 1.38, 95% CI: 1.07, 1.78; p=0.01) and live-birth rate (OR 2.07, 95% CI: 1.45, 2.97; p<0.01), compared to men who did not undergo VR.
Conclusions
The findings of this systematic review and meta-analysis suggest that VR has a positive impact on pregnancy and live birth rates after ICSI. However, biases like small sample sizes and heterogeneous populations highlight the need for larger, well-designed prospective studies to validate these findings.
2.Impact of Varicocele Repair on Assisted Reproductive Technique Outcomes in Infertile Men: A Systematic Review and Meta-Analysis
Ayad PALANI ; Rossella CANNARELLA ; Ramadan SALEH ; Gianmaria SALVIO ; Ahmed M. HARRAZ ; Andrea CRAFA ; Fahmi BAHAR ; Kadir BOCU ; Naveen KUMAR ; Priyank KOTHARI ; Germar-Michael PINGGERA ; Selahittin CAYAN ; Giovanni M. COLPI ; Widi ATMOKO ; Rupin SHAH ; Ashok AGARWAL
The World Journal of Men's Health 2025;43(2):344-348
Purpose:
In this systematic review and meta-analysis, we investigated assisted reproductive technology (ART) success in infertile men with clinical varicocele and abnormal semen parameters who underwent varicocele repair (VR) before the ART procedure as compared to those who did not.
Materials and Methods:
A comprehensive search of the Scopus, PubMed, Embase, and Cochrane Library databases was conducted using a specific query string to identify studies examining the impact of VR on ART outcomes, including fertilization rate, clinical pregnancy, pregnancy loss, and live-birth rate, until October 2023. Outcomes were analyzed based on the type of ART. Studies on VR in infertile men with non-obstructive azoospermia and those who underwent ART only due to female factor infertility were excluded from the study.
Results:
Out of 1,554 articles reviewed, only 9 met the inclusion criteria for the study. All the included articles were observational studies. The variability in study quality in the included literature resulted in a moderate overall risk of bias. Data analysis showed that for intrauterine insemination, there was no difference in the clinical pregnancy rate (odds ratio [OR] 1.01, 95% confidence interval [CI]: 0.42, 2.45; p=0.97). However, for intracytoplasmic sperm injection (ICSI), men with VR showed a significant improvement in fertilization rate (mean difference 10.9, 95% CI: 5.94, 15.89; p<0.01), clinical pregnancy rate (OR 1.38, 95% CI: 1.07, 1.78; p=0.01) and live-birth rate (OR 2.07, 95% CI: 1.45, 2.97; p<0.01), compared to men who did not undergo VR.
Conclusions
The findings of this systematic review and meta-analysis suggest that VR has a positive impact on pregnancy and live birth rates after ICSI. However, biases like small sample sizes and heterogeneous populations highlight the need for larger, well-designed prospective studies to validate these findings.
3.Impact of Varicocele Repair on Assisted Reproductive Technique Outcomes in Infertile Men: A Systematic Review and Meta-Analysis
Ayad PALANI ; Rossella CANNARELLA ; Ramadan SALEH ; Gianmaria SALVIO ; Ahmed M. HARRAZ ; Andrea CRAFA ; Fahmi BAHAR ; Kadir BOCU ; Naveen KUMAR ; Priyank KOTHARI ; Germar-Michael PINGGERA ; Selahittin CAYAN ; Giovanni M. COLPI ; Widi ATMOKO ; Rupin SHAH ; Ashok AGARWAL
The World Journal of Men's Health 2025;43(2):344-348
Purpose:
In this systematic review and meta-analysis, we investigated assisted reproductive technology (ART) success in infertile men with clinical varicocele and abnormal semen parameters who underwent varicocele repair (VR) before the ART procedure as compared to those who did not.
Materials and Methods:
A comprehensive search of the Scopus, PubMed, Embase, and Cochrane Library databases was conducted using a specific query string to identify studies examining the impact of VR on ART outcomes, including fertilization rate, clinical pregnancy, pregnancy loss, and live-birth rate, until October 2023. Outcomes were analyzed based on the type of ART. Studies on VR in infertile men with non-obstructive azoospermia and those who underwent ART only due to female factor infertility were excluded from the study.
Results:
Out of 1,554 articles reviewed, only 9 met the inclusion criteria for the study. All the included articles were observational studies. The variability in study quality in the included literature resulted in a moderate overall risk of bias. Data analysis showed that for intrauterine insemination, there was no difference in the clinical pregnancy rate (odds ratio [OR] 1.01, 95% confidence interval [CI]: 0.42, 2.45; p=0.97). However, for intracytoplasmic sperm injection (ICSI), men with VR showed a significant improvement in fertilization rate (mean difference 10.9, 95% CI: 5.94, 15.89; p<0.01), clinical pregnancy rate (OR 1.38, 95% CI: 1.07, 1.78; p=0.01) and live-birth rate (OR 2.07, 95% CI: 1.45, 2.97; p<0.01), compared to men who did not undergo VR.
Conclusions
The findings of this systematic review and meta-analysis suggest that VR has a positive impact on pregnancy and live birth rates after ICSI. However, biases like small sample sizes and heterogeneous populations highlight the need for larger, well-designed prospective studies to validate these findings.
4.Impact of Varicocele Repair on Assisted Reproductive Technique Outcomes in Infertile Men: A Systematic Review and Meta-Analysis
Ayad PALANI ; Rossella CANNARELLA ; Ramadan SALEH ; Gianmaria SALVIO ; Ahmed M. HARRAZ ; Andrea CRAFA ; Fahmi BAHAR ; Kadir BOCU ; Naveen KUMAR ; Priyank KOTHARI ; Germar-Michael PINGGERA ; Selahittin CAYAN ; Giovanni M. COLPI ; Widi ATMOKO ; Rupin SHAH ; Ashok AGARWAL
The World Journal of Men's Health 2025;43(2):344-348
Purpose:
In this systematic review and meta-analysis, we investigated assisted reproductive technology (ART) success in infertile men with clinical varicocele and abnormal semen parameters who underwent varicocele repair (VR) before the ART procedure as compared to those who did not.
Materials and Methods:
A comprehensive search of the Scopus, PubMed, Embase, and Cochrane Library databases was conducted using a specific query string to identify studies examining the impact of VR on ART outcomes, including fertilization rate, clinical pregnancy, pregnancy loss, and live-birth rate, until October 2023. Outcomes were analyzed based on the type of ART. Studies on VR in infertile men with non-obstructive azoospermia and those who underwent ART only due to female factor infertility were excluded from the study.
Results:
Out of 1,554 articles reviewed, only 9 met the inclusion criteria for the study. All the included articles were observational studies. The variability in study quality in the included literature resulted in a moderate overall risk of bias. Data analysis showed that for intrauterine insemination, there was no difference in the clinical pregnancy rate (odds ratio [OR] 1.01, 95% confidence interval [CI]: 0.42, 2.45; p=0.97). However, for intracytoplasmic sperm injection (ICSI), men with VR showed a significant improvement in fertilization rate (mean difference 10.9, 95% CI: 5.94, 15.89; p<0.01), clinical pregnancy rate (OR 1.38, 95% CI: 1.07, 1.78; p=0.01) and live-birth rate (OR 2.07, 95% CI: 1.45, 2.97; p<0.01), compared to men who did not undergo VR.
Conclusions
The findings of this systematic review and meta-analysis suggest that VR has a positive impact on pregnancy and live birth rates after ICSI. However, biases like small sample sizes and heterogeneous populations highlight the need for larger, well-designed prospective studies to validate these findings.
5.Impact of Varicocele Repair on Assisted Reproductive Technique Outcomes in Infertile Men: A Systematic Review and Meta-Analysis
Ayad PALANI ; Rossella CANNARELLA ; Ramadan SALEH ; Gianmaria SALVIO ; Ahmed M. HARRAZ ; Andrea CRAFA ; Fahmi BAHAR ; Kadir BOCU ; Naveen KUMAR ; Priyank KOTHARI ; Germar-Michael PINGGERA ; Selahittin CAYAN ; Giovanni M. COLPI ; Widi ATMOKO ; Rupin SHAH ; Ashok AGARWAL
The World Journal of Men's Health 2025;43(2):344-348
Purpose:
In this systematic review and meta-analysis, we investigated assisted reproductive technology (ART) success in infertile men with clinical varicocele and abnormal semen parameters who underwent varicocele repair (VR) before the ART procedure as compared to those who did not.
Materials and Methods:
A comprehensive search of the Scopus, PubMed, Embase, and Cochrane Library databases was conducted using a specific query string to identify studies examining the impact of VR on ART outcomes, including fertilization rate, clinical pregnancy, pregnancy loss, and live-birth rate, until October 2023. Outcomes were analyzed based on the type of ART. Studies on VR in infertile men with non-obstructive azoospermia and those who underwent ART only due to female factor infertility were excluded from the study.
Results:
Out of 1,554 articles reviewed, only 9 met the inclusion criteria for the study. All the included articles were observational studies. The variability in study quality in the included literature resulted in a moderate overall risk of bias. Data analysis showed that for intrauterine insemination, there was no difference in the clinical pregnancy rate (odds ratio [OR] 1.01, 95% confidence interval [CI]: 0.42, 2.45; p=0.97). However, for intracytoplasmic sperm injection (ICSI), men with VR showed a significant improvement in fertilization rate (mean difference 10.9, 95% CI: 5.94, 15.89; p<0.01), clinical pregnancy rate (OR 1.38, 95% CI: 1.07, 1.78; p=0.01) and live-birth rate (OR 2.07, 95% CI: 1.45, 2.97; p<0.01), compared to men who did not undergo VR.
Conclusions
The findings of this systematic review and meta-analysis suggest that VR has a positive impact on pregnancy and live birth rates after ICSI. However, biases like small sample sizes and heterogeneous populations highlight the need for larger, well-designed prospective studies to validate these findings.
6.Impact of Varicocele on Testicular Oxidative Stress and Sperm Parameters in Experimental Animals: A Systematic Review and Meta-Analysis
Giorgio Ivan RUSSO ; Ramadan SALEH ; Federica FINOCCHI ; Almas Ramadhani JUMA ; Damayanthi DURAIRAJANAYAGAM ; Oguzhan KAHRAMAN ; Emrullah SÖĞÜTDELEN ; Ioannis SOKOLAKIS ; Ranjit B. VISHWAKARMA ; Fahmi BAHAR ; Ahmed M. HARRAZ ; Parviz KAVOUSSI ; Widi ATMOKO ; Eric CHUNG ; Naveen KUMAR ; Wael ZOHDY ; Amarnath RAMBHATLA ; Mohamed ARAFA ; Nguyen Ho Vinh PHUOC ; Gianmaria SALVIO ; Aldo E. CALOGERO ; Tuncay TOPRAK ; Germar-Michael PINGGERA ; Rossella CANNARELLA ; Giovanni COLPI ; Taha Abo-Almagd Abdel-Meguid HAMODA ; Rupin SHAH ; Ashok AGARWAL
The World Journal of Men's Health 2024;42(3):563-573
Purpose:
Varicocele has been associated with high seminal oxidative stress (OS), impaired semen quality, and reduced male fertility potential. However, the exact mechanism(s) underlying the development of varicocele-mediated infertility and the cause-effect relationship between varicocele and testicular dysfunction are not fully understood. The aim of this systematic review and meta-analysis (SRMA) is to investigate the impact of varicocele on testicular OS markers and sperm parameters in experimental animals with varicocele as compared to animals without varicocele.
Materials and Methods:
A literature search was performed using the Scopus and PubMed databases on studies that investigated testicular OS markers and sperm parameters in animals with varicocele. The primary outcomes included malondialdehyde (MDA) (nmol/mg) levels whereas the secondary outcomes included total sperm count (×106), sperm vitality (%), total sperm motility (%), and sperm DNA fragmentation (SDF) (%). Standardized mean difference (SMD) (95% confidence interval [CI]) was chosen to express the effect size. The quality of the included studies was evaluated using the Cambridge Quality Checklist.
Results:
Out of 76 identified articles, 6 studies on rats were included in the meta-analysis. The analysis showed a significant increase of MDA (SMD: 15.61 [1.93, 29.29]; p=0.03) in rats with varicocele vs. controls. We also observed a significant decrease in total sperm count (SMD: -17.45 [-28.97, -5.93]; p<0.01), sperm vitality (SMD: -16.41 [-26.30, -6.52]; p<0.01), total sperm motility (SMD: -17.67 [-24.90, -10.44]; p<0.01), and a significant increase of SDF (SMD: 7.41 [1.23, 13.59]; p=0.02), in rats with varicocele vs. controls. The quality of the included studies was ranked as high.
Conclusions
This SRMA indicates a significant increase in levels of testicular MDA and SDF and a reduction of sperm quality in experimental animals with varicocele. These findings support the potential role of testicular OS in the development of varicocele-induced testicular damage.
7.Sperm banking before gonadotoxic treatment: is it worth the effort?
Kilian VOMSTEIN ; Elisabeth REISER ; Germar M PINGGERA ; Peter TOERZSOEK ; Susanne DEININGER ; Thomas KRIESCHE ; Wolfgang BIASIO ; Lukas LUSUARDI ; Bettina TOTH
Asian Journal of Andrology 2021;23(5):490-494
We aimed to compare the sperm quality in different cancer types and benign diseases before gonadotoxic treatment, and assess the usage rate of cryopreserved sperm for assisted reproductive treatment (ART). This retrospective study was conducted at two university clinics between January 2008 and July 2018. A total of 545 patients suffering from cancer or benign diseases were included in the study. The pretreatment sperm analyses were based on the World Health Organization (WHO) guidelines. Patients with testicular malignancy (TM) showed a significantly lower sperm count (median [interquartile range]: 18.7 × 10
8.Impact of Antioxidant Therapy on Natural Pregnancy Outcomes and Semen Parameters in Infertile Men: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Ashok AGARWAL ; Rossella CANNARELLA ; Ramadan SALEH ; Ahmed M. HARRAZ ; Hussein KANDIL ; Gianmaria SALVIO ; Florence BOITRELLE ; Shinnosuke KURODA ; Ala’a FARKOUH ; Amarnath RAMBHATLA ; Armand ZINI ; Giovanni COLPI ; Murat GÜL ; Parviz KAVOUSSI ; Taha Abo-Almagd Abdel-Meguid HAMODA ; Edmund KO ; Gokhan CALIK ; Tuncay TOPRAK ; Germar-Michael PINGGERA ; Hyun Jun PARK ; Ramy Abou GHAYDA ; Suks MINHAS ; Gian Maria BUSETTO ; Mustafa Emre BAKIRCIOĞLU ; Ates KADIOGLU ; Eric CHUNG ; Giorgio Ivan RUSSO ; Aldo E. CALOGERO ; Rafael F. AMBAR ; Channa N. JAYASENA ; Rupin SHAH
The World Journal of Men's Health 2023;41(1):14-48
Purpose:
Seminal oxidative stress (OS) is a recognized factor potentially associated with male infertility, but the efficacy of antioxidant (AOX) therapy is controversial and there is no consensus on its utility. Primary outcomes of this study were to investigate the effect of AOX on spontaneous clinical pregnancy, live birth and miscarriage rates in male infertile patients. Secondary outcomes were conventional semen parameters, sperm DNA fragmentation (SDF) and seminal OS.
Materials and Methods:
Literature search was performed using Scopus, PubMed, Ovid, Embase, and Cochrane databases.Only randomized controlled trials (RCTs) were included and the meta-analysis was conducted according to PRISMA guidelines.
Results:
We assessed for eligibility 1,307 abstracts, and 45 RCTs were finally included, for a total of 4,332 infertile patients.We found a significantly higher pregnancy rate in patients treated with AOX compared to placebo-treated or untreated controls, without significant inter-study heterogeneity. No effects on live-birth or miscarriage rates were observed in four studies.A significantly higher sperm concentration, sperm progressive motility, sperm total motility, and normal sperm morphology was found in patients compared to controls. We found no effect on SDF in analysis of three eligible studies. Seminal levels of total antioxidant capacity were significantly higher, while seminal malondialdehyde acid was significantly lower in patients than controls. These results did not change after exclusion of studies performed following varicocele repair.
Conclusions
The present analysis upgrades the level of evidence favoring a recommendation for using AOX in male infertility to improve the spontaneous pregnancy rate and the conventional sperm parameters. The failure to demonstrate an increase in live-birth rate, despite an increase in pregnancy rates, is due to the very few RCTs specifically assessing the impact of AOX on live-birth rate. Therefore, further RCTs assessing the impact of AOX on live-birth rate and miscarriage rate, and SDF will be helpful.
9.Effects of Varicocele Repair on Sperm DNA Fragmentation and Seminal Malondialdehyde Levels in Infertile Men with Clinical Varicocele:A Systematic Review and Meta-Analysis
Rossella CANNARELLA ; Rupin SHAH ; Ramadan SALEH ; Florence BOITRELLE ; Taha Abo-Almagd Abdel-Meguid HAMODA ; Rajender SINGH ; Gianmaria SALVIO ; Tuncay TOPRAK ; Marco FALCONE ; Murat GUL ; Fotios DIMITRIADIS ; Amarnath RAMBHATLA ; Giorgio I. RUSSO ; Edmund KO ; Armand ZINI ; Parviz KAVOUSSI ; Nguyen Ho Vinh PHUOC ; Hussein KANDIL ; Ramy Abou GHAYDA ; Ponco BIROWO ; Nazim GHERABI ; Erman CEYHAN ; Jie DONG ; Vineet MALHOTRA ; Damayanthi DURAIRAJANAYAGAM ; Bircan KOLBASI ; Fahmi BAHAR ; Gokhan CALIK ; Selahittin ÇAYAN ; Germar-Michael PINGGERA ; Aldo E. CALOGERO ; Osvaldo RAJMIL ; Taymour MOSTAFA ; Widi ATMOKO ; Ahmed M. HARRAZ ; Tan V. LE ; Jean de la ROSETTE ; Lukman HAKIM ; Edoardo PESCATORI ; Oleg SERGEYEV ; Ayman RASHED ; Pallavi SAINI ; Ashok AGARWAL
The World Journal of Men's Health 2024;42(2):321-337
Purpose:
Varicoceles can be a source of elevated seminal oxidative stress (OS) and sperm DNA fragmentation (SDF). However, it remains unclear whether varicocele repair (VR) could reduce these parameters. This systematic review and meta-analysis (SRMA) aims to investigate the impact of VR on SDF and seminal malondialdehyde (MDA).
Materials and Methods:
A literature search was performed in Scopus, PubMed, Ovid, Embase, and Cochrane databases. This SRMA included randomized controlled trials and observational studies reporting the pre- and postoperative levels of SDF and seminal OS in infertile men with clinical varicocele that underwent VR. Subgroup analyses included techniques of VR and SDF testing. The effect size was expressed as standardized mean difference (SMD).
Results:
Out of 1,632 abstracts assessed for eligibility, 29 studies with 1,491 infertile men were included. The analysis showed a significant reduction in SDF after VR, compared to preoperative values (SMD −1.125, 95% confidence interval [CI] −1.410, −0.840; p<0.0001) with high inter-study heterogeneity (I2=90.965%). Reduction in SDF was evident with microsurgical technique and non-microsurgical inguinal approaches (SMD −1.014, 95% CI −1.263, −0.765; p<0.0001, and SMD −1.495, 95% CI −2.116, −0.873; p<0.0001), respectively. Reduction in SDF was significant irrespective of testing was done by sperm chromatin dispersion (SMD −2.197, 95% CI −3.187, −1.207; p<0.0001), sperm chromatin structure assay (SMD −0.857, 95% CI −1.156, −0.559; p<0.0001) or TUNEL (SMD −1.599, 95% CI −2.478, −0.719; p<0.0001). A significant decrease in seminal MDA levels was observed following VR (SMD −2.450, 95% CI −3.903 to −0.997, p=0.001) with high inter-study heterogeneity (I2=93.7%).
Conclusions
Using pre- and post-intervention data, this SRMA indicates a significant reduction in SDF and seminal MDA levels in infertile men with clinical varicocele treated with VR. These findings may have important implications for the future management of this selected group of infertile patients.
10.Regenerative Therapy in Erectile Dysfunction:A Survey on Current Global Practice Trends and GAF Expert Recommendations
Manaf Al HASHIMI ; Germar-M PINGGERA ; Taymour MOSTAFA ; Amarnath RAMBHATLA ; Taha HAMODA ; Rupin SHAH ; Eric CHUNG ; Ahmed HARRAZ ; Mohamed ARAFA ; Tuncay TOPRAK ; Omer RAHEEM ; Carlo GIULIONI ; Ponco BIROWO ; Luca BOERI ; Yassir JASSIM ; Priyank KOTHARI ; Ranjit VISHWAKARMA ; Bahadir SAHIN ; Widi ATMOKO ; Safar GAMIDOV ; Cesar ROJAS-CRUZ ; Darren KATZ ; Adriano FREGONESI ; Nazim GHERABI ; Armand ZINI ; Christopher Chee Kong HO ; Mohamed S. AL-MARHOON ; Marlon MARTINEZ ; Giorgio Ivan RUSSO ; Ayman RASHED ; Gian Maria BUSETTO ; Edmund KO ; Hyun Jun PARK ; Selahittin CAYAN ; Ramadan SALEH ; Osvaldo RAJMIL ; Dong Suk KIM ; Giovanni COLPI ; Ryan SMITH ; Maged RAGAB ; Ates KADIOGLU ; Quang NGUYEN ; Kadir BOCU ; Ahmed EL-SAKKA ; Charalampos THOMAS ; Hussain M ALNAJJAR ; Hiva ALIPOUR ; Ashok AGARWAL
The World Journal of Men's Health 2025;43(2):359-375
Purpose:
This study aimed to examine current global practices in regenerative therapy (RT) for erectile dysfunction (ED) and to establish expert recommendations for its use, addressing the current lack of solid evidence and standardized guidelines.
Materials and Methods:
A 39-question survey was developed by senior Global Andrology Forum (GAF) experts to comprehensively cover clinical aspects of RT. This was distributed globally via a secure online Google Form to ED specialists through the GAF website, international professional societies, and social media, the responses were analyzed and presented for frequencies as percentages. Consensus on expert recommendations for RT use was achieved using the Delphi method.
Results:
Out of 479 respondents from 62 countries, a third reported using RT for ED. The most popular treatment was low-intensity shock wave therapy (54.6%), followed by platelet-rich plasma (24.5%) and their combination (14.7%), with stem cell therapy being the least used (3.7%). The primary indication for RT was the refractory or adverse effects of PDE5 inhibitors, with the best effectiveness reported in middle-aged and mild-to-moderate ED patients. Respondents were confident about its overall safety, with a significant number expressing interest in RT’s future use, despite pending guidelines support.
Conclusions
This inaugural global survey reveals a growing use of RT in ED treatment, showcasing its diverse clinical applications and potential for future widespread adoption. However, the lack of comprehensive evidence and clear guidelines requires further research to standardize RT practices in ED treatment.