Antiviral fibrils of self-assembled peptides with tunable compositions.

The lasting threat of viral pandemics necessitates the development of tailorable first-response antivirals with specific but adaptive architectures for treatment of novel viral infections. Here, such an antiviral platform has been developed based on a mixture of hetero-peptides self-assembled into functionalized ß-sheets capable of specific multivalent binding to viral protein complexes. One domain of each hetero-peptide is designed to specifically bind to certain viral proteins, while another domain self-assembles into fibrils with epitope binding characteristics determined by the types of peptides and their molar fractions. The self-assembled fibrils maintain enhanced binding to viral protein complexes and retain high resilience to viral mutations. This method is experimentally and computationally tested using short peptides that specifically bind to Spike proteins of SARS-CoV-2. This platform is efficacious, inexpensive, and stable with excellent tolerability.

Systematic review comparing uretero-enteric stricture rates between open cystectomy with ileal conduit, robotic cystectomy with extra-corporeal ileal conduit and robotic cystectomy with intra corporeal ileal conduit formation.

Cystectomy is the gold standard treatment for muscle invasive bladder cancer. Robotic cystectomy has become increasingly popular owing to quicker post- operative recovery, less blood loss and less post-operative pain. Urinary diversion is increasingly being performed with an intracorporeal technique. Uretero-enteric strictures (UES) cause significant morbidity for patients. UES for open cystectomy is 3-10%, but the range is much wider (0-25%) for robotic surgery. We aim to perform systematic review for studies comparing all 3 techniques, to assess for ureteric stricture rates. A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement (Page et al. in BMJ 29, 2021). PubMed, Scopus and Embase databases were searched for the period January 2003 to June 2023 inclusive for relevant publications.The primary outcome was to identify ureteric stricture rates for studies comparing open cystectomy and urinary diversion, robotic cystectomy with extracorporeal urinary diversion (ECUD) and robotic cystectomy with intracorporeal urinary diversion (ICUD). Three studies were identified and included 2185 patients in total. The open operation had the lowest stricture rate (9.6%), compared to ECUD (12.4%) and ICUD (15%). ICUD had the longest time to stricture (7.55 months), ECUD (4.85 months) and the open operation (4.75 months). Open operation had the shortest operating time. The Bricker anastomoses was the most popular technique. Open surgery has the lowest rates of UES compared to both robotic operations. There is a learning curve involved with performing robotic cystectomy and urinary diversion, this may need to be considered to decide whether the technique is comparable with open cystectomy UES rates. Further research, including Randomised Control Trials (RCT), needs to be undertaken to determine the best surgical option for patients to minimise risks of UES.

Self-Assembling Peptides with Insulin-Like Growth Factor Mimicry.

Growth factor (GF) mimicry involves recapitulating the signaling of larger molecules or cells. Although GF mimicry holds considerable promise in tissue engineering and drug design applications, difficulties in targeting the signaling molecule to the site of delivery and dissociation of mimicking peptides from their target receptors continue to limit its clinical application. To address these challenges, we utilized a self-assembling peptide (SAP) platform to generate synthetic insulin-like growth factor (IGF)-signaling, self-assembling GFs. Our peptide hydrogels are biocompatible and bind target IGF receptors in a dose-dependent fashion, activate proangiogenic signaling, and facilitate formation of angiogenic microtubules in vitro. Furthermore, infiltrated hydrogels are stable for weeks to months. We conclude that the enhanced targeting and long-term stability of our SAP/GF mimicry implants may improve the efficacy and safety of future GF mimic therapeutics.

Transregional Study Highlighting the Increasing Burden of Urology Cancer Multidisciplinary Team Meetings Around the UK.

Introduction The urology multidisciplinary team meeting (MDT) is the key weekly meeting that allows the opportunity to review results and discuss management plans for all urological cancers within a department. As populations age and cancer detection and management improve, the demand for the MDT will increase. We conducted a collaborative transregional study within the UK to evaluate the current workload on the urology MDT. Methods The study was divided into two parts: a multicenter retrospective audit and a snapshot survey. Three UK hospitals in Birmingham, Liverpool, and Cardiff were recruited into the multicenter study. Each hospital provided full MDT lists for all weekly meetings between August 2017 and 2022. Retrospective data gathered included the number of patients discussed per week, the average age of patients per week, the time allocated to their weekly MDT, and the total number of consultants in the department. The second part of the study involved the distribution of an online questionnaire to urologists across the UK to obtain a snapshot picture with the above parameters. Results Snapshot data from 34 different UK hospitals showed MDT length ranged from 1-6 hours, patients discussed ranged from 10-90 per week, and the maximum average discussion time was 3.8 minutes per case. Furthermore, 76% (N = 28/37) of respondents said unnecessary cases were discussed. Varied suggestions were provided on how the MDT could be improved. Multicenter five-year data showed a rise in mean total numbers of patients discussed per week in all centers: a 34.8% increase in Birmingham (from 34.5 patients to 46.5 patients), a 23.5% increase in Liverpool (27.2 patients to 33.6 patients), and a 38.8% increase in Cardiff (22.7 patients to 31.5 patients). Hours per meeting were Birmingham (2), Liverpool (3), and Cardiff (4), which meant the average minutes per patient discussion were Birmingham (2.6), Liverpool (5.4), and Cardiff (7.6). Conclusion There is a rapidly rising trend across UK regions for the number of patients being discussed in the urology MDT meeting. The MDT structure and function across the country are highly variable. There is consensus that the MDT discusses cases that are unnecessary, and this has been recognized for many years. Widespread implementation of the latest MDT management guidelines is urgently required to ensure MDT meetings are able to function effectively and efficiently into the future.

High-dose-rate brachytherapy for airway malignancy a single institution experience.

PURPOSE: To evaluate clinical outcomes of endobronchial malignancy treated using high-dose-rate endobronchial brachytherapy (HDREB). METHODS AND MATERIALS: A retrospective chart review was conducted for all patients treated with HDREB for malignant airway disease between 2010 and 2019 at a single institution. Most patients had a prescription of 14 Gy in two fractions given a week apart. The Wilcoxon signed rank test and paired samples t test were used to compare changes in mMRC dyspnea scale prior to and after brachytherapy at first followup appointment. Toxicity data were collected for dyspnea, hemoptysis, dysphagia, and cough. RESULTS: A total of 58 patients were identified. Most (84.5%) had primary lung cancer with advanced cancers, stage III or IV (86%). Eight were treated while admitted in the ICU. Previous external beam radiotherapy (EBRT) was received by 52%. An improvement in dyspnea was seen in 72%, with an mMRC dyspnoea scale score improvement of 1.13 points (p < 0.001). Most (22, 88%) had an improvement in hemoptysis and 18 out of 37 (48.6%) had an improvement in cough. Grade four to five events occurred in 8 (13%) at the median time of 2.5 months from brachytherapy. Twenty-two patients (38%) had complete obstruction of the airway treated. Median progression free survival was 6.5 months and median survival was 10 months. CONCLUSIONS: We report a significant symptomatic benefit among patients receiving brachytherapy with endobronchial malignancy, with rates of treatment related toxicities similar to prior studies. Our study identified new subgroups of patients, ICU patients & those with complete obstruction, who benefited from HDREB.

Priapism in a Patient with Rectal Adenocarcinoma.

BACKGROUND: Priapism is a very rare complication of malignancy and is usually accompanied by locally advanced or widely metastatic disease. We describe a case of priapism arising in a 46-year-old male with localised rectal cancer that was responding to therapy. CASE PRESENTATION: This patient had just completed two weeks of neoadjuvant, long-course chemoradiation when he presented with persistent painful penile erection. Assessment and diagnosis were delayed for more than 60 h, and although a cause could not be determined from imaging, a near complete radiological response of the primary rectal cancer was seen. His symptoms were refractory to urologic intervention and were associated with extreme psychological distress. He re-presented shortly thereafter with extensively metastatic disease in the lungs, liver, pelvis, scrotum, and penis; additionally, multiple venous thromboses were identified, including in the dorsal penile veins. His priapism was not reversible and was associated with a considerable symptom burden for the remainder of his life. His malignancy did not respond to first-line palliative chemotherapy or radiation, and his clinical course was further complicated by obstructive nephropathy, ileus, and genital skin breakdown with a suspected infection. We initiated comfort measures, and he ultimately died in hospital less than five months after his initial presentation. CONCLUSION: Priapism in cancer is usually related to tumour infiltration of the penis and corporal bodies resulting in poor venous and lymphatic drainage. The management is palliative and can include chemotherapy, radiation, surgical shunting, and potentially penectomy; however, conservative penis-sparing therapy may be reasonable in patients with limited life expectancy.

Emergency Urology procedures during the COVID-19 pandemic in the UK: A 3-month prospective study.

OBJECTIVE: COVID-19 resulted in Regional tiered restrictions being introduced across the UK with subsequent implications for planned and emergency surgical care. Specific to Merseyside, Tier 4, Tier 2 and Tier 5 restrictions were introduced in late 2020 and early 2021. The purpose of this study was to examine the nature and workload of emergency urological procedures during three different national lockdown Tiers in the North West of England. METHOD: A 3-month prospective study examining all emergency urological activity was conducted from November 2020 when Tier 4 restrictions were introduced and included Tier 2 restrictions in December and then concluded at the end of January 2021 when Tier 5 restrictions were in place. Data was obtained by identifying patients using the electronic theatre listing system. RESULTS: A total of 71 emergency cases were performed (24 in November (Tier 4), 28 in December (Tier 2), 19 in January 2021 (Tier 5)) with 15 different types of procedures performed. The most frequently performed procedure was stent insertion (36), followed by scrotal exploration (10). The least commonly performed procedure was suprapubic catheter insertion under general anaesthesia (1). One patient required transfer to a different hospital. In total 6 calls were made by general surgery and 3 by gynaecology for urgent urological assistance in theatre. Three urology patients returned to the theatre as emergencies following elective procedures. CONCLUSION: Unlike the Spring lockdown, acute urological presentations requiring operative intervention still presented daily. Of the 71 cases performed, most occurred in Tier 2. Stent insertion was the most commonly performed procedure, with the majority of the cases performed by registrars.

Angiogenic Hydrogels to Accelerate Early Wound Healing.

Diabetes mellitus affects an increasing proportion of the population, and is projected to double by 2060. Comorbidities contribute to an interrupted healing process which is delayed, prolonged, and associated with increased susceptibility to infection and unresolved inflammation. This leads to chronic nonhealing wounds and potential amputation. Here, the use of a bioactive angiogenic peptide-based hydrogel, SLan, is examined to improve early wound healing in diabetic rats, and its performance is compared to clinically utilized biosynthetic peptide-based materials such as Puramatrix. Streptozotocin-treated diabetic rats underwent 8 mm biopsy wounding in their dorsum. Wounds are treated with either Low (1 w%) SLan, High (4 w%) SLan, phosphate buffered saline (PBS), Puramatrix, or K2 (an unfunctionalized nonbioactive control sequentially similar to SLan), covered with Tegaderm, and monitored on for a month; animals are sacrificed for histomorphic analyses and immunostaining. Pharmacokinetic analysis showing no trafficking of peptides from the wound into the circulation. SLan groups show similar wound contraction as control groups (Puramatrix, PBS, and K2), however, showing marked improvement in healing in earlier time points, including increased deposition of new mature blood vessels. Altogether the results suggest this material can be used to "jumpstart" the diabetic wound healing process.

Photon versus proton whole ventricular radiotherapy for non-germinomatous germ cell tumors: A report from the Children's Oncology Group.

PURPOSE: To determine if proton therapy reduces doses to cranial organs at risk (OARs) as compared to photon therapy in children with non-germinomatous germ cell tumors (NGGCT) receiving whole ventricular radiotherapy (WVRT). METHODS AND MATERIALS: Dosimetric data for patients with NGGCT prospectively enrolled in stratum 1 of the Children's Oncology Group study ACNS1123 who received 30.6 Gy WVRT were compared. Target segmentation was standardized using a contouring atlas. Doses to cranial OARs were compared between proton and photon treatments. Clinically relevant dose-volume parameters that were analyzed included mean dose and dose to 40% of the OAR volume (D40). RESULTS: Mean and D40 doses to the supratentorial brain, cerebellum, and bilateral temporal, parietal, and frontal lobes were statistically significantly lower amongst proton-treated patients, as compared to photon-treated patients. In a subgroup analysis of patients uniformly treated with a 3-mm planning target volume, patients who received proton therapy continued to have statistically significantly lower doses to brain OARs. CONCLUSIONS: Children treated with proton therapy for WVRT had lower doses to normal brain structures, when compared to those treated with photon therapy. Proton therapy should be considered for patients receiving WVRT for NGGCT.

Is There a Role for Antifungal Prophylaxis in Patients Undergoing Penile Prosthesis Surgery? A Systematic Review.

OBJECTIVE: The aim of this study is to review the literature on the use of antifungal prophylaxis in penile prosthesis (PP) surgery and provide a summary on its efficacy as an adjunct to current prophylactic regimes in patients undergoing PP surgery. MATERIALS AND METHODS: PubMed, Medline, and EMBASE databases were systematically searched up to May 2020. All included studies were analysed and the information extracted included author, title of study, year of publication, type of study, journal of publication, and main findings regarding post PP implantation fungal infections. RESULTS: Nine relevant studies were included in this review, comprising retrospective single-centre studies and retrospective multicentre studies ranging from 2017 to 2020. Fungal infections were found responsible for 11.1% of all PP infections, with a greater risk in patients with diabetes, obesity, and from warmer climates. Current American Urological Association (AUA) and European Association of Urology (EAU) prophylaxis guidelines do not incorporate the use of antifungals. Trials of antifungal prophylaxis regimes combined with antibiotic prophylaxis have demonstrated a reduction in PP fungal infections. CONCLUSIONS: Fungal infections represent a significant proportion of implant infections and therefore antifungal prophylaxis is warranted. Future studies comparing the efficacy of traditional antibiotic prophylaxis as set out by AUA/EAU with novel prophylaxis regimes including the addition of an antifungal may provide more definitive guidance on this issue. Until then antifungal prophylaxis in all patients undergoing PP procedures may provide a significant cost-effect benefit.

A 3D Bioprinted Material That Recapitulates the Perivascular Bone Marrow Structure for Sustained Hematopoietic and Cancer Models.

Translational medicine requires facile experimental systems to replicate the dynamic biological systems of diseases. Drug approval continues to lag, partly due to incongruencies in the research pipeline that traditionally involve 2D models, which could be improved with 3D models. The bone marrow (BM) poses challenges to harvest as an intact organ, making it difficult to study disease processes such as breast cancer (BC) survival in BM, and to effective evaluation of drug response in BM. Furthermore, it is a challenge to develop 3D BM structures due to its weak physical properties, and complex hierarchical structure and cellular landscape. To address this, we leveraged 3D bioprinting to create a BM structure with varied methylcellulose (M): alginate (A) ratios. We selected hydrogels containing 4% (w/v) M and 2% (w/v) A, which recapitulates rheological and ultrastructural features of the BM while maintaining stability in culture. This hydrogel sustained the culture of two key primary BM microenvironmental cells found at the perivascular region, mesenchymal stem cells and endothelial cells. More importantly, the scaffold showed evidence of cell autonomous dedifferentiation of BC cells to cancer stem cell properties. This scaffold could be the platform to create BM models for various diseases and also for drug screening.

Implantable anti-angiogenic scaffolds for treatment of neovascular ocular pathologies.

The retinal physiology can accrue oxidative damage and inflammatory insults due to age and metabolic irregularities. Two notable diseases that involve retinal and choroidal neovascularization are proliferative diabetic retinopathy and wet age-related macular degeneration. Currently, these diseases are mainly treated with anti-VEGF drugs (VEGF = vascular endothelial growth factor), generally on a monthly dosage scheme. We discuss recent developments for the treatment of these diseases, including bioactive tissue-engineered materials, which may reduce frequency of dosage and propose a path forward for improving patient outcomes. Graphical abstract Development of materials for long-term intravitreal delivery for management of posterior segment diseases.

A self-assembled peptide hydrogel for cytokine sequestration.

Cytokine-directed monocyte infiltration is involved in multiple pathological processes. Immuno-isolating matrices that can sequester cell-released chemokines in a microenvironment may prolong the viability and functionality of implanted materials. We describe a self-assembling peptide-based hydrogel that can capture the cytokine CCL2 released in the extracellular space by immune cells and stromal cells. The shear-responsive matrix can absorb and retain this signaling molecule needed for the chemotaxis of the infiltrating monocytes and their differentiation into phagocytic macrophages. Such cytokine-sequestering biomaterials may be useful as adjunctive materials with the delivery of exogenous implants or cell suspensions for tissue regeneration, without the administration of systemic immunosuppressants. Our work highlights the versatility of nanofibrous peptide hydrogels for modulating the biological response in tissue niches.

Angiogenic Self-Assembling Peptide Scaffolds for Functional Tissue Regeneration.

Implantation of acellular biomimetic scaffolds with proangiogenic motifs may have exciting clinical utility for the treatment of ischemic pathologies such as myocardial infarction. Although direct delivery of angiogenic proteins is a possible treatment option, smaller synthetic peptide-based nanostructured alternatives are being investigated due to favorable factors, such as sustained efficacy and high-density epitope presentation of functional moieties. These peptides may be implanted in vivo at the site of ischemia, bypassing the first-pass metabolism and enabling long-term retention and sustained efficacy. Mimics of angiogenic proteins show tremendous potential for clinical use. We discuss possible approaches to integrate the functionality of such angiogenic peptide mimics into self-assembled peptide scaffolds for application in functional tissue regeneration.

A case of a chronic salmonella infection following Roux-en-Y gastric bypass surgery, treated successfully by a laparoscopic cholecystectomy.

We report a case of chronic infection caused by Salmonella and cured by a laparoscopic cholecystectomy after Roux-en-Y gastric bypass (RYGB) surgery for obesity. This patient presented with a 2-year history of chronic abdominal pain, loose stools and excessive weight loss. Her stool and urine cultures were positive for Salmonella Despite multiple courses of antibiotics, she remained positive.After undergoing a laparoscopic cholecystectomy, the patient became asymptomatic and stools remained negative. In chronic carriers for Salmonella, the gall bladder is the common reservoir for the bacteria and removing it is usually curative.The possibility that the source of the may be in the biliary limb of her bariatric procedure and not in the gall bladder remained a concern.In patients who have had a RYGB, cholecystectomy is an effective treatment.All patients presenting with abdominal symptoms following RYGB should have stool and urine cultures taken as part of their work up.

Port site endometrioma: a rare cause of abdominal wall pain following laparoscopic surgery.

Endometriomas are a rare cause of abdominal wall pain. We report a case of a port site endometrioma presenting with an umbilical swelling. The patient underwent a laparoscopy for pelvic endometriosis 6 months previously and presented with a swelling around her umbilical port site scar associated with cyclical pain during menses. Ultrasound scan reported a well-defined lesion in the umbilicus and MRI scanning excluded other pathology. As she was symptomatic, she underwent an exploration of the scar and excision of the endometrioma with resolution of her symptoms. Precautions should be taken to reduce the risk of endometrial seeding during laparoscopic surgery. All tissues should be removed in an appropriate retrieval bag and the pneumoperitoneum should be deflated completely before removing ports to reduce the chimney effect of tissue being forced through the port site. The diagnosis should be considered in all women of reproductive age presenting with a painful port site scar.

Targeting c-FOS and DUSP1 abrogates intrinsic resistance to tyrosine-kinase inhibitor therapy in BCR-ABL-induced leukemia.

Tyrosine-kinase inhibitor (TKI) therapy for human cancers is not curative, and relapse occurs owing to the continued presence of tumor cells, referred to as minimal residual disease (MRD). The survival of MRD stem or progenitor cells in the absence of oncogenic kinase signaling, a phenomenon referred to as intrinsic resistance, depends on diverse growth factors. Here we report that oncogenic kinase and growth-factor signaling converge to induce the expression of the signaling proteins FBJ osteosarcoma oncogene (c-FOS, encoded by Fos) and dual-specificity phosphatase 1 (DUSP1). Genetic deletion of Fos and Dusp1 suppressed tumor growth in a BCR-ABL fusion protein kinase-induced mouse model of chronic myeloid leukemia (CML). Pharmacological inhibition of c-FOS, DUSP1 and BCR-ABL eradicated MRD in multiple in vivo models, as well as in mice xenotransplanted with patient-derived primary CML cells. Growth-factor signaling also conferred TKI resistance and induced FOS and DUSP1 expression in tumor cells modeling other types of kinase-driven leukemias. Our data demonstrate that c-FOS and DUSP1 expression levels determine the threshold of TKI efficacy, such that growth-factor-induced expression of c-FOS and DUSP1 confers intrinsic resistance to TKI therapy in a wide-ranging set of leukemias, and might represent a unifying Achilles' heel of kinase-driven cancers.

Trends in Upper Tract Stone Disease in England: Evidence from the Hospital Episodes Statistics Database.

AIMS: The study aimed to determine the current trends in urolithiasis-related admissions and associated interventions in England between 2006/2007 and 2013/2014 utilizing Hospital Episode Statistics (HES) online data. MATERIAL AND METHODS: Data was extracted from the online HES data set for each year from 2006/2007 to 2013/2014 inclusive. Admissions and procedural interventions were identified from their corresponding OPCS-4 and ICD-10 codes. RESULTS: Finished consultant episodes (FCEs) for urolithiasis have increased by 20% over the last 7 years, with 93,039 FCEs in the year 2013/2014. Based on English population statistics, the lifetime prevalence of urolithiasis based on hospital-related admission/intervention data for 2013/2014 is 14%. The biggest increases were seen in those aged ≥75 years (up by 51%, n = 2,853). Total interventions have increased from 28,624 to 42,068, with increased rates of shock wave lithotripsy (26%), ureteroscopy (URS; 86%) and percutaneous nephrolithotomy (149%). Emergency URS procedures have increased by 38%. Day-case rates for ureteric and renal URS, in 2013/2014, were 22 and 21%, respectively. CONCLUSIONS: Over the last 7 years, there is a rising prevalence of kidney stone disease with associated increase in the number of interventions related to it. Both elective and emergency URS procedures are increasing, with a rising trend for day-case URS. Similar trends are seen worldwide and future resource planning for urolithiasis is needed to match the increase in demand.