Multi-Institutional Outcomes of Dorsal Onlay Buccal Mucosal Graft Urethroplasty in Patients With Postprostatectomy, Postradiation Anastomotic Stenosis.

PURPOSE: The treatment of urethral stenosis after a combination of prostatectomy and radiation therapy for prostate cancer is understudied. We evaluate the clinical and patient-related outcomes after dorsal onlay buccal mucosal graft urethroplasty (D-BMGU) in men who underwent prostatectomy and radiation therapy. MATERIALS AND METHODS: A multi-institutional, retrospective review of men with vesicourethral anastomotic stenosis or bulbomembranous urethral stricture disease after radical prostatectomy and radiation therapy from 8 institutions between 2013 to 2021 was performed. The primary outcomes were stenosis recurrence and development of de novo stress urinary incontinence. Secondary outcomes were surgical complications, changes in voiding, and patient-reported satisfaction. RESULTS: Forty-five men were treated with D-BMGU for stenosis following prostatectomy and radiation. There was a total of 7 recurrences. Median follow-up in patients without recurrence was 21 months (IQR 12-24). There were no incidents of de novo incontinence, 28 patients were incontinent pre- and postoperatively, and of the 6 patients managed with suprapubic catheter preoperatively, 4 were continent after repair. Following repair, men had significant improvement in postvoid residual, uroflow, International Prostate Symptom Score, and International Prostate Symptom Score quality-of-life domain. Overall satisfaction was +2 or better in 86.6% of men on the Global Response Assessment. CONCLUSIONS: D-BMGU is a safe, feasible, and effective technique in patients with urethral stenosis after a combination of prostatectomy and radiation therapy. Although our findings suggest this technique may result in lower rates of de novo urinary incontinence compared to conventional urethral transection and excision techniques, head-to-head comparisons are needed.

Gastrointestinal adverse events and weight reduction in people with type 2 diabetes treated with tirzepatide in the SURPASS clinical trials.

AIMS: To evaluate gastrointestinal adverse events (AEs) and the impact of nausea, vomiting or diarrhoea (N/V/D) and any gastrointestinal (GI) AEs overall on weight change with tirzepatide across the SURPASS-1 to -5 clinical trials. MATERIALS AND METHODS: Participants with type 2 diabetes were randomized to receive once-weekly tirzepatide (5, 10 or 15 mg) or comparator (placebo, semaglutide 1 mg once weekly, or titrated daily basal insulins) as monotherapy or added on to background antihyperglycaemic medication(s). This post hoc analysis subdivided participants within each trial into subgroups that self-reported (yes/no) any N/V/D or GI AEs. Change from baseline in body weight at the primary timepoint was assessed within each trial and subgroup. Mediation analyses were conducted to evaluate the contribution of direct and indirect (mediated by N/V/D or GI AEs) effects of tirzepatide on weight change versus comparators. RESULTS: Across the SURPASS-1 to -5 trials (N = 6263), nausea (12%-24%), diarrhoea (12%-22%), and vomiting (2%-13%) were the most common GI AEs reported with tirzepatide; these were transient and of mild-to-moderate severity. Mean weight reduction at the primary timepoint with tirzepatide was consistent between participants who reported N/V/D (-6.2 to -14.9 kg) and those who did not report N/V/D (-6.2 to -13.3 kg). Mean weight reduction was significantly (P < 0.01) greater with tirzepatide compared with placebo, semaglutide 1 mg, and basal insulins within the N/V/D and GI AEs subgroups. Mediation analyses suggested minimal contribution (<6%) of N/V/D and GI AEs to the overall difference in weight change between tirzepatide and comparators. CONCLUSIONS: Superior weight reduction with tirzepatide versus comparators appears to be independent of reported N/V/D or GI AEs.

Fragility of overactive bladder medication clinical trials: A systematic review.

PURPOSE: Overactive bladder (OAB) syndrome significantly impairs quality of life, often necessitating pharmacological interventions with associated risks. The fragility of OAB trial outcomes, as measured by the fragility index (FI: smallest number of event changes to reverse statistical significance) and quotient (FQ: FI divided by total sample size expressed as a percentage), is critical yet unstudied. MATERIALS AND METHODS: We conducted a systematic search for randomized controlled trials on OAB medications published between January 2000 and August 2023. Inclusion criteria were trials with two parallel arms reporting binary outcomes related to OAB medications. We extracted trial details, outcomes, and statistical tests employed. We calculated FI and FQ, analyzing associations with trial characteristics through linear regression. RESULTS: We included 57 trials with a median sample size of 211 participants and a 12% median lost to follow-up. Most studies investigated anticholinergics (37/57, 65%). The median FI/FQ was 5/3.5%. Larger trials were less fragile (median FI 8; FQ 1.0%) compared to medium (FI: 4; FQ 2.5%) and small trials (FI: 4; FQ 8.3%). Double-blinded studies exhibited higher FQs (median 2.9%) than unblinded trials (6.7%). Primary and secondary outcomes had higher FIs (median 5 and 6, respectively) than adverse events (FI: 4). Each increase in 10 participants was associated with a +0.19 increase in FI (p < 0.001). CONCLUSIONS: A change in outcome for a median of five participants, or 3.5% of the total sample size, could reverse the direction of statistical significance in OAB trials. Studies with larger sample sizes and efficacy outcomes from blinded trials were less fragile.

Development of Biological Coating from Novel Halophilic Exopolysaccharide Exerting Shelf-Life-Prolonging and Biocontrol Actions for Post-Harvest Applications.

The literature presents the preserving effect of biological coatings developed from various microbial sources. However, the presented work exhibits its uniqueness in the utilization of halophilic exopolysaccharides as food coating material. Moreover, such extremophilic exopolysaccharides are more stable and economical production is possible. Consequently, the aim of the presented research was to develop a coating material from marine exopolysaccharide (EPS). The significant EPS producers having antagonistic attributes against selected phytopathogens were screened from different marine water and soil samples. TSIS01 isolate revealed the maximum antagonism well and EPS production was selected further and characterized as Bacillus tequilensis MS01 by 16S rRNA analysis. EPS production was optimized and deproteinized EPS was assessed for biophysical properties. High performance thin layer chromatography (HPTLC) analysis revealed that EPS was a heteropolymer of glucose, galactose, mannose, and glucuronic acid. Fourier transform infrared spectroscopy, X-ray diffraction, and UV-visible spectra validated the presence of determined sugars. It showed high stability at a wide range of temperatures, pH and incubation time, ≈1.63 × 106 Da molecular weight, intermediate solubility index (48.2 ± 3.12%), low water holding capacity (12.4 ± 1.93%), and pseudoplastic rheologic shear-thinning comparable to xanthan gum. It revealed antimicrobial potential against human pathogens and antioxidants as well as anti-inflammatory potential. The biocontrol assay of EPS against phytopathogens revealed the highest activity against Alternaria solani. The EPS-coated and control tomato fruits were treated with A. solani suspension to check the % disease incidence, which revealed a significant (p < 0.001) decline compared to uncoated controls. Moreover, it revealed shelf-life prolonging action on tomatoes comparable to xanthan gum and higher than chitosan. Consequently, the presented marine EPS was elucidated as a potent coating material to mitigate post-harvest losses.

A Contemporary Analysis of Combat-related Urological Injuries: Data From the Department of Defense Trauma Registry.

PURPOSE: There has been little to no literature published on combat-related genitourinary injuries beyond 2013. With the goal of enhancing medical readiness prior to deployment and making recommendations to improve the long-term rehabilitation of service members as they become civilians, we sought to describe the incidence of combat-related genitourinary injuries and interventions from January 1, 2007, to March 17, 2020. MATERIALS AND METHODS: We conducted a retrospective analysis of the Department of Defense Trauma Registry, which is a prospectively maintained database, for the time between 2007 and 2020. We used predefined search criteria to primarily identify any casualties that arrived at a military treatment facility with urological-based injuries. RESULTS: The registry contained 25,897 adult casualties, of which 7.2% sustained urological injuries. The median age was 25. Explosive injuries (64%) and firearms (27%) predominated. The median injury severity score was 18 (IQR 10-29). Most patients survived until hospital discharge (94%). The most frequently injured organs were the scrotum (60%), testes (53%), penis (30%), and kidneys (30%). Massive transfusion protocols were activated in 35% of all patients who sustained a urological injury and accounted for 28% of all protocols between 2007 and 2020. CONCLUSIONS: The incidence of genitourinary trauma persistently increased for both military and civilian personnel as the U.S. remained actively engaged in major military conflicts during this period. Patients with genitourinary trauma in this data set were often associated with high injury severity scores and required an increased number of immediate and long-term resources for survival and rehabilitation.

Patient-Reported Outcomes Over 24 Months in Pediatric CKD: Findings From the MyKidneyHealth Cohort Study.

RATIONALE & OBJECTIVE: The lived experience of children with chronic kidney disease (CKD) is poorly characterized. We examined the associations between patient-reported outcome (PRO) scores measuring their fatigue, sleep health, psychological distress, family relationships, and global health with clinical outcomes over time in children, adolescents, and younger adults with CKD and investigated how the PRO scores of this group compare with those of other children, adolescents, and younger adults. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 212 children, adolescentss, and adults aged 8 to 21 years with CKD and their parents recruited from 16 nephrology programs across North America. PREDICTORS: CKD stage, disease etiology, and sociodemographic and clinical variables. OUTCOME: PRO scores over 2 years. ANALYTICAL APPROACH: We compared PRO scores in the CKD sample with a nationally representative general pediatric population (ages 8 to 17 years). Change of PROs over time and association of sociodemographic and clinical variables with PROs were assessed using multivariable regression models. RESULTS: For all time points, 84% of the parents and 77% of the children, adolescents, and younger adults completed PRO surveys . The baseline PRO scores for the participants with CKD revealed a higher burden of fatigue, sleep-related impairment, psychological distress, impaired global health, and poorer family relationships compared with the general pediatric population, with median score differences≥1 SD for fatigue and global health. The baseline PRO scores did not differ by CKD stage or glomerular versus nonglomerular etiology. Over 2 years, PROs were stable with a<1-point annual change on average on each measure and intraclass correlation coefficients ranging from 0.53 to 0.79, indicating high stability. Hospitalization and parent-reported sleep problems were associated with worse fatigue, psychological health, and global health scores (all P<0.04). LIMITATIONS: We were unable to assess responsiveness to change with dialysis or transplant. CONCLUSIONS: Children with CKD experience a high yet stable burden of impairment across numerous PRO measures, especially fatigue and global health, independent of disease severity. These findings underscore the importance of assessing PROs, including fatigue and sleep measures, in this vulnerable population. PLAIN-LANGUAGE SUMMARY: Children with chronic kidney disease (CKD) have many treatment demands and experience many systemic effects. How CKD impacts the daily life of a child is poorly understood. We surveyed 212 children, adolescents, and younger adults with CKD and their parents over 24 months to assess the participants' well-being over time. Among children, adolescents, and younger adults with CKD we found a very high and persistent burden of psychological distress that did not differ by degree of CKD or type of kidney disease. The participants with CKD endorsed greater impairment in fatigue and global health compared with healthy children, adolescents, and younger adults, and parent-reported sleep problems were associated with poorer patient-reported outcome (PRO) scores across all domains. These findings emphasize the importance of including PRO measures, including fatigue and sleep measures, into routine clinical care to optimize the lived experience of children with CKD.

Systolic blood pressure reduction with tirzepatide in patients with type 2 diabetes: insights from SURPASS clinical program.

BACKGROUND: Tirzepatide, a once-weekly glucose-dependent insulinotropic polypeptide/ glucagon-like peptide-1 receptor agonist, is approved in the United States, Europe and Japan for the treatment of type 2 diabetes. Across the SURPASS-1 to -5 clinical studies, tirzepatide 5, 10 and 15 mg demonstrated significant improvements in glycated haemoglobin A1c (HbA1c) (- 1.9 to - 2.6%), body weight (- 6.6 to - 13.9%) and systolic blood pressure (SBP) (- 2.8 to - 12.6 mmHg) at the end of study treatment. METHODS: Post-hoc mediation analyses were conducted to evaluate weight-loss dependent and weight-loss independent effects of tirzepatide on SBP reductions across the 5 SURPASS studies. The safety population (all randomized patients who took at least 1 dose of study drug) of each study was analyzed. Additional analyses were conducted at individual study level or pooled across 5 SURPASS trials. RESULTS: The difference in mean SBP change from baseline at 40 weeks (total effect) between the tirzepatide and comparator groups was - 1.3 to - 5.1 mmHg (tirzepatide 5 mg), - 1.7 to - 6.5 mmHg (tirzepatide 10 mg) and - 3.1 to - 11.5 mmHg (tirzepatide 15 mg). These SBP reductions were primarily mediated through weight loss, with different degrees of contributions from weight-loss independent effects across the different trials. In the SURPASS-4 study, which enrolled patients with established cardiovascular disease, weight-loss independent effects explained 33% to 57% of difference in SBP change between tirzepatide and insulin glargine groups. In a pooled analysis of the SURPASS-1 to -5 studies, there was a significant (p < 0.001) but weak correlation (r = 0.18 to 0.22) between change in body weight and SBP. Reductions in SBP with tirzepatide were not dependent on concomitant antihypertensive medications at baseline as similar reductions were observed whether participants were receiving them or not (interaction p = 0.77). The largest SBP reductions were observed in the highest baseline category (> 140 mmHg), while those in the first quartile of baseline SBP category (< 122 mmHg) observed no further decrease in SBP. CONCLUSIONS: Tirzepatide-induced SBP reduction was primarily mediated through weight loss, with different degrees of contributions from weight-loss independent effects across the different trials. SBP reduction was not dependent on antihypertensive medication use but dependent on baseline SBP value, alleviating theoretical concerns of hypotension.

Saroglitazar suppresses the hepatocellular carcinoma induced by intraperitoneal injection of diethylnitrosamine in C57BL/6 mice fed on choline deficient, l-amino acid- defined, high-fat diet.

BACKGROUND: Saroglitazar is a novel PPAR-α/γ agonist with predominant PPAR-α activity. In various preclinical models, saroglitazar has been shown to prevent & reverse symptoms of NASH. In view of these observations, and the fact that NASH is a progressive disease leading to HCC, we hypothesized that saroglitazar may prevent the development of HCC in rodents. METHODS: HCC was induced in C57BL/6 mice by a single intraperitoneal injection of 25 mg/kg diethylnitrosamine (DEN) at the age of 4 weeks and then feeding the animal a choline-deficient, L-amino acid- defined, high-fat diet (CDAHFD) for the entire study duration. Eight weeks after initiation of CDAHFD, saroglitazar (1 and 3 mg/kg) treatment was started and continued for another 27 weeks. RESULTS: Saroglitazar treatment significantly reduced the liver injury markers (serum ALT and AST), reversed hepatic steatosis and decreased the levels of pro-inflammatory cytokines like TNF-α in liver. It also resulted in a marked increase in serum adiponectin and osteopontin levels. All disease control animals showed hepatic tumors, which was absent in saroglitazar (3 mg/kg)- treatment group indicating 100% prevention of hepatic tumorigenesis. This is the first study demonstrating a potent PPARα agonist causing suppression of liver tumors in rodents, perhaps due to a strong anti-NASH activity of Saroglitazar that overrides its rodent-specific peroxisome proliferation activity. CONCLUSION: The data reveals potential of saroglitazar for chemoprevention of hepatocellular carcinoma in patients with NAFLD/NASH.

Pelvic radiation-induced urinary strictures: etiology and management of a challenging disease.

Radiation is a common treatment modality for pelvic malignancies. While it can be effective at cancer control, downstream effects can manifest months to years after treatment, leaving patients with significant morbidity. Within urology, a particularly difficult post-radiation consequence is urinary tract stricture, either of the urethra, bladder neck, or ureter. In this review, we will discuss the mechanism of radiation damage and treatment options for these potentially devastating urinary sequelae.

Donor specific antibody surveillance among pediatric kidney transplant programs: A report from the improving renal outcome collaborative.

BACKGROUND: Kidney transplantation (KT) is the preferred treatment for children with end-stage kidney disease. Recent advances in immunosuppression and advances in donor specific antibody (DSA) testing have resulted in prolonged allograft survival; however, standardized approaches for surveillance DSA monitoring and management of de novo (dn) DSA are widely variable among pediatric KT programs. METHODS: Pediatric transplant nephrologists in the multi-center Improving Renal Outcomes Collaborative (IROC) participated in a voluntary, web-based survey between 2019 and 2020. Centers provided information pertaining to frequency and timing of routine DSA surveillance and theoretical management of dnDSA development in the setting of stable graft function. RESULTS: 29/30 IROC centers responded to the survey. Among the participating centers, screening for DSA occurs, on average, every 3 months for the first 12 months post-transplant. Antibody mean fluorescent intensity and trend most frequently directed changes in patient management. Increased creatinine above baseline was reported by all centers as an indication for DSA assessment outside of routine surveillance testing. 24/29 centers would continue to monitor DSA and/or intensify immunosuppression after detection of antibodies in the setting of stable graft function. In addition to enhanced monitoring, 10/29 centers reported performing an allograft biopsy upon detection of dnDSA, even in the setting of stable graft function. CONCLUSIONS: This descriptive report is the largest reported survey of pediatric transplant nephrologist practice patterns on this topic and provides a reference for monitoring dnDSA in the pediatric kidney transplant population.

Electrophysiological evaluation following development of new and persistent left bundle branch block after transcatheter aortic valve replacement: A single center pilot study.

INTRODUCTION: New and persistent left bundle branch block (NP-LBBB) following Transcatheter Aortic Valve Replacement (TAVR) is an ongoing concern with incidence ranging from as low as 4% to up to 65% (varying for different types of valves). Such patients are at risk of developing high-grade atrioventricular block (HAVB) warranting permanent pacemaker (PPM) implantation. However, currently, there are no consensus guidelines or large prospective studies to risk stratify these patients for safer discharge after TAVR. OBJECTIVES: To provide insight from a single center study on using modified electrophysiology (EP) study to risk stratify post-TAVR patients to outpatient monitoring for low-risk versus pacemaker implantation for high-risk patients. METHODS AND RESULTS: Between June 2020 and March 2023, all patients who underwent a TAVR procedure (324 patients) at our institution were screened for development of NP-LBBB post-operatively. Out of 26 patients who developed NP-LBBB, after a pre-specified period of observation, 18 patients were deemed eligible for a modified EP study to assess His-Ventricular (HV) interval. 11 out of 18 patients (61.1%) had normal HV interval (HV < 55 ms). Three out of 18 patients (16.7%) had HV prolongation (55 ms < HV < 70 ms) without significant HV prolongation (defined as an increase in HV interval > 30%) with intra-procedural procainamide challenge. Four out of 18 patients (22.2%) had significant HV prolongation (HV > 70 ms) warranting PPM implantation based on a multidisciplinary approach and shared decision-making with the patients. Total of 50% of patients discharged with PPM (two out of four patients) were noted to be pacemaker dependent based on serial device interrogations. All patients who did not receive PPM were discharged with ambulatory monitoring with 30-day event monitor and did not develop HAVB on serial follow-up. CONCLUSION: Normal HV interval up to 55 ms on modified EP study after TAVR and development of NP-LBBB can be utilized as a threshold for risk stratification to facilitate safe discharge. The optimal upper limit of HV interval threshold remains unclear in determining appropriate candidacy for PPM.

COVID-19 in pediatric kidney transplantation: a follow-up report of the Improving Renal Outcomes Collaborative.

BACKGROUND: We report follow-up data from an ongoing prospective cohort study of COVID-19 in pediatric kidney transplantation through the Improving Renal Outcomes Collaborative (IROC). METHODS: Patient-level data from the IROC registry were combined with testing, indication, and outcomes data collected to describe the epidemiology of COVID testing, treatment, and clinical outcomes; determine the incidence of a positive COVID-19 test; describe rates of COVID-19 testing; and assess for clinical predictors of a positive COVID-19 test. RESULTS: From September 2020 to February 2021, 21 centers that care for 2690 patients submitted data from 648 COVID-19 tests on 465 patients. Most patients required supportive care only and were treated as outpatients, 16% experienced inpatient care, and 5% experienced intensive care. Allograft complications were rare, with acute kidney injury most common (7%). There was 1 case of respiratory failure and 1 death attributed to COVID-19. Twelve centers that care for 1730 patients submitted complete testing data on 351 patients. The incidence of COVID-19 among patients at these centers was 4%, whereas the incidence among tested patients was 19%. Risk factors to predict a positive COVID-19 test included age > 12 years, symptoms consistent with COVID-19, and close contact with a confirmed case of COVID-19. CONCLUSIONS: Despite the increase in testing and positive tests over this study period, the incidence of allograft loss or death related to COVID-19 remained extremely low, with allograft loss or death each occurring in < 1% of COVID-19-positive patients and in less than < 0.1% of all transplant patients within the IROC cohort. A higher resolution version of the Graphical abstract is available as Supplementary information.

Evaluation of the Co-inoculation Effect of Rhizobium and Plant Growth Promoting Non-rhizobial Endophytes on Vigna radiata.

A unique feature of leguminous plants is the establishment of symbiotic bacterial genera inside root or stem nodules that is being recently re-evaluated for investigating the micro-flora discrete to nitrogen fixation. The present research was carried out to evaluate non-rhizobial endophytes and Rhizobium from root nodules of Vigna radiata and ascertain their co-inoculation effect in pot and field conditions. Each strain displayed one or more plant growth-promoting behaviors in varying degrees. The ability to fix nitrogen was observed in all strains; however, a noticeable enhancement in nitrogen fixation was observed when all three strains were co-inoculated. All three strains were found to possess the nifH gene, which plays a key role in the nitrogen fixation process. However, only Rhizobium sp. AAU B3 also had the nodD gene present. Furthermore, combinations of all three strains produced the highest levels of phosphate solubilization, potash mobilisation, Indole Acetic Acid (IAA), and the stress-relieving enzyme 1-aminocyclopropane-1-carboxylic acid (ACC) deaminase. Interestingly, the succession of the root nodule formation within root hairs seedlings was observed under a fluorescence microscope and two NRE were found to be located inside the root nodules, indicating that they are endophytic. Additionally, a pot and field investigation revealed that the combination of chosen Rhizobium and NRE strains had a favorable impact on the growth and yield characteristics of a green gram. Selected bio-inoculants can reduce the utilization of synthetic fertilizers by 75%, which might lead to the restoration of the soil's health. Therefore, these bio-inoculants might be explored commercially for sustainable agriculture production.

What are the predictors of delayed cerebral ischaemia (DCI) after aneurysmal subarachnoid haemorrhage? An up-to-date systematic review.

PURPOSE: Delayed Cerebral Ischaemia (DCI) remains an important preventable driver of poor outcome in aneurysmal subarachnoid haemorrhage (aSAH). Our ability to predict DCI is based on historical patient cohorts, which use inconsistent definitions for DCI. In 2010, a definition of DCI was agreed upon and published by a group of aSAH experts. The aim of this study was to identify predictors using this agreed definition of DCI. METHODS: We conducted a literature search of Medline (PubMed) to identify articles published since the publication of the 2010 consensus definition. Risk factors and prediction models for DCI were included if they: (1) adjusted for confounding factors or were derived from randomised trials, (2) were derived from prospectively collected data and (3) included adults with aSAH. The strength of studies was assessed based on quality, risk of bias and applicability of studies using PROBAST. RESULTS: Eight studies totalling 4,542 patients were included from 105 relevant articles from 4,982 records. The most common reason for not including studies was failure to use the consensus definition of DCI (75%). No prediction models were identified in the eligible studies. Significant risk factors for DCI included the presence of onsite neuro-interventional services, high Neuropeptide Y, admission leucocytosis, neutrophil:lymphocyte >5.9 and Fisher Grade > 2. All studies had a high or unclear risk of bias. CONCLUSIONS: Only a few studies with high risk of bias have investigated the predictors using consensus-defined DCI. Further studies are warranted to clarify risk factors of DCI in the modern era.

Radiological follow-up of endovascularly treated intracranial aneurysms: a survey of current practice in the UK and Ireland.

PURPOSE: Due to the risk of intracranial aneurysm (IA) recurrence and the potential requirement for re-treatment following endovascular treatment (EVT), radiological follow-up of these aneurysms is necessary. There is little evidence to guide the duration and frequency of this follow-up. The aim of this study was to establish the current practice in neurosurgical units in the UK and Ireland. METHODS: A survey was designed with input from interventional neuroradiologists and neurosurgeons. Neurovascular consultants in each of the 30 neurosurgical units providing a neurovascular service in the UK and Ireland were contacted and asked to respond to questions regarding the follow-up practice for IA treated with EVT in their department. RESULTS: Responses were obtained from 28/30 (94%) of departments. There was evidence of wide variations in the duration and frequency of follow-up, with a minimum follow-up duration for ruptured IA that varied from 18 months in 5/28 (18%) units to 5 years in 11/28 (39%) of units. Young patient age, previous subarachnoid haemorrhage and incomplete IA occlusion were cited as factors that would prompt more intensive surveillance, although larger and broad-necked IA were not followed-up more closely in the majority of departments. CONCLUSIONS: There is a wide variation in the radiological follow-up of IA treated with EVT in the UK and Ireland. Further standardisation of this aspect of patient care is likely to be beneficial, but further evidence on the behaviour of IA following EVT is required in order to inform this process.

Aneurysm management in patients over 80 years old with good grade subarachnoid haemorrhage.

BACKGROUND: An increasing proportion of aneurysmal subarachnoid haemorrhage (aSAH) occurs in older patients, in whom there is widespread variability in treatment rates due to a different balance of risks. Our aim was to compare outcomes of patients over 80 years old with good grade aSAH who underwent treatment of their aneurysm with those who did not. METHODS: Adult patients with good grade aSAH admitted to tertiary regional neurosciences centres contributing to the UK and Ireland Subarachnoid Haemorrhage Database (UKISAH) and a cohort of consecutive patients admitted from three regional cohorts were included for analysis. Outcomes were functional outcome at discharge, three months and survival at discharge. RESULTS: In the UKISAH, patients whose aneurysm was treated were more likely to have a favourable outcome at discharge (OR 2.34, CI 1.12-4.91, p = .02), at three months (OR 2.29, CI 1.11-4.76, p = .04), and lower mortality (10% vs. 29%, OR 0.83, CI 0.72-0.94, p < .01). In the regional cohort, a similar pattern was seen, but after correction for frailty and comorbidity there was no difference in survival (HR 0.45, CI 0.12-1.68, p = .24) or favourable outcome at discharge (OR 0.83, CI 0.23-2.94, p = .77) and at three months (OR 1.03, CI 0.25-4.29, p = .99). CONCLUSIONS: Better early functional outcomes in those undergoing aneurysm treatment appear to be explained by differences in frailty and comorbidity. Therefore, treatment decisions in this patient group are finely balanced with no clear evidence overall of either benefit or harm in this cohort.

A survey of the radiological follow-up of unruptured intracranial aneurysms in the United Kingdom.

OBJECTIVE: Unruptured intracranial aneurysms (UIA) are common. For many the treatment risks outweigh their risk of subarachnoid haemorrhage and patients undergo surveillance imaging. There is little data to inform if and how to monitor UIAs resulting in widely varying practices. This study aimed to determine the current practice of unruptured UIA surveillance in the United Kingdom. METHODS: A questionnaire was designed to address the themes of surveillance protocols for UIA including when surveillance is initiated, how frequently it is performed, and when it is terminated. Additionally, how aneurysm growth is managed and how clinically meaningful growth is defined were explored. The questionnaire was distributed to members of the British Neurovascular Group using probability-based cluster and non-probability purposive sampling methods. RESULTS: Responses were received from 30 of the 30 (100.0%) adult neurosurgical units in the United Kingdom of which 27 (90.0%) routinely perform surveillance for aneurysm growth. Only four units had a unit policy. The mean patient age up to which a unit would initiate follow-up of a low-risk UIA was 65.4 ± 9.0 years. The time points at which imaging is performed varied widely. There was an even split between whether units use a fixed duration of follow-up or an age threshold for terminating surveillance. Forty percent of units will follow-up patients more than 5 years from diagnosis. The magnitude in the change in size that was felt to constitute growth ranged from 1 to 3mm. No units routinely used vessel wall imaging although 27 had access to 3T MRI capable of performing it. CONCLUSIONS: There is marked heterogeneity in surveillance practices between units in the United Kingdom. This study will help units better understand their practice relative to their peers and provide a framework forplanning further research on aneurysm growth.

Tirzepatide vs Insulin Lispro Added to Basal Insulin in Type 2 Diabetes: The SURPASS-6 Randomized Clinical Trial.

Importance: Tirzepatide is a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist used for the treatment of type 2 diabetes. Efficacy and safety of adding tirzepatide vs prandial insulin to treatment in patients with inadequate glycemic control with basal insulin have not been described. Objective: To assess the efficacy and safety of tirzepatide vs insulin lispro as an adjunctive therapy to insulin glargine. Design, Setting, and Participants: This open-label, phase 3b clinical trial was conducted at 135 sites in 15 countries (participants enrolled from October 19, 2020, to November 1, 2022) in 1428 adults with type 2 diabetes taking basal insulin. Interventions: Participants were randomized (in a 1:1:1:3 ratio) to receive once-weekly subcutaneous injections of tirzepatide (5 mg [n = 243], 10 mg [n = 238], or 15 mg [n = 236]) or prandial thrice-daily insulin lispro (n = 708). Main Outcomes and Measures: Outcomes included noninferiority of tirzepatide (pooled cohort) vs insulin lispro, both in addition to insulin glargine, in HbA1c change from baseline at week 52 (noninferiority margin, 0.3%). Key secondary end points included change in body weight and percentage of participants achieving hemoglobin A1c (HbA1c) target of less than 7.0%. Results: Among 1428 randomized participants (824 [57.7%] women; mean [SD] age, 58.8 [9.7] years; mean [SD] HbA1c, 8.8% [1.0%]), 1304 (91.3%) completed the trial. At week 52, estimated mean change from baseline in HbA1c with tirzepatide (pooled cohort) was -2.1% vs -1.1% with insulin lispro, resulting in mean HbA1c levels of 6.7% vs 7.7% (estimated treatment difference, -0.98% [95% CI, -1.17% to -0.79%]; P < .001); results met noninferiority criteria and statistical superiority was achieved. Estimated mean change from baseline in body weight was -9.0 kg with tirzepatide and 3.2 kg with insulin lispro (estimated treatment difference, -12.2 kg [95% CI, -13.4 to -10.9]). The percentage of participants reaching HbA1c less than 7.0% was 68% (483 of 716) with tirzepatide and 36% (256 of 708) with insulin lispro (odds ratio, 4.2 [95% CI, 3.2-5.5]). The most common adverse events with tirzepatide were mild to moderate gastrointestinal symptoms (nausea: 14%-26%; diarrhea: 11%-15%; vomiting: 5%-13%). Hypoglycemia event rates (blood glucose level <54 mg/dL or severe hypoglycemia) were 0.4 events per patient-year with tirzepatide (pooled) and 4.4 events per patient-year with insulin lispro. Conclusions and Relevance: In people with inadequately controlled type 2 diabetes treated with basal insulin, weekly tirzepatide compared with prandial insulin as an additional treatment with insulin glargine demonstrated reductions in HbA1c and body weight with less hypoglycemia. Trial Registration: ClinicalTrials.gov Identifier: NCT04537923.

The roaring 2020s: a new decade of systemic therapy for renal cell carcinoma.

PURPOSE OF REVIEW: The genomic and immunologic profiling of renal cell carcinoma (RCC) has provided the impetus for advancements in systemic treatments using combination therapy - either with immune check point inhibitor (ICI) + ICI or with ICI + targeted therapy. This approach has been examined in several landmark trials, treating both clear cell (ccRCC) and nonclear cell (nccRCC) histologies. In this review, we highlight systemic therapy advancements made in this new decade, the 2020s. RECENT FINDINGS: Targeting the programmed death receptor 1/PD-L1 pathway has created more tolerable and effective immunotherapy regimens, expanding the applications of ICIs. These new applications, paired with trial data, include ICI monotherapy in nccRCC and adjuvant pembrolizumab in resected, high-risk RCC. In addition, ICI + ICI and ICI + TKI combination therapy have demonstrated oncologic efficacy in advanced ccRCC and sarcomatoid RCC. Similar progress has been noted regarding new targeted therapies. Along the hypoxia inducible factor pathway, belzutifan has received FDA approval in von Hippel-Lindau-associated RCC. In addition, in papillary RCC, agents such as cabozantinib target the MET proto-oncogene pathway and have demonstrated impressive oncologic outcomes. SUMMARY: The 2020s utilize the molecular profiling of advanced RCC as a scaffold for recent trials in immunotherapy and targeted therapies. Going forward, emphasizing patient-reported outcomes and careful clinical trial construction remain critical to improve systemic therapy in RCC.

Clinical relevance of globotriaosylceramide accumulation in Fabry disease and the effect of agalsidase beta in affected tissues.

Fabry disease (FD) is a rare lysosomal storage disorder, characterized by a reduction in α-galactosidase A enzyme activity and the progressive accumulation of globotriaosylceramide (GL3) and its metabolites in the cells of various organs. Agalsidase beta, an enzyme replacement therapy (ERT), is approved for use in patients with FD in Europe, Canada, Australia, South America, and Asia, and is the only ERT approved for use in the United States. In this review, we discuss the clinical relevance of GL3 accumulation, the effect of agalsidase beta on GL3 in target tissues, and the association between treatment-related tissue GL3 clearance and long-term structure, function, or clinical outcomes. Accumulation of GL3 in the kidney, heart, vasculature, neurons, skin, gastrointestinal tract and auditory system correlates to cellular damage and irreversible organ damage, as a result of sclerosis, fibrosis, apoptosis, inflammation, and endothelial dysfunction. Damage leads to renal dysfunction and end-stage renal disease; myocardial hypertrophy with heart failure and arrhythmias; ischemic stroke; neuropathic pain; skin lesions; intestinal ischemia and dysmotility; and hearing loss. Treatment with agalsidase beta is effective in substantially clearing GL3 in a range of cells from the tissues affected by FD. Agalsidase beta has also been shown to slow renal decline and lower the overall risk of clinical progression, demonstrating an indirect link between treatment-related GL3 clearance and stabilization of FD.