Pediatric Prostatic Alveolar Rhabdomyosarcoma Presenting with Metastatic Spinal Cord Compression in the Thoracic Spine: A Case Report and Review of the Literature.

Rhabdomyosarcoma (RMS) is a pediatric malignancy with a variable prognosis depending on tumor stage and genotype. There has been a significant improvement in survival rates over the past decades. However, aggressive variants can metastasize to locations that are difficult to treat. We report a case of prostatic alveolar rhabdomyosarcoma with metastases to the bone marrow and thoracic spine in a child. The patient was treated with a multimodal approach that included surgical resection of the epidural mass; the administration of vincristine, dactinomycin, and cyclophosphamide; and radiotherapy. Unfortunately, after six months, the patient showed disease progression and was started on secondary-line treatment. This case illustrates the difficulties in managing end-stage metastatic rhabdomyosarcoma and is the first report of prostatic rhabdomyosarcoma presenting with spinal cord compression in a child.

Approaches, Strategies and Procedures for Identifying Anti-Inflammatory Drug Lead Molecules from Natural Products.

Natural products (NPs) have played a vital role in human survival for millennia, particularly for their medicinal properties. Many traditional medicine practices continue to utilise crude plants and animal products for treating various diseases, including inflammation. In contrast, contemporary medicine focuses more on isolating drug-lead compounds from NPs to develop new and better treatment drugs for treating inflammatory disorders such as inflammatory bowel diseases. There is an ongoing search for new drug leads as there is still no cure for many inflammatory conditions. Various approaches and technologies are used in drug discoveries from NPs. This review comprehensively focuses on anti-inflammatory small molecules and describes the key strategies in identifying, extracting, fractionating and isolating small-molecule drug leads. This review also discusses the (i) most used approaches and recently available techniques, including artificial intelligence (AI), (ii) machine learning, and computational approaches in drug discovery; (iii) provides various animal models and cell lines used in in-vitro and in-vivo assessment of the anti-inflammatory potential of NPs.

Newer therapies and surgical management of ketamine-induced uropathy: A review.

BACKGROUND AND AIMS: Ketamine use as a recreational drug is becoming more popular nowadays. Ketamine-induced uropathy (KIU) is a late finding observed with long-term use of ketamine. A systematic review of Ketamine-Induced Uropathy was performed to emphasise its key clinical manifestations, mechanism of action and establish an effective treatment pathway. METHODS AND RESULTS: A literature search was conducted in MEDLINE via Pubmed and Cochrane using the keywords ketamine and bladder, ketamine and uropathy, and ketamine and epidemiology. The search strategy was limited to articles published from 2000 to 2023. Both animal and human studies were included. A total of 101 papers were reviewed based on topic relevance from the title and abstracts available. While ketamine is a controlled drug in the United Kingdom (UK) and other countries, 283 ketamine-related deaths have been reported in the UK. There is no definite pathogenesis but multiple potential mechanisms that cause KIU and its related symptoms. KIU involves chronic inflammation of the bladder, ureteral wall thickening, hydronephrosis and finally, chronic renal failure. A multidisciplinary approach is paramount when managing these patients to break the vicious cycle. The mainstay of medical and surgical treatment pathways is continued abstinence to prevent symptom relapse. This review included the pathophysiology, novel medical treatments and surgical management of KIU. CONCLUSION: KIU is a rare but significantly disabling condition often seen among ketamine abusers. With the rising trend in drug addiction, KIU is expected to be more common. Unfortunately, it is a late complication in chronic ketamine abusers and is only partially reversible even with abstinence. This review discusses this rare entity's newer medical treatments and surgical options.

Gynaecological organ involvement in females undergoing radical cystectomy: a multicentre study.

OBJECTIVE: To report the incidence of malignancy in gynaecological organs removed during radical cystectomy (RC). PATIENTS AND METHODS: A retrospective multicentre study of 1600 RCs at three high-volume institutions between January 2009 and March 2022 was performed. Pathological findings in gynaecological organs in female RC specimens were reviewed. Multivariable logistic regression analyses were used to identify predictors of malignant gynaecological organ involvement (GOI) at time of RC. RESULTS: Overall, 302 females with a median (interquartile range) age of 68 (61-75) years underwent RC for clinical (c)Ta-T4 bladder cancer. In all, 56 patients (18.5%) received neoadjuvant chemotherapy. Malignant GOI was seen in 20 patients (6.6%); the most common single sites of GOI were the uterus (five patients) and vaginal wall (four), followed by cervix (one), and ovaries (one). Nine patients had involvement of more than one gynaecological organ. No females had a primary gynaecological malignancy detected incidentally at RC. Patients with GOI were more likely to have cT3/T4 stage (P < 0.001), preoperative hydronephrosis (P = 0.004), lymphovascular invasion (P = 0.002), and squamous cell carcinoma (P = 0.005) than those without GOI. On multivariable analysis, cT4 stage was an independent predictor of malignant GOI (odds ratio 88.3, 95% confidence interval 10.1-1214; P < 0.001). CONCLUSION: To our knowledge, we present the largest multi-institutional study examining malignant GOI in females with bladder cancer undergoing RC. The rate of GOI at the time of RC is low and associated with higher clinical stage. In the absence of clinical or radiological evidence of sexual organ involvement, our results do not support their routine removal at the time of RC.

The Ethnopharmacology, Phytochemistry and Bioactivities of the Corymbia Genus (Myrtaceae).

Plants have been vital to human survival for aeons, especially for their unique medicinal properties. Trees of the Eucalyptus genus are well known for their medicinal properties; however, little is known of the ethnopharmacology and bioactivities of their close relatives in the Corymbia genus. Given the current lack of widespread knowledge of the Corymbia genus, this review aims to provide the first summary of the ethnopharmacology, phytochemistry and bioactivities of this genus. The Scopus, Web of Science, PubMed and Google Scholar databases were searched to identify research articles on the biological activities, phytochemistry and ethnomedical uses of Corymbia species. Of the 115 Corymbia species known, 14 species were found to have ethnomedical uses for the leaves, kino and/or bark. Analysis of the references obtained for these 14 Corymbia spp. revealed that the essential oils, crude extracts and compounds isolated from these species possess an array of biological activities including anti-bacterial, anti-fungal, anti-protozoal, anti-viral, larvicidal, insecticidal, acaricidal, anti-inflammatory, anti-oxidant, anti-cancer and anti-diabetic activities, highlighting the potential for this under-studied genus to provide lead compounds and treatments for a host of medical conditions.

Assessment of routine same-day discharge surgery for robot-assisted radical prostatectomy.

INTRODUCTION: It is important for robotic surgery to be cost-effective, especially by reducing the length of stay (LOS). Therefore, we developed a protocol for day-case robot-assisted radical prostatectomy (RARP). This study aimed to validate this as a safe practice of care and to assess the potential benefits to the hospital and patient. METHODS: In this single-centre study, all patients booked for RARP between April 2022 and October 2022 were screened for suitability for day case. All tumour types were included. Exclusion criteria were a history of complex abdominal surgeries, salvage prostatectomy, body mass index (BMI) > 35 and patient living alone or > 150 km away from the hospital. All day-case RARPs were performed as a morning case with a protocol for review throughout the day with evening discharge if mobilising independently and eating/drinking well. The primary outcome of the study was success rate of discharge home on day of surgery (DOS) with secondary outcomes of readmissions and complications. A patient questionnaire was completed at home including both visual analogue scale (VAS) for pain and satisfaction rating. RESULTS: Forty-five patients underwent day-case RARP over a 6-month period with minimum of 30 days of follow-up. 41/45 (91%) had successful DOS discharge home. The four admissions overnight were due to dizziness, low oxygen saturation, intraoperative complications and a diagnosis of COVID-19. There were no readmissions and no 30-day complications. The most common issues at home were catheter discomfort and constipation with low mean VAS pain score and low nausea reported. The overall patient satisfaction rating was very high at 4.8/5, and 97% said they would recommend to a family member. The cost saving for the hospital was 400 pounds per patient. CONCLUSION: Day-case procedure is a viable, safe and efficient pathway for appropriately selected and counselled patients undergoing RARP.

Industrial Graphene Coating of Low-Voltage Copper Wires for Power Distribution.

Copper (Cu) is the electrical conductor of choice in many categories of electrical wiring, with household and building installation being the major market of this metal. This work demonstrates the coating of Cu wires-with diameters relevant for low-voltage (LV) applications-with graphene. The chemical vapor deposition (CVD) coating process is rapid, safe, scalable, and industrially compatible. Graphene-coated Cu wires display good oxidation resistance and increased electrical conductivity (up to 1% immediately after coating and up to 3% after 24 months), allowing for wire diameter reduction and thus significant savings in wire production costs. Combined spectroscopic and diffraction analysis indicates that the conductivity increase is due to a change in Cu crystallinity induced by the coating process conditions, while electrical testing of aged wires shows that graphene plays a major role in maintaining improved electrical performances over long periods of time. Finally, graphene coating of Cu wires using an ambient-pressure roll-to-roll (R2R) CVD reactor is demonstrated. This enables the in-line production of graphene-coated metallic wires as required for industrial scale-up.

Early Clinical Development of Lufotrelvir as a Potential Therapy for COVID-19.

Lufotrelvir was designed as a first in class 3CL protease inhibitor to treat COVID-19. Development of lufotrelvir was challenged by its relatively poor stability due to its propensity to epimerize and degrade. Key elements of process development included improvement of the supply routes to the indole and lactam fragments, a Claisen addition to homologate the lactam, and a subsequent phosphorylation reaction to prepare the prodrug as well as identification of a DMSO solvated form of lufotrelvir to enable long-term storage. As a new approach to preparing the indole fragment, a Cu-catalyzed C-O coupling using oxalamide ligands was demonstrated. The control of process-related impurities was essential to accommodate the parenteral formulation. Isolation of an MEK solvate followed by the DMSO solvate ensured that all impurities were controlled appropriately.

Urinary Bladder Diverticulum: A Single-Center Experience in the Management of Refractory Lower Urinary Symptoms Using a Robotic Platform.

Introduction Urinary bladder diverticulum (UBD) is commonly seen in urological practice and, in most cases, does not need treatment specifically directed towards it. However, it can give rise to symptoms that are not distinct from this finding. This makes the evaluation and management of this complex patient group challenging. We present our experience with robotic bladder diverticulectomy (RBD) for acquired bladder diverticulum to assess the outcomes and safety of this procedure when patient symptoms have failed to respond to either medical or surgical treatment directed at other associated contributing factors. Methods We retrospectively collected data on all patients who underwent RBD for persistent lower urinary tract symptoms (LUTS) at Royal Surrey County Hospital, Guildford, between 2016 and 2021, including baseline characteristics, urodynamic findings, intraoperative and postoperative outcomes, and a six-month follow-up. Patients who were diagnosed with cancer in the diverticulum, associated pathology that may contribute to their symptoms, or who had concomitant procedures at the time of RBD were excluded from this study. Results We had six patients who underwent RBD; the median age and body mass index (BMI) were 63.8 years (range 48-73) and 27.1 kg/m2 (range 24-32), respectively. The most common presenting symptoms were refractory LUTS and recurrent urinary tract infections (UTIs). The urodynamic evaluation revealed varying findings like bladder outlet obstruction (BOO), poor compliance, and equivocal readings in these patients. All patients reported incomplete bladder emptying and double voiding, with half practicing clean intermittent self-catheterization (CISC). Diverticulum size averaged 9.4 cm (range 8.5-12). The median operative time and blood loss were 166 mins (range 150-180) and 75 mls (range 50-100), respectively. The average length of stay was 1.6 days (range 1-3). Three patients developed UTIs within a month after surgery, requiring a course of oral antibiotics. Post-void residual (PVR) measured an average of 32.6 mls (range 0-161) postoperatively compared to a preoperative average of 249 mls (range 125-400), showing a two-tailed p-value of 0.016. The International Prostate Symptom Score (IPSS) score for these patients showed an average of 27.83 (range 24-31) preoperatively compared to the postoperative average of eight (range 7-12), showing a two-tailed p-value of 0.0001. Final histology showed no malignancy, and all patients reported symptom improvement, with none requiring CISC after surgery. Conclusion RBD is a safe and effective procedure in carefully selected patients with refractory LUTS and UTIs showing good postoperative and functional outcomes. The presence of a large diverticulum can have a complex effect on bladder dynamics. In the era of robotic surgery and enhanced recovery, discussion about diverticulectomy should be encouraged after proper evaluation and counseling for patients who have failed to improve with other measures of treatment for their symptoms.

Self-removal of catheter after robot-assisted radical prostatectomy: a feasibility study.

Self-removal of urinary catheter as an option after robot-assisted radical prostatectomy (RARP) has never been explored in literature. We report the feasibility and outcome of the first study of this novel concept in our hospital. We conducted a prospective audit of self-TWOC (trial without catheter) in men who underwent consecutive RARP in our centre between April 2022 and September 2022. Men who had self-TWOC filled a questionnaire about the outcomes of self-TWOC. Carbon footprint and carbon offset for each hospital TWOC avoided were calculated. Of the 129 who underwent self-TWOC, 112 filled the questionnaire and were hence included in the final analysis. Self-TWOC was successful in all the 112 (100%) men in the study. 99.1% of men were satisfied with self-TWOC at home. We managed to avoid 79.6 ± 36.72 km of travel and 77 min of travel time for every self-TWOC. This also saved 85£/patient on clinic expenses and fuel cost savings of 9.87-15.99£ per patient depending on car engine size/type. The carbon footprint calculated was 20 kg CO2 assuming average engine sized diesel/petrol cars and 10 kg CO2 for an average UK petrol hybrid car. The calculated carbon offset per patient for diesel/petrol cars: 0.32£, petrol hybrid: 0.16£. Self-TWOC for 80-160 patients will save the carbon emissions equivalent to that of a passenger on a London-New York Trans-Atlantic flight. Self-TWOC is safe, affordable and is sustainable to the environment. Widespread acceptance of this practice change will be a small, but steady step towards greener health systems across the world.

Prognostic Role of CD68+ and CD163+ Tumour-Associated Macrophages and PD-L1 Expression in Oral Squamous Cell Carcinoma: A Meta-Analysis.

Background: Oral squamous cell carcinoma (OSCC) is a common malignant cancer in humans. An abundance of tumour associated macrophages (TAMs) create an immunosuppressive tumour microenvironment (TME). TAM markers (CD163 and CD68) are seen to serve as prognostic factors in OSCC. PD-L1 has seen to widely modulate the TME but its prognostic significance remains controversial. The aim of this meta-analysis is to evaluate the prognostic role of CD163+, CD68+ TAMs and PD-L1 in OSCC patients. Methods: Searches in PubMed, Scopus and Web of Science were performed; 12 studies were included in this meta-analysis. Quality assessment of included studies was performed according to REMARK guidelines. Risk of bias across studies was investigated according to the rate of heterogeneity. Meta-analysis was performed to investigate the association of all three biomarkers with overall survival (OS). Results: High expression of CD163+ TAMs were associated with poor overall survival (HR = 2.64; 95% Cl: [1.65, 4.23]; p < 0.0001). Additionally, high stromal expression of CD163+ TAMs correlated with poor overall survival (HR = 3.56; 95% Cl: [2.33, 5.44]; p < 0.00001). Conversely, high CD68 and PD-L1 expression was not associated with overall survival (HR = 1.26; 95% Cl: [0.76, 2.07]; p = 0.37) (HR = 0.64; 95% Cl: [0.35, 1.18]; p = 0.15). Conclusion: In conclusion, our findings indicate CD163+ can provide prognostic utility in OSCC. However, our data suggests CD68+ TAMs were not associated with any prognostic relevance in OSCC patients, whereas PD-L1 expression may prove to be a differential prognostic marker dependent on tumour location and stage of progression.

Development of a robust induced pluripotent stem cell atrial cardiomyocyte differentiation protocol to model atrial arrhythmia.

BACKGROUND: Atrial fibrillation is the most common arrhythmia syndrome and causes significant morbidity and mortality. Current therapeutics, however, have limited efficacy. Notably, many therapeutics shown to be efficacious in animal models have not proved effective in humans. Thus, there is a need for a drug screening platform based on human tissue. The aim of this study was to develop a robust protocol for generating atrial cardiomyocytes from human-induced pluripotent stem cells. METHODS: A novel protocol for atrial differentiation, with optimized timing of retinoic acid during mesoderm formation, was compared to two previously published methods. Each differentiation method was assessed for successful formation of a contractile syncytium, electrical properties assayed by optical action potential recordings and multi-electrode array electrophysiology, and response to the G-protein-gated potassium channel activator, carbamylcholine. Atrial myocyte monolayers, derived using the new differentiation protocol, were further assessed for cardiomyocyte purity, gene expression, and the ability to form arrhythmic rotors in response to burst pacing. RESULTS: Application of retinoic acid at day 1 of mesoderm formation resulted in a robust differentiation of atrial myocytes with contractile syncytium forming in 16/18 differentiations across two cell lines. Atrial-like myocytes produced have shortened action potentials and field potentials, when compared to standard application of retinoic acid at the cardiac mesoderm stage. Day 1 retinoic acid produced atrial cardiomyocytes are also carbamylcholine sensitive, indicative of active Ikach currents, which was distinct from ventricular myocytes and standard retinoic addition in matched differentiations. A current protocol utilizing reduced Activin A and BMP4 can produce atrial cardiomyocytes with equivalent functionality but with reduced robustness of differentiation; only 8/17 differentiations produced a contractile syncytium. The day 1 retinoic acid protocol was successfully applied to 6 iPSC lines (3 male and 3 female) without additional optimization or modification. Atrial myocytes produced could also generate syncytia with rapid conduction velocities, > 40 cm s-1, and form rotor style arrhythmia in response to burst pacing. CONCLUSIONS: This method combines an enhanced atrial-like phenotype with robustness of differentiation, which will facilitate further research in human atrial arrhythmia and myopathies, while being economically viable for larger anti-arrhythmic drug screens.

The Role of Allylic Strain for Conformational Control in Medicinal Chemistry.

It is axiomatic in medicinal chemistry that optimization of the potency of a small molecule at a macromolecular target requires complementarity between the ligand and target. In order to minimize the conformational penalty on binding, both enthalpically and entropically, it is therefore preferred to have the ligand preorganized in the bound conformation. In this Perspective, we highlight the role of allylic strain in controlling conformational preferences. Allylic strain was originally described for carbon-based allylic systems, but the same principles apply to other types of structure with sp2 or pseudo-sp2 arrangements. These systems include benzylic (including heteroaryl methyl) positions, amides, N-aryl groups, aryl ethers, and nucleotides. We have derived torsion profiles from small molecule X-ray structures for these systems. Through multiple examples, we show how these effects have been applied in drug discovery and how they can be used prospectively to influence conformation in the design process.

Action Potential Morphology Accurately Predicts Proarrhythmic Risk for Drugs With Potential to Prolong Cardiac Repolarization.

BACKGROUND: Drug-induced or acquired long QT syndrome occurs as a result of the unintended disruption of cardiac repolarization due to drugs that block cardiac ion channels. These side effects have been responsible for the withdrawal of a range of drugs from market and are a common reason for termination of the development of new drugs in the preclinical stage. Existing approaches to risk prediction are expensive and overly sensitive meaning that recently there have been renewed efforts, largely driven by the comprehensive proarrhythmic assay initiative, to develop more accurate methods for allocation of proarrhythmic risk. METHODS: In this study, we aimed to quantify changes in the morphology of the repolarization phase of the cardiac action potential as an indicator of proarrhythmia, supposing that these shape changes might precede the emergence of ectopic depolarizations that trigger arrhythmia. To do this, we describe a new method of quantifying action potential morphology by measuring the radius of curvature of the repolarization phase both in simulated action potentials, as well as in action potentials measured from induced pluripotent stem cell-derived cardiomyocytes. Features derived from the curvature signal were used as inputs for logistic regressions to predict proarrhythmic risk. RESULTS: Optimal risk classifiers based on morphology were able to correctly classify risk to drugs in the comprehensive proarrhythmic assay initiative panels with very high accuracy (0.9375) and outperformed conventional metrics based on action potential duration at 90% repolarization, triangulation, and charge movement (qNet). CONCLUSIONS: Analysis of action potential morphology in response to proarrhythmic drugs improves prediction of torsadogenic risk. Furthermore, morphology metrics can be measured directly from the action potential, potentially eliminating the burden of undertaking complex screens of potency and drug-binding kinetics against multiple cardiac ion channels. As such, this method has the potential to improve and streamline regulatory assessment of proarrhythmia in preclinical drug development.

Functional and oncological outcomes of robot-assisted radical prostatectomy in obese men: a matched-pair analysis.

Robot-assisted radical prostatectomy (RARP) in men with body mass index (BMI) ≥ 35 kg/m2 is considered technically challenging. We conducted a retrospective matched-pair analysis to compare the oncological and functional outcomes of RARP in men with BMI ≥ 35 kg/m2. We interrogated our prospectively maintained RARP database and identified 1273 men who underwent RARP from January 2018 till June 2021. Among them, 43 had BMI ≥ 35 kg/m2, and 1230 had BMI < 35 kg/m2. A 1:1 genetic matching was performed between these two groups for PSA, Gleason grades, clinical stage, D'Amico risk stratification, and nerve-spare extent. Continence rates and biochemical rates on 1-year follow-up were analysed. We performed statistical analysis using SPSS, and Paired tests were done using Wilcoxon sign rank-sum test. p < 0.05 was considered statistically significant. The two groups were comparable in almost all parameters except for age. Console time (p = 0.20) and estimated blood loss (p > 0.90) were not significantly different. There was no blood transfusion, open conversion or (Clavien-Dindo grade ≥ 3) intra/postoperative complication in either of the two groups. The two groups did not have any difference in biochemical recurrence rates (BCR) on 1-year follow-up (p > 0.90). Men with BMI ≥ 35 achieved continence rates equivalent to men with BMI < 35 within 1 year. On logistic regression analysis, age (p < 0.001) and extent of nerve sparing (p = 0.026) emerged as significant factors influencing continence recovery. RARP is safe in men with BMI ≥ 35 kg/m2. The 1-year continence and oncological outcomes are similar to matched men with BMI < 35 kg/m2 undergoing RARP.

Simultaneous excision of pelvic lipoma and robot-assisted radical prostatectomy.

Lipoma is a benign mesenchymal tumour that can develop in any part of the body containing adipose tissue. Very few cases of pelvic lipomas have been reported in the literature. Due to their location and slow growth, pelvic lipomas are often asymptomatic for a prolonged time. Thus, on diagnosis, they are usually found to be of considerable size. Due to their size, pelvic lipomas can present causing bladder outlet obstruction, lymphoedema, abdominal and pelvic pain, and constipation, as well as present with deep vein thrombosis (DVT) like symptoms. Patients with cancer have a much higher risk of developing DVT. Here, we describe a case of an incidental finding of pelvic lipoma mimicking DVT in a patient with organ-confined prostate cancer. He eventually underwent simultaneous robot-assisted radical prostatectomy and lipoma excision.

An investigation of the allylation cascade reactions of substituted indigos.

In a continuation of the exploration of indigo cascade reactions, a series of -OMe, -Ph, -Br and -NO2 substituted indigos 1a-i were synthesised to probe electronic effects upon the outcome of allylation cascade reactions. When indigos 1a-i in the presence of base were reacted with allyl bromide, spiroindolinepyridoindolones 17-25 (36-75%) were obtained as the major products in each case, marking a shift in outcome relative to that previously reported for unsubstituted indigo. In electron-rich derivatives (-OMe, -Ph), C-allylspiroindolinepyridoindolediones 26-29 (3-11%) were also isolated, which are most likely formed via a Claisen rearrangement of the respective spiroindolinepyridoindolones 18-21. Additionally, the isolation of diallylbiindolone 16, oxazinobiindole 30 and N,N'-diallyl-3,3'-bis(allyloxy)biindole 31 each represented novel polyheterocyclic derivatives, providing intriguing new mechanistic insights, reaction pathways and in the case of 30 the first common heterocyclic skeletal outcome shared in both allylation and propargylation cascade reactions of indigo.