Search

Greyscale and color doppler ultrasound are the standard when investigating testicular lesions. However, they cannot provide information on the microvasculature. As such, differentiating benign from malignant tumors is challenging. Contrast-enhanced ultrasound (CEUS) uses ultrasound contrast agents that are exclusively intravascular to image the microvasculature. This review assessed CEUS outcomes in investigating intratesticular lesions and concluded that qualitative CEUS provides the most advantage by confirming vascularity, thus differentiating non-neoplastic from neoplastic lesions with added confidence, allowing for appropriate management. Whilst results for quantitative CEUS are promising in distinguishing malignant from benign neoplasms, further research on its benefits is required.

There is growing interest in the use of contrast-enhanced ultrasound (CEUS) in diagnostic and interventional radiology. CEUS applications in interventional radiology are performed with intravascular or intracavitary administration of microbubble-based US contrast agents to allow for real-time evaluation of their distribution within the vascular bed or in body cavities, respectively, providing additional information beyond gray-scale US alone. The most common interventional-radiology-related CEUS applications in children have been extrapolated from those in adults, and they include the use of CEUS to guide lesion biopsy and to confirm drain placement in pleural effusions and intra-abdominal fluid collections. Other applications are emerging in interventional radiology for use in adults and children, including CEUS to optimize sclerotherapy of vascular malformations, to guide arthrography, and for lymphatic interventions. In this review article we present a wide range of interventional-radiology-related CEUS applications, emphasizing the current and potential uses in children. We highlight the technical parameters of the CEUS examination and discuss the main imaging findings.

In pediatric and adult populations, intravenous contrast-enhanced ultrasound (CEUS) remains off-label for imaging of organs other than the liver and heart. This limited scope inhibits potential benefits of the new modality from a more widespread utilization. Yet, CEUS is potentially useful for imaging small organs such as the thyroid gland, lymph nodes, testes, ovaries and uterus, with all having locations and vasculature favorable for this type of examination. In the adult population, the utility of CEUS has been demonstrated in a growing number of studies for the evaluation of these small organs. The aim of this article is to present a review of pediatric CEUS of the thyroid gland, lymph nodes, testes, ovaries and uterus as well as to draw from the adult literature indications for possible applications in children. Supplementary Information The online version contains supplementary material available at 10.1007/s00247-021-05006-x.

Lung cancer is one of the commonest malignancies worldwide and necessitates both early and personalised treatment. A key requirement is histological sampling with immunohistochemistry obtained usually from percutaneous biopsy. Conventionally thoracic biopsies are performed using CT guidance, but more recently, there has been development of physician led ultrasound biopsy for pleural lesions. Contrast-enhanced ultrasound (CEUS) has been increasingly used in interventional procedures and is able to offer benefits for thoracic biopsies including improving lesional visualisation and characterisation, targeting viable tissue and avoiding critical vascular structures as well as evaluating for the presence of post-procedural complications. This educational review aims to benefits of the role of CEUS in thoracic biopsies.

The aim of this study is to assess the additional benefit of contrast-enhanced ultrasound (CEUS) over conventional ultrasonography (US) in identifying intra-testicular abnormalities among observers of different experiences. In this study, 91 focal testicular lesions (46 neoplastic, 45 non-neoplastic) imaged with gray-scale US/Doppler US and CEUS were classified using a 5-point scale. Three experienced and four inexperienced observers rated each lesion using gray-scale/color Doppler US alone and then with the addition of CEUS. Improved diagnostic specificity and accuracy with the addition of CEUS was observed for both experienced (specificity: 71.1% vs. 59.3%, p = 0.005; accuracy: 83.5% vs. 76.9%, p = 0.003) and inexperienced observers (specificity: 75.6% vs. 51.7%, p = 0.005; accuracy: 80.2% vs. 72.0%, p0.001). Significant inter-observer variability between the experienced and inexperienced observers when assessing conventional US alone was eliminated with the addition of CEUS. CEUS improves diagnostic accuracy of focal intra-testicular lesions for both experienced and inexperienced observers and reduces inter-observer variability in inexperienced operators.

OBJECTIVES The purpose of this study was to quantify contrast-enhanced ultrasound enhancement of focal fatty sparing (FFS) and focal fatty infiltration (FFI) and compare it with adjacent liver parenchyma. METHODS This was a retrospective observational study yielding 42 cases in the last 4 years. Inclusion criteria were a focal liver lesion, adequate video availability, and an established diagnosis of FFS or FFI based on clinical or imaging follow-up or a second modality. Contrast-enhanced ultrasound examinations were performed with a standard low-mechanical index technique. Commercially available software calculated quantitative parameters for a focal liver lesion and a reference area of liver parenchyma, producing relative indices. RESULTS In total, 42 patients were analyzed (19 male) with a median age of 18 (interquartile range, 42) years and a median lesion diameter of 30 (interquartile range, 16) mm. The cohort included 26 with FFS and 16 with FFI. Subjectively assessed, 27% of FFS and 25% of FFI were hypoenhancing in the arterial phase, and 73% of FFS and 75% of FFI were isoenhancing. In the venous and delayed phases, all lesions were isoenhancing. The peak enhancement (P = .001), wash-in area under the curve (P

Background Acute Kidney Injury (AKI) is a common complication of COVID-19 critical illness but the pathophysiology is uncertain. Some evidence has indicated that a vascular aetiology may be implicated. We used contrast enhanced ultrasound (CEUS) and echocardiography to study renal perfusion and global blood flow and compared our findings with measurements taken in a group of septic shock patients and healthy volunteers. Methods Prospective case-control study. Renal perfusion variables were assessed with contrast enhanced ultrasound (CEUS); macrovascular blood flow was assessed using Doppler analysis of large renal vessels; echocardiography was used to assess right and left heart function and cardiac output. Results CEUS derived parameters were reduced in in COVID-19 associated AKI compared to healthy controls (perfusion index 3415 v 548 a.u., p = 0·001; renal blood volume 7794 v 3338 a.u., p = 0·04). Renal arterial flow quantified using time averaged peak velocity (TAPV) was also reduced compared to healthy controls (36·6 v 20·9 cm/s, p = 0.004) despite cardiac index being similar between groups (2.8 v 3.7 L/min/m2, p = 0.07). There were no differences in CEUS derived or cardiac parameters between COVID-19 and septic shock patients but patients with septic shock had more heterogeneous perfusion variables. Conclusion Both large and small vessel blood flow is reduced in patients with COVID-19 associated AKI compared to healthy controls, which does not appear to be a consequence of right or left heart dysfunction. A reno-vascular pathogenesis of COVID-19 AKI seems likely.

Although often asymptomatic and detected incidentally, varicocele is a relatively common problem in patients who seek medical attention for infertility problems. Ultrasound (US) is the imaging modality of choice for evaluation, but there is no consensus on the diagnostic criteria, classification, and examination technique. In view of this uncertainty, the Scrotal and Penile Imaging Working Group of the European Society of Urogenital Radiology (ESUR-SPIWG) undertook a systematic review of the available literature on this topic, to use as the basis for evidence-based guidelines and recommendations. This paper provides the results of the systematic review on which guidelines were constructed.

Ultrasonography (US) is the first-line modality for the evaluation of vascular pathology. Although well-established for many diseases, US has inherent limitations that can occasionally hinder an accurate diagnosis. The value of US was improved by the introduction of microbubbles as ultrasonographic contrast agents (UCAs) and the emergence of contrast-enhanced ultrasonography (CEUS), following the introduction of second-generation UCAs and the emergence of modern contrast-specific techniques. CEUS offers valuable information about vascular disease, both on a macrovascular and a microvascular level, with well-established applications for carotid disease, post-interventional follow-up of abdominal aortic aneurysms, and the assessment of portal vein thrombosis. The purpose of this review is to discuss the principles of CEUS and to present an overview of its vascular applications.

A 64-year-old male, with a history of chronic urinary outflow obstruction secondary to benign prostatic hyperplasia, presented with haematuria and urinary retention following spontaneous removal of his long-term catheter. The patient was septic on admission and a CT examination of the abdomen and pelvis showed an acutely inflamed urinary bladder diverticulum and extensive intra-abdominal free air. The patient was treated medically for emphysematous cystitis centred on a perforated bladder diverticulum, which was thought to be caused by the underlying infectious/inflammatory process. Alternative aetiologies for free air in the abdomen such a traumatic bladder perforation and gastrointestinal perforation were considered and excluded. The patient responded well to medical management and was discharged after an 11 day in-patient stay.

As a relatively new sonographic technique, tissue elastography has emerged as a qualitative and potentially quantitative adjunctive tool to provide additional information on tissue stiffness, aiming to further improve diagnostic confidence in discriminating benign from malignant focal testicular lesions. The purpose of this review is to provide an overview of the elastography techniques used to assess focal testicular lesions and their typical appearance on tissue elastography.

// Elgilda Musi 1 , Gary K. Schwartz 1 , 2 , Jae Hyuk Yoo 3 , Shannon J. Odelberg 3 , 4 , 6 , Dean Y. Li 3 , 5 , 6 , 7 , Michael Y. Bonner 8 , Ponniah Selvakumar 9 , Shikha Rao 8 , Linda C. Gilbert 8 , 10 , Justin Elsey 8 and Jack L. Arbiser 8 , 10 1 Department of Medicine, Columbia University Medical Center, New York, New York, USA 2 Herbert Irving Comprehensive Cancer Center, Columbia University College of Medicine, New York, New York, USA 3 Department of Medicine, Program in Molecular Medicine, University of Utah, Salt Lake City, Utah, USA 4 Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, Utah, USA 5 Department of Human Genetics, University of Utah, Salt Lake City, Utah, USA 6 Department of Internal Medicine, Division of Cardiovascular Medicine, University of Utah, Salt Lake City, Utah, USA 7 Department of Oncological Sciences, University of Utah, Salt Lake City, Utah, USA 8 Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia, USA 9 Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada 10 Veterans Affairs Medical Center, Decatur, Georgia, USA Correspondence to: Jack L. Arbiser, email: jarbise@emory.edu Keywords: melanoma; chemotherapy Received: April 09, 2019 Accepted: June 05, 2019 Published: July 09, 2019 ABSTRACT Uveal melanoma is a rare but often lethal malignancy and is the leading cause of death due to an ophthalmic condition. Uveal melanoma is often diagnosed at a late stage and has a strong propensity to hepatic metastasis. Recently, the most common driver mutations in uveal melanoma have been identified, predominantly in the G-proteins GNAQ. This pattern differs from that of cutaneous melanoma in which Braf and Nras predominate. There are no current clinically used agents that target GNAQ mutations, unlike the use of Braf inhibitors in cutaneous melanoma. We tested the novel agent Tris DBA palladium and found that it was markedly more effective against GNAQ mutant melanomas than wild type uveal melanomas. Given that ARF6 has recently been discovered as a node in GNAQ mutations, we evaluated the efficacy of Tris DBA palladium on ARF6 signaling and found that it was effective in inhibiting ARF6 activation. Finally, Tris DBA palladium was orally effective against GNAQ mutant melanoma in vivo . Tris DBA Palladium deserves further evaluation as a systemic agent for uveal melanoma.

Background Renal patients with a tunnelled haemodialysis line are at risk of fibrin ‘sheath’ formation which can lead to occlusion. Dysfunctional lines are best treated by catheter exchange with a new subcutaneous tunnel; however, there is a risk of scarring, venous stenosis, potential loss of valuable access as well as the risk of infection. Method We report a retrospective review of our experience using tunnelled line intraluminal plasty (TuLIP) in 11 patients over 16 months with fibrin sheath formation on pre-existing tunnelled haemodialysis catheters. Result All patients responded well to treatment with median line patency post TuLIP reaching 112 days. Conclusion TuLIP may have a role in extending catheter lifespan and delaying more invasive intervention.

Promoting intestinal epithelial regeneration remains a major medical challenge. Female patients taking nonsteroidal anti-inflammatory drugs are less likely to have upper gastrointestinal bleeding and ulcers than males. Using a nonsteroidal anti-inflammatory drug-induced intestinal damage mouse model, we verified that female mice recover faster than males following acute intestinal insult. Using ex vivo intestinal organoid cultures, we showed that estrogen is necessary and sufficient in enhancing the female organoid formation from breached isolated crypts via the estrogen receptor β receptor. Thus, estrogen promotes female intestinal epithelial organoid regeneration to lower the incidence of intestinal bleeding and ulceration. Animal studies were approved by University of Utah IACUC under protocol number 16-05012 and 18-02010. Key words: estrogen; non-steroidal anti-inflammatory drugs; regeneration; small bowel; stem cells; upper gastrointestinal bleeding

BACKGROUND Ultrasound (US) is the primary modality for the investigation of scrotal pathology, including both intra- and paratesticular abnormalities. OBJECTIVE To describe the abnormalities of the paratesticular space. MATERIALS/METHODS The paratesticular space contains the epididymis, spermatic cord and the tunica vaginalis cavity and is affected by a variety of inflammatory or tumoral entities. Differential diagnosis based on US criteria is frequently problematic, as the findings are non-specific. RESULTS Some general rules apply: (i) unlike testicular lesions, extra-testicular entities are usually benign in the adult, (ii) the first steps to accurate diagnosis include careful localization of the lesion and assessment of its consistency (solid or cystic) and (iii) magnetic resonance imaging can be useful for further tissue characterization of lesions suspected to contain fat, but surgical biopsy will often provide the definite diagnosis. Contrast-enhanced ultrasound (CEUS) has been applied with limited experience indicating a narrow role, primarily for the differential diagnosis of echogenic cystic entities and the delineation of a necrotic abscess from a solid neoplasm. DISCUSSION The various abnormalities are discussed and illustrated. CONCLUSION This manuscript summarizes the literature on paratesticular lesions and the value of US in diagnosis.

Simple Summary Innovative strategies to reduce immune suppression and activate tumor-specific immunity are needed to help patients who do not respond or become resistant to immune checkpoint blockade therapies. In this study, we demonstrate that the addition of a cancer vaccine targeting a tumor-associated antigen to a checkpoint inhibitor-based immunotherapy induces greater numbers of proliferative, activated, and cytotoxic tumor-infiltrating T cells, leading to improved antitumor activity in tumors otherwise resistant to immunotherapy. Our results provide the rationale for the addition of cancer vaccines in combination immunotherapy approaches being evaluated in the clinic. Abstract Resistance to immune checkpoint blockade therapy has spurred the development of novel combinations of drugs tailored to specific cancer types, including non-inflamed tumors with low T-cell infiltration. Cancer vaccines can potentially be utilized as part of these combination immunotherapies to enhance antitumor efficacy through the expansion of tumor-reactive T cells. Utilizing murine models of colon and mammary carcinoma, here we investigated the effect of adding a recombinant adenovirus-based vaccine targeting tumor-associated antigens with an IL-15 super agonist adjuvant to a multimodal regimen consisting of a bifunctional anti-PD-L1/TGF-βRII agent along with a CXCR1/2 inhibitor. We demonstrate that the addition of vaccine induced a greater tumor infiltration with T cells highly positive for markers of proliferation and cytotoxicity. In addition to this enhancement of cytotoxic T cells, combination therapy showed a restructured tumor microenvironment with reduced Tregs and CD11b+Ly6G+ myeloid cells. Tumor-infiltrating immune cells exhibited an upregulation of gene signatures characteristic of a Th1 response and presented with a more diverse T-cell receptor (TCR) repertoire. These results provide the rationale for the addition of vaccine-to-immune checkpoint blockade-based therapies being tested in the clinic.

Aim The diabetic foot attack (DFA) is perhaps the most devastating form of diabetic foot infection, presenting with rapidly progressive skin and tissue necrosis, threatening both limb and life. However, clinical outcome data in this specific group of patients are not available. Methods Analysis of 106 consecutive patients who underwent emergency hospitalisation for DFA (TEXAS Grade 3B or 3D and Infectious Diseases Society of America (IDSA) Class 4 criteria). Outcomes evaluated were: 1) Healing 2) major amputation 3) death 4) not healed. The first outcome reached in one of these four categories over the follow-up period (18.4±3.6 months) was considered. We also estimated amputation free survival. Results Overall, 57.5% (n=61) healed, 5.6% (n=6) underwent major amputation, 23.5% (n=25) died without healing and 13.2% (n=14) were alive without healing. Predictive factors associated with outcomes were: Healing (age100 mg/L, p=0.001; gram+ve organisms, p=0.0013; dialysis, p= 0.001), and for death (age>60, p= 0.0001; gram+ve organisms p=0.004; presence of PAD, p=0.0032; CRP, p=0.034). The major amputation free survival was 71% during the first 12 months from admission, however it had reduced to 55.4% by the end of the follow-up period. Conclusions In a unique population of hospitalised individuals with DFA, we report excellent healing and limb salvage rates using a dedicated protocol in a multidisciplinary setting. An additional novel finding was the concerning observation that such an admission was associated with high 18-month mortality, almost all of which was after discharge from hospital.

Imaging plays a crucial role in the evaluation of scrotal trauma. Among the imaging modalities, greyscale ultrasound and Colour Doppler ultrasound (CDUS) are the primary techniques with the selective utilisation of advanced techniques such as contrast-enhanced ultrasound (CEUS) and elastography. Despite ultrasound being the mainstay of imaging scrotal trauma, its diagnostic performance is not fully established. Considering these difficulties and their impact on clinical practice, the Scrotal and Penile Imaging Working Group of the European Society of Urogenital Radiology (ESUR-SPIWG) established an expert task force to review the current literature and consolidate their expertise on examination standards and imaging appearances of various entities in scrotal trauma. This paper provides the position statements agreed on by the task force with the aim of providing guidance for the use of imaging especially multiparametric US in scrotal trauma. Key Points • Greyscale and Colour Doppler ultrasound are the mainstay of imaging in patients with scrotal trauma. • Contrast-enhanced ultrasound and elastography are the advanced techniques useful as a problem-solving modality in equivocal cases. • This paper summarises the position statements of the ESUR-SPIWG on the appropriate utilisation of multiparametric ultrasound and other imaging modalities in the evaluation of scrotal trauma.

A 65-year-old woman presented with haematuria and hypovolaemic shock. Her medical history includes International Federation of Gynaecology and Obstetrics (FIGO) stage IIIC2 serous endometrial carcinoma diagnosed 5 years previously, which was treated with transabdominal hysterectomy and bilateral

The ability to perform an invasive procedure in a child with minimum discomfort and maximum success is paramount. The ability of interventional radiology to offer timely, minimally invasive procedures as transformed many events in the child. Often the minimally invasive interventional procedure is performed in the traditional imaging scenario under fluoroscopic, computed tomography or increasing under magnetic resonance guidance. However, using just ultrasound guidance is often a suitable technique, as this modality is child-friendly and without ionising radiation. The ability to further improve the technical success of a procedure, such as a biopsy from viable tissue, is considerably improved with the addition of an ultrasound contrast agent. The safety record of these agents and the ability to image in most areas of the body, intravascular or intracavitary, allows for the continuing development and success of ultrasound-guided interventional procedures in children.

Ultrasound (US) plays a pivotal role in the diagnostic approach of paediatric scrotal disease. Grayscale and Doppler US imaging techniques offer detailed anatomic and physiological information. Contrast-enhanced ultrasound (CEUS) is a valuable complementary technique in many common paediatric scrotal abnormalities including spermatic cord torsion, inflammatory conditions, trauma and neoplasms. CEUS allows increased sensitivity for evaluation of tissue perfusion and vasculature architecture, is able to delineate ischaemic tissue, for evidence of infarction in the setting of spermatic cord torsion. In the case of trauma lack of enhancement on CEUS would indicate necrotic tissue or a haematoma. In complicated epididymo-orchitis CEUS characterizes abscess formation or venous infarction. A CEUS examination would finally exclude any internal vascularity in a complex cystic structure or demonstrate the vascular architecture in detail and enhancement pattern in real time, indicating the diagnosis of a neoplasm.

The rise in multidrug-resistant (MDR) organisms portends a serious global threat to the health care system with nearly untreatable infectious diseases, including pneumonia and its often fatal sequelae, acute respiratory distress syndrome (ARDS) and sepsis. Gram-negative bacteria (GNB), including Acinetobacter baumannii, Pseudomonas aeruginosa, and carbapenemase-producing Klebsiella pneumoniae (CPKP), are among the World Health Organization’s and National Institutes of Health’s high-priority MDR pathogens for targeted development of new therapies. Here, we show that stabilizing the host’s vasculature by genetic deletion or pharmacological inhibition of the small GTPase ADP-ribosylation factor 6 (ARF6) increases survival rates of mice infected with A. baumannii, P. aeruginosa, and CPKP. We show that the pharmacological inhibition of ARF6-GTP phenocopies endothelium-specific Arf6 disruption in enhancing the survival of mice with A. baumannii pneumonia, suggesting that inhibition is on target. Finally, we show that the mechanism of protection elicited by these small-molecule inhibitors acts by the restoration of vascular integrity disrupted by GNB lipopolysaccharide (LPS) activation of the TLR4/MyD88/ARNO/ARF6 pathway. By targeting the host’s vasculature with small-molecule inhibitors of ARF6 activation, we circumvent microbial drug resistance and provide a potential alternative/adjunctive treatment for emerging and reemerging pathogens.

Testicular trauma is common, usually trivial and rarely requires hospital attendance, but if it does, then imaging becomes essential as scrotal assessment may be difficult due to pain and/or scrotal disruption. Ultrasound (US) assumes a crucial role as other cross-sectional modalities have a limited use in the acute presentation. Despite the acceptable accuracy of conventional US techniques, there are limitations which hinder a thorough evaluation, critically the assessment of tissue viability, crucial for clinical management and prognosis. Contrast-enhanced ultrasound (CEUS) has been shown to offer improved flow visualisation and tissue perfusion compared with conventional Doppler techniques. CEUS can accurately and confidently demonstrate the viability of testicular parenchyma, delineate fracture lines and haematomas and guide treatment for testis-sparing surgery or orchidectomy. The purpose of this review is to present the literature, familiarise physicians with the principles of CEUS and findings of scrotal trauma and illustrate the main abnormalities through characteristic and educative cases.

The clinical success of uterine artery embolization is determined by its endpoint. An aggressive UAE could lead to endometritis and increases the risk of unintended embolization of other organs. Conversely, an incomplete procedure may result in a poor clinical outcome due to regrowth of the fibroids. We present a case with innovative use of intraoperative contrast-enhanced ultrasonography (CEUS) for the assessment of vascularity of the targeted fibroid to determine the endpoint of embolization perioperatively. We aim to report a case of the use of intraoperative CEUS during UAE to highlight the potential pitfall of its use and provide a review of its application in the literature. Our case affirms the reported usefulness and the practical feasibility to assess the vascularity of fibroids during UAE and highlights that caution should be made by operators in cases of multiple fibroids.

The rise in multidrug resistant (MDR) organisms portends a serious global threat to the healthcare system with nearly untreatable infectious diseases, including pneumonia and its often fatal sequelae, acute respiratory distress syndrome (ARDS) and sepsis. Gram-negative bacteria (GNB) including Acinetobacter baumannii, Pseudomonas aeruginosa, and carbapenemase-producing Klebsiella pneumoniae (CPKP), are among the World Health Organization and National Institutes of Health’s high priority MDR pathogens for targeted development of new therapies. Here we show that stabilizing the host’s vasculature by genetic deletion or pharmacological inhibition of the small GTPase ADP-ribosylation factor 6 (ARF6) increases survival rates of mice infected with A. baumannii, P. aeruginosa, CPKP pneumonia. We show that pharmacological inhibition of ARF6-GTP phenocopies endothelial-specific Arf6 disruption in enhancing survival of mice with A. baumannii pneumonia, suggesting that inhibition is on target. Finally, we show that the mechanism of protection elicited by these small molecule inhibitors is by restoration of vascular integrity disrupted by GNB lipopolysaccharide (LPS) activation of TLR4/MyD88/ARNO/ARF6 pathway. By targeting the host’s vasculature with small molecule inhibitors of ARF6 activation, we circumvent microbial drug resistance and provide a potential alternative/adjunctive treatment for emerging and re-emerging pathogens.

Background: Acute Kidney Injury (AKI) is a common complication of COVID-19 critical illness but the pathophysiology is uncertain. Some evidence has indicated that a vascular aetiology may be implicated. We used contrast enhanced ultrasound (CEUS) and echocardiography to study renal perfusion and global blood flow and compared our findings with measurements taken in a group of septic shock patients and healthy volunteers. Method: Prospective case-control study. Renal perfusion variables were assessed with contrast enhanced ultrasound (CEUS); macrovascular blood flow was assessed using Doppler analysis of large renal vessels; echocardiography was used to assess right and left heart function and cardiac output. Findings: CEUS derived parameters were reduced in in COVID-19 associated AKI compared to healthy controls (perfusion index 3415 v 548 a.u., p=0·001; renal blood volume 7794 v 3338 a.u., p=0·04). Renal arterial flow quantified using time averaged peak velocity (TAPV) was also reduced compared to healthy controls (36·6 v 20·9 cm/s, p=0.004) despite cardiac index being similar between groups (2.8 v 3.7 L/min/m2, p=0.07). There were no differences in CEUS derived or cardiac parameters between COVID-19 and septic shock patients but patients with septic shock had more heterogeneous perfusion variables. Interpretation:Both large and small vessel blood flow is reduced in patients with COVID-19 associated AKI compared to healthy controls, which does not appear to be a consequence of right or left heart dysfunction. A reno-vascular pathogenesis of COVID-19 AKI seems likely. Funding: Royal Centre for Defence Medicine (UK Ministry of Defence), 2019; European Society of Intensive Care Medicine Point of Care Ultrasound award, 2019 Declaration of Interests: All authors declare that they have no conflicts of interest. Ethics Approval Statement: Yorkshire and Humber (Leeds East) Research Ethics committee (18/YH/0371).

Tramadol is widely used globally and is the second most prescribed opioid in the United States. It treats moderate to severe pain but lethal opioid-induced respiratory depression is uncommon even in large overdose. It is unknown why tramadol spares respiration. Here we show its active metabolite, desmetramadol, is as effective as morphine, oxycodone and fentanyl in eliciting G protein coupling at the human µ opioid receptor (MOR), but surprisingly, supratherapeutic concentrations spare human MOR-mediated βarrestin2 recruitment thought to mediate lethal opioid-induced respiratory depression.

Turgut, Ahmet Tuncay (isu author) Varicoceles are relatively common particularly in asymptomatic men and are even more prevalent in subfertile men, representing the most common potentially correctable cause of male infertility. Ultrasound (US) is the imaging modality of choice for varicocele evaluation, but there is no widely accepted consensus on examination technique, diagnostic criteria, or classification. In view of this uncertainty, the guideline writing group (WG) of the European Society of Urogenital Radiology (ESUR) Scrotal and Penile Imaging Working Group (ESUR-SPIWG) undertook a literature review and assessment of the quality of relevant evidence. The group then produced evidence-based recommendations for varicocele US examination, interpretation, and classification by consensus agreement. The results are presented in the form of 15 clinical questions with a brief summary of the relevant evidence and the authorised recommendations from the SPIWG. This paper provides a short summary of the evidence evaluation and the complete recommendations. Key Points center dot Varicocele is a common clinical problem; it is highly prevalent amongst subfertile men and the most common potentially correctable cause of male infertility. center dot Ultrasound is the imaging modality of choice for varicocele assessment, but there is no generally agreed consensus on the US examination technique or the criteria that should be used for diagnosis, grading, and classification. center dot This paper summarises the recommendations of the ESUR-SPIWG for standardising the US assessment of varicoceles. This includes examination technique, image interpretation, classification, and reporting. WOS:000501139000002 31332561 Q1

In TRANSFORM, de novo kidney transplant recipients received either everolimus in combination with reduced-exposure calcineurin inhibitor (EVR+rCNI) at standard EVR pre-dose concentrations of 3���8 ng/mL or mycophenolic acid plus standard-exposure CNI (MPA+sCNI). The authors analyzed the incidence of wound healing adverse events (WHAEs) over the 2-year study period 15. Patients were randomized to either EVR+rCNI or MPA+sCNI, both combined with induction therapy and steroids 19. The safety population consisted of 2,026 patients (EVR+rCNI: 1,014, MPA+sCNI: 1,012). The proportion of patients with at least 1 WHAE was comparable between EVR+rCNI and MPA+sCNI treatment groups [20.6% vs. 17.3%; risk ratio (RR): 1.19; 95% confidence interval (CI): 0.99, 1.43] at month 24. The numerical difference between EVR+rCNI and MPA+sCNI was mainly caused by an increased proportion of EVR patients with lymphocele and wound dehiscence [7.5% vs. 5.1% (RR: 1.46; 95% CI: 1.04, 2.05) and 3.9% vs. 1.8% (RR: 2.22; 95%CI: 1.28, 3.84), respectively] 20. The immediate introduction of EVR+rCNI after kidney transplantation was associated with an overall comparable incidence of WHAEs versus current standard-of-care over the 24-month study period. There was an increased relative risk of experiencing lymphocele and wound dehiscence but the absolute risks were rather low in both groups 21. NCT01950819.

Objectives To present our series of patients with penetrating renal trauma treated at two urban major trauma centres and to discuss the contemporary management of such injuries. Methods We reviewed prospective urological trauma databases for all patients presenting with penetrating renal trauma between January 2005 and October 2016. Patient demographics, clinical characteristics, imaging, management and follow-up data were analysed. Results Over the 11-year period, 63 patients presented with penetrating renal injuries. The vast majority of patients were male (n = 61; 96.8%), with a mean (range) age of 27.4 (14-71) years. Injuries were equally common on either side (31 left, 32 right). The most common mechanism of injury was stabbing (n = 55; 87.3%), followed by gunshot (n = 7; 11.1%) and crossbow injuries (n = 1; 1.6%). All patients underwent contrast-enhanced computed tomography. Using the American Association for the Surgery of Trauma renal injury grading system, 11 (17.5%) had grade II, 26 (41.3%) had grade III and 26 (41.3%) had grade IV injury. The most common associated injuries were thoracic (n = 23; 36.5%), liver (n = 11; 17.5%), splenic (n = 10; 15.9%), gastrointestinal tract (n = 8; 12.7%) and musculoskeletal (n = 6; 9.5%). At presentation, 16 patients (25.4%) were haemodynamically unstable. The majority of patients did not require blood transfusion (n = 56; 88.9%), while transfusion of >5 units was rare (n = 4; 6.3%). Fifty-two patients (82.5%) were managed by observation alone, while 10 (15.9%) underwent emergency angiography and embolization. Patients with grade IV injury were more likely to require embolization than those with grade III injury; however, the difference was not significant (26.9% vs 15.4%; P = 0.29). One patient (1.6%) underwent retroperitoneal exploration of their renal injury and was managed conservatively. Eight patients underwent laparotomy for other visceral injuries while their renal injury was managed conservatively. Renal artery pseudoaneurysm developed in five patients (7.9%) and one patient (1.6%) developed renal arteriovenous malformation. No patients underwent nephrectomy and no mortality was reported. Conclusions The vast majority of patients with penetrating renal injuries can be safely managed non-operatively in this setting. Selective renal artery embolization is an effective option for patients in an unstable condition, with excellent outcomes. Associated thoracic or visceral injuries requiring operative management are common in penetrating renal trauma, while urologists should limit or have a high threshold for surgical intervention.

The introduction of ultrasound contrast agents has rendered contrast-enhanced ultrasound (CEUS) a valuable complementary technique to address clinically significant problems. This pictorial review describes the use of CEUS guidance in abdominal intervention and illustrates such application for a range of clinical indications. Clinical application of CEUS discussed include commonly performed abdominal interventional procedures, such as biopsy, drainage, nephrostomy, biliary intervention, abdominal tumor ablation and its subsequent monitoring, and imaging of vascular complications following abdominal intervention. The purpose of this article is to further familiarize readers with the application of CEUS, particularly its specific strength over alternative imaging modalities, in abdominal intervention.

Vascular diseases account for a significant proportion of abdominal pathology and represent a common referral source for abdominal ultrasonographic examinations. B-mode, color Doppler, and spectral Doppler analyses are well-established in the evaluation of abdominal blood vessels although they may occasionally be limited by lower sensitivity for slow flow visualization or the deeper location of abdominal vascular structures. The introduction of microbubbles as ultrasonographic contrast agents has rendered contrast-enhanced ultrasound (CEUS), a valuable complementary ultrasonographic technique, which is capable of addressing clinically significant problems and guiding patient management. The purpose of this pictorial review is to analyze the use of CEUS in the evaluation of abdominal vascular pathology and illustrate such applications by presenting representative images. Pathology discussed includes abdominal aortic aneurysm, post-endovascular treatment aorta, portal vein thrombosis, abdominal vascular trauma, and organ transplantation along with its complications. Electronic supplementary material The online version of this article (doi:10.1007/s00261-017-1329-7) contains supplementary material, which is available to authorized users.

Identification of extrahepatic metastases (EHM) of hepatocellular carcinoma (HCC) has been paradoxically increasing due to an increase in the survival of HCC patients. However, metastasis of HCC to the skeletal muscle tissue is extremely rare. We describe a unique case of HCC metastasizing to the paravertebral muscle. A 55-year-old man with a history of hepatitis B cirrhosis underwent partial liver resection with complete removal of HCC. Three months later, a computed tomography (CT) scan showed intrahepatic recurrence. The tumors were treated with yttrium-90 microspheres, trans-catheter arterial chemoembolization, and sorafenib. Six months later, a CT scan showed an enhancing lesion of the left paravertebral muscle that on biopsy were consistent with metastatic HCC. The tumor was treated with stereotactic hypo-fractionated image-guided radiation therapy (SHFRT). A follow-up scan 3 mo post-radiotherapy revealed a stable appearance of the paravertebral muscle metastasis. Because of the progression in the intrahepatic tumors, the patient was treated with capecitabine, which was changed to dasatinib 6 mo later. The patient passed away three years after the primary surgical resection. Management of EHM poses an extreme challenge. This is the first case of HCC with EHM to the paravertebral muscle in which stability of disease was achieved using SHFRT. This case highlights the importance of early detection of hepatitis B viral infection and initiation of anti-viral therapy to decrease recurrence of HCC and prevent EHM.

We report a case of a 72-year-old male with a cascade of complications being diagnosed as an acute cholecystitis. The cascade includes iatrogenic pulling of coils, which were placed for treatment of right hepatic artery pseudoaneurysm, into the common bile duct (CBD) in an attempt for removal of the misplaced/migrated CBD plastic stent inserted by endoscopic retrograde cholangiopancreatography (ERCP). The case demonstrates a series of mishaps leading to a rare complication of iatrogenic migration of transarterial coil in the gastrointestinal tract. This could be the first case of coil migration as a complication of ERCP due to suboptimal stenting/removal techniques.

In this 12-month, multicenter, randomized, open-label, noninferiority study, de novo renal transplant recipients (RTxRs) were randomized (1:1) to receive everolimus plus low-dose tacrolimus (EVR+LTac) or mycophenolate mofetil plus standard-dose Tac (MMF+STac) with induction therapy (basiliximab or rabbit anti-thymocyte globulin). Noninferiority of composite efficacy failure rate (treated biopsy-proven acute rejection [tBPAR]/graft loss/death/loss to follow-up) in EVR+LTac versus MMF+STac was missed by 1.4%, considering the noninferiority margin of 10% (24.6% vs. 20.4%; 4.2% [-3.0, 11.4]). Incidence of tBPAR (19.1% vs. 11.2%; p < 0.05) was significantly higher, while graft loss (1.3% vs. 3.9%; p < 0.05) and composite of graft loss/death/lost to follow-up (6.1% vs. 10.5%, p = 0.05) were significantly lower in EVR+LTac versus MMF+STac groups, respectively. Mean estimated glomerular filtration rate was similar between EVR+LTac and MMF+STac groups (63.1 [22.0] vs. 63.1 [19.5] mL/min/1.73 m2 ) and safety was comparable. In conclusion, EVR+LTac missed noninferiority versus MMF+STac based on the 10% noninferiority margin. Further studies evaluating optimal immunosuppression for improved efficacy will guide appropriate dosing and target levels of EVR and LTac in RTxRs.

Background: Cardiac recovery in response to mechanical unloading by left ventricular assist devices (LVADs) has been demonstrated in subgroups of patients with chronic heart failure (HF). Hallmarks of HF are depletion and disorganization of the transverse tubular system (t-system) in cardiomyocytes. Here, we investigated remodeling of the t-system in human end-stage HF and its role in cardiac recovery. Methods: Left ventricular biopsies were obtained from 5 donors and 26 patients with chronic HF undergoing implantation of LVADs. Three-dimensional confocal microscopy and computational image analysis were applied to assess t-system structure, density, and distance of ryanodine receptor clusters to the sarcolemma, including the t-system. Recovery of cardiac function in response to mechanical unloading was assessed by echocardiography during turndown of the LVAD. Results: The majority of HF myocytes showed remarkable t-system remodeling, particularly sheet-like invaginations of the sarcolemma. Circularity of t-system components was decreased in HF versus controls (0.37±0.01 versus 0.46±0.02; P 2 ; P P P P 1 µm did not improve after mechanical unloading. In addition, calcium transients were recorded in field-stimulated isolated human cardiomyocytes and analyzed with respect to local t-system density. Calcium release in HF myocytes was restricted to regions proximal to the sarcolemma. Local calcium upstroke was delayed (23.9±4.9 versus 10.3±1.7 milliseconds; P P Conclusions: The t-system in end-stage human HF presents a characteristic novel phenotype consisting of sheet-like invaginations of the sarcolemma. Our results suggest that the remodeled t-system impairs excitation-contraction coupling and functional recovery during chronic LVAD unloading. An intact t-system at the time of LVAD implantation may constitute a precondition and predictor for functional cardiac recovery after mechanical unloading.

Patient: Male, 50 Final Diagnosis: Pulmonary fibrosis Symptoms: Short of breath Medication: — Clinical Procedure: — Specialty: Transplantology Objective: Adverse events of drug therapy Background: Mycophenolate mofetil (MMF) induced lung disease has been described in only a few isolated reports. We report a case of fatal respiratory failure associated with MMF after kidney transplantation. Case Report: A 50-year-old Hispanic male with a history of end-stage renal disease secondary to hypertension underwent deceased donor kidney transplantation. His preoperative evaluations were normal except for a chest x-ray which showed bilateral interstitial opacities. Tacrolimus and MMF were started on the day of surgery. His postoperative course was uneventful and he was discharged on postoperative day 5. One month later, he presented with shortness of breath and a cough with blood-tinged sputum. His respiratory condition deteriorated rapidly, requiring intubation. Chest computer tomography (CT) demonstrated patchy ground-glass opacities with interlobular septal thickening. Comprehensive pulmonary, cardiac, infectious, and immunological evaluations were all negative. Open lung biopsy revealed extensive pulmonary fibrosis with no evidence of infection. He temporarily improved after discontinuation of tacrolimus and MMF, however, on resuming MMF his respiratory status deteriorated again and he subsequently died from hypoxic respiratory failure. Conclusions: An awareness of pulmonary lung disease due to MMF is important to prevent adverse outcomes after organ transplantation. MMF must be used with utmost care in recipients with underlying lung disease as their pulmonary condition might make them more susceptible to any harmful effects of MMF.

We report a rare case of allograft loss from acute Page kidney secondary to trauma that occurred 12 years after kidney transplantation. A 67-year-old Caucasian male with a past surgical history of kidney transplant presented to the emergency department at a local hospital with left lower abdominal tenderness. He recalled that his cat, which weighs 15 lbs, jumped on his abdomen 7 d prior. On physical examination, a small tender mass was noticed at the incisional site of the kidney transplant. He was producing a normal amount of urine without hematuria. His serum creatinine level was slightly elevated from his baseline. Computer tomography revealed a large subscapular hematoma around the transplant kidney. The patient was observed to have renal trauma grade II at the hospital over a period of three days, and he was finally transferred to a transplant center after his urine output significantly decreased. Doppler ultrasound demonstrated an extensive peri-allograft hypoechoic area and abnormal waveforms with absent arterial diastolic flow and a patent renal vein. Despite surgical decompression, the allograft failed to respond appropriately due to the delay in surgical intervention. This is the third reported case of allograft loss from acute Page kidney following kidney transplantation. This case reinforces that kidney care differs if the kidney is solitary or a transplant. Early recognition and aggressive treatments are mandatory, especially in a case with Doppler signs that are suggestive of compression.

Primary testicular lymphoma is rare and appears with nonspecific findings on grayscale and color Doppler sonography. We present 8 patients further examined with contrast-enhanced sonography, strain elastography, and histologic analysis after orchiectomy. Seven of 8 patients had a diagnosis of large B-cell lymphoma, and 1 of 8 had a diagnosis of granulocytic sarcoma, with solitary lesions (2 of 8), multiple lesions (3 of 8), or entire testicular involvement (3 of 8). Lesions appeared hypoechoic (7 of 8) or isoechoic (1 of 8), all with increased vascularity on color Doppler sonography and a nonbranching linear pattern of intratumoral vessels (7 of 8). Contrast-enhanced ultrasound (CEUS) confirmed this pattern and showed increased enhancement in all lesions. On strain elastography, all lesions were hard, with an elasticity score of greater than 4. Multiparametric sonography of testicular lymphoma identifies increased vascularity on color Doppler and contrast-enhanced ultrasound and increased lesion stiffness on strain elastography.

Background. The safety profiles of standard therapy versus everolimus with reduced-exposure calcineurin inhibitor (CNI) therapy using contemporary protocols in de novo kidney transplant recipients have not been compared in detail. Methods. TRANSFORM was a randomized, international trial in which de novo kidney transplant patients were randomized to everolimus with reduced-exposure CNI (N = 1014) or mycophenolic acid (MPA) with standard-exposure CNI (N = 1012), both with induction and corticosteroids. Results. Within the safety population (everolimus 1014, MPA 1012), adverse events with a suspected relation to study drug occurred in 62.9% versus 59.2% of patients given everolimus or MPA, respectively (P = 0.085). Hyperlipidemia, interstitial lung disease, peripheral edema, proteinuria, stomatitis/mouth ulceration, thrombocytopenia, and wound healing complications were more frequent with everolimus, whereas diarrhea, nausea, vomiting, leukopenia, tremor, and insomnia were more frequent in the MPA group. The incidence of viral infections (17.2% versus 29.2%; P < 0.001), cytomegalovirus (CMV) infections (8.1% versus 20.1%; P < 0.001), CMV syndrome (13.6% versus 23.0%, P = 0.044), and BK virus (BKV) infections (4.3% versus 8.0%, P < 0.001) were less frequent with everolimus. CMV infection was less common with everolimus versus MPA after adjusting for prophylaxis therapy in the D+/R− subgroup (P < 0.001). Study drug was discontinued more frequently due to rejection or impaired healing with everolimus, and more often due to BKV infection or BKV nephropathy with MPA. Conclusions. De novo everolimus with reduced-exposure CNI yielded a comparable incidence, though a distinctly different pattern, of adverse events versus current standard of care. Both regimens are safe and effective, yet their distinct profiles may enable tailoring for individual kidney transplant recipients

IntroductionSeptic acute kidney injury (AKI) is the most common complication of septic shock and increases mortality. A large body of experimental data suggests alterations in renal perfusion occur, but this is yet to be fully assessed in humans. The aim of the current study is to observe the macro and microcirculations in both the systemic and renal circulations in a cohort of patients with early septic shock.Methods and analysisSingle-centre, prospective, longitudinal, observational study of 50 patients with septic shock. Renal microcirculatory assessment will be performed with contrast-enhanced ultrasound, the sublingual microcirculation assessed with incident dark field microscopy and transthoracic echocardiography used to assess global flow. Patients will be enrolled as soon as possible after admission to the intensive care unit and then at +24,+48 and +96 hours. Blood samples of circulatory and renal biomarkers will be collected. Sample groups will be defined by the presence or absence of AKI and then subclassified by the severity (Kidney Disease Improving Global Outcomes (KDIGO) criteria), variables will be compared within and between groups over time.Ethics and disseminationResearch Ethics Committee (REC) approval has been granted for this study by Yorkshire and the Humber, Leeds West Research Ethics Committee (18/YH/0371) and due to the nature of the patients enrolled with septic shock, capacity for informed consent is likely to be lacking. Therefore, a personal consultee (friend or relative) will be consulted or a nominated consultee (clinician) in their absence. After capacity is regained, consent will then be sought from the patient in accordance with the Mental Capacity Act, UK (2005). This consent process has been approved following REC review. Results will be published in a relevant peer-reviewed journal and presented at academic meetings.

A 43-year-old man presented with blunt trauma to the penis during sexual intercourse when he felt a snap, instant pain and rapid detumescence and swelling. On examination, there was a visible haematoma and swelling at the dorsum of his penis. There was no blood in the meatus and he was able to pass

A 57-year-old woman with metastatic oral squamous cell carcinoma presented to the emergency department with massive haemoptysis. Her blood pressure was 96/69 mm Hg with a heart rate of 65 beats per minute. Laboratory tests showed a mild coagulopathy (INR 1.3) for which vitamin K and tranexemic

Immune checkpoint inhibitor (ICI) treatment has recently become a first-line therapy for many non–small cell lung cancer (NSCLC) patients. Unfortunately, most NSCLC patients are refractory to ICI monotherapy, and initial attempts to address this issue with secondary therapeutics have proven unsuccessful. To identify entities precluding CD8(+) T cell accumulation in this process, we performed unbiased analyses on flow cytometry, gene expression, and multiplexed immunohistochemical data from a NSCLC patient cohort. The results revealed the presence of a myeloid-rich subgroup, which was devoid of CD4(+) and CD8(+) T cells. Of all myeloid cell types assessed, neutrophils were the most highly associated with the myeloid phenotype. Additionally, the ratio of CD8(+) T cells to neutrophils (CD8/PMN) within the tumor mass optimally distinguished between active and myeloid cases. This ratio was also capable of showing the separation of patients responsive to ICI therapy from those with stable or progressive disease in 2 independent cohorts. Tumor-bearing mice treated with a combination of anti-PD1 and SX-682 (CXCR1/2 inhibitor) displayed relocation of lymphocytes from the tumor periphery into a malignant tumor, which was associated with induction of IFN-γ–responsive genes. These results suggest that neutrophil antagonism may represent a viable secondary therapeutic strategy to enhance ICI treatment outcomes.

Introduction: Cerebral cavernous angiomas with a documented symptomatic hemorrhage (CASH) are associated with an exceptionally high risk of recurrent hemorrhage and serious morbidity. It is unclear if peripheral blood plasma biomarkers implicated in disease biology can differentiate CASH, and whether the same or different biomarkers can distinguish cases who would rebleed. Methods: Eighteen plasma molecules with postulated mechanistic roles in this disease were quantified in 114 patients and 12 healthy subjects. The best biomarker combination differentiating CASH in the prior year (+/- 30 days) was derived by minimizing the Akaike Information Criterion (AIC), and was validated using statistical and machine-learning simulations. This was compared to the biomarker predicting bleeding in the subsequent year (+/- 30 days), and both explanatory and predictive biomarkers were followed longitudinally in a subset of cases. Results: Nine plasma molecules had significantly different levels expressed in CASH patients (p Conclusions: Our results suggest shared and unique biomarkers of recent symptomatic hemorrhage and of future bleeding in cavernous angiomas. This may be applied for risk stratification in clinical trials, and potentially developed as a tool in clinical practice.

Radical orchifunicolectomy has traditionally been the main clinical treatment for small testicular masses (STMs); however STMs represent a constantly increasing and often incidental finding. Since many of them result benign, a more conservative testis-sparing surgery was proposed, but it requires a preliminary differentiation between benign and malignant masses: this however remains challenging. Although common understanding in radiology and oncology is that perfusion patterns might provide a useful information about the type of masses, no guidelines or consensus is available for the differentiation of STMs. We propose to build a dictionary of relevant perfusion patterns, extracted using non-negative matrix factorization on pixel-wise time-intensity curves from contrast-enhanced ultrasound data. When data from a lesion are reconstructed using this dictionary, a vector containing the frequency of utilization of each pattern can be used as a tissue signature. Using this signature, a support vector machine classifier has been trained, and the cross validated accuracy reached 100% in our pilot cohort.

One of the features of diabetic patients with critical limb ischemia is the predominance of diffuse obstructive lesions in the distal, sub-popliteal arteries. The introduction of endovascular procedures in the routine of vascular surgery allowed for the expansion of therapeutic options in the diverse areas of vascular disease. Percutaneous angioplasty for below-the-knee and below-the-ankle vascular disease has shown to be feasible and safe, achieving successful revascularization, necessary for limb salvage and ulcer healing, and avoiding amputations. In addition to the traditional approach, there has been an evolution of newer technologies and adjunctive endovascular devices. Furthermore, alternative techniques such as pedal-plantar loop technique and retrograde percutaneous access have been shown to further increase intervention success. The rapid pace of development of various endovascular techniques allows interventionists to treat increasingly complex and distal patterns of disease. The aim of the current article is to summarize the principles of endovascular revascularization and currently available advanced techniques which facilitate clinically driven, more complete revascularization to facilitate wound healing and achieve limb salvage.