Potential of an mRNA-Based Urine Assay (Xpert® Bladder Cancer Detection1) in Hematuria Patients - Results from a Cohort Study.

BACKGROUND AND OBJECTIVE: Assessment of patients with hematuria (aH) remains a challenge in urological practice, balancing the benefits of diagnosing a potentially underlying bladder cancer (UCa) against the risks of possibly unnecessary diagnostic interventions. This study analyzes the potential of an mRNA-based urine assay, the Xpert® Bladder Cancer Detection- CE-IVD (Xpert BC-D), in patients with hematuria. MATERIALS AND METHODS: Overall, 368 patients with newly observed painless hematuria and no history of UCa were included in this observational study. Patients received urological workup, including urethrocystoscopy (WLC), upper tract imaging, urine cytology and Xpert BC-D. Patients with positive WLC were recommended to undergo tumor resection (TUR-B). RESULTS: After excluding non-assessable cases, 324 patients were considered for analysis (188 males, 136 females; median age: 61 years). Eight of twenty-eight patients with a positive TUR-B had Ta low grade (LG) tumors; the others were diagnosed with high grade (HG) lesions (Ta: 4, CIS: 2, T1:11, > T1:3). The Xpert BC-D was more sensitive than urine cytology (96% vs. 61%) (p = 0.002). Increased risk ratios (RR) were observed for gross hematuria, gender, urine cytology, and positive Xpert BC-D (all p < 0.05). Age and positive Xpert BC-D remained independent predictors of UCa in multivariate analysis. Simulating a triage with WLC restricted to patients with positive Xpert BC-D could have saved 240 (74.1%) assessments at the cost of missing one pTa LG tumor. CONCLUSIONS: The results suggest a potential role for Xpert BC-D in preselecting patients with hematuria for either further invasive diagnosis or an alternate diagnostic procedure.

Oligoadenylate synthetase 1 displays dual antiviral mechanisms in driving translational shutdown and protecting interferon production.

In response to viral infection, how cells balance translational shutdown to limit viral replication and the induction of antiviral components like interferons (IFNs) is not well understood. Moreover, how distinct isoforms of IFN-induced oligoadenylate synthetase 1 (OAS1) contribute to this antiviral response also requires further elucidation. Here, we show that human, but not mouse, OAS1 inhibits SARS-CoV-2 replication through its canonical enzyme activity via RNase L. In contrast, both mouse and human OAS1 protect against West Nile virus infection by a mechanism distinct from canonical RNase L activation. OAS1 binds AU-rich elements (AREs) of specific mRNAs, including IFNß. This binding leads to the sequestration of IFNß mRNA to the endomembrane regions, resulting in prolonged half-life and continued translation. Thus, OAS1 is an ARE-binding protein with two mechanisms of antiviral activity: driving inhibition of translation but also a broader, non-canonical function of protecting IFN expression from translational shutdown.

Systematic P2Y receptor survey identifies P2Y11 as modulator of immune responses and virus replication in macrophages.

The immune system is in place to assist in ensuring tissue homeostasis, which can be easily perturbed by invading pathogens or nonpathogenic stressors causing tissue damage. Extracellular nucleotides are well known to contribute to innate immune signaling specificity and strength, but how their signaling is relayed downstream of cell surface receptors and how this translates into antiviral immunity is only partially understood. Here, we systematically investigated the responses of human macrophages to extracellular nucleotides, focusing on the nucleotide-sensing GPRC receptors of the P2Y family. Time-resolved transcriptomic analysis showed that adenine- and uridine-based nucleotides induce a specific, immediate, and transient cytokine response through the MAPK signaling pathway that regulates transcriptional activation by AP-1. Using receptor trans-complementation, we identified a subset of P2Ys (P2Y1, P2Y2, P2Y6, and P2Y11) that govern inflammatory responses via cytokine induction, while others (P2Y4, P2Y11, P2Y12, P2Y13, and P2Y14) directly induce antiviral responses. Notably, P2Y11 combined both activities, and depletion or inhibition of this receptor in macrophages impaired both inflammatory and antiviral responses. Collectively, these results highlight the underappreciated functions of P2Y receptors in innate immune processes.

Case report: Allogeneic stem cell transplantation for type B insulin resistance.

Type B insulin resistance (TBIR) is a rare, often fulminant form of insulin resistance caused by autoantibodies against the insulin receptor. If left untreated, its mortality is high. Various immunosuppressive regimens have shown efficacy, but treatment effects are variable and time-delayed, and drug-induced complications may arise. We report a patient with TBIR arising as a complication of Wiskott-Aldrich syndrome. Stable remission of TBIR was achieved through allogeneic peripheral blood stem cell transplantation (PBSCT) over a follow-up period of more than 1.5 years. We thus demonstrate that PBSCT can be considered a treatment option in TBIR where conventional immunosuppressive therapy is ineffective or contraindicated.

Adipokines as Clinically Relevant Therapeutic Targets in Obesity.

Adipokines provide an outstanding role in the comprehensive etiology of obesity and may link adipose tissue dysfunction to further metabolic and cardiovascular complications. Although several adipokines have been identified in terms of their physiological roles, many regulatory circuits remain unclear and translation from experimental studies to clinical applications has yet to occur. Nevertheless, due to their complex metabolic properties, adipokines offer immense potential for their use both as obesity-associated biomarkers and as relevant treatment strategies for overweight, obesity and metabolic comorbidities. To provide an overview of the current clinical use of adipokines, this review summarizes clinical studies investigating the potential of various adipokines with respect to diagnostic and therapeutic treatment strategies for obesity and linked metabolic disorders. Furthermore, an overview of adipokines, for which a potential for clinical use has been demonstrated in experimental studies to date, will be presented. In particular, promising data revealed that fibroblast growth factor (FGF)-19, FGF-21 and leptin offer great potential for future clinical application in the treatment of obesity and related comorbidities. Based on data from animal studies or other clinical applications in addition to obesity, adipokines including adiponectin, vaspin, resistin, chemerin, visfatin, bone morphogenetic protein 7 (BMP-7) and tumor necrosis factor alpha (TNF-α) provide potential for human clinical application.

Implications of Senescent Cell Burden and NRF2 Pathway in Uremic Calcification: A Translational Study.

Increased senescent cell burden and dysregulation of the nuclear factor erythroid 2-related factor 2 (NRF2) pathway have been associated with numerous age-related pathologies; however, their role in promoting vascular calcification (VC) in chronic kidney disease (CKD) has yet to be determined. We investigated whether senescence and NRF2 pathways may serve as drivers of uremia-induced VC using three complementary approaches: a novel model of induced VC in 5/6-nephrectomized rats supplemented with high phosphate and vitamin D; epigastric arteries from CKD patients with established medial calcification; and vascular smooth muscle cells (VSMCs) incubated with uremic serum. Expression of p16Ink4a and p21Cip1, as well as γ-H2A-positive cells, confirmed increased senescent cell burden at the site of calcium deposits in aortic sections in rats, and was similarly observed in calcified epigastric arteries from CKD patients through increased p16Ink4a expression. However, uremic serum-induced VSMC calcification was not accompanied by senescence. Expression of NRF2 and downstream genes, Nqo1 and Sod1, was associated with calcification in uremic rats, while no difference was observed between calcified and non-calcified EAs. Conversely, in vitro uremic serum-driven VC was associated with depleted NRF2 expression. Together, our data strengthen the importance of senescence and NRF2 pathways as potential therapeutic options to combat VC in CKD.

Lifestyle aspects in a contemporary middle-European cohort of patients undergoing androgen deprivation therapy for advanced prostate cancer: data from the non-interventional LEAN study.

Androgen deprivation therapy (ADT) in men with prostate cancer (PCa) is associated with significant side effects. With the transition of PCa from a foudroyant course to a chronic disease, managing these side effects has become increasingly important. There is growing evidence that nutritional changes and physical activity are beneficial in these patients. Here we examine the impact of written patient information on the physical activity and dietary habits of PCa patients receiving ADT and behaviour changes between baseline and 1 year, in the open-label, non-interventional LEAN study. In total, 959 patients with advanced hormone-sensitive PCa requiring ADT with the Leuprorelin Sandoz® implant were included from January 2014 to July 2015 and followed for ≥ 12 months. At the start of the study, urologists received a questionnaire concerning the written information provided to patients regarding their disease, patient advocacy groups, diet and physical activity. Patients received a questionnaire on their dietary habits and physical activity at the start and end of the study. Urologists from 147 study centres and 540 patients responded to the questionnaires. While 69 % of these patients received disease-specific information, only 30 % and 17 % received information regarding nutrition and physical activity, respectively. The majority of urologists estimate that their patients rarely or never follow guidance on nutrition or physical activity, yet > 90 % of patients indicate they would make use of this information, if provided. Few patients showed behavioural changes between baseline and 1 year without evident differences between patients that received information and those that did not.

Transcriptional licensing is required for Pyrin inflammasome activation in human macrophages and bypassed by mutations causing familial Mediterranean fever.

Pyrin is a cytosolic immune sensor that nucleates an inflammasome in response to inhibition of RhoA by bacterial virulence factors, triggering the release of inflammatory cytokines, including IL-1ß. Gain-of-function mutations in the MEFV gene encoding Pyrin cause autoinflammatory disorders, such as familial Mediterranean fever (FMF) and Pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND). To precisely define the role of Pyrin in pathogen detection in human immune cells, we compared initiation and regulation of the Pyrin inflammasome response in monocyte-derived macrophages (hMDM). Unlike human monocytes and murine macrophages, we determined that hMDM failed to activate Pyrin in response to known Pyrin activators Clostridioides difficile (C. difficile) toxins A or B (TcdA or TcdB), as well as the bile acid analogue BAA-473. The Pyrin inflammasome response was enabled in hMDM by prolonged priming with either LPS or type I or II interferons and required an increase in Pyrin expression. Notably, FMF mutations lifted the requirement for prolonged priming for Pyrin activation in hMDM, enabling Pyrin activation in the absence of additional inflammatory signals. Unexpectedly, in the absence of a Pyrin response, we found that TcdB activated the NLRP3 inflammasome in hMDM. These data demonstrate that regulation of Pyrin activation in hMDM diverges from monocytes and highlights its dysregulation in FMF.

New Opioid Persistence in Veterans Following Major and Minor Surgery.

INTRODUCTION: Opioids are often a mainstay of managing postsurgical pain. Persistent use of opioids for more than 90 days after surgery is problematic, and the incidence of this adverse outcome has been reported in the civilian population ranging from 0.4% to 7%. Veterans compose a special population exposed to trauma and stressful situations and consequently face increased risk for habit-forming behavior and drug overdose. This evaluation determined the prevalence of opioid persistence after surgery and its relationship to patient characteristics in a military veteran population. METHODS: A retrospective chart review was completed on 1,257 veterans who were opioid naive and had undergone a surgical procedure between January 2017 and May 2018. Patient characteristics, health conditions, and discharge opioid medications were recorded, and the incidence of persistent opioid use beyond 90 days was determined. RESULTS: The incidence of opioid persistence following major (3.3%) and minor (3.4%) procedures was similar. The incidence in patients younger than 45 years (3.3%), between 45 and 64 years (4.3%), and 65 years and older (2.2%) was also determined to be similar. Univariate patient factors associated with an increased risk for persistent opioid use include cancer (odds ratio [OR], 2.13; 95% CI, 1.11-4.09), mental health disorders (OR, 2.32; 95% CI, 1.17-4.60), and substance use disorders (OR, 2.09; 95% CI, 1.09-4.00). CONCLUSIONS: Among a cohort of over 1,200 opioid-naïve veterans undergoing surgery at a VA Medical Center, just over 3% went on to develop persistent opioid use beyond 3 months following their procedure. Persistent use was not found to be related to the type of procedure (major or minor) or patient age. Significant patient-level risk factors for opioid persistence were cancer and a history of mental health and substance use disorders.

Leptin treatment has vasculo-protective effects in lipodystrophic mice.

Lipodystrophy syndromes (LDs) are characterized by loss of adipose tissue, metabolic complications such as dyslipidemia, insulin resistance, and fatty liver disease, as well as accelerated atherosclerosis. As a result of adipose tissue deficiency, the systemic concentration of the adipokine leptin is reduced. A current promising therapeutic option for patients with LD is treatment with recombinant leptin (metreleptin), resulting in reduced risk of mortality. Here, we investigate the effects of leptin on endothelial to mesenchymal transition (EndMT), which impair the functional properties of endothelial cells and promotes atherogenesis in LD. Leptin treatment reduced inflammation and TGF-ß2-induced expression of mesenchymal genes and prevented impairment of endothelial barrier function. Treatment of lipodystrophic- and atherosclerosis-prone animals (Ldlr-/-; aP2-nSrebp1c-Tg) with leptin reduced macrophage accumulation in atherosclerotic lesions, vascular plaque protrusion, and the number of endothelial cells with mesenchymal gene expression, confirming a reduction in EndMT in LD after leptin treatment. Treatment with leptin inhibited LD-mediated induction of the proatherosclerotic cytokine growth/differentiation factor 15 (GDF15). Inhibition of GDF15 reduced EndMT induction triggered by plasma from patients with LD. Our study reveals that in addition to the effects on adipose tissue function, leptin treatment exerts beneficial effects protecting endothelial function and identity in LD by reducing GDF15.

Ageing - Oxidative stress, PTMs and disease.

Post-translational modifications (PTMs) have been proposed as a link between the oxidative stress-inflammation-ageing trinity, thereby affecting several hallmarks of ageing. Phosphorylation, acetylation, and ubiquitination cover >90% of all the reported PTMs. Several of the main PTMs are involved in normal "healthy" ageing and in different age-related diseases, for instance neurodegenerative, metabolic, cardiovascular, and bone diseases, as well as cancer and chronic kidney disease. Ultimately, data from human rare progeroid syndromes, but also from long-living animal species, imply that PTMs are critical regulators of the ageing process. Mechanistically, PTMs target epigenetic and non-epigenetic pathways during ageing. In particular, epigenetic histone modification has critical implications for the ageing process and can modulate lifespan. Therefore, PTM-based therapeutics appear to be attractive pharmaceutical candidates to reduce the burden of ageing-related diseases. Several phosphorylation and acetylation inhibitors have already been FDA-approved for the treatment of other diseases and offer a unique potential to investigate both beneficial effects and possible side-effects. As an example, the most well-studied senolytic compounds dasatinib and quercetin, which have already been tested in Phase 1 pilot studies, also act as kinase inhibitors, targeting cellular senescence and increasing lifespan. Future studies need to carefully determine the best PTM-based candidates for the treatment of the "diseasome of ageing".

Characterizing the Heart Rate Effects From Administration of Sugammadex to Reverse Neuromuscular Blockade: An Observational Study in Patients.

BACKGROUND: Reversal of neuromuscular blockade (NMB) with sugammadex can cause marked bradycardia and asystole. Administration of sugammadex typically occurs in a dynamic period when anesthetic adjuvants and gas concentrations are being titrated to achieve emergence. This evaluation examined the heart rate (HR) responses to sugammadex to reverse moderate to deep NMB during a steady-state period and sought mechanisms for HR changes. METHODS: Patients with normal sinus rhythm, who were undergoing elective surgery that included rocuronium for NMB, were evaluated. After surgery, while at steady-state surgical depth anesthesia with sevoflurane and mechanical ventilation, patients received either placebo or 2 or 4 mg/kg of sugammadex to reverse moderate to deep NMB. Study personnel involved in data analysis were blinded to treatment. Continuous electrocardiogram (ECG) was recorded from the 5 minutes before and 5 minutes after sugammadex/placebo administration. R-R intervals were converted to HR and averaged in 1-minute increments. The maximum prolongation of an R-R interval after sugammadex was converted to an instantaneous HR. RESULTS: A total of 63 patients were evaluated: 8 received placebo, and 38 and 17 received 2 and 4 mg/kg sugammadex. Age, body mass index, and patient factors were similar in groups. Placebo did not elicit HR changes, whereas sugammadex caused maximum instantaneous HR slowing (calculated from the longest R-R interval), ranging from 2 to 19 beats/min. There were 7 patients with maximum HR slowing >10 beats/min. The average HR change and 95% confidence interval (CI) during the 5 minutes after 2 mg/kg sugammadex were 3.1 (CI, 2.3-4.1) beats/min, and this was not different from the 4 mg/kg sugammadex group (4.1 beats/min [CI, 2.5-5.6]). HR variability derived from the standard deviation of consecutive R-R intervals increased after sugammadex. CONCLUSIONS: Sugammadex to reverse moderate and deep NMB resulted in a fast onset and variable magnitude of HR slowing in patients. A difference in HR slowing as a function of dose did not achieve statistical significance. The observational nature of the investigation prevented a full understanding of the mechanism(s) of the HR slowing.

Renal function and lipid metabolism are major predictors of circumpapillary retinal nerve fiber layer thickness-the LIFE-Adult Study.

BACKGROUND: Circumpapillary retinal nerve fiber layer thickness (cpRNFLT) as assessed by spectral domain optical coherence tomography (SD-OCT) is a new technique used for the detection and evaluation of glaucoma and other optic neuropathies. Before translating cpRNFLT into clinics, it is crucially important to investigate anthropometric, biochemical, and clinical parameters potentially affecting cpRNFLT in a large population-based dataset. METHODS: The population-based LIFE-Adult Study randomly selected 10,000 participants from the population registry of Leipzig, Germany. All participants underwent standardized systemic assessment of various cardiometabolic risk markers and ocular imaging, including cpRNFLT measurement using SD-OCT (Spectralis, Heidelberg Engineering). After employing strict SD-OCT quality criteria, 8952 individuals were analyzed. Multivariable linear regression analyses were used to evaluate the independent associations of various cardiometabolic risk markers with sector-specific cpRNFLT. For significant markers, the relative strength of the observed associations was compared to each other to identify the most relevant factors influencing cpRNFLT. In all analyses, the false discovery rate method for multiple comparisons was applied. RESULTS: In the entire cohort, female subjects had significantly thicker global and also sectoral cpRNFLT compared to male subjects (p < 0.05). Multivariable linear regression analyses revealed a significant and independent association between global and sectoral cpRNFLT with biomarkers of renal function and lipid profile. Thus, thinner cpRNFLT was associated with worse renal function as assessed by cystatin C and estimated glomerular filtration rate. Furthermore, an adverse lipid profile (i.e., low high-density lipoprotein (HDL) cholesterol, as well as high total, high non-HDL, high low-density lipoprotein cholesterol, and high apolipoprotein B) was independently and statistically significantly related to thicker cpRNFLT. In contrast, we do not observe a significant association between cpRNFLT and markers of inflammation, glucose homeostasis, liver function, blood pressure, or obesity in our sector-specific analysis and globally. CONCLUSIONS: Markers of renal function and lipid metabolism are predictors of sectoral cpRNFLT in a large and deeply phenotyped population-based study independently of previously established covariates. Future studies on cpRNFLT should include these biomarkers and need to investigate whether incorporation will improve the diagnosis of early eye diseases based on cpRNFLT.

Perioperative Outcomes of Transurethral Resection, Open Prostatectomy, and Laser Therapy in the Surgical Treatment of Benign Prostatic Obstruction: A "Real-World" Data Analysis from the URO-Cert Prostate Centers.

INTRODUCTION: The aim of the study is to compare length of hospital stay, transfusion rates, and re-intervention rates during hospitalization for transurethral resection of the prostate (TUR-P), open prostatectomy (OP), and laser therapy (LT) for surgical treatment of benign prostatic obstruction (BPO). METHODS: URO-Cert is an organization, in which clinical data of prostatic diseases from 2 university, 19 public, and 3 private hospitals and 270 office-based urologists are collected in order to document treatment quality. Data on diagnostics, therapy, and course of disease are recorded web based. The analysis includes datasets from 2005 to 2017. RESULTS: Of 10,420 patients, 8,389 were treated with TUR-P, 1,334 with OP, and 697 with LT. Median length of hospital stay was 6 days (IQR: 4-7) for TUR-P, 9 days (IQR: 7-11) for OP, and 5 days (IQR: 4-6) for LT (p < 0.001). Risk for a hospital stay ≥7 days was higher for OP versus TUR-P (OR: 7.25; 95% CI = 6.27-8.36; p < 0.001) and LT (OR: 17.89; 95% CI = 14.12-22.65; p < 0.001) and higher for TUR-P versus LT (OR: 2.47; 95% CI = 2.03-3.01; p < 0.001). OP had a significantly higher risk for transfusions than TUR-P (OR: 2.44; 95% CI = 1.74-3.41; p < 0.001) and LT (OR: 3.32; 95% CI = 1.56-7.01; p < 0.001). Transfusion rates were not significantly different between TUR-P and LT (OR: 1.36; 95% CI = 0.66-2.79; p = 0.51). Risk of re-intervention was not different between all 3 approaches. CONCLUSION: OP was associated with higher transfusion rates and longer hospital stay than TUR-P and LT. Risk of transfusion was not different between TUR-P and LT, but TUR-P was inferior to LT concerning length of hospital stay. Re-intervention rates during hospitalization did not differ between the groups.

Problems and puzzles in echinoderm demography / Problemas y acertijos en la demografía de los equinodermos

Introduction: There are problems and puzzles in understanding reproduction, growth and mortality in echinoderm life cycles. Objective: Explore problems and puzzles in life cycles that are important and challenging. Methods: The literature is used to elucidate problems associated with all life stages. Results: Sources of larvae that settle at a site are explored using oceanographic modelling and genetic methods. There are few studies that have estimated larval mortality in the plankton under field conditions and results differ from experimental results or patterns of settlement. In a small number of studies, mortality rate of newly settled larvae appears to change rapidly as individuals grow. There are problems measuring size, and measurement bias that interferes with many tagging methods used to estimate growth. There also are problems with the use of natural growth lines and commonly used software to estimate both growth and mortality from size-frequency data. An interesting puzzle is that echinoderms may show negative senescence with mortality rate decreasing with size. There is a problem in fertilization success based on density so there should not be rare species where sexes are separate with free spawning of gametes yet there seem to be rare echinoderms. Conclusions: All parts of echinoderm life cycles provide problems and puzzles that are important and challenging.

Introducción: Existen problemas y acertijos en la comprensión de la reproducción, el crecimiento y la mortalidad en los ciclos de vida de los equinodermos. Objetivo: Explorar los problemas y acertijos en los ciclos de vida que son importantes y desafiantes. Métodos: La literatura es usada para dilucidar los problemas asociados con todas las etapas de vida. Resultados: Las fuentes de larvas que se asientan en un sitio se exploran usando modelos oceanográficos y métodos genéticos. Existen pocos estudios que han estimado la mortalidad larval del plancton bajo condiciones de campo y los resultados difieren de los resultados experimentales o los patrones de asentamiento. En un número pequeño de estudios, la tasa de mortalidad de las larvas recién asentadas parece cambiar rápidamente a medida que los organismos crecen. Existen problemas para medir tamaños y el sesgo de medición interfiere con el uso de muchos métodos de marcado para estimar el crecimiento. También hay problemas con el uso de las líneas de crecimiento natural y con los programas comúnmente usados para estimar tanto el crecimiento como la mortalidad a partir de datos de frecuencia de tamaño. Un acertijo interesante es que los equinodermos pueden mostrar senescencia negativa con una tasa de mortalidad que disminuye con el tamaño. Existe un problema con el éxito de la fertilización basado en la densidad, por lo que no debería haber especies raras cuando los sexos están separados y existe un desove libre de gametos, sin embargo, parece haber equinodermos raros. Conclusiones: Todas las partes de los ciclos de vida de los equinodermos proveen problemas y acertijos que son importantes y desafiantes.

Stage and Grade Migration in Prostate Cancer Treated With Radical Prostatectomy in a Large German Multicenter Cohort.

INTRODUCTION: Overdiagnosis and overtherapy in prostate cancer (PCa) treatment should be avoided, which has led to an awareness of the need to decrease treatment in cases of low-risk PCa with radical prostatectomy (RP). Simultaneously, prostate-specific antigen testing has become less popular in the last few years, which has resulted in higher cancer grade and stage at diagnosis. We evaluated stage and grade migration in the disease of patients treated with RP in a large German cohort. PATIENTS AND METHODS: Overall, 4842 patients undergoing RP between 2000 and 2019 were included. Age, prostate-specific antigen level, biopsy, and pathologic Gleason score as well as clinical and pathologic stage were collected. D'Amico risk groups and Gleason score were evaluated over different time points. RESULTS: We detected a significant grade migration toward higher grade. The proportion of biopsy Gleason sum ≤ 6 dropped from 45.8% to 20.6% between ≤ 2010 and 2017-2019. Further, the proportion of patients with low D'Amico risk scores also decreased by almost 50% (20.8% vs 12.2%). Finally, the proportion of non-organ-confined PCa increased over time, and the proportion of postoperative Gleason sum ≤ 6 decreased from 20% to 10% over time. CONCLUSION: Taken together, data indicate a significant preoperative grade and stage migration toward disease of higher grade in RP-treated PCa. Between the years 2000 and 2019, the proportion of biopsy Gleason sum ≤ 6 and the proportions of D'Amico low risk disease decreased by approximately 50% (respectively, 45% to 20% and 20.8% to 12.2%). This might indicate better patient selection for RP, but might also be a telltale sign of the rising mortality and morbidity of PCa.

Eosinophilic cystitis mimicking bladder cancer-considerations on the management based upon a case report and a review of the literature.

The hypereosinophilic syndrome (HES) is a rare disorder characterized by hypereosinophilia and infiltration of various organs with eosinophils. Eosinophilic cystitis (EC), mimicking bladder cancer clinically but also in ultrasound and in radiographic imaging, is one potential manifestation of the HES occurring in adults as well as in children. This case report describes the course of disease in a 57-year-old male presenting with severe gait disorders and symptoms of a low compliance bladder caused by a large retropubic tumor. After extensive urine and serologic examination and histologic confirmation of EC the patient was subjected to medical treatment with cetirizine and prednisolone for 5 weeks. While gait disorders rapidly resolved, micturition normalized only 10 months after initiation of therapy. Based upon this course the authors recommend patience and reluctance concerning radical surgical intervention in EC. Key Points • Eosinophilic cystitis is a rare condition with app. 200 cases reported, so far. • Etiology of eosinophilic cystitis is obscure, but allergies and parasitic infections may trigger the disease. • Genetic alterations (e.g., BRAF mutations) may predispose for the disease • Corticosteroids and antihistamines are the backbone of therapy and may be complemented by antibiotics and non-steroidal anti-inflammatory drugs in case of concomitant (underlying) infections. • As recovery can occur even after a long time, radical surgery should be restricted to highly selected cases.

Insights in the regulation of trimetylamine N-oxide production using a comparative biomimetic approach suggest a metabolic switch in hibernating bears.

Experimental studies suggest involvement of trimethylamine N-oxide (TMAO) in the aetiology of cardiometabolic diseases and chronic kidney disease (CKD), in part via metabolism of ingested food. Using a comparative biomimetic approach, we have investigated circulating levels of the gut metabolites betaine, choline, and TMAO in human CKD, across animal species as well as during hibernation in two animal species. Betaine, choline, and TMAO levels were associated with renal function in humans and differed significantly across animal species. Free-ranging brown bears showed a distinct regulation pattern with an increase in betaine (422%) and choline (18%) levels during hibernation, but exhibited undetectable levels of TMAO. Free-ranging brown bears had higher betaine, lower choline, and undetectable TMAO levels compared to captive brown bears. Endogenously produced betaine may protect bears and garden dormice during the vulnerable hibernating period. Carnivorous eating habits are linked to TMAO levels in the animal kingdom. Captivity may alter the microbiota and cause a subsequent increase of TMAO production. Since free-ranging bears seems to turn on a metabolic switch that shunts choline to generate betaine instead of TMAO, characterisation and understanding of such an adaptive switch could hold clues for novel treatment options in burden of lifestyle diseases, such as CKD.

Predisposing and Precipitating Factors Associated With Postoperative Delirium in Patients Undergoing Cardiac Surgery at a Veterans Affairs Medical Center: A Pilot Retrospective Analysis.

OBJECTIVE: Patients treated at Veterans Affairs (VA) medical centers are in poorer health, experience more medical and psychiatric conditions, and make greater use of medical resources than do patients in the general population. In the present pilot study, the authors examined their recent experience at a VA medical center to determine the incidence and risk factors associated with the development of postoperative delirium in VA patients after cardiac surgery and hypothesized that the risk factors for postoperative delirium after cardiac surgery are different between VA and non-VA patients. DESIGN: Retrospective cohort study. SETTING: Clement J. Zablocki Veterans Affairs Medical Center. PARTICIPANTS: The study comprised 250 consecutive patients undergoing cardiac surgery from July 2014 to March 2016. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographics, coexisting diseases, and medications were obtained from the VA electronic medical record. The European System for Cardiac Operative Evaluation II mortality risk index was calculated for each patient. The type and duration of the procedure and the duration of bypass were recorded. Intraoperative crystalloid, colloid, cell saver, and blood product volumes were compiled. Progress notes and International Classification of Diseases, Tenth Revision, Clinical Modification codes were searched for documentation of postoperative delirium. Thirty-eight patients (15.2%) developed postoperative delirium. Stepwise logistic regression analysis demonstrated that the European System for Cardiac Operative Evaluation II mortality risk index (odds ratio [OR] 1.036, 95% confidence interval [CI] [1.003-1.070]; p = 0.0344), congestive heart failure (OR 2.223 [95% CI 1.046-4.722]; p = 0.0377), pre-existing cognitive impairment (OR 5.147 [95% CI 1.994-13.28]; p = 0.0007), and the presence of a neuropsychiatric disorder (OR 2.015 [95% CI 1.004-4.043]; p = 0.0487) were predisposing factors associated with higher odds of postoperative delirium. The duration of surgery; transfusion of blood products (including packed red blood cells, fresh frozen plasma, and platelets); the durations of mechanical ventilation and conscious sedation (using either propofol or dexmedetomidine); and the length of intensive care unit stay were precipitating factors associated with higher odds of postoperative delirium. CONCLUSIONS: The results demonstrate that congestive heart failure, pre-existing cognitive impairment, and the presence of a neuropsychiatric disorder are predisposing risk factors for postoperative delirium after cardiac surgery in VA patients, whereas the duration of surgery, transfusion of blood products, durations of mechanical ventilation and conscious sedation, and length of intensive care unit stay are precipitating factors for postoperative delirium. These findings in VA patients generally are similar to those observed in the civilian population despite the differences between these cohorts.

Titration of sevoflurane anesthesia to optimize the time to regain airway reflexes in patients undergoing elective surgery: A randomized clinical trial comparing desflurane and sevoflurane anesthesia.

BACKGROUND: Desflurane has adverse environmental effects, but has clinical advantages to speed emergence and return of protective airway reflexes compared with sevoflurane. We hypothesized that weaning of the inspired sevoflurane during the final 15 minutes of surgery would eliminate differences in airway reflex recovery between these agents. METHODS: After obtaining IRB approval and informed consent, 40 patients undergoing elective surgery (≥1-hour) randomly received desflurane or sevoflurane. Patients swallowed 20 mL of water without drooling or coughing, and then received sedation and PONV pre-medication. Anesthesia was induced using propofol and fentanyl and maintained with desflurane or sevoflurane through a laryngeal mask airway maintaining a bispectral index of 45-50 and 50-60 during the final 15 minutes before surgery end. Cardiorespiratory variables and age-adjusted minimal alveolar concentration were recorded. The duration between anesthetic discontinuation and first appropriate response to command was measured; the laryngeal mask airway was removed. Two minutes after responding to command, patients were positioned semi-upright and attempted to swallow water. If successful swallowing was not achieved, the test was repeated every 4 minutes after each failure until successful swallowing was achieved. RESULTS: Average anesthetic concentration and bispectral index was similar in patients receiving desflurane vs sevoflurane. Response times after discontinuation of anesthetics were similar. There were no differences in the recovery of swallowing ability between desflurane and sevoflurane groups. CONCLUSION: Weaning of sevoflurane during the final 15 minutes of surgery eliminates clinical advantages of the more rapid return of airway reflexes with desflurane.