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As there is limited literature on paratesticular tumors of müllerian and mesothelial origin, we reviewed archived cases of serous borderline tumors (n = 15), low-grade serous carcinoma (n = 1), well-differentiated papillary mesothelial tumors (WDPMTs; n = 2), and mesothelioma (n = 12), for relevant clinicopathologic features. Molecular profiling data from the American Association for Cancer Research (AACR) GENIE registry was accessed for 8 additional patients with testicular mesothelioma. For tumors of mesothelial origin, the median age at surgical excision was 62 years, the median size was 4.5 cm, and they consistently exhibited positivity for mesothelial markers (CK5/6, calretinin, WT1, and D2-40). Recurrent alterations of the NF2 gene were identified in 3 of 8 patients (38%), and alterations of BAP1 and CDKN2A were relatively infrequent. While one patient with WDPMT had a recurrence, a second patient with WDPMT progressed to a biphasic mesothelioma 2 years after initial resection. For tumors of müllerian origin, the median age at surgical excision was 45 years, the median size was 2.5 cm, and these exhibited consistent positivity for ER, WT1, and PAX8. Although no recurrences were documented in patients with serous borderline tumors, a single patient with a low-grade serous carcinoma developed widely metastatic disease and died of disease-related complications. Our study emphasizes the need for close clinical follow-up in patients with WDPMT and highlights the prognostic significance of documenting invasive behavior in tumors of müllerian origin as they can have an aggressive clinical course. Finally, our results suggest that NF2 alterations may play an important role in the pathogenesis of testicular mesothelioma.

ZusammenfassungZur Therapie des metastasierten hormonsensitiven oder kastrationsresistenten Prostatakarzinoms (mHSPC, mCRPC) gab es in den letzten Jahren zahlreiche neue Erkenntnisse aus klinischen Studien. Die neu zugelassenen Behandlungsoptionen machen die Therapieplanung und Therapiesequenz anspruchsvoller. Hinzu kommt, dass die Lokaltherapie des metastasierten Prostatakarzinoms zunehmend an Bedeutung gewinnt. Im neuen Update 6.2 der S3-Leitlinie zum Prostatakarzinom vom Oktober 2021 wurden die neuen Entwicklungen bei den Empfehlungen zur Behandlung des mHSPC und mCRPC umgesetzt, deren wichtigsten Neuerungen und die daraus resultierenden Empfehlungen für die Praxis dargestellt werden.

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): BIOTRONIK SE & Co. KG Background and Purpose Atrial fibrillation (AF) detection and subsequent treatment is known to be sub-optimal in the general population. It is unclear how implanted devices with atrial sensing contribute to AF diagnosis. This study compares real-world AF diagnosis rates in patients with ICDs without (single chamber ICD, VR ICD) and with atrial sensing (dual chamber ICD, DR ICD) and contrasts them with detection rates in trials which are estimated to be 200 per 1000 person years (Reinhold, 2018). Methods Linked primary care data from the Clinical Practice Research Datalink (CPRD), secondary care data from Hospital Episode Statistics (HES) and mortality statistics from the Office of National Statistics (ONS) were used. All patients who received a VR- or DR ICD between 1 April 2016 and 31 October 2020, with at least 12 months primary care registration and no AF diagnosis prior to ICD implant were included in the analysis. Time to AF detection was calculated; in Cox proportional hazards regression analysis comorbidities, age, gender, and disease aetiology were adjusted for. Stroke rates were estimated for the total cohort. Results 835 patients with a VR ICD and 1034 patients with a DR ICD were identified. Both patient groups had similar comorbidity profiles, with VR ICD patients being on average younger (mean 57.5±13.9 vs 61.5±15.4 years). During 2700 and 3600 person-years follow-up the incidence of new AF diagnoses was 45.6 (CI: 37.6-53.7) per 1000 person years in VR ICD and 54.7 (CI: 47.1-62.4) per 1000 person-years in DR ICD patients. Median time to AF diagnosis was also similar at 36.3 (IQR: 26-49.6) and 36.9 (IQR: 25.2-51.5) months, respectively. In the adjusted analysis, ICD-10 or SNOMED coded diagnosis of AF was not significantly different between groups (HR: 0.88 [95% CI 0.70-1.10]; p-value=0.3). Stroke rates in the total cohort (with or without AF) were 5.7% in the VR ICD and 3.4% in the DR ICD cohort at 36 months. Conclusion The analysis highlights a difference between the rate of clinically relevant AF observed in patients with cardiac implanted electronic devices (CIED) in clinical trials and in real-world practice. The occurrence of stroke appears to also be higher in real world practice than in clinical trial populations and this is particularly marked in patients with VR ICD. These findings could indicate low use of remote monitoring or clinician uncertainty about the clinical relevance of CIED-detected AF in the real world. The latter may be because of a still accumulating body of predictive evidence towards the surveillance of AF. We propose that consistent use of remote monitoring with daily transmission in combination with CIEDs with atrial sensing will enable improvement of care.

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): BIOTRONIK SE & Co. KG Background Limited real-world data are available on the risk of non-elective heart failure-related hospitalization (HFH) in patients with de-novo cardiac implantable electronic devices. Purpose The aim of this study was to quantify and compare the risk of HFH in two distinct HF cohorts: those with cardiac resynchronisation therapy devices including a defibrillator (CRT-D) and those with dual chamber implantable cardioverter defibrillators (DR-ICD). Methods Linked primary care data from the Clinical Practice Research Datalink (CPRD), secondary care data from Hospital Episode Statistics (HES) and mortality statistics from the Office of National Statistics (ONS) were used, reflecting a representative sample of patients treated within NHS England. Patients with a diagnosis or treatment for HF who received a de-novo CRT-D or DR-ICD between 1 April 2016 and 31 October 2019 were included. The study follow-up period extended to 31 October 2020. We calculated the median time to first post-implantation HFH and for those affected, the time from first-to-second and second-to-third admission. Univariable and multivariable Cox proportional hazards regression models were used to derive hazard ratios (HRs) and quantify the association between device type and admission. Results were adjusted for age, sex, and comorbidities. Results Data were analysed from 2,883 CRT-D (mean age 68.8 years, 79% male, median follow-up 39 months) and 1,643 DR-ICD (mean age 66.6 years, 80% male, median follow-up 41 months) patients. The CRT-D cohort had more baseline comorbidities. At 12 and 36-months post-implantation, the percentage of patients with at least one all-cause or CV-related hospital admission was similar between cohorts, but the percentage with a HFH differed. The risk of first HFH was greater in the CRT-D cohort than the DR-ICD cohort (HR=1.18; CI: 1.07–1.29; p0.9; third admission HR=1.05; CI: 0.86–1.27; p=0.6). The incident HFH risk for the CRT-D cohort increased from 17.3 per 100 person years for a first event to 46.6 per 100 person years for a second event and further increased to 76.3 per 100 patient years for the third event. Conclusions Patients implanted with a CRT-D are at greater risk of first post-implant HFH, likely due to these patients having more severe HF. However, when the population is restricted to patients with a previous post-implant HFH, the risk is similar in patients with CRT-D and DR-ICD devices. For both devices, any HFH is associated with an increased risk of subsequent HFH. Future research should seek to identify strategies to reduce repeated HFH in these patient groups.

Introduction and hypothesis This study analyzes the long-term results of supratrigonal cystectomy and augmentation cystoplasty in patients with severe ulcerative interstitial cystitis/bladder pain syndrome (IC/BPS) and reduced bladder capacity. Methods Outcome data were retrospectively and prospectively collected and analyzed in women who underwent supratrigonal cystectomy and augmentation cystoplasty for ulcerative IC/BPS at Muenster University Hospital between 1991 and 2006. We used cross-tabulation and Pearson’s Chi-squared test to examine how outcome is influenced by age, preoperative functional bladder volume, and choice of augmentation material. Results After a median 171-month follow-up, analysis could be done in 26 of 27 patients. Persistent pain necessitated early revision in 2 patients (7.7%). Mean postoperative O’Leary Sant IC Score was 12.7 in the prospectively questioned patients. Responses to Patient Global Impression of Improvement (PGI-I) were: “very much better” in 15 cases (65.2%) and “much better” in 7 (30.4%). Twelve patients (52.2%) emptied their augmented bladder voluntarily, whereas 7 (32%) needed intermittent self-catheterization (ISC). The rate of patients requiring ISC tended to be lower when detubularized ileocecal bowel was used. All 5 patients (19.2%) with late relapse of ulcerative IC/BPS needed ISC. Conclusions Severe ulcerative IC/BPS can be curatively treated in some patients by supratrigonal cystectomy and augmentation, which is associated with a high satisfaction rate and few long-term complications even over a very long follow-up. In our analysis, the need for ISC is a risk factor for late relapse, although ileocecal augmentation could increase the proportion of patients with sufficient voluntary micturition.

A) Detection of a deletion event in LuCaP 86.2. This samples also displays signals of wildtype genomic DNA, displaying an AR-V567es positive sub-clone. B) Detection of an inversion event in LuCaP 136s2. Abbreviations: BPH, benign prostate hyperplasia

Purpose:Androgen receptor splice variants are known to facilitate resistance of prostate cancer cells toward antihormonal therapies. However, detection of the most prominent variant, AR-V7, on its own, is not sufficiently accurate for prediction of response. Thus, simultaneous detection of other variants might improve prediction. AR-V567es has been shown to be expressed in late stages of prostate cancer. Yet, there have been discrepant results regarding incidence of AR-V567es. We therefore aimed to perform a comprehensive comparison of different detection approaches for AR-V567es mRNA.Experimental Design:We compared a custom-made, probe-based PCR assay with 6 published AR-V567es detection PCR assays in distinct samples, that is, cancer cell lines, LuCaP xenografts, primary and metastatic tumor samples, and circulating tumor cells (CTC).Results:Using distinct approaches, we concordantly detected expression of AR-V567es in only three of 45 samples (LuCaP xenografts 86.2 and 136s2 as well as one CTC sample). We observed varying results in all other samples. Specificity analysis displayed nonspecific binding of 5 previously published PCR assays to AR full-length mRNA in the absence of AR-V567es.Conclusions:Validation of biomarker detection approaches is one of the most critical steps before transfer into clinical application. By performing comparative analysis of different detection approaches, we revealed eminent variability among previously described systems. Furthermore, we demonstrate an overestimation of AR-V567es in prostate cancer, presumably due to nonspecific detection of AR-FL mRNA. Therefore, any correlation between AR-V567es expression and clinical responses is highly doubtful and does not reflect the biological nature of the disease.

A) Genomic structure of the AR gene. B) Sequences of exon 4/8 spanning primers used in 6 different PCR assays (except PCR assay #4). C) PCR assay #4 (22) would lead to two distinct PCR products with the respective size, i.e. AR-V567es and AR-FL. Abbreviations: AR-FL, full length AR; bp, base pairs

Delta Ct values of AR-FL, AR-V3, AR-V7 and AR-V9 in LuCaP xenografts (Ct ARs - Ct RPL37A)

A) Expression of AR-FL in LuCaP xenografts displaying significantly lower expression of AR-FL in LuCaP xenograft 136s2. B/C/D) Expression of AR splice variants AR-V3 (C), AR-V7 (D) and AR-V9. Abbreviations: NTC, non-template control

HighlightsHorticultural oil thermotherapy sprayer was developed for use in perennial fruit crops.Prototype design included air-shear nozzles to spray at eight customized heights.Field evaluation provided adequate spray coverage.Abstract. Spray drift and residues of synthetic chemicals used in crop pest management are major concerns in agricultural industry. Therefore, exploration of alternative pest management technologies is necessary to minimize lasting pesticide residues without compromising biological efficacy. As such, this study reports the design and evaluation of a new horticultural oil thermotherapy (HOT) application system intended to increase biological efficacy of low-residue horticultural oils through addition of heat. A field-scale system has been constructed to apply thermotherapy onto tree fruit and berry crop canopies. This system uses a custom heating unit to preheat the spray liquid, reaching the nozzles at temperatures up to 99°C depending on application requirement. The spray delivery and temperature profiles generated by the prototyped HOT system were evaluated at three horizontal distances from the nozzle exit (0.6, 1.5, and 2.1 m) using a smart spray analytical system developed by our research group. Typical to tree fruit sprayers, higher spray delivery was collected at 0.6 m distance and trended to decrease with increasing distance from the nozzles. The spray plume temperature also decreased with increasing distance from the nozzle. The prototype was evaluated in a pear orchard providing adequate spray coverage at bottom (75% average at 1.2 m AGL) and middle (53% average at 2.4 m AGL) canopy zones. However, the coverage in the top canopy zone (3.6 m AGL) was less than 8% and will require adjustments to the nozzle assembly. Overall, configuration refinements and calibration adjustments will be required in the prototyped HOT system depending on the crop growth stage and canopy architecture for optimal application efficacy. The developed system, with due optimization, will be critical in providing evidence supporting the feasibility of HOT applications. Keywords: Alternative pest management, Application technology, Horticultural oil, Thermotherapy, Spray efficacy.

BACKGROUND: Temsirolimus is a mTOR inhibitor approved for the first-line treatment of advanced or metastatic renal cell carcinoma (a/mRCC) with poor prognosis. In treatment of a/mRCC several prognostic scoring systems are used. We assessed the prognostic value of these scores in a large temsirolimus treated cohort and compared the results with the physician’s prognosis. METHODS: A German multicenter registry (STAR-TOR) for a/mRCC patients (NCT00700258) was established to evaluate the efficacy and safety of temsirolimus 25 mg weekly in a routine clinical setting. These prospective data were systematically analyzed and followed-up by an independent clinical research organization to compare established prognostic scores (MSKCC, IMDC and Hudes) with the risk assessment by treating physicians based on their medical expertise and match them with survival outcomes. RESULTS: This interim analysis included 547 patients between 02/2008 and 05/2015 in 87 centers. Either prognostic tool resulted in significant and clinically meaningful differentiation between good, intermediate and poor prognosis. However, physician’s prognosis identified more patients with good prognosis (9.1% vs. 1.3%). In patients with good physician’s prognosis and intermediate prognosis by MSKCC, overall survival was nearly doubled compared to consensual intermediate prognosis (26.6 vs. 13.6 months), albeit without reaching statistical significance (P=0.09). For poor prognosis assessed by the physician, MSKCC performed statistically better for differentiation between poor and intermediate prognosis with a median overall survival of 10.3 vs. 5.5 months (P

There have been numerous new findings from clinical trials in recent years regarding the treatment of metastatic hormone-sensitive or castration-resistant prostate cancer. The newly approved treatment options make therapy planning and therapy sequencing more challenging. In addition, local therapy of metastatic prostate cancer is becoming increasingly important. In the new German guidelines on prostate cancer (version 6.2, October 2021), new developments in the recommendations for the treatment of mHSPC and mCRPC were implemented, and their most important resulting recommendations for the clinical practice are presented in this review.Zur Therapie des metastasierten hormonsensitiven oder kastrationsresistenten Prostatakarzinoms (mHSPC, mCRPC) gab es in den letzten Jahren zahlreiche neue Erkenntnisse aus klinischen Studien. Die neu zugelassenen Behandlungsoptionen machen die Therapieplanung und Therapiesequenz anspruchsvoller. Hinzu kommt, dass die Lokaltherapie des metastasierten Prostatakarzinoms zunehmend an Bedeutung gewinnt. Im neuen Update 6.2 der S3-Leitlinie zum Prostatakarzinom vom Oktober 2021 wurden die neuen Entwicklungen bei den Empfehlungen zur Behandlung des mHSPC und mCRPC umgesetzt, deren wichtigsten Neuerungen und die daraus resultierenden Empfehlungen für die Praxis dargestellt werden.

BACKGROUND Partial resuscitative endovascular balloon occlusion of the aorta (pREBOA) is a technology that occludes aortic flow and allows for controlled deflation and restoration of varying distal perfusion. Carotid flow rates (CFRs) during partial deflation are unknown. Our aim was to measure CFR with the different pREBOA balloon volumes and correlate those to the proximal mean arterial pressure (PMAP) and a handheld pressure monitoring device (COMPASS; Mirador Biomedical, Seattle, WA). METHODS Ten swine underwent a hemorrhagic injury model with carotid and iliac arterial pressures monitored via arterial lines. Carotid and aortic flow rates were monitored with Doppler flow probes. A COMPASS was placed to monitor proximal pressure. The pREBOA was inflated for 15 minutes then partially deflated for an aortic flow rate of 0.7 L/min for 45 minutes. It was then completely deflated. Proximal mean arterial pressures and CFR were measured, and correlation was evaluated. Correlation between CRF and COMPASS measurements was evaluated. RESULTS Carotid flow rate increased 240% with full inflation. Carotid flow rate was maintained at 100% to 150% of baseline across a wide range of partial deflation. After full deflation, CFR transiently decreased to 45% to 95% of baseline. There was strong positive correlation (r > 0.85) between CFR and PMAP after full inflation, and positive correlation with partial inflation (r > 0.7). Carotid flow rate had strong correlation with the COMPASS with full REBOA (r > 0.85) and positive correlation with pREBOA (r > 0.65). CONCLUSION Carotid flow rate is increased in a hemorrhagic model during full and partial inflation of the pREBOA and correlates well with PMAP. Carotid perfusion appears maintained across a wide range of pREBOA deflation and could be readily monitored with a handheld portable COMPASS device instead of a standard arterial line setup.

BACKGROUND Partial resuscitative endovascular balloon occlusion of the aorta (pREBOA) attempts to minimize ischemia/reperfusion injury while controlling hemorrhage. There are little data on optimal methods to evaluate and titrate partial flow, which typically requires invasive arterial line monitoring. We sought to examine the use of a miniaturized handheld digital pressure device (COMPASS; Mirador Biomedical, Seattle, WA) for pREBOA placement and titration of flow. METHODS Ten swine underwent standardized hemorrhagic shock. Carotid and iliac pressures were monitored with both arterial line and COMPASS devices, and flow was monitored by aortic and superior mesenteric artery flow probes. Partial resuscitative endovascular balloon occlusion of the aorta was inflated to control hemorrhage for 15 minutes before being deflated to try targeting aortic flow of 0.7 L/min (using only the COMPASS device) by an operator blinded to the arterial line pressures and aortic flow. Correlations between COMPASS and proximal/distal arterial line were evaluated, as well as actual aortic flow. RESULTS There was strong correlation between the distal mean arterial pressure (MAP) and the distal COMPASS MAP (r = 0.979, p < 0.01), as well as between the proximal arterial line and the proximal COMPASS on the pREBOA (r = 0.989, p < 0.01). There was a significant but weaker correlation between the distal compass MAP reading and aortic flow (r = 0.47, p < 0.0001), although it was not clinically significant and predicted flow was not achieved in a majority of the procedures. Of 10 pigs, survival times ranged from 10 to 120 minutes, with a mean survival of 50 minutes, and 1 pig surviving to 120 minutes. CONCLUSION Highly reliable pressure monitoring is achieved proximally and distally without arterial lines using the COMPASS device on the pREBOA. Despite accurate readings, distal MAPs were a poor indicator of aortic flow, and titration based upon distal MAPs did not provide reliable results. Further investigation will be required to find a suitable proxy for targeting specific aortic flow levels using pREBOA.

High temperature particle flow properties necessary to predict granular flow behavior for solar thermal energy storage applications were measured and calculated for Carbobead CP 30/60 up to 800 °C. The measured properties included elastic and shear moduli, particle–particle coefficients of static sliding and rolling friction, and particle–particle coefficients of restitution. Poisson’s ratio was calculated with elastic and shear moduli. The flow properties were used as inputs for a numerical model using the discrete element method to examine granular flows along an inclined plane at high temperature. The flow behavior was strongly influenced by the coefficients of static friction, which impacted the particle residence time, shear effects from the side walls, and particle flow mass flux. An 8.7%, 15.6%, and 8.5% increase and 37.9% decrease in steady state mass flow rate was observed for 200 °C, 400 °C, 600 °C, and 800 °C, respectively, when compared to room temperature simulations. A 52%, 59%, and 33% decrease in the time to reach steady state was observed for 200 °C, 400 °C, and 600 °C, respectively, while a 53% increase in time was observed for 800 °C. A significant delay in the flow development at 800 °C was observed due to significantly higher frictional forces.

The synthesis of nitrogen containing heterocycles is of particular interest in the pharmaceutical industry due to the range of biological activities exhibited by such compounds. Their synthesis using multicomponent reactions saves steps and minimizes waste generation. The bismuth (III) chloride multicomponent synthesis of a series of hexahydroimidazo[1, 2-a]pyridines is reported. Bismuth (III) compounds are especially attractive from a green chemistry perspective because they are remarkably nontoxic, non-corrosive and relatively inexpensive. The reported method avoids chromatography and an aqueous waste stream to afford the products in a very mass efficient manner.

Granular flows of sintered bauxite proppants were examined along an inclined plane for solar thermal energy storage applications. Granular flow properties needed to drive numeric granular models were measured for improved numerical model predictions for Carbobead CP 50/140, 40/100, and 30/60 particles. Particle shape and size distributions were determined by coupling optical microscopy to an in-house image processing algorithm. The impulse excitation technique was used to measure elastic and shear moduli, and compute Poisson’s ratio. The coefficient of static sliding friction was measured using the slip-stick method, and the static rolling friction was determined from measured shear on particles positioned between two hot-pressed plates. The coefficient of restitution was measured by dropping particles on a surface and determining the kinetic energy before and after impact with the surface using high resolution particle tracking velocimetry. Particle size did not significantly impact the coefficients of restitution and static rolling friction, however, particle shape distribution resulted in a large variation in measurements. An inclined flow experiment was performed to characterize granular flows of Carbobead CP 30/60 particles using particle image velocimetry. Numerical models of the experiment using discrete element method were generated with the measured mechanical properties as inputs for comparison with experimental results. A constant directional torque rolling friction model best predicted bulk granular flow behavior. Good agreement between the model and experiment was achieved at ambient, steady state conditions, with average velocity differences

Die spanische Hygia-Studie hat aufgrund der generellen Empfehlung, Antihypertensiva bevorzugt abends zu verordnen, zu erheblichen Irritationen gefuhrt – insbesondere da die Laienpresse, aber auch medizinische Medien dies geradezu begeistert kommentiert haben. Die Diskussion uber die optimale Einnahmezeit fur Antihypertensiva zeigt wieder einmal, wie gefahrlich der unkritische Umgang mit Studiendaten sein kann. Auf mogliche Risiken wurde dabei nicht hingewiesen. Die Hygia-Studie verglich bei 19.084 Patienten eine morgendliche mit einer abendlichen Einnahme der Antihypertensiva unter Kontrolle einer 48 h-Blutdruckmessung (!). Es zeigte sich eine signifikant bessere Senkung des Blutdrucks und der Rate kardio- und zerebrovaskularer Ereignisse unter abendlicher Einnahme. Die Daten sind wissenschaftlich wertvoll. Allerdings sind die Schlussfolgerungen aufgrund der Daten nicht nachvollziehbar, widersprechen vielen anderen Studien und sind fur bestimmte Patientengruppen gefahrlich. Zusatzlich finden sich methodische Mangel. Deshalb ist eine generelle abendliche Einnahme nicht gerechtfertigt und aufgrund der vielfaltigen, individuell sehr unterschiedlichen pathophysiologischen Befunde des nachtlichen Blutdruckverhaltens unsinnig. Grundsatzlich ermoglicht die ambulante 24 h-Blutdruckmessung (ABDM) eine bessere Einschatzung des individuellen kardio- und zerebrovaskularen Risikos und verhindert eine Fehleinschatzung des Blutdrucks und damit eine uberflussige bzw. unzureichende Therapie. Die ABDM bietet statt einer generellen Empfehlung die Moglichkeit einer zeitlich individuell angepassten Therapie. Einer abendlichen Einnahme von Antihypertensiva bei der prognostisch ungunstigen nachtlichen Hypertonie sollte immer eine ABDM vorausgehen, um das Risiko nachtlicher ischamischer Risiken durch zu starke Blutdruckabfalle zu vermeiden.

Background Controversy exists as to whether the threshold for blood pressure-lowering treatment should differ between people with and without type 2 diabetes. We aimed to investigate the effects of blood pressure-lowering treatment on the risk of major cardiovascular events by type 2 diabetes status, as well as by baseline levels of systolic blood pressure. Methods We conducted a one-stage individual participant-level data meta-analysis of major randomised controlled trials using the Blood Pressure Lowering Treatment Trialists' Collaboration dataset. Trials with information on type 2 diabetes status at baseline were eligible if they compared blood pressure-lowering medications versus placebo or other classes of blood pressure-lowering medications, or an intensive versus a standard blood pressure-lowering strategy, and reported at least 1000 persons-years of follow-up in each group. Trials exclusively on participants with heart failure or with short-term therapies and acute myocardial infarction or other acute settings were excluded. We expressed treatment effect per 5 mm Hg reduction in systolic blood pressure on the risk of developing a major cardiovascular event as the primary outcome, defined as the first occurrence of fatal or non-fatal stroke or cerebrovascular disease, fatal or non-fatal ischaemic heart disease, or heart failure causing death or requiring hospitalisation. Cox proportional hazard models, stratified by trial, were used to estimate hazard ratios (HRs) separately by type 2 diabetes status at baseline, with further stratification by baseline categories of systolic blood pressure (in 10 mm Hg increments from Findings We included data from 51 randomised clinical trials published between 1981 and 2014 involving 358 533 participants (58% men), among whom 103 325 (29%) had known type 2 diabetes at baseline. The baseline mean systolic/diastolic blood pressure of those with and without type 2 diabetes was 149/84 mm Hg (SD 19/11) and 153/88 mm Hg (SD 21/12), respectively. Over 4·2 years median follow-up (IQR 3·0–5·0), a 5 mm Hg reduction in systolic blood pressure decreased the risk of major cardiovascular events in both groups, but with a weaker relative treatment effect in participants with type 2 diabetes (HR 0·94 [95% CI 0·91–0·98]) compared with those without type 2 diabetes (0·89 [0·87–0·92]; pinteraction=0·0013). However, absolute risk reductions did not differ substantially between people with and without type 2 diabetes because of the higher absolute cardiovascular risk among participants with type 2 diabetes. We found no reliable evidence for heterogeneity of treatment effects by baseline systolic blood pressure in either group. In keeping with the primary findings, analysis using stratified network meta-analysis showed no evidence that relative treatment effects differed substantially between participants with type 2 diabetes and those without for any of the drug classes investigated. Interpretation Although the relative beneficial effects of blood pressure reduction on major cardiovascular events were weaker in participants with type 2 diabetes than in those without, absolute effects were similar. The difference in relative risk reduction was not related to the baseline blood pressure or allocation to different drug classes. Therefore, the adoption of differential blood pressure thresholds, intensities of blood pressure lowering, or drug classes used in people with and without type 2 diabetes is not warranted. Funding British Heart Foundation, UK National Institute for Health Research, and Oxford Martin School.

Inflammatory cell infiltration is central to healing after acute myocardial infarction (AMI). The relation of regional inflammation to edema, infarct size (IS), microvascular obstruction (MVO), intramyocardial hemorrhage (IMH), and regional and global LV function is not clear. Here we noninvasively characterized regional inflammation and contractile function in reperfused AMI in pigs using fluorine (19F) cardiovascular magnetic resonance (CMR). Adult anesthetized pigs underwent left anterior descending coronary artery instrumentation with either 90 min occlusion (n = 17) or without occlusion (sham, n = 5). After 3 days, in surviving animals a perfluorooctyl bromide nanoemulsion was infused intravenously to label monocytes/macrophages. At day 6, in vivo 1H-CMR was performed with cine, T2 and T2* weighted imaging, T2 and T1 mapping, perfusion and late gadolinium enhancement followed by 19F-CMR. Pigs were sacrificed for subsequent ex vivo scans and histology. Edema extent was 35 ± 8% and IS was 22 ± 6% of LV mass. Six of ten surviving AMI animals displayed both MVO and IMH (3.3 ± 1.6% and 1.9 ± 0.8% of LV mass). The 19F signal, reflecting the presence and density of monocytes/macrophages, was consistently smaller than edema volume or IS and not apparent in remote areas. The 19F signal-to-noise ratio (SNR) > 8 in the infarct border zone was associated with impaired remote systolic wall thickening. A whole heart value of 19F integral (19F SNR × milliliter) > 200 was related to initial LV remodeling independently of edema, IS, MVO, and IMH. Thus, 19F-CMR quantitatively characterizes regional inflammation after AMI and its relation to edema, IS, MVO, IMH and regional and global LV function and remodeling., Basic Research in Cardiology, 117 (1), ISSN:0300-8428, ISSN:1435-1803

Introduction: This analysis, based on pre- and postoperative urodynamic data, is the first to elucidate the influence of the Adjustable Transobturator Male System (ATOMS, A.M.I. GmbH, Feldkirch, Austria) on the lower urinary tract and disclose possible obstructive properties. Methods: A prospective study was performed in patients who had stress urinary incontinence and were scheduled for ATOMS implantation after radical prostatectomy. Apart from continence assessment (24-hour pad test, International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form [ICIQ-SF]), urodynamic testing was done with International Continence Society (ICS)-standardized pressure-flow analysis before and after ATOMS implantation/adjustment. The Wilcoxon signed-rank test was used for statistical analysis. Results: The analysis included 12 consecutive patients from two centers (mean age 69 years) with a mean followup of 246 days. Median urine leakage dropped from 240 (72-1250) to 70 (0-700) g/24 hours postoperatively, with a pad reduction of 4 to 0.9 pads/ day. Pressure-flow analysis revealed a significant change only in the bladder outlet obstruction index (BOOI). The bladder contractility index, intravesical pressure conditions, and uroflowmetry were not significantly affected. None of the patients showed de novo obstruction postoperatively in the ICS analysis. Conclusions: The ATOMS significantly increases the BOOI in conjunction with good continence results. However, no case reached pathological level according to the BOOI and thus there is no potential danger to the lower urinary tract or urethral integrity. Sin financiación 2.052 JCR (2021) Q4, 68/90 Urology & Nephrology 0.440 SJR (2021) Q3, 56/108 Urology No data IDR 2021 UEM

(1) Background: This study examined outcomes of second-line ATOMS implantation after failure of the fixed male sling (FMS) AdVance/AdVance XP. (2) Methods: A retrospective multicenter cohort analysis was carried out in men implanted with an ATOMS between 2011 and 2020 after failure of an AdVance/AdVance XP. Success was assessed on the basis of objective (dryness, 0–1 pad/24 h or >20 g/24 h pad test) and subjective results (PGI-I). We performed the Wilcoxon rank sum test, Fisher’s exact test, logistic regression, and multivariate analysis. (3) Results: The study included 88 patients from 9 centers with a mean age of 71.3 years. No Clavien–Dindo > II complications occurred within the first 3 months after ATOMS implantation. A total of 10 cases (9%) required revision in the ensuing clinical course. After a mean follow-up of 42.5 months, 76.1% achieved social continence, and 56.8% used no pads at all. Mean urine leakage/24 h dropped from 422 g (3.9 pads) to 38 g (0.69 pads) and the mean ICIQ-SF decreased from 16.25 to 5.3 (p < 0.0001). PROMs (patient-reported outcome measures) showed improvement in 98.9% of cases, and 63.6% gave a “very much better” PGI-I rating. Multivariate analysis identified a lower probability of achieving maximum satisfaction for the following factors: the AdVance XP as first-line therapy (OR 0.35), a lower ICIQ-SF question 1 (OR 0.26), status post-irradiation (OR 0.14), and more severe pain prior to ATOMS implantation (OR 0.51). (4) Conclusions: Implantation of an ATOMS is an effective and safe second-line treatment option for recurrent urinary incontinence after implantation of an AdVance/AdVance XP sling. High patient satisfaction was demonstrated in a long-term follow-up.

Significance RTS,S/AS01 is a circumsporozoite protein (CSP)-based malaria vaccine that confers partial protection against malaria in endemic areas. Recent reports have elucidated structures of monoclonal antibodies that bind to the central (NPNA) repeat region of CSP and that inhibit parasite invasion. Antigen configuration and copy number of CSP repeats displayed on a tobacco mosaic virus (TMV) particle platform were studied. A TMV vaccine containing CSP repeats displayed as a loop induced 10× better antibody titer than a nearly full-length CSP in mice. In rhesus model, this translated to a 5× improvement in titer. Rhesus antibodies potently inhibited parasite invasion up to 11 mo after vaccination. An optimized epitope-focused, repeat-only CSP vaccine may be sufficient or better than the existing CSP vaccines., Plasmodium falciparum vaccine RTS,S/AS01 is based on the major NPNA repeat and the C-terminal region of the circumsporozoite protein (CSP). RTS,S-induced NPNA-specific antibody titer and avidity have been associated with high-level protection in naïve subjects, but efficacy and longevity in target populations is relatively low. In an effort to improve upon RTS,S, a minimal repeat-only, epitope-focused, protective, malaria vaccine was designed. Repeat antigen copy number and flexibility was optimized using the tobacco mosaic virus (TMV) display platform. Comparing antigenicity of TMV displaying 3 to 20 copies of NPNA revealed that low copy number can reduce the abundance of low-affinity monoclonal antibody (mAb) epitopes while retaining high-affinity mAb epitopes. TMV presentation improved titer and avidity of repeat-specific Abs compared to a nearly full-length protein vaccine (FL-CSP). NPNAx5 antigen displayed as a loop on the TMV particle was found to be most optimal and its efficacy could be further augmented by combination with a human-use adjuvant ALFQ that contains immune-stimulators. These data were confirmed in rhesus macaques where a low dose of TMV-NPNAx5 elicited Abs that persisted at functional levels for up to 11 mo. We show here a complex association between NPNA copy number, flexibility, antigenicity, immunogenicity, and efficacy of CSP-based vaccines. We hypothesize that designing minimal epitope CSP vaccines could confer better and more durable protection against malaria. Preclinical data presented here supports the evaluation of TMV-NPNAx5/ALFQ in human trials.

Purpose The aim was to study the correlation between cuff size and outcome after implantation of an AMS 800 artificial urinary sphincter. Methods A total of 473 male patients with an AMS 800 sphincter implanted between 2012 and 2014 were analyzed in a retrospective multicenter cohort study performed as part of the Central European Debates on Male Incontinence (DOMINO) Project. Results Single cuffs were implanted in 54.5% and double cuffs in 45.5% of the patients. The cuffs used had a median circumference of 4.5 cm. Within a median follow of 18 months, urethral erosion occurred in 12.8% of the cases and was associated significantly more often with small cuff sizes (P

ZusammenfassungDie Durchführung der radikalen Prostatektomie hat sich in den letzten 200 Jahren deutlich verändert; gerade in den letzten 50 Jahren entwickelte sich die Technik deutlich weiter. Als Meilensteine dürfen zum einen die Arbeiten von Walsh in den späten 70er und frühen 80er Jahren angesehen werden, welche zu einer signifikanten Reduktion der Morbidität des Eingriffes führten, zum anderen die Einführung (Roboter-assistierter) minimal-invasiver Operationstechniken. Den absoluten Goldstandard bzgl. des Zuganges gibt es bis heute nicht. Innovative Ansätze, z. B. die Zuhilfenahme der sog. „augmented reality“ werden aktuell bzgl. ihres Potentials evaluiert. Dieser Übersichtsartikel in der Jubiläumsausgabe des Urologen beschäftigt sich mit den Meilensteinen der Entwicklung dieses für die Urologie wichtigen Eingriffs.

A novel method for pairing surface irradiation and volumetric absorption from Monte Carlo ray tracing to computational heat transfer models is presented. The method is well-suited to directionally and spatially complex concentrated radiative inputs (e.g., solar receivers and reactors). The method employs a generalized algorithm for directly mapping absorbed rays from a Monte Carlo ray tracing model to boundary or volumetric source terms in the computational mesh. The algorithm is compatible with unstructured, two and three-dimensional meshes with varying element shapes. Four case studies were performed on a directly irradiated, windowed solar thermochemical reactor model to validate the method. The method was shown to conserve energy and preserve spatial variation when mapping rays from a Monte Carlo ray tracing model to a computational heat transfer model in ansys fluent.

Californium-252 (252Cf) is considered essential by the National Institute of Standards and Technology for the calibration of neutron instrumentation and dosimetry. Californium-252 has a relatively short half-life of 2.645 y; consequently, it must be replaced frequently to produce an adequate neutron flux for calibration. The user community is currently looking for a replacement for 252Cf. The patented technology described herein has a high probability of being that replacement. A preferred method to replace 252Cf would use an affordable and easily maintained neutron source that generates neutrons in an energy spectrum as close to that of 252Cf as possible. Deuterium-tritium (D-T) neutron generators are both affordable and easily maintained, which makes them highly attractive for replacing 252Cf. The patented technology discussed in this paper simulates the 252Cf fission spectrum through a D-T neutron generator by using spectral subtraction. The primary spectrum is built using principally (n,xn) and (n,n') reactions in a variety of materials. In conjunction with the primary spectrum, an engineered background spectrum is generated using a second set of materials. This engineered background spectrum corrects for differences between the primary and desired spectra. This subtraction technique generates a spectrum very similar to 252Cf while maintaining a reasonable flux. Further, by choosing different scattering materials, any fission spectrum can be matched, including the thermal and epithermal components. This flexibility expands the potential use of this technology beyond simulating 252Cf to any desired neutron spectrum below 14 MeV.

Findings 33 trials met the inclusion criteria, and included 260 447 participants with 15 012 cancer events. Median follow-up of included participants was 4?2 years (IQR 3?0?5?0). In the individual participant data meta-analysis comparing each drug class with all other comparators, no associations were identified between any antihypertensive drug class and risk of any cancer (HR 0?99 [95% CI 0?95?1?04] for ACEIs; 0?96 [0?92?1?01] for ARBs; 0?98 [0?89?1?07] for 13 blockers; 1?01 [0?95?1?07] for thiazides), with the exception of calcium channel blockers (1?06 [1?01?1?11]). In the network meta-analysis comparing drug classes against placebo, we found no excess cancer risk with any drug class (HR 1?00 [95% CI 0?93?1?09] for ACEIs; 0?99 [0?92?1?06] for ARBs; 0?99 [0?89?1?11] for 13 blockers; 1?04 [0?96?1?13] for calcium channel blockers; 1?00 [0?90?1?10] for thiazides). Summary Background Some studies have suggested a link between antihypertensive medication and cancer, but the evidence is so far inconclusive. Thus, we aimed to investigate this association in a large individual patient data meta-analysis of randomised clinical trials. Methods We searched PubMed, MEDLINE, The Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from Jan 1, 1966, to Sept 1, 2019, to identify potentially eligible randomised controlled trials. Eligible studies were randomised controlled trials comparing one blood pressure lowering drug class with a placebo, inactive control, or other blood pressure lowering drug. We also required that trials had at least 1000 participant years of follow-up in each treatment group. Trials without cancer event information were excluded. We requested individual participant data from the authors of eligible trials. We pooled individual participant-level data from eligible trials and assessed the effects of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), 13 blockers, calcium channel blockers, and thiazide diuretics on cancer risk in one-stage individual participant data and network meta-analyses. Cause-specific fixed-effects Cox regression models, stratified by trial, were used to calculate hazard ratios (HRs). The primary outcome was any cancer event, defined as the first occurrence of any cancer diagnosed after randomisation. This study is registered with PROSPERO (CRD42018099283). Findings 33 trials met the inclusion criteria, and included 260 447 participants with 15 012 cancer events. Median follow-up of included participants was 4 & middot;2 years (IQR 3 & middot;0 & ndash;5 & middot;0). In the individual participant data meta-analysis comparing each drug class with all other comparators, no associations were identified between any antihypertensive drug class and risk of any cancer (HR 0 & middot;99 [95% CI 0 & middot;95 & ndash;1 & middot;04] for ACEIs; 0 & middot;96 [0 & middot;92 & ndash;1 & middot;01] for ARBs; 0 & middot;98 [0 & middot;89 & ndash;1 & middot;07] for 13 blockers; 1 & middot;01 [0 & middot;95 & ndash;1 & middot;07] for thiazides), with the exception of calcium channel blockers (1 & middot;06 [1 & middot;01 & ndash;1 & middot;11]). In the network meta-analysis comparing drug classes against placebo, we found no excess cancer risk with any drug class (HR 1 & middot;00 [95% CI 0 & middot;93 & ndash;1 & middot;09] for ACEIs; 0 & middot;99 [0 & middot;92 & ndash;1 & middot;06] for ARBs; 0 & middot;99 [0 & middot;89 & ndash;1 & middot;11] for 13 blockers; 1 & middot;04 [0 & middot;96 & ndash;1 & middot;13] for calcium channel blockers; 1 & middot;00 [0 & middot;90 & ndash;1 & middot;10] for thiazides). Interpretation We found no consistent evidence that antihypertensive medication use had any effect on cancer risk. Although such findings are reassuring, evidence for some comparisons was insufficient to entirely rule out excess risk, in particular for calcium channel blockers.

Background In metastatic clear cell renal cell carcinoma (ccRCC), different combination therapies, each including anti-PD-1 immune checkpoint blockade (ICB), are applied as first-line treatment. Robust predictive biomarkers for rational upfront therapy decisions are lacking, although they are urgently needed. Recently, we showed that CTLA4 promoter methylation predicts response to ICB in melanoma. Here, we aimed to investigate CTLA4 methylation in ccRCC and its utility to serve as a predictive biomarker for anti-PD-1 based ICB in metastatic ccRCC. Methods CTLA4 methylation was analyzed with regard to transcriptional gene activity (mRNA expression), intratumoral immune cell composition, and clinical course in two ccRCC cohorts obtained from The Cancer Genome Atlas (TCGA cohort, n=533) and the University Hospital Bonn (UHB Non-ICB Cohort, n=116). In addition, CTLA4 methylation as well as CD8+ T cell infiltrates and PD-L1 expression were evaluated in pre-treatment samples from a multicenter cohort (RCC-ICB Cohort, n=71). Patients included in the RCC-ICB Cohort were treated with either first line anti-PD-1 based combination therapy (n=25) or monotherapy post–tyrosine kinase inhibition in second line or later. Analyses were performed with regard to treatment response according to RECIST, progression-free survival (PFS), event-free survival (EFS), and overall survival (OS) following treatment initiation. Results CTLA4 promoter hypomethylation was significantly correlated with CTLA4 mRNA expression, lymphocyte infiltration, and poor OS in both primary ccRCC cohorts (TCGA: HR 0.30 (95% CI 0.18 to 0.49), p, publishedVersion

The Spanish Hygia study has led to considerable irritation due to the general recommendation to prescribe antihypertensives preferably to be taken in the evening, especially since the lay press as well as medical media made enthusiastic comments. The discussion about the optimal time to take antihypertensive drugs shows once again how dangerous the uncritical handling of study data can be. No possible risks were pointed out. The Hygia study compared 19,084 patients with morning and evening intake of antihypertensive drugs under the control of a 48‑h blood pressure measurement (!). There was a significantly better reduction in blood pressure and the rate of cardiovascular and cerebrovascular events with evening intake. The data are scientifically valuable; however, the conclusions are incomprehensible based on the data, contradict many other studies and are dangerous for certain patient groups. There are also methodological shortcomings. Therefore, a general evening intake is not justified and nonsensical due to the diverse, individually very different pathophysiological findings of the nocturnal blood pressure behavior. Basically, the outpatient 24‑h blood pressure measurement (ABPM) enables a better assessment of the individual cardiovascular and cerebrovascular risks and prevents an incorrect assessment of the blood pressure and thus unnecessary or sufficient treatment. Instead of a general recommendation, the ABPM offers the option of an individually tailored treatment. Taking antihypertensive drugs in the evening should always be preceded by an ABDM in the case of prognostically unfavorable nocturnal hypertension in order to avoid the risk of nocturnal ischemic risks due to excessive drops in blood pressure.

Papillary renal cell carcinoma (PRCC) is currently divided in 2 subtypes. We reviewed a large cohort of PRCC and correlated subtype, morphological features and diagnostic marker expression with overall survival (OS) to uncover differences between the 2 subtypes. Three hundred seventy-six renal tumors initially diagnosed as PRCC with clinical and survival data were collected from the participating centers. Two hundred forty-six tumors were classified as PRCC1 (65.4%) and 130 as PRCC2 (34.6%) and graded according to the 2016 World Health Organization/International Society of Urological Pathology grading system. Morphological features (abundant cytoplasm, necrosis, fibrous stroma, foamy macrophages and psammoma bodies) were noted. Immunohistochemical stains (MIB1, p53, Racemase, EMA, CK7, CK20, E-Cadherin) were performed using tissue microarrays. χ2-Tests, log-rank tests and uni- and multivariate Cox regression analysis were performed. Both subtypes displayed different morphological features and immunohistochemical profiles: abundant cytoplasm was more frequent in PRCC2, while foamy macrophages were more common in PRCC1. Abundant cytoplasm and presence of psammoma bodies were associated with poorer OS. PRCC1 showed more frequent CK7 expression, PRCC2 more frequent E-Cadherin, p53 and higher MIB1 expression (>15%). Expression of Racemase and CK7 was associated with better OS, while high MIB1 (>15%) was associated with poorer OS. In multivariate analysis, the only independent predictors of OS were proliferation (MIB1), tumor stage, metastasis and age at surgery. Subtype was not an independent prognostic factor. Therefore, PRCC subtype on its own is not suitable for estimating survival. More data focusing on PRCC tumor biology is needed to define prognostic subgroups, especially in PRCC2.