US of the Penis: Beyond Erectile Dysfunction.

High-frequency US, with a linear transducer and gray-scale, color, and spectral Doppler US techniques, is the primary imaging modality for evaluation of the penis. It can allow delineation of anatomy and assessment of dynamic blood flow; it is easily available and noninvasive or minimally invasive; it is cost effective; and it is well tolerated by patients. US assessment after pharmacologic induction of erection is an additional tool in assessing patients with suspected vasculogenic impotence, and also in selected patients with penile trauma and suspected Peyronie disease. Penile injuries, life-threatening infections, and vascular conditions such as priapism warrant rapid diagnosis to prevent long-term morbidities due to clinical misdiagnosis or delayed treatment. US can facilitate a timely diagnosis in these emergency conditions, even at the point of care such as the emergency department, which can facilitate timely treatment. In addition, color and spectral Doppler US are valuable applications in the follow-up of patients treated with endovascular revascularization procedures for vasculogenic erectile dysfunction. Image optimization and attention to meticulous techniques including Doppler US is vital to improve diagnostic accuracy. Radiologists should be familiar with the detailed US anatomy, pathophysiologic characteristics, scanning techniques, potential pitfalls, and US manifestations of a wide spectrum of vascular and nonvascular penile conditions to suggest an accurate diagnosis and direct further management. The authors review a range of common and uncommon abnormalities of the penis, highlight their key US features, discuss differential diagnosis considerations, and briefly review management. ©RSNA, 2024 Supplemental material is available for this article.

Hybrid operating room with ceiling mounted imaging system assisted pre-operative and intra-operative lung nodule localization for thoracoscopic resections: a 5-year case series.

BACKGROUND: Video-assisted thoracoscopic (VATS) lung resections are increasingly popular and localization techniques are necessary to aid resection. We describe our experience with hybrid operating room (OR) cone-beam computed tomography (CT) assisted pre-operative and intra-operative lesion localization of lung nodules for VATS wedge resections, including our novel workflow using the hybrid OR cone-beam CT to re-evaluate patients who have undergone pre-operative localization for those who are unsuitable for intra-operative localization. METHODS: Retrospective analysis of all consecutive patients with small (≤ 20 mm), deep (≥ 10 mm distance from pleura) and/or predominantly ground-glass nodules selected for lesion localization in the Interventional Radiology suite followed by re-evaluation with cone-beam CT in the hybrid OR (pre-operative), or in the hybrid OR alone (intra-operative), prior to intentional VATS wedge performed by a single surgeon at our centre from January 2017 to December 2021. RESULTS: 30 patients with 36 nodules underwent localization. All nodules were successfully resected with a VATS wedge resection, although 10% of localizations had hookwire or coil dislodgement. The median effective radiation dose in the pre-operative group was 10.4 mSV including a median additional radiation exposure of 0.9 mSV in the hybrid OR for reconfirmation of hookwire or coil position prior to surgery (p = 0.87). The median effective radiation dose in the intra-operative group was 3.2 mSV with a higher mean rank than the intra-operative group, suggesting a higher radiation dose (p = 0.01). CONCLUSIONS: We demonstrate that our multidisciplinary approach utilizing the hybrid OR is safe and effective. Intra-operative localization is associated with lower radiation doses. Routine use of cone-beam CT to confirm the position of the physical marker prior to surgery in the hybrid OR helps mitigate consequences of localization failure with only a modest increase in radiation exposure.

Impact of catheter tip to hepatic vein ostium distance on the validity and prognostication of hepatic venous pressure gradient in cirrhosis.

Hepatic venous pressure gradient (HVPG) is an accurate measure of portal hypertension in cirrhosis. However, the effect of catheter tip distance from hepatic vein ostium (HVO) on HVPG is unknown. We performed a retrospective study on 228 patients with 307 HVPGs in our institution. The objectives of this study were to assess the effect of catheter position on the validity of HVPG and its prognostication in cirrhosis. In this study, free hepatic vein pressure (FHVP) was considered optimal when difference between FHVP and inferior vena cava pressure was ≤ 2 mmHg. HVPG progressively decreased (p < 0.001) when measured at increasing distance from HVO due to an increasing FHVP (p = 0.036) but an unchanged wedged hepatic vein pressure (p = 0.343). Catheter tip distance > 5 to ≤ 8 cm [odds ratio {OR} 0.16 (95% CI 0.05-0.47), p = 0.001] and > 8 cm [OR 0.14 (95% CI 0.04-0.47), p = 0.002] compared to ≤ 3 cm from HVO were independent predictors of not achieving optimal FHVP. Baseline HVPG ≥ 16 mmHg was strongly associated with deaths due to cirrhosis and liver transplantation for end-stage liver disease compared to HVPG < 16 mmHg when FHVP was optimal (p < 0.001) but not when it was suboptimal (p = 0.359). Our study showed that FHVP is spuriously elevated when measured at > 5 cm from HVO, resulting in inaccurately low HVPG.

Multimodal molecular landscape of response to Y90-resin microsphere radioembolization followed by nivolumab for advanced hepatocellular carcinoma.

BACKGROUND: Combination therapy with radioembolization (yttrium-90)-resin microspheres) followed by nivolumab has shown a promising response rate of 30.6% in a Phase II trial (CA209-678) for advanced hepatocellular carcinoma (HCC); however, the response mechanisms and relevant biomarkers remain unknown. METHODS: By collecting both pretreatment and on-treatment samples, we performed multimodal profiling of tissue and blood samples and investigated molecular changes associated with favorable responses in 33 patients from the trial. RESULTS: We found that higher tumor mutation burden, NCOR1 mutations and higher expression of interferon gamma pathways occurred more frequently in responders. Meanwhile, non-responders tended to be enriched for a novel Asian-specific transcriptomic subtype (Kaya_P2) with a high frequency of chromosome 16 deletions and upregulated cell cycle pathways. Strikingly, unlike other cancer types, we did not observe any association between T-cell populations and treatment response, but tumors from responders had a higher proportion of CXCL9+/CXCR3+ macrophages. Moreover, biomarkers discovered in previous immunotherapy trials were not predictive in the current cohort, suggesting a distinctive molecular landscape associated with differential responses to the combination therapy. CONCLUSIONS: This study unraveled extensive molecular changes underlying distinctive responses to the novel treatment and pinpointed new directions for harnessing combination therapy in patients with advanced HCC.

The Role of Drug-Coated Balloon in Haemodialysis Arteriovenous Fistula Stenosis Management.

Arteriovenous fistula (AVF) stenosis is a common problem leading to dialysis access dysfunction. The conventional balloon (CB) is the most commonly used device during angioplasty but suffers from poor durability of results due to neointimal hyperplasia-mediated recurrence. The drug-coated balloon (DCB) is an adjunct to balloon angioplasty that reduces neointimal hyperplasia, thereby improving post-angioplasty patency. Despite the heterogeneity of DCB clinical trials to date, the evidence suggests that DCBs of different brands are not necessarily equal, and that patient selection, adequate lesion preparation and proper DCB procedural technique are important to realize the benefit of DCB angioplasty.

Intraprocedural, Intra-Arterial CT Foot Perfusion Examination for Assessment of Endovascular Therapy in Patients With Critical Limb Ischemia: A Prospective Pilot Study.

BACKGROUND: Current techniques to evaluate computed tomography (CT) foot perfusion in patients with critical limb ischemia use high contrast doses and cannot be used during endovascular procedures. CT perfusion of the foot with intra-arterial contrast injection during endovascular treatment in a hybrid angiography CT suite might solve these problems. PURPOSE: The main objective of this study was to evaluate whether intra-arterial CT foot perfusion using a hybrid CT angiosystem is feasible during endovascular treatment for critical limb ischemia. MATERIAL AND METHODS: This prospective pilot study investigated intraprocedural, intra-arterial CT perfusion of the foot using a hybrid CT angiosystem in 12 patients before and after endovascular treatment for critical limb ischemia. Time to peak (TTP) and arterial blood flow were measured before and after treatment and compared using a paired t test. RESULTS: All 24 CT perfusion maps could be calculated adequately. The contrast volume used for one perfusion CT scan was 4.8 ml. The mean TTP before treatment was 12.8 seconds (standard deviation [SD] 2.8) and the mean TTP posttreatment was 8.4 seconds (SD 1.7), this difference being statistically significant (p=.001). Tendency toward increased blood flow after treatment, 340 ml/min/100 ml (SD 174) vs 514 ml/min/100 ml (SD 366) was noticed (p=.104). The mean effective radiation dose was 0.145 mSv per scan. CONCLUSION: Computed tomography perfusion of the foot with low contrast dose intra-arterial contrast injection during endovascular treatment in a hybrid angiography CT suite is a feasible technique. CLINICAL IMPACT: Intra-arterial CT foot perfusion using a hybrid CT-angiography system is a feasible new technique during endovascular therapy for critical limb ischemia to assess the results of the treament. Future research is necessary in defining endpoints of endovascular treatment and establishing its role in limb salvage prognostication.

Vascular complications related to image-guided percutaneous thermal ablation of hepatic tumors

Percutaneous thermal ablation of hepatic tumors is accepted as a safe, reliable, and cost-effective therapeutic option for treating hepatocellular carcinoma and hepatic metastases. However, operators should be familiar with the myriad of vascular and non-vascular complications that can occur post-ablation and that are described in the literature. This review will focus on the various vascular complications related to percutaneous thermal ablation of hepatic tumors and discuss strategies to avoid and manage these complications.

Endovascular salvage of failing arterio-venous fistulas utilising sirolimus eluting balloons: Six months results from the ISABELLA trial.

BACKGROUND: Aim of this pilot clinical study was to evaluate the safety and efficacy of the Selution Sustained Limus Release (SLR)™ sirolimus-eluting balloon (SEB) for improving failing arterio-venous fistulas (AVF) patency in Asian haemodialysis patients. METHODS: Prospective single-centre, multi-investigator, non-consecutive, non-blinded single arm trial. Forty end-stage renal failure Asian patients with a dysfunctional AVF underwent SEB angioplasty between May and November 2020. All stenotic lesions were prepared with high pressure non-compliant balloon angioplasty prior to SEB angioplasty. Endpoints of interest included target lesion primary patency and circuit access patency and safety through 30 days. All patients received dual antiplatelet therapy for 1 month and were followed up with Duplex ultrasound at 6 months. RESULTS: There was one subject dropout so final n = 39 patients (mean age 65.0 ± 11.9; males = 26 (66.7%)) and n = 43 target lesions treated. Main indication for intervention was dropping access flow (24/39; 61.5%) and most common target lesion was in the juxta-anastomosis (24/43; 54.5%). There was 100% technical and procedural success. There were no adverse events related to the SEB. Target lesion primary patency rates at 3 and 6 months were 39/41 (95.1%) and 28/39 (71.8%) respectively. Access circuit patency rates at 3 and 6 months were 35/37 (94.6%) and 22/35 (62.9%) respectively. There were 3 (7.7%) deaths all attributable to patients' underlying co-morbidities. CONCLUSIONS: Fistuloplasty using the novel Selution SLR™ SEB for dysfunctional AVF circuits seems a safe and effective modality in Asian haemodialysis patients at 6 months but larger randomised controlled studies are required now to determine its true efficacy against plain balloon angioplasty.

Ranger™ paclitaxel-coated balloon versus conventional balloon angioplasty for treatment of failing arteriovenous fistulas and grafts in haemodialysis patients: A retrospective cohort study.

BACKGROUND: Aim was to compare the safety and patency efficacy outcomes between Ranger™ paclitaxel-coated balloon (PCB)- versus conventional balloon angioplasty (POBA) in the treatment of haemodialysis access-related conduit stenosis. METHODS: Retrospective single-centre, multi-investigator, consecutive, double-arm comparative cohort study. About 130 end-stage renal failure Asian patients with dysfunctional arteriovenous fistula (AVF) or arteriovenous graft underwent PCB or POBA fistuloplasty between November 2018 and June 2020. All stenotic lesions were prepared with high pressure non-compliant balloon angioplasty prior to PCB angioplasty. All patients received at least one antiplatelet agent for 3 months duration post procedure. RESULTS: Mean age was 66.0 ± 10 years and 79/130 (61%) were males. PCB arm (n = 65) versus POBA arm (n = 65). Majority were AVFs circuits (122/130, 94%). Main indication for intervention was dropping access flow (98/130, 76%). About 172 lesions were treated (56% POBA, 44% PCB), and the juxta-anastomosis (JAS) was the main target lesion (87/172, 51%). There were no significant differences in safety outcomes (30-day adverse events, access thrombosis, abandoned AVF and death) between treatment groups. Mean time to target lesion reintervention (TLR) was longer in PCB-treated lesions (7.1 ± 2.7 vs 5.8 ± 3.2 months, p = 0.03), especially amongst recurrent lesions (7.3 ± 2.4 vs 5.7 ± 3.2, p = 0.02). Mean time to circuit reintervention was also longer in PCB-treated circuits (6.9 ± 2.8 vs 5.8 ± 3.7months, p = 0.04). There were 16 deaths (12%), all attributed to patient's underlying comorbidities. CONCLUSIONS: Fistuloplasty with Ranger™ PCB for failing arteriovenous circuits in end-stage renal failure patients, is a safe and efficacious modality compared to POBA in terms of longer freedom from TLR.

Use of the triple coaxial (triaxial) microcatheter system in superselective arterial embolisation for complex interventional cases: an initial experience with the system.

LEARNING OBJECTIVE: To share our experience in utilising the triple coaxial (triaxial) system in superselective cannulation of arteries for complex embolisation procedures. BACKGROUND: Percutaneous transcatheter selective embolisation is widely performed for a myriad of oncologic (e.g., trans-arterial chemo- or radio-embolisation) and non-oncologic (e.g., for embolisation of bleeding and benign conditions such as uterine fibroid and benign prostate hyperplasia) purposes. The cornerstone of such embolisation procedures is to achieve superselective cannulation of the arterial supply to the tumour/organ, preventing the complication of non-target embolisation. However, a multitude of factors, such as complex vascular anatomy, can pose challenges to achieving this goal. CLINICAL FINDINGS/PROCEDURAL DETAILS: The triaxial system utilises two smaller microcatheters telescoped through each other over a microwire. We have adopted the triaxial system for specific cases due to its perceived superior torquability and trackability compared to the conventional coaxial system, in which superselective cannulation is anticipated to be challenging. The triaxial system is also favourable in situations where the inner microcatheter needs to be "sacrificed" after administering the embolics (e.g., after administering radioisotopes in radioembolisation, N-butyl cyanoacrylate [NBCA] glue or ethylene-vinyl alcohol copolymer [EvOH] Onyx). Through a case series with procedural details such as fluoroscopic time, contrast administered, etc., we hope to illustrate the utility and efficacy of the triaxial system as well as present pitfalls in its usage. CONCLUSION: The triaxial system appears to be a valuable system for certain complex embolisation procedures and could be better suited than the conventional coaxial systems in these specific circumstances.

Study protocol for a Prospective, Randomized controlled trial of stEnt graft and Drug-coated bAlloon Treatment for cephalic arch stenOsis in dysfunctional arteRio-venous fistulas (PREDATOR).

BACKGROUND: Treatment of cephalic arch stenosis (CAS) is associated with high risk of failure and complications. Although stent-graft (SG) placement has improved patency rates, stent edge restenosis has been raised as a potential limiting factor for SG usage in CAS. This study aims to evaluate the safety and efficacy of combining stent graft placement with paclitaxel-coated balloon (PCB) angioplasty versus PCB alone in the treatment of CAS. METHODS: This is an investigator-initiated, prospective, international, multicenter, open-label, randomized control clinical trial that plans to recruit 80 patients, who require fistuloplasty from dysfunctional arteriovenous fistula (AVF) from CAS. Eligible participants are randomly assigned to receive treatment with SG and PCB or PCB alone in a 1:1 ratio post-angioplasty (n = 40 in each arm). Randomization is stratified by de novo or recurrent lesion, and the participants are followed up for 1 year. The primary endpoints of the study are target lesion primary patency (TLPP) and access circuit primary patency (ACPP) rates at 6-months. The secondary endpoints are TLPP and ACPP at 3- and 12-month; target lesion and access circuit assisted primary and secondary patency rates at 3, 6, and 12-months and the total number of interventions; complication rate; and cost-effectiveness. DISCUSSION: This study will evaluate the clinical efficacy and safety of combination SG and PCB implantation compared to PCB alone in the treatment of CAS for hemodialysis patients.

A Randomized Phase 2 Trial of Nivolumab Versus Nivolumab-Ipilimumab Combination in EGFR-Mutant NSCLC.

Introduction: Although immune checkpoint inhibitors (ICIs) have dramatically improved outcomes for nononcogene-addicted NSCLC, monotherapy with programmed cell death protein-1 (PD1) inhibition has been associated with low efficacy in the EGFR-mutant setting. Given the potential for synergism with combination checkpoint blockade, we designed a trial to test the activity of combination nivolumab (N)-ipilimumab (NI) in EGFR-mutant NSCLC. Methods: This is a randomized phase 2 study (NCT03091491) of N versus NI combination in EGFR tyrosine kinase inhibitor (TKI)-resistant NSCLC, with crossover permitted on disease progression. The primary end point was the objective response rate, and the secondary end points included progression-free survival, overall survival, and safety of ICI after EGFR TKI. Results: Recruitment ceased owing to futility after 31 of 184 planned patients were treated. A total of 15 patients received N and 16 received NI combination. There were 16 patients (51.6%) who had programmed death-ligand (PDL1) 1 greater than or equal to 1%, and 15 (45.2%) harbored EGFR T790M. Five patients derived clinical benefits from ICI with one objective response (objective response rate 3.2%), and median progression-free survival was 1.22 months (95% confidence interval: 1.15-1.35) for the overall cohort. None of the four patients who crossed over achieved salvage response by NI. PDL1 and tumor mutational burden (TMB) were not able to predict ICI response. Rates of all grade immune-related adverse events were similar (80% versus 75%), with only two grade 3 events. Conclusions: Immune checkpoint inhibition is ineffective in EGFR TKI-resistant NSCLC. Whereas a small subgroup of EGFR-mutant NSCLC may be immunogenic and responsive to ICI, better biomarkers are needed to select appropriate patients.

Recurrent Stenoses in Arteriovenous Fistula (AVF) for Dialysis Access: cuttIng ballooN angioplaSTy combined wITh paclitaxel drUg-coaTed balloon angioplasty, an observatIONal study (INSTITUTION Study).

PURPOSE: To study the safety and efficacy of cutting balloon angioplasty (CBA) followed by paclitaxel drug-coated balloon (PCB) angioplasty for recurrent venous lesions in arteriovenous fistulas (AVFs). MATERIALS AND METHODS: We conducted a prospective single-arm cohort study of CBA followed by PCB angioplasty for recurrent AVF stenoses between September 2017 and April 2019. In total, 44 participants were recruited. Target lesions were included if they had recurred within 12 months post-angioplasty, were > = 0.5 cm upstream from the arteriovenous anastomosis, and did not involve the central veins. Up to two non-target lesions per circuit/participant with the same definition were allowed. Lesions were considered separate when there was an intervening 2-cm segment of normal vessel. Technical success was defined as complete lesion effacement on angioplasty. End-points of target and circuit patency were evaluated clinically at 3, 6, and 12 months post-procedure. RESULT: Technical success was 96% (42/44): Two participants were excluded from analysis due to the need for high-pressure balloon angioplasty as the target lesions did not efface with CBA. The median follow-up duration was 337.5 days. Mean stenosis pre- and post-angioplasty was 69.0% (51.6-84.8) and 20.8% (0-44.8), respectively. The target lesion primary, primary assisted and circuit patency for the entire study population (n = 42) were 61.6 ± 7.8%, 92.7 ± 4.0%, and 54.7 ± 7.9%, respectively, at 12 months. For participants without non-target lesions (n = 22), the rates were 77.3 ± 8.9%, 90.9 ± 6.1%, and 60.7 ± 11.0%, respectively, at 12 months. CONCLUSION: CBA followed by PCB angioplasty appears safe and feasible for treatment of recurrent venous lesions in dysfunctional AVFs.

A Tale of Two Organ Systems: Imaging Review of Diseases Affecting the Thoracic and Neurological Systems. Part 2.

In an era of rapidly expanding knowledge and sub-specialization, it is becoming increasingly common to focus on one organ system. However, the human body is intimately linked, and disease processes affecting one region of the body not uncommonly affect the other organ systems as well. Understanding diseases from a macroscopic perspective, rather than a narrow vantage point, enables efficient and accurate diagnosis. This tenet holds true for diseases affecting both the thoracic and neurologic systems; in isolation, the radiologic appearance of disease in one organ system may be nonspecific, but viewing the pathophysiologic process in both organ systems may markedly narrow the differential considerations, and potentially lead to a definitive diagnosis. In this article, we discuss a variety of disease entities known to affect both the thoracic and neurological systems, either manifesting simultaneously or at different periods of time. Some of these conditions may show neither thoracic nor neurological manifestations. These diseases have been systematically classified into infectious, immune-mediated/ inflammatory, vascular, syndromic/ hereditary and neoplastic disorders. The underlying pathophysiological mechanisms linking both regions and radiologic appearances in both organ systems are discussed. When appropriate, brief clinical and diagnostic information is provided. Ultimately, accurate diagnosis will lead to expedited triage and prompt institution of potentially life-saving treatment for these groups of complex disorders.

A Tale of Two Organ Systems: Imaging review of diseases affecting the thoracic and neurological systems. Part 1.

In an era of rapidly expanding knowledge and sub-specialization, it is becoming increasingly common to focus on one organ system. However, the human body is intimately linked, and disease processes affecting one region of the body not uncommonly affect the other organ systems as well. Understanding diseases from a macroscopic perspective, rather than a narrow vantage point, enables efficient and accurate diagnosis. This tenet holds true for diseases affecting both the thoracic and neurological systems; in isolation, the radiologic appearance of disease in one organ system may be nonspecific, but viewing the pathophysiologic process in both organ systems may markedly narrow the differential considerations, and potentially lead to a definitive diagnosis. In this article, we discuss a variety of disease entities known to affect both the thoracic and neurological systems, either manifesting simultaneously or at different periods of time. Some of these conditions may show neither thoracic nor neurological manifestations. These diseases have been systematically classified into infectious, immune-mediated / inflammatory, vascular, syndromic / hereditary and neoplastic disorders. The underlying pathophysiological mechanisms linking both regions and radiologic appearances in both organ systems are discussed. When appropriate, brief clinical and diagnostic information is provided. Ultimately, accurate diagnosis will lead to expedited triage and prompt institution of potentially life-saving treatment for these groups of complex disorders.

SIroliMus coated angioPlasty versus plain balloon angioplasty in the tREatment of dialySis acceSs dysfunctION (IMPRESSION): study protocol for a randomized controlled trial.

BACKGROUND: Percutaneous transluminal angioplasty is the current standard treatment for arteriovenous fistula (AVF) stenosis. The mid- and long-term patency with plain balloon angioplasty (PBA) is however far from satisfactory. While paclitaxel-coated balloon angioplasty has been shown to be superior to PBA, concern over its safety profile has recently arisen after a reported possible increased mortality risk with a meta-analysis of large lower limb studies. An angioplasty balloon with a new type of drug coating, the sirolimus-coated balloon (SCB), has been proven to improve patency in the coronary arteries. However, its effect on AV access has yet to be studied. METHODS/DESIGN: This is an investigator-initiated, prospective, multicenter, double-blinded, randomized controlled clinical trial to assess the effectiveness of SCB compared to PBA in improving the patency of AVF after angioplasty. A total of 170 patients with mature AVF that requires PTA due to AVF dysfunction will be randomly assigned to treatment with a SCB or PBA at a 1:1 ratio, stratified by location of AVF and followed up for up to 1 year. The inclusion criteria include [1] adult patient aged 21 to 85 years who requires balloon angioplasty for dysfunctional arteriovenous fistula [2]; matured AVF, defined as being in use for at least 1 month prior to the angioplasty; and [3] successful angioplasty of the underlying stenosis with PBA, defined as less than 30% residual stenosis on digital subtraction angiography (DSA) and restoration of thrill in the AVF on clinical examination. The exclusion criteria include thrombosed or partially thrombosed access circuit at the time of treatment, presence of symptomatic or angiographically significant central vein stenosis that requires treatment with more than 30% residual stenosis post angioplasty, and existing stent placement within the AVF circuit. The primary endpoint of the study is access circuit primary patency at 6 months. The secondary endpoints are target lesion primary patency; access circuit-assisted primary patency; access circuit secondary patency at 3, 6, and 12 months; target lesion restenosis rate at 6 months; total number of interventions; complication rate; and cost-effectiveness. The trial is supported by Concept Medical. DISCUSSION: This study will evaluate the clinical efficacy and safety of SCB compared to PBA in the treatment of AVF stenosis in hemodialysis patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT04409912 . Registered on 1 June 2020.