Primary non-refluxing megaureter: Natural history, follow-up and treatment.

Primary non-refluxing megaureter (PMU) is a congenital dilation of the ureter which is not related to vesicoureteral reflux, duplicated collecting systems, ureterocele, ectopic ureter, or posterior urethral valves and accounts for 5 to 10% of all prenatal hydronephrosis (HN) cases. The etiology is a dysfunction or stenosis of the distal ureter. Most often PMU remains asymptomatic with spontaneous resolution allowing for non-operative management. Nevertheless, in selective cases such as the development of febrile urinary tract infections, worsening of the ureteral dilatation, or reduction in relative renal function, surgery should be considered. CONCLUSION: Ureteral replantation with excision of the dysfunctional ureteral segment and often ureteral tapering is the gold-standard procedure for PMU, although endoscopic treatment has been shown to have a fair success rate in many studies. In this review, we discuss the natural history, follow-up, and treatment of PMU. WHAT IS KNOWN: • PMU is the result of an atonic or stenotic segment of the distal ureter, resulting in congenital dilation of the ureter, and is frequently diagnosed on routine antenatal ultrasound. WHAT IS NEW: • Most often, PMU remains asymptomatic and clinically stable, allowing for non-operative management. • Nevertheless, since symptoms can appear even after years of observation, long-term ultrasound follow-up is recommended, even up to young adulthood, if hydroureteronephrosis persists. • Ureteral replantation is the gold standard in case surgery is needed. In selected cases, however, HPBD could be a reasonable alternative.

Intrinsic ureteric obstruction secondary to endometriosis: a rare clinical entity causing obstructive uropathy and renal failure.

Ureteral endometriosis is rare and can be a silent clinical entity, which can potentially lead to serious complications such as obstructive uropathy, sepsis and renal failure. A high clinical suspicion is required especially in childbearing age groups due to non-specific presentation such as renal colic, recurrent urinary tract infection (UTI), renal failure or asymptomatic hydronephrosis.A woman in her 40s presented with febrile UTI and flank pain. She reportedly suffered from recurrent UTIs in the past. Initial workup revealed an infected, obstructed left renal collecting system with gross hydronephrosis and hydroureter to the distal ureter on a significant gynaecological background of severe endometriosis requiring hysterectomy in the past.CT showed chronic obstructive changes and soft tissue nodules within the renal pelvis with no radio-opaque stones. She underwent emergent ureteric stent insertion. Functional imaging demonstrated only 1% contribution of the left kidney with a preserved estimated glomerular filtration rate of 65 mL/min/1.73 m2Endoscopic evaluation of ureters found extensive soft tissue lesions throughout the dilated left collecting system with biopsy-confirmed endometriosis. Subsequently, she underwent laparoscopic nephroureterectomy due to extensive ureteric involvement and chronically obstructed non-functioning kidney. Histopathology demonstrated completely obstructing ureteral endometriosis.Ureteric obstruction secondary to endometriosis can be due to extrinsic or intrinsic disease. In addition to initial assessment with CT urogram MRI may be helpful to evaluate soft tissue thickening. Endoscopic assessment with ureteroscopy and biopsy is required for tissue diagnosis. Surgery is often the treatment of choice, ranging from ureteroureterostomy, ureteroneocystostomy or nephroureterectomy in severe cases.Ureteral endometriosis is a rare clinical entity, clinicians should remain vigilant about common presentations of this rare entity, early diagnosis and prompt treatment is crucial to prevent progression to renal failure.

Robotic Assisted En-Bloc Removal of Kidney, Ureter and Bladder Wall for Endometriosis.

STUDY OBJECTIVE: To highlight a case where a nephroureterectomy and partial bladder cystectomy needed to be done due to endometriosis. DESIGN: A video article demonstrating a case study and the surgical management. SETTING: Ureteral endometriosis is a complex form of endometriosis [1]. If left untreated, the ureter can become significantly compressed leading to hydroureter, hydronephrosis and complete loss of kidney function [2]. INTERVENTIONS: This is a case of a 29-year-old patient with pelvic pain and cyclical rectal bleeding. Further investigation showed significant left hydronephrosis and almost complete loss of left kidney function (8% on renogram). MRI revealed endometriosis involving the posterior bladder wall and distal left ureter, a large full-thickness sigmoid nodule and a large left endometrioma. The patient underwent a robotic-assisted left nephroureterectomy, partial cystectomy (bladder), excision of pelvic endometriosis and sigmoid resection. This procedure was performed jointly with the gynecologist, urologist, and colorectal surgeon and the SOSURE technique was employed [3]. The specimen (left kidney, whole length of ureter and bladder wall around ureteric orifice) was removed en-bloc through a small 3cm extension of the umbilical incision. As the distance between the sigmoid nodule and the anal verge was 35cm, which was above the limit of the transanal circular stapler, a limited resection was performed over a discoid excision. The patient made a good recovery postoperatively. CONCLUSION: Ureteral endometriosis is an indolent and aggressive condition which can lead to silent kidney loss. It is essential that hydronephrosis and hydroureter is ruled out in cases with deep endometriosis. Isolated hydronephrosis should also prompt a suspicion for endometriosis.

Minimal-invasive ileal ureter replacement for the management of multiple ureteral polyps: the initial experience.

PURPOSE: To present our initial experience in the management of multiple ureteral polyps with robotic or laparoscopic ileal ureter replacement (IUR). METHODS: Eight consecutive patients diagnosed with multiple ureteral polyps underwent robotic or laparoscopic IUR between July 2019 and November 2022. Unilateral IUR was performed in 5 patients with polyps in the left (n = 3) or right (n = 2) side, and 3 patients with bilateral multiple polyps underwent bilateral IUR. Demographic characteristics, perioperative data and follow-up outcomes were prospectively collected. RESULTS: A cohort of 5 male and 3 female patients (11 ureters) with a mean age of 32.8 ± 11.3 years were included. Among these patients, 5 presented with recurrent flank pain, 1 had hematuria, and 2 were asymptomatic. Four patients experienced prior failed surgical interventions. The mean length of diseased ureter was 11.9 ± 4.7 cm, with more than 10 cm in eight sides. All procedures were performed successfully. The mean operation time was 319 ± 87.6 min with 3 patients who simultaneously underwent intraoperative ureteroscopy. The mean length of ileal graft was 23.8 ± 5.8 cm. During the mean follow-up of 20.4 ± 12.8 months, one major complication, specifically incision infection, and four minor complications, including urinary infection (n = 3) and metabolic acidosis (n = 1), were observed. All patients presented symptom-free, with improved/stabilized hydronephrosis and no signs of restenosis. CONCLUSION: Robotic or laparoscopic IUR is a feasible, safe, and effective surgical option for patients with long ureteral defects caused by multiple polyps.

A nomogram to predict the absence of clinically significant prostate cancer in males with negative MRI

PURPOSE: To create a nomogram to predict the absence of clinically significant prostate cancer (CSPCa) in males with non-suspicion multiparametric magnetic resonance imaging (mpMRI) undergoing prostate biopsy (PBx). MATERIALS AND METHODS: We identified consecutive patients who underwent 3T mpMRI followed by PBx for suspicion of PCa or surveillance follow-up. All patients had Prostate Imaging Reporting and Data System score 1-2 (negative mpMRI). CSPCa was defined as Grade Group ≥2. Multivariate logistic regression analysis was performed via backward elimination. Discrimination was evaluated with area under the receiver operating characteristic (AUROC). Internal validation with 1,000x bootstrapping for estimating the optimism corrected AUROC. RESULTS: Total 327 patients met inclusion criteria. The median (IQR) age and PSA density (PSAD) were 64 years (58-70) and 0.10 ng/mL2 (0.07-0.15), respectively. Biopsy history was as follows: 117 (36%) males were PBx-naive, 130 (40%) had previous negative PBx and 80 (24%) had previous positive PBx. The majority were White (65%); 6% of males self-reported Black. Overall, 44 (13%) patients were diagnosed with CSPCa on PBx. Black race, history of previous negative PBx and PSAD ≥0.15ng/mL2 were independent predictors for CSPCa on PBx and were included in the nomogram. The AUROC of the nomogram was 0.78 and the optimism corrected AUROC was 0.75. CONCLUSIONS: Our nomogram facilitates evaluating individual probability of CSPCa on PBx in males with PIRADS 1-2 mpMRI and may be used to identify those in whom PBx may be safely avoided. Black males have increased risk of CSPCa on PBx, even in the setting of PIRADS 1-2 mpMRI.

A Retrospective Analysis of the 1-Year Graft Survival Rate in Indonesian Renal Transplant Recipients With Multiple Renal Arteries.

BACKGROUND: Renal transplantation is the preferred treatment for end-stage renal disease because of its association with improved survival and quality of life. The debate over multiple renal arteries (MRA) vs a single renal artery regarding kidney function, posttransplant complications, and graft and patient survival remains ongoing. Our goal was to determine the 1-year graft survival rate among renal transplant recipients with MRA at Cipto Mangunkusumo Hospital in Jakarta. METHODS: A retrospective study was conducted between January 2012 and December 2020, including all kidney transplant candidates with MRA. Data on graft survival, patient demographics, previous renal transplantation, duration of hemodialysis, and delayed graft function were collected and analyzed using SPSS 24. Kaplan-Meier plots and Cox regression analyses were used to determine risk factors for 1-year survival. RESULTS: Among 752 renal transplant recipients, 104 cases had MRA. The majority were men (71.5%), and the median age of recipients was 47 years. One-year graft survival was observed in 96% of cases, whereas patient survival was 97.7%. No significant difference was found in graft survival based on the number of arteries (single renal artery vs MRA), length of hemodialysis, or previous renal transplantation. However, delayed graft function was significantly associated with graft survival. CONCLUSION: This study highlights that 1-year graft survival in renal transplant recipients with MRA is not significantly affected by the length of hemodialysis before surgery or previous renal transplantation.

Localized amyloidosis of the ureter: a case report.

BACKGROUND: Amyloidosis is a collection of disorders characterized by the extracellular deposition of amyloid, a specialized fibrous protein, in diverse tissues, leading to functional impairments. CASE PRESENTATION: A 70-year old Asian-Japanese female was referred to our department for further examination of her left hydronephrosis come from lower ureteral obstruction. Contrast enhanced CT and retrograde pyelo-nephrography revealed left ureteral tumor. Though ureteroscropic biopsy did not show malignant pathological findings, ureteroscopic image suspected malignant disease, thus nephroureterectomy was performed. Pathological findings revealed localized ureteral amyloidosis. Whole body examination including gastro endoscopy and cardio ultrasonography could not reveal amyloidosis except ureter. She was free from recurrence 9 months postoperatively. CONCLUSION: We herein report a rare case of localized ureteral amyloidosis.

[Effects of delayed ureteral stents removal during the COVID-19 pandemic on the quality of life and psychological status of postoperative patients with urinary calculi].

OBJECTIVE: To explore the impacts of delayed ureteral stent removal on the quality of life (QoL) and mental health of urinary calculi postoperative patients due to the corona virus disease 2019(COVID-19) pandemic. METHODS: The demographic and clinical data of patients with ureteral stent placement after urinary endoscopic lithotripsy and returned to Peking University People's Hospital for stent removal from December 2019 to June 2020 were collected. Ureteral stent symptoms questionnaire (USSQ) score and the outcome 20-item self-rating anxiety scale (SAS) and self-rating depression scale (SDS) were collected to estimate the QoL and mental status. The USSQ consisted of 44 questions in 6 domains (including urinary symptom, physical pain, general health, work performance, sexual function, and ureteral stent related infection). For most questions in each domain, its score was a five-point Likert-type scale from 1 to 5, and a small proportion of questions was quantified by 1 to 4 or 1 to 7 scale. SAS and SDS both contained 20 questions used to assess a patient's level of anxiety and depression. Its scoring for each item was on a four-point Likert-type scale from 1 to 4. A total score (ranging from 20 to 80) was the main statistical indicator. The level of clinical anxiety and depression was quantified by using standard scores (total score multiplied by 1.25 to produce integers). And the multi-group structural equation model was constructed by analysis of moment structure (AMOS) analysis. RESULTS: Overall, 71 patients were enrolled for analysis. It was found that the median duration of ureteral stent time differed significantly between the control and delayed groups for 32 (30, 33) d and 94.5 (88, 103) d, respectively. The delayed group resulted in higher scores in the USSQ multidimensional, which included urinary symptoms, general health, work performance and ureteral stent related infections. Anxiety and depression were also significantly serious in the delayed group than in the control group. A longer indwelling time of a ureteral stent could exacerbate the effects of urinary symptoms and physical pain on work performance (P=0.029 < 0.05). Among them, the patients with severe urinary symptoms leading to poor work performance were most significantly affected by prolonged ureteral stent duration time (CR=2.619>1.96). CONCLUSION: Patients with delayed ureteral stent removal due to the COVID-19 had resulted in worse QoL and mental status. Stents related symptoms are more severe in patients with higher anxiety and depression degree during COVID-19. To improve the QoL and mental health of patients after urinary calculi surgery during COVID-19, it is still not recommended to prolong the stent duration time or corresponding intervention measures should be taken.

Laparoscopic ureteroneocystostomy in the treatment of urinary incontinence due to ectopy of the ureters in female dogs: A pilot study.

Ureteral ectopia is rare and requires surgical treatment after a thorough diagnostic workup. Open surgical techniques for repositioning ectopic ureters have been known for many years and are well described in the literature. However, to the best of our knowledge, no laparoscopic method of correcting this pathology has been described, which, in our opinion, would benefit the animal in terms of the healing process and overall clinical outcomes. This study aimed to evaluate the possibility of laparoscopic treatment of ureteral ectopia, which causes urinary incontinence in dogs. All of the operated ten dogs presented in this study were client-owned females with symptoms of urinary incontinence due to a unilateral intramural ectopic ureter. A three-trocar laparoscopic technique was used to perform the ureteroneocystostomy of the ectopic ureter. In this article, clinicopathological data, imaging features, procedural findings, complications, and short- and long-term outcomes are presented. The procedure was feasible in all cases. No major postoperative complications were observed. Among the minor complications, slight hematuria was observed in three dogs, which resolved spontaneously. In the period of at least one year after surgery, no negative impact of the procedure was observed. Seven of the ten operated dogs regained urinary continence. The remaining three dogs required additional surgery (urethral bulking) because of a lack of improvement after adjuvant pharmacological treatment. Overall, good-to-excellent long-term outcomes can be achieved; however, dogs that remain incontinent after laparoscopic ureteroneocystostomy may require additional treatment.

Altered expression, but small contribution, of the histone demethylase KDM6A in obstructive uropathy in mice.

Epigenetic processes have emerged as important modulators of kidney health and disease. Here, we studied the role of KDM6A (a histone demethylase that escapes X-chromosome inactivation) in kidney tubule epithelial cells. We initially observed an increase in tubule cell Kdm6a mRNA in male mice with unilateral ureteral obstruction (UUO). However, tubule cell knockout of KDM6A had relatively minor consequences, characterized by a small reduction in apoptosis, increase in inflammation and downregulation of the peroxisome proliferator-activated receptor (PPAR) signaling pathway. In proximal tubule lineage HK-2 cells, KDM6A knockdown decreased PPARγ coactivator-1α (PGC-1α) protein levels and mRNA levels of the encoding gene, PPARGC1A. Tubule cell Kdm6a mRNA levels were approximately 2-fold higher in female mice than in male mice, both under sham and UUO conditions. However, kidney fibrosis after UUO was similar in both sexes. The findings demonstrate Kdm6a to be a dynamically regulated gene in the kidney tubule, varying in expression levels by sex and in response to injury. Despite the context-dependent variation in Kdm6a expression, knockout of tubule cell KDM6A has subtle (albeit non-negligible) effects in the adult kidney, at least in males.

Clinical factors distinguishing renal infarction from acute pyelonephritis: A randomly matched retrospective case-control study.

INTRODUCTION: Renal infarction (RI) is rare but clinically important because the appropriate treatment depends on the time of diagnosis. RI is often misdiagnosed as acute pyelonephritis (APN) because both diseases have nonspecific symptoms such as flank pain and abdominal pain. We identified predictors for distinguishing RI from APN. METHODS: The data of patients visited the emergency department and diagnosed with RI or APN from March 2016 to May 2020 were prospectively collected and retrospectively analyzed. Patients aged under 18 years, with a history of trauma, or incomplete medical records were excluded. Using a matching ratio of 1:5, RI patients were randomly matched to APN patients. Multivariable logistic regression analysis was performed to identify factors that could distinguish RI from APN. In addition, we constructed a decision tree to identify patterns of risk factors and develop prediction algorithms. RESULTS: The RI and APN groups included 55 and 275 patients, respectively. Multivariable logistic regression analysis showed that male sex (OR, 6.161; p = 0.009), atrial fibrillation (AF) (OR, 14.303; p = 0.021), costovertebral angle tenderness (CVAT) (OR, 0.106; p < 0.001), aspartate transaminase (AST) level > 21.50 U/L (OR, 19.820; p < 0.001), C-reactive protein (CRP) level < 19.75 mg/L (OR, 10.167; p < 0.001), and pyuria (OR, 0.037; p < 0.001) were significantly associated with RI distinguishing from APN. CONCLUSION: Male sex, AF, no CVAT, AST level > 21.50 U/L, CRP level < 19.75 mg/L, and no pyuria were significant factors that could distinguish RI from APN.

Preoperative stricture length measurement does not predict postoperative outcomes in robotic ureteral reconstructive surgery.

PURPOSE: We sought to determine whether preoperative stricture length measurement affected the choice of procedure performed, its correlation to intraoperative stricture length, and postoperative outcomes. METHODS: The Collaborative of Reconstructive Robotic Ureteral Surgery (CORRUS) database was queried for patients undergoing robotic ureteral reconstructive surgery from 2013 to 2021 who had surgical stricture length measurement. From this cohort, we identified patients with and without preoperative stricture length measurement via retrograde pyelogram or antegrade nephrostogram. Outcomes evaluated included intraoperative complications, 30-day complications greater than Clavien-Dindo grade II, hardware-free status, and need for additional procedures. RESULTS: Of 153 patients with surgical stricture length measurements, 102 (66.7%) had preoperative radiographic measurement. No repair type was more likely to have preoperative measurement. The Pearson correlation coefficient between surgical and radiographic stricture length measurements was + 0.79. The average surgical measurement was 0.71 cm (± 1.52) longer than radiographic assessment. Those with preoperative imaging waited on average 5.0 months longer for surgery, but this finding was not statistically significant (p = 0.18). There was no statistically significant difference in intraoperative complications, 30-day complication rates, hardware-free status at last follow-up, or need for additional procedures between patients with and without preoperative measurement. The only significant predictive factor was preoperative stricture length on 30-day postoperative complications. CONCLUSIONS: Despite relatively high prevalence of preoperative radiographic stricture length measurement, there are few measures where it offers clinically meaningful diagnostic information towards the definitive surgical management of ureteral stricture disease.

Renal Artery Thrombosis After Laparoscopic Living-Donor Nephrectomy: A Case Report.

Renal transplantation is the most successful treatment for end-stage renal disease, and the number of living-donor nephrectomies has been rising over the years due to the advantages it offers over deceased donors. Although this surgery is considered safe, it can be associated with complications amplified by the fact that it is performed on a healthy individual. Renal artery thrombosis is a rare disease that needs prompt diagnosis and treatment to avoid renal function deterioration, which becomes even more important in cases of solitary kidneys. We report the first case of renal artery thrombosis after laparoscopic living-donor nephrectomy treated with catheter-directed thrombolysis.

Early diagnosis and management of arterio-ureteral fistulas: A literature review.

OBJECTIVES: Arterio-ureteralfistula (AUF) is an infrequent but potentially life-threatening condition. The aim of this study was reviewing the literature to build a flow-chart useful for an early and effective diagnosis and treatment of this pathology. MATERIALS AND METHODS: A literature search in PubMed was conducted. In addition, retrieved articles were cross-referenced. Data parameters included oncologic, vascular and urological history, diagnostics, treatment, and follow up were collected using a standard template by 2 independent reviewers. RESULTS: A total of 140 cases of AUF out of 172 available in the literature at the time of the review, were considered. All patients presented gross hematuria. Chronic indwelling ureteral catheter (CIUC); history of pelvic surgery (HPS) and history of pelvic radiotherapy (HRT) were present respectively in 81%, 62.1%and 58.6% of the sample. The most predominant location of AUF was at the common iliac artery ureteral crossing. Angiography with provocative measures had the highest diagnostic sensitivity (50%) and endovascular treatment with stent-graft placement across the fistula is the current state of the art treatment choice. CONCLUSIONS: Failure to diagnose can postpone a potentially life-saving targeted therapy and lead to complications. The identifi-cation of the Trifecta hematuria, history of pelvic surgery (HPS) and history of pelvic radiotherapy (HPR) would allow the identity-fication of patients at high risk of AUF, who may benefit from more sensitive early diagnostic investigations such as CT angiography and provocative angiography. The treatment of choice in case of AUF to date consist in endovascular prosthesis placement.

Urinary biomarkers to predict acute kidney damage and mortality in COVID-19.

INTRODUCTION: Acute kidney injury (AKI) is a frequent condition in patients hospitalized for COVID-19. There are only a few reports on the use of urinary biomarkers in COVID-19 and no data so far comparing the prognostic use of individual biomarkers in the prediction of adverse outcomes. MATERIALS AND METHODS: We performed a prospective mono-centric study on the value of urinary biomarkers in predicting the composite endpoint of a transfer to the intensive care unit, the need for renal replacement therapy, mechanical ventilation, and in-hospital mortality. 41 patients hospitalized for COVID-19 were enrolled in this study. Urine samples were obtained shortly after admission to assess neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), calprotectin, and vascular non-inflammatory molecule-1 (vanin-1). RESULTS: We identified calprotectin as a predictor of a severe course of the disease requiring intensive care treatment (AUC 0.728, p = 0.016). Positive and negative predictive values were 78.6% and 76.9%, respectively, using a cut-off concentration of 127.8 ng/mL. NGAL tended to predict COVID-19-associated AKI without reaching statistical significance (AUC 0.669, p = 0.053). The best parameter in the prediction of in-hospital mortality was NGAL as well (AUC 0.674, p = 0.077). KIM-1 and vanin-1 did not reach significance for any of the investigated endpoints. CONCLUSION: While KIM-1 and vanin-1 did not provide prognostic clinical information in the context of COVID-19, the present study shows that urinary calprotectin is moderately predictive of the need for intensive care unit (ICU) admission, and NGAL may be modestly predictive of AKI in COVID-19. Calprotectin and NGAL show promise as potential helpful adjuncts in the identification of patients at increased risk of poor outcomes or complications in COVID-19.

Iatrogenic Ureterocolic Fistula in Pediatric Age Group: A Case Report and Review of the Literature.

Ureteral injury is one of the major complications related to colorectal and gynecologic procedures. Injuries are sometimes identified intraoperatively, but the diagnosis of ureteral injury is often delayed. Ureterocolic fistula is a relatively rare condition and mostly due to obstructing calculi, diverticular disease of the colon, radiotherapy, cancer, or trauma. Here in, we present a boy with an iatrogenic left ureterocolic fistula following multiple colonic surgeries that were complicated by an un-noticed left ureteric injury. This injury was not diagnosed early and the patient presented later with recurrent UTIs and decreased left differential renal function which necessitated open left nephroureterectomy.

A case of ureteral stenosis due to ureteritis probably associated with rheumatoid arthritis.

Ureteritis associated with the immunological disorder is rarely reported, and most cases in this category are small vessel vasculitis and immunoglobulin G4-related disease. Rheumatoid arthritis (RA)-associated ureteritis is uncommon, and underlying aetiology is unclear. We present a patient with ureteritis who had a medical history of RA and was successfully treated with steroids and immunosuppressant. A 49-year-old woman who had been treated for RA and atopic dermatitis suffered from gross haematuria for 5 successive days. Contrast-enhanced computed tomography (CT) showed right-dominant upper urinary tract dilatation with enhanced thickened wall. The haematuria continued accompanied with intermittent right back and lower abdominal pain, and the following CT image taken after 3 months presented the progression to bilateral hydronephrosis. Ureteral stents were placed, and antibiotic therapy was introduced for obstructive pyelonephritis. Ureterocystoscopy and following biopsy from the upper ureteral tract showed a chronic inflammatory change in the histopathology, and we finally considered the stenosing ureteritis to be caused by immune-mediated mechanism related to RA. After starting steroid therapy with methotrexate, therapeutic response was obtained to remove the stents. In the cases of ureteritis or ureteral stenosis of unknown aetiology with a medical history of immunological disorders, we should consider the underlying immune-activated state and try to test contrast-enhanced CT and histological examination before performing a surgical procedure. After excluding the common causes of ureteritis or ureteral stenosis, these tests would support the appropriate diagnosis.