Tumour budding as a prognostic biomarker in biopsies and resections of neoadjuvant-treated rectal adenocarcinoma.

BACKGROUND: Tumour budding (TB) is a marker of tumour aggressiveness which, when measured in rectal cancer resection specimens, predicts worse outcomes and response to neoadjuvant therapy. We investigated the utility of TB assessment in the setting of neoadjuvant treatment. METHODS AND RESULTS: A single-centre, retrospective cohort study was conducted. TB was assessed using the hot-spot International Tumour Budding Consortium (ITBCC) method and classified by the revised ITBCC criteria. Haematoxylin and eosin (H&E) and AE1/AE3 cytokeratin (CK) stains for ITB (intratumoural budding) in biopsies with PTB (peritumoural budding) and ITB (intratumoural budding) in resection specimens were compared. Logistic regression assessed budding as predictors of lymph node metastasis (LNM). Cox regression and Kaplan-Meier analyses investigated their utility as a predictor of disease-free (DFS) and overall (OS) survival. A total of 146 patients were included; 91 were male (62.3%). Thirty-seven cases (25.3%) had ITB on H&E and 79 (54.1%) had ITB on CK assessment of biopsy tissue. In univariable analysis, H&E ITB [odds (OR) = 2.709, 95% confidence interval (CI) = 1.261-5.822, P = 0.011] and CK ITB (OR = 2.165, 95% CI = 1.076-4.357, P = 0.030) predicted LNM. Biopsy-assessed H&E ITB (OR = 2.749, 95% CI = 1.258-6.528, P = 0.022) was an independent predictor of LNM. In Kaplan-Meier analysis, ITB identified on biopsy was associated with worse OS (H&E, P = 0.003, CK: P = 0.009) and DFS (H&E, P = 0.012; CK, P = 0.045). In resection specimens, CK PTB was associated with worse OS (P = 0.047), and both CK PTB and ITB with worse DFS (PTB, P = 0.014; ITB: P = 0.019). In multivariable analysis H&E ITB predicted OS (HR = 2.930, 95% CI = 1.261-6.809) and DFS (HR = 2.072, 95% CI = 1.031-4.164). CK PTB grading on resection also independently predicted OS (HR = 3.417, 95% CI = 1.45-8.053, P = 0.005). CONCLUSION: Assessment of TB using H&E and CK may be feasible in rectal cancer biopsy and post-neoadjuvant therapy-treated resection specimens and is associated with LNM and worse survival outcomes. Future management strategies for rectal cancer might be tailored to incorporate these findings.

Follow-up of urolithiasis patients after treatment: an algorithm from the EAU Urolithiasis Panel.

OBJECTIVE: To develop a follow-up algorithm for urinary stone patients after definitive treatment. MATERIALS AND METHODS: The panel performed a systematic review on follow-up of urinary stone patients after treatment (PROSPERO: CRD42020205739). Given the lack of comparative studies we critically evaluated the literature and reached a consensus on the follow-up scheme. RESULTS: A total of 76 studies were included in the analysis, including 17 RCTs. In the stone-free general population group, 71-100% of patients are stone-free at 12 months while 29-94% remain stone-free at 36 months. We propose counselling these patients on imaging versus discharge after the first year. The stone-free rate in high-risk patients not receiving targeted medical therapy is < 40% at 36 months, a fact that supports imaging, metabolic, and treatment monitoring follow-up once a year. Patients with residual fragments ≤ 4 mm have a spontaneous expulsion rate of 18-47% and a growth rate of 10-41% at 12 months, supporting annual imaging follow-up. Patients with residual fragments > 4 mm should be considered for surgical re-intervention based on the low spontaneous expulsion rate (13% at 1 year) and high risk of recurrence. Plain film KUB and/or kidney ultrasonography based on clinicians' preference and stone characteristics is the preferred imaging follow-up. Computed tomography should be considered if patient is symptomatic or intervention is planned. CONCLUSIONS: Based on evidence from the systematic review we propose, for the first time, a follow-up algorithm for patients after surgical stone treatment balancing the risks of stone recurrence against the burden of radiation from imaging studies.

ChatGPT in urology practice: revolutionizing efficiency and patient care with generative artificial intelligence.

PURPOSE OF REVIEW: ChatGPT has emerged as a potentially useful tool for healthcare. Its role in urology is in its infancy and has much potential for research, clinical practice and for patient assistance. With this narrative review, we want to draw a picture of what is known about ChatGPT's integration in urology, alongside future promises and challenges. RECENT FINDINGS: The use of ChatGPT can ease the administrative work, helping urologists with note-taking and clinical documentation such as discharge summaries and clinical notes. It can improve patient engagement through increasing awareness and facilitating communication, as it has especially been investigated for uro-oncological diseases. Its ability to understand human emotions makes ChatGPT an empathic and thoughtful interactive tool or source for urological patients and their relatives. Currently, its role in clinical diagnosis and treatment decisions is uncertain, as concerns have been raised about misinterpretation, hallucination and out-of-date information. Moreover, a mandatory regulatory process for ChatGPT in urology is yet to be established. SUMMARY: ChatGPT has the potential to contribute to precision medicine and tailored practice by its quick, structured responses. However, this will depend on how well information can be obtained by seeking appropriate responses and asking the pertinent questions. The key lies in being able to validate the responses, regulating the information shared and avoiding misuse of the same to protect the data and patient privacy. Its successful integration into mainstream urology needs educational bodies to provide guidelines or best practice recommendations for the same.

Outcomes of Flexible Ureteroscopy vs Extracorporeal Shock Wave Lithotripsy for Renal Stones in Pediatric Patients: A European Association of Urology Urolithiasis Guidelines Systematic Review and Meta-Analysis.

PURPOSE: We sought to determine which treatment between flexible ureteroscopy and shock wave lithotripsy has a better stone-free rate in pediatric patients (<18 years) with renal or proximal ureteric stones (<2 cm). Subanalysis for all outcomes for randomized controlled trials only. MATERIALS AND METHODS: Using PubMed, Web of Science, and the Cochrane database, we identified studies (randomized clinical trials and prospective comparative nonrandomized studies) published until August 2022 reporting surgical outcomes of pediatrics patients undergoing flexible ureteroscopy and shock wave lithotripsy with renal or proximal ureteric stones <2 cm (PROSPERO ID: CRD42022378790). Only randomized controlled trials were considered for meta-analysis. Stone-free rate, operative time, and complications were analyzed. Analysis was performed in R. RESULTS: A total of 6 studies identified, of which 3 were randomized clinical trials and 4 had data on renal stones. A total of 669 patients were analyzed. Mean age ranged from 4.4 to 12.4 years. The shock wave lithotripsy group presented a range of stone-free rate between 21 and 90% while the flexible ureteroscopy group presented a range of stone-free rates between 37% and 97%. Meta-analysis of randomized controlled trials only (n=302) demonstrated significantly higher stone-free rate in flexible ureteroscopy vs shock wave lithotripsy (RR = 1.17, 95% CI: 1.04-1.33, P = 0.01), operative time (mean difference = +16.4 minutes, 95% CI: 7.3-25.5, P < 0.01) and hospital stay (mean difference = +0.25 days, 95% CI: 0.14-0.36, P < 0.001). But no difference in fluoroscopy exposure time (mean difference = -21.0 seconds, 95% CI: -42.6 to 0.56, P = 0.07), Clavien I-II (RR = 1.23, 95% CI: 0.71-2.12, P = 0.45) or Clavien III-V complications (RR = 1.04, 95% CI: 0.32-3.42, P = 0.95). CONCLUSIONS: Flexible ureteroscopy has a significantly higher stone-free rate than shock wave lithotripsy, with no difference in complication rate or fluoroscopy exposure time, and significantly higher operative times and hospital stay. However, the current evidence base for this is weak and further randomized trials are needed.

Outcomes of alpha-blockers as medical expulsive therapy following shockwave lithotripsy: a systematic review and meta-analysis.

OBJECTIVES: To determine stone-free rate following shockwave lithotripsy (SWL) with/without alpha-blockers as well as complication rates (individual and classified using the Clavien-Dindo system). MATERIALS AND METHODS: We performed a systematic review of all randomized controlled trials that included more than 20 patients (age > 18 years) and examined the use of alpha-blockers after SWL. Meta-analysis was performed using 'metafor' in R. We report risk ratios (RRs) with 95% confidence intervals (95% CIs). The PROSPERO ID for the trial was: CRD42021248108. RESULTS: We assessed 158 full-text articles and included a total of 21 studies in our review. There were 1445 patients receiving alpha-blockers and 1478 control patients. Those receiving alpha-blockers were significantly more likely to be stone-free (RR 1.12, 95% CI 1.07-1.16; P < 0.001). This effect was robust to 'trim-and-fill' adjustment. In those taking alpha-blockers there was a significant reduction in Clavien III-V complications and, on trim-and-fill adjustment, a significant reduction in Clavien I-II complications. There were also significant reduction in rates of steinstrasse, pain and requirement for auxiliary procedures. There was no significant difference in retreatment rates. These effects were robust to trim-and-fill adjustment. CONCLUSIONS: There is a modest increase in stone-free rates in those receiving alpha-blockers following SWL, with a reciprocal modest risk reduction for steinstrasse, pain and auxiliary procedures. However, alpha-blockers do not reduce the risk of requiring retreatment.

Does pre-stenting influence outcomes of shockwave lithotripsy? A systematic review and meta-analysis.

OBJECTIVE: To determine whether preoperative use of JJ stents in patients undergoing shockwave lithotripsy (SWL) impacts on stone clearance and the rate of postoperative complications. PATIENTS AND METHODS: We screened multiple databases from inception to January 2021, using the relevant search terms for SWL in patients with a preoperative stent. Inclusion criteria were randomised controlled trials of ≥20 patients aged >18 years who had had SWL with a JJ stent. This review has been registered in the International Prospective Register of Systematic Reviews (PROSPERO; registration number CRD42023443195). Statistical analysis was performed using 'meta' in R. RESULTS: There were seven eligible studies (403 patients receiving JJ stents and 394 controls). There was no significant difference in the stone-free rate (SFR) following SWL with a JJ stent compared to SWL alone. When considering the complication rates, there was a significantly reduced risk of steinstrasse in patients with a JJ stent. However, there was no significant difference in the risk of other complications including pain, fever, and haematuria, and no significant difference in the likelihood of requiring auxiliary procedures or re-treatment. CONCLUSIONS: There was a reduced risk of steinstrasse in patients undergoing SWL with a JJ stent compared to SWL alone. However, there was no significant difference in the risk of other postoperative complications. Use of a JJ stent had no effect on the efficacy of SWL, with no significant difference in the SFR.

Complication rate after pediatric shock wave lithotripsy according to Clavien-Dindo grading system: results from a systematic review and meta-analysis of the existing literature.

PURPOSE: Shockwave lithotripsy (SWL) is a minimally invasive technique utilized for renal and ureteric stones in children. Despite being considered safe, certain complications have been recorded. We performed this systematic review and meta-analysis to provide a pooled analysis of Clavien-Dindo graded complications after SWL in children. METHODS: MEDLINE/PubMed, Scopus and Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews, were screened from inception to 12/02/2022 by two authors independently. Only randomized controlled trials providing Clavien-Dindo classification or relevant clinical information were considered eligible. Overall complications were calculated using the aggregate number of each complication divided by the total number of patients in studies with data. RESULTS: Pooled analysis revealed that from children treated with SWL, 27.7% [95% CI 13.1-49.4] suffered Clavien I complications, 4.9% [95% CI 3.1-7.6] Clavien II complications, 2.7% [95% CI 1.6-4.7] Clavien III complications, 2.3% [95% CI 1.3-4] Clavien IV complications, while no Clavien V complications were recorded. In total, 28.1% [95% CI 15.6-45.3] of children suffered minor complications (Clavien-Dindo I-II), while 3% [95% CI 1.8-5] major complications (Clavien-Dindo III-V). Pooled analysis revealed that 10.7% [95% CI 3.2-30.1] of patients suffered macroscopic hematuria, 7.3% [95% CI 2.1-22.7] pain, 5.5% [95% CI 3.3-9] steinstrasse, 5.3% [95% CI 3-9.3] fever, 2.2% [95% CI 0.8-5.6] sepsis, 1.1% [95% CI 0.3-3.7] urinoma, 1% [95% CI 0.4-2.7] symptomatic hematoma and 1% [95% CI 0.3-2.7] asymptomatic hematoma. Need for re-treatment was 42.6% [95% CI 31.4-54.7] and need for auxiliary procedures was 11.8% [95% CI 8.5-16.1]. CONCLUSION: SWL is an irreplaceable tool for treating urolithiasis in children. Although a minimally invasive technique, parents and children should be adequately informed about the risk of minor/major complications.

Endourological Options for Small (< 2 cm) Lower Pole Stones - Does the Lower Pole Angle Matter?

PURPOSE OF REVIEW: Small renal stones in the lower pole are often difficult to treat. The angle of the lower pole to the renal pelvis (lower pole angle) is a limiting factor to rendering the patient stone free. This review explores the definitions of the lower pole angle, the various treatment options available, and how outcomes are influenced by the angle. RECENT FINDINGS: It is clear the lower pole angle definition varies widely depending on described technique and imaging modality. However, it is clear that outcomes are worse with a steeper angle, especially for shock wave lithotripsy and retrograde intrarenal surgery (RIRS). Percutaneous nephrolithotomy has similar reported outcomes to RIRS, and there is limited evidence it may be superior for steeper angles over RIRS. Lower pole stones can be technically challenging and adequate assessment prior to choosing operative approach is key.

Outcomes of Paediatric Cystine Stone Management: Results of a Systematic Review.

PURPOSE OF REVIEW: We wanted to analyse the outcomes of surgical (SWL, URS, PCNL) and medical management of cystine stones in the paediatric population in terms of stone-free status and complication rates, based on all the available literature evidence. RECENT FINDINGS: A systematic review of literature was performed for all studies with paediatric cystine stone management. Twelve studies met the eligibility criteria, of which 4 analysed outcomes of SWL, 2 of URS and 3 of PCNL and 3 focused on the effect of either alkalising agents (potassium citrate, citric acid) or cysteine-binding thiol (CBT) agents (tiopronin, penicillamine). The reported SFR in studies ranged from 50 to 83%, 59 to 100% and 63 to 80.6%, with a complication rate of 2.8-51%, 14-27% and 12.9-15.4% with SWL, URS and PCNL, respectively. Paediatric cystine stones treatment should aim at complete stone clearance, preservation of renal function and prevention of further recurrences. SWL achieves inferior results in case of cystine stones. URS and PCNL are safe and effective procedures in the paediatric population, with a low rate of major complications. Adherence to medical prevention therapies may prolong recurrence-free periods.

Enhanced Remdesivir Analogues to Target SARS-CoV-2.

We report the short synthesis of novel C-nucleoside Remdesivir analogues, their cytotoxicity and an in vitro evaluation against SARS-CoV-2 (CoV2). The described compounds are nucleoside analogues bearing a nitrogen heterocycle as purine analogues. The hybrid structures described herein are designed to enhance the anti-CoV2 activity of Remdesivir. The compounds were evaluated for their cytotoxicity and their anti-CoV2 effect. We discuss the impact of combining both sugar and base modifications on the biological activities of these compounds, their lack of cytotoxicity and their antiviral efficacy.

Natural history of small asymptomatic kidney and residual stones over a long-term follow-up: systematic review over 25 years.

OBJECTIVE: To systematically review the natural history of small asymptomatic kidney and residual stones, as the incidental identification of small, asymptomatic renal calculi has risen with increasing use of high-resolution imaging. MATERIALS AND METHODS: We reviewed the natural history of small asymptomatic kidney and residual stones using the Cochrane and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology. We searched MEDLINE, Scopus, EMBASE, EBSCO, Cochrane library and Clinicaltrials.gov using themes of 'asymptomatic', 'nephrolithiasis', 'observation', 'symptoms', 'admission', 'intervention' and similar allied terms for all English language articles from 1996 to 2020 (25 years). Inclusion criteria were studies with ≥50 patients, stones ≤10 mm, and a mean follow-up of ≥24 months. Primary outcomes were occurrence of symptoms, emergency admission, and interventions. RESULTS: Our literature search returned 2247 results of which 10 papers were included in the final review. Risk of symptomatic episodes ranged from 0% to 59.4%. Meta-analysis did not identify any significant difference in the likelihood of developing symptoms when comparing stones <5 mm to those >5 mm, nor those <10 mm to those >10 mm. Risk of admission varied from 14% to 19% and the risk of intervention from 12% to 35%. Meta-analysis showed a significantly decreased likelihood of intervention for stones <5 vs >5 mm and <10 vs >10 mm. Studies had variable risk of bias due to heterogeneous reporting of outcome measures with significant likelihood that observed differences in results were compatible with chance alone (Symptoms: I2 =0%, Cochran's Q = 3.09, P = 0.69; Intervention: I2 =0%, Cochran's Q = 1.76, P = 0.88). CONCLUSIONS: The present systematic review indicates that stone size is not a reliable predictor of symptoms; however, risk of intervention is greater for stones >5mm vs <5 mm and >10 vs <10 mm. This review will inform urologists as they discuss management strategies with patients who have asymptomatic renal stones and offer insight to committees during the development of evidence-based guidelines.

Ten-year survival outcomes after radical nephroureterectomy with a risk-stratified approach using prior diagnostic ureteroscopy: a single-institution observational retrospective cohort study.

OBJECTIVES: To evaluate the long-term oncological outcomes of patients with upper tract urothelial carcinoma (UTUC) undergoing radical nephroureterectomy (RNU) and the impact of diagnostic ureteroscopy (URS) on survival outcomes. MATERIALS AND METHODS: A retrospective analysis of all consecutive patients undergoing RNU for suspected UTUC at a UK tertiary referral centre from a prospectively maintained database was conducted. The primary outcome measures were 5- and 10-year cancer-specific survival (CSS). The secondary outcomes were: overall survival (OS), recurrence-free survival (RFS), impact of prior diagnostic URS on OS, CSS and intravesical RFS (intravesical-RFS), and predictors of intravesical recurrence. Statistical analysis was performed in R using the 'survminer' and 'survival' packages. The Kaplan-Meier method was used to calculate survival functions and these were expressed in graphical form. Uni-/multivariate survival analyses were performed using the Cox proportional hazard regression model. Statistical significance in this study was set at P < 0.05. RESULTS: A total of 422 patients underwent RNU with confirmed UTUC. The median (interquartile range) follow-up of patients with confirmed UTUC was 9.2 (5.6-12.7) years. The 5- and 10-year CSS rates were 70.5% (95% confidence interval [CI] 65.9-74.9) and 67.1% (95% CI 62.4-71.6), respectively. OS (HR 1.04 [95% CI 0.78-1.38]; P = 0.46) and CSS (HR 0.96 [95% CI 0.68-1.34]; P = 0.81) were similar in the diagnostic URS and the direct RNU cohorts. intravesical RFS was superior for the direct RNU cohort (HR 1.94 [95% CI 1.19-3.17]; P = 0.008). In multivariate analysis, prior URS, T2 stage, proximal ureter tumour and bladder cancer history were predictors of metachronous bladder recurrence. CONCLUSION: This single-centre retrospective cohort study reports the long-term oncological outcomes of RNU with a median follow-up of 9.2 years, serving as a reference standard in counselling patients undergoing RNU. Stage and grade of the RNU specimen were the only two studied factors that appeared to adversely impact long-term CSS and OS. Our results suggest that the risk of intravesical recurrence is increased nearly twofold in patients who have undergone diagnostic URS prior to RNU. Prior URS, however, does not appear to adversely impact long-term CSS and OS. The authors suggest that a risk-stratified approach be adopted, wherein diagnostic URS is offered only in equivocal cases.

Emergency upper urinary tract decompression: double-J stent or nephrostomy? A European YAU/ESUT/EULIS/BSIR survey among urologists and radiologists.

PURPOSE: To evaluate the decompression of the pelvicalyceal system between urologists and radiologists. METHODS: A survey was distributed to urologists and to radiologists comparing double-J stent (DJS), percutaneous nephrostomy (PN) and primary ureteroscopy (URS) for three clinical scenarios (1-febrile hydronephrosis; 2-obstruction and persistent pain; 3-obstruction and anuria) before and after reading literature The survey included perception on radiation dose, cost and quality of life (QoL). RESULTS: Response rate was 40% (366/915). 93% of radiologists believe that DJS offers a better QOL compared to 70.6% of urologists (p = 0.006). 28.4% of urologists consider PN to be more expensive compared to 8.9% of radiologists (p = 0.006). 75% of radiologists believe that radiation exposure is higher with DJS as opposed to 33.9% of urologists. There was not a difference in the decompression preference in the first scenario. After reading the literature, 28.6% of radiologists changed their opinion compared to 5.2% of urologists (p < 0.001). The change favored DJS. In the second scenario, responders preferred equally DJS and they did not change their opinion. In the third scenario, 41% of radiologists chose PN as opposed to 12.6% of urologists (p < 0.001). After reading the literature, 17.9% of radiologists changed their opinion compared to 17.9% of urologists (p < 0.001), in favor of DJS. Although the majority of urologists (63.4%) consistently perform primary URS, only 3, 37 and 21% preferred it for the first, second and third scenarios, respectively. CONCLUSION: The decision on the type of drainage of a stone-obstructing hydronephrosis should be individualized.

Repurposing N-hydroxy thienopyrimidine-2,4-diones (HtPD) as inhibitors of human cytomegalovirus pUL89 endonuclease: Synthesis and biological characterization.

The terminase complex of human cytomegalovirus (HCMV) is required for viral genome packaging and cleavage. Critical to the terminase functions is a metal-dependent endonuclease at the C-terminus of pUL89 (pUL89-C). We have previously reported metal-chelating N-hydroxy thienopyrimidine-2,4-diones (HtPD) as inhibitors of human immunodeficiency virus 1 (HIV-1) RNase H. In the current work, we have synthesized new analogs and resynthesized known analogs of two isomeric HtPD subtypes, anti-HtPD (13), and syn-HtPD (14), and characterized them as inhibitors of pUL89-C. Remarkably, the vast majority of analogs strongly inhibited pUL89-C in the biochemical endonuclease assay, with IC50 values in the nM range. In the cell-based antiviral assay, a few analogs inhibited HCMV in low µM concentrations. Selected analogs were further characterized in a biophysical thermal shift assay (TSA) and in silico molecular docking, and the results support pUL89-C as the protein target of these inhibitors. Collectively, the biochemical, antiviral, biophysical, and in silico data reported herein indicate that the isomeric HtPD chemotypes 13-14 can serve as valuable chemical platforms for designing improved inhibitors of HCMV pUL89-C.

Changes in Urine Composition and Risk of Kidney Stone Disease Following Bariatric Surgery: A Systematic Review over Last 2 Decades.

PURPOSE OF REVIEW: The association of kidney stone disease (KSD) and gastrointestinal (GI) surgery has been well established. With a rising obesity crisis, we wanted to see the correlation of urinary composition in patients undergoing bariatric surgery and their risk of KSD. The objective of this paper is to perform a systematic review and meta-analysis of literature to evaluate the changes in urinary composition and risk of KSD following bariatric surgery. RECENT FINDINGS: A total of seven studies (2498 patients) underwent bariatric surgery with a mean age of 46.7 years and a male:female ratio of 1:3. The most popular bariatric surgery was the Roux-en-Y procedure. Meta-analysis of the studies showed that significant decrease in urinary calcium, citrate, and urate, and increase in urinary oxalate. There was also a nonsignificant volume reduction in the post-operative cohort. The decrease in urinary citrate and increase in urinary oxalate are both predisposing factors of stone formation. There is strong evidence that bariatric surgery results in significant changes in urine composition in keeping with the increased risk of developing KSD. This identifies useful therapeutic targets in the prophylactic management of patients who have undergone bariatric surgery.

Zika Virus Inhibitors Based on a 1,3-Disubstituted 1H-Pyrazolo[3,4-d]pyrimidine-amine Scaffold.

To search for Zika virus (ZIKV) antivirals, we have further explored previously reported 7H-pyrrolo[2,3-d]pyrimidines by examining an alternative substitution pattern of their central scaffold, leading to compound 5 with low micromolar antiviral activity. To circumvent the synthetic difficulties associated with compound 5, we have exploited a 1H-pyrazolo[3,4-d]pyrimidine scaffold and performed structure-activity relationship studies on its peripheral rings A and B. While ring B is less sensitive to structural modifications, an electron-withdrawing group at the para position of ring A is preferred for enhanced antiviral activity. Overall, we have not only discovered an alternative substitution pattern centered on a 1H-pyrazolo[3,4-d]pyrimidine scaffold but also generated anti-ZIKV compounds including 6 and 13, which possess low micromolar antiviral activity and relatively low cytotoxicity. These compounds represent new chemotypes that will be further optimized in our continued efforts to discover anti-ZIKV agents.

Natural History of Post-Treatment Kidney Stone Fragments: A Systematic Review and Meta-Analysis.

PURPOSE: We assessed the literature around post-treatment asymptomatic residual stone fragments and performed a meta-analysis. The main outcomes were intervention rate and disease progression. MATERIALS AND METHODS: We searched Ovid®, MEDLINE®, Embase™, the Cochrane Library and ClinicalTrials.gov using search terms: "asymptomatic", "nephrolithiasis", "ESWL", "PCNL", "URS" and "intervention." Inclusion criteria were all studies with residual renal fragments following treatment (shock wave lithotripsy, ureteroscopy or percutaneous nephrolithotomy). Analysis was performed using 'metafor' in R and bias determined using Newcastle-Ottawa scale. RESULTS: From 273 articles, 18 papers (2,096 patients) had details of intervention rate for residual fragments. Aggregate intervention rates for ≤4 mm fragments rose from 19% (20 months) to 22% (50 months), while >4 mm fragments rose from 22% to 47%. Aggregate disease progression rates for ≤4 mm rose from 25% to 47% and >4 mm rose from 26% to 88%. However, there was substantial difference in definition of "disease progression." Meta-analysis comparing >4 mm against ≤4 mm fragments: intervention rate for >4 mm (vs ≤4 mm): OR=1.50 (95% CI 0.70-2.30), p <0.001, I2=67.6%, tau2=0.48, Cochran's Q=11.4 (p=0.02) and Egger's regression: z=3.11, p=0.002. Disease progression rate for >4 mm: OR=0.06 (95% CI -0.98-1.10), p=0.91, I2=53.0%, tau2=0.57, Cochran's Q=7.11 (p=0.07) and Egger's regression: z=-0.75, p=0.45. Bias analysis demonstrated a moderate risk. CONCLUSIONS: Larger post-treatment residual fragments are significantly more likely to require further intervention especially in the long term. Smaller fragments, although less likely to require further intervention, still carry that risk. Notably, there is no significant difference in disease progression between fragment sizes. Patients with residual fragments should be appropriately counselled and informed decision-making regarding further management should be done.

Risk of UTI in kidney stone formers: a matched-cohort study over a median follow-up of 19 years.

PURPOSE: To describe risk of UTI in Stone formers comparing to non-stone formers. METHODS: Retrospective cohort study using electronic records for patients across southern England. Stone formers referred to a tertiary referral centre in Southern England, comparator patients were age and sex matched with 3:1 ratio from same database. Those with no documentation were excluded. UTI defined using ICD-10 codes. Risk of UTI presented as hazard ratio with 95% confidence interval, generated using cox regression. Sample size calculated using 80% power and significance set at 0.05. RESULTS: Eight hundred and nineteen stone formers were included after 1000 records were screened for inclusion, with 2477 age and sex matched non-stone formers extracted from the same database. Sample size was calculated at 287 per group. Stone formers were at significantly increased risk of developing a UTI (HR 5.67; 95% CI 4.52-7.18, p < 0.001). Median follow-up was 19 years (IQR: 15-22). CONCLUSIONS: Kidney stone formers are at increased risk of developing urinary tract infections.

Comparison of Primary and Delayed Ureteroscopy for Ureteric Stones: A Prospective Non-Randomized Comparative Study.

BACKGROUND: Primary ureteroscopy (P-URS) has been shown to be as safe and as efficacious as preoperative stent insertion followed by a delayed ureteroscopy (D-URS). However, studies are of limited patient cohort. METHODS: A prospective study comparing P-URS and laser fragmentation for ureteric stones to those who received a stent insertion followed by D-URS and stone fragmentation. RESULTS: A total of 367 consecutive patients were included. P-URS was conducted on 235 patients and D-URS on 132 patients. There was no overall difference between patient or stone demographics between the 2 groups, although there were more proximal ureteric and pelvi-ureteric junction stones in the preoperative stent group. The mean operative times were comparable with a stone free rate of 97 and 94% in the preoperative stent and no-stent groups, respectively. The overall complication rates were comparable. CONCLUSION: The current study provides evidence for the feasibility, safety, and efficacy of P-URS for ureteric calculi in a publicly funded healthcare setting with results comparable to those patients with a preoperative stent and delayed procedure. Therefore, cumulatively, P-URS could lead to less hospitalization, length of stay, stent-related morbidity, and ultimately will be more cost-effective.

4,7-Disubstituted 7H-Pyrrolo[2,3-d]pyrimidines and Their Analogs as Antiviral Agents against Zika Virus.

Discovery of compound 1 as a Zika virus (ZIKV) inhibitor has prompted us to investigate its 7H-pyrrolo[2,3-d]pyrimidine scaffold, revealing structural features that elicit antiviral activity. Furthermore, we have demonstrated that 9H-purine or 1H-pyrazolo[3,4-d]pyrimidine can serve as an alternative core structure. Overall, we have identified 4,7-disubstituted 7H-pyrrolo[2,3-d]pyrimidines and their analogs including compounds 1, 8 and 11 as promising antiviral agents against flaviviruses ZIKV and dengue virus (DENV). While the molecular target of these compounds is yet to be elucidated, 4,7-disubstituted 7H-pyrrolo[2,3-d]pyrimidines and their analogs are new chemotypes in the design of small molecules against flaviviruses, an important group of human pathogens.