ObjectiveTo study short-term (<90 days) morbidity and mortality following radical cystectomy (RC) for bladder cancer and identify modifiable risk factors associated with these.DesignSystematic ...review.MethodsThe systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed and EMBASE were searched for relevant papers on 11 June 2019 and rerun on 27 May 2020. Studies reporting complications, reoperations, length of stay and mortality within 90 days were included. Studies were reviewed according to criteria from the Oxford Centre for Evidence-Based Medicine and the quality of evidence was assessed using the Newcastle–Ottawa Scale.ResultsThe search retrieved 1957 articles. Sixty-six articles were included. The quality of evidence was poor to good. Most studies were retrospective, and no randomised clinical trials were identified. Of included studies a median of 6 Martin criteria for reporting complications after surgery were fulfilled. The Clavien-Dindo classification for grading complications was most frequently used. The weighted overall complication rate after RC was 34.9% (range 28.8–68.8) for in-house complications, 39.0% (range 27.3–80.0) for 30-day complications and 58.5% (range 36.1–80.5) for 90-day complications. The most common types of complications reported were gastrointestinal (29.0%) and infectious (26.4%). The weighted mortality rate was 2.4% (range 0.9–4.7) for in-house mortality, 2.1% (0.0–3.7) for 30-day mortality and 4.7% (range 0.0–7.0) for 90-day mortality. Age and comorbidity were identified as the best predictors for complications following RC.ConclusionShort-term morbidity and mortality are high following RC. Reporting of complications is heterogeneous and the quality of evidence is generally low. There is a continuous need for randomised studies to address any intervention that can reduce morbidity and mortality following RC.PROSPERO registration number104937.
Prostate cancer (PCa) cells become castrate-resistant after initial tumor regression following castration-based lowering of testosterone (T). De-novo intra-tumoral steroid synthesis is a suggested ...biological mechanism of castration resistant PCa, but the regulators are unknown. Testicular T production is controlled by the luteinizing hormone/choriogonadotropin receptor (LHCGR). To elucidate the influence of LHCGR on PCa development the presence and effects of LHCGR in PCa and whether LHCGR in serum holds prognostic information in PCa patients is investigated. LHCGR expression was investigated by RT-PCR, WB, IHC, qPCR in PCa cell lines and prostatic tissue. Steroid production was measured in media from cell lines with LC-MS/MS and expression of steroidogenic enzymes with qPCR. Serum LHCGR (sLHCGR) was measured with ELISA in PCa patients (N = 157). Presence of LHCGR was established in prostatic tissue and PCa cell lines. Cell proliferation increased by 1.29-fold in LNCaP (P = 0.007) and 1.33-fold in PC-3 cells (P = 0.0007), when stimulated by luteinizing hormone. Choriogonadotropin stimulation decreased proliferation 0.93-fold in DU145 cells (P = 0.05), but none of the treatments altered steroid metabolite secretion. Low sLHCGR concentration was associated with a higher risk of biochemical failure after radical prostatectomy (HR = 3.05, P = 0.06) and castration resistance (HR = 6.92, P = 0.004) compared to high sLHCGR concentration. LHCGR is expressed in PCa and may exert a growth regulatory role in PCa derived cell lines. A potential prognostic role of sLHCGR for determining recurrence risk in PCa patients is found in this pilot study but needs verification in larger cohorts.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Translocases of the AAA+ (ATPases Associated with various cellular Activities) family are powerful molecular machines that use the mechano‐chemical coupling of ATP hydrolysis and conformational ...changes to thread DNA or protein substrates through their central channel for many important biological processes. These motors comprise hexameric rings of ATPase subunits, in which highly conserved nucleotide‐binding domains form active‐site pockets near the subunit interfaces and aromatic pore‐loop residues extend into the central channel for substrate binding and mechanical pulling. Over the past 2 years, 41 cryo‐EM structures have been solved for substrate‐bound AAA+ translocases that revealed spiral‐staircase arrangements of pore‐loop residues surrounding substrate polypeptides and indicating a conserved hand‐over‐hand mechanism for translocation. The subunits' vertical positions within the spiral arrangements appear to be correlated with their nucleotide states, progressing from ATP‐bound at the top to ADP or apo states at the bottom. Studies describing multiple conformations for a particular motor illustrate the potential coupling between ATP‐hydrolysis steps and subunit movements to propel the substrate. Experiments with double‐ring, Type II AAA+ motors revealed an offset of hydrolysis steps between the two ATPase domains of individual subunits, and the upper ATPase domains lacking aromatic pore loops frequently form planar rings. This review summarizes the critical advances provided by recent studies to our structural and functional understanding of hexameric AAA+ translocases, as well as the important outstanding questions regarding the underlying mechanisms for coordinated ATP‐hydrolysis and mechano‐chemical coupling.
The optimal timing of radiotherapy after radical prostatectomy for prostate cancer is uncertain. We aimed to compare the efficacy and safety of adjuvant radiotherapy versus an observation policy with ...salvage radiotherapy for prostate-specific antigen (PSA) biochemical progression.
We did a randomised controlled trial enrolling patients with at least one risk factor (pathological T-stage 3 or 4, Gleason score of 7–10, positive margins, or preoperative PSA ≥10 ng/mL) for biochemical progression after radical prostatectomy (RADICALS-RT). The study took place in trial-accredited centres in Canada, Denmark, Ireland, and the UK. Patients were randomly assigned in a 1:1 ratio to adjuvant radiotherapy or an observation policy with salvage radiotherapy for PSA biochemical progression (PSA ≥0·1 ng/mL or three consecutive rises). Masking was not deemed feasible. Stratification factors were Gleason score, margin status, planned radiotherapy schedule (52·5 Gy in 20 fractions or 66 Gy in 33 fractions), and centre. The primary outcome measure was freedom from distant metastases, designed with 80% power to detect an improvement from 90% with salvage radiotherapy (control) to 95% at 10 years with adjuvant radiotherapy. We report on biochemical progression-free survival, freedom from non-protocol hormone therapy, safety, and patient-reported outcomes. Standard survival analysis methods were used. A hazard ratio (HR) of less than 1 favoured adjuvant radiotherapy. This study is registered with ClinicalTrials.gov, NCT00541047.
Between Nov 22, 2007, and Dec 30, 2016, 1396 patients were randomly assigned, 699 (50%) to salvage radiotherapy and 697 (50%) to adjuvant radiotherapy. Allocated groups were balanced with a median age of 65 years (IQR 60–68). Median follow-up was 4·9 years (IQR 3·0–6·1). 649 (93%) of 697 participants in the adjuvant radiotherapy group reported radiotherapy within 6 months; 228 (33%) of 699 in the salvage radiotherapy group reported radiotherapy within 8 years after randomisation. With 169 events, 5-year biochemical progression-free survival was 85% for those in the adjuvant radiotherapy group and 88% for those in the salvage radiotherapy group (HR 1·10, 95% CI 0·81–1·49; p=0·56). Freedom from non-protocol hormone therapy at 5 years was 93% for those in the adjuvant radiotherapy group versus 92% for those in the salvage radiotherapy group (HR 0·88, 95% CI 0·58–1·33; p=0·53). Self-reported urinary incontinence was worse at 1 year for those in the adjuvant radiotherapy group (mean score 4·8 vs 4·0; p=0·0023). Grade 3–4 urethral stricture within 2 years was reported in 6% of individuals in the adjuvant radiotherapy group versus 4% in the salvage radiotherapy group (p=0·020).
These initial results do not support routine administration of adjuvant radiotherapy after radical prostatectomy. Adjuvant radiotherapy increases the risk of urinary morbidity. An observation policy with salvage radiotherapy for PSA biochemical progression should be the current standard after radical prostatectomy.
Cancer Research UK, MRC Clinical Trials Unit, and Canadian Cancer Society.
This paper demonstrates the feasibility of implementing real-time state estimators for active distribution networks in field-programmable gate arrays (FPGAs) by presenting an operational prototype. ...The prototype is based on a linear state estimator that uses synchrophasor measurements from phasor measurement units. The underlying algorithm is the sequential discrete Kalman filter (SDKF), an equivalent formulation of the DKF for the case of uncorrelated measurement noise. In this regard, this paper formally proves the equivalence of SDKF and the DKF, and highlights the suitability of the SDKF for an FPGA implementation by means of a computational complexity analysis. The developed prototype is validated using a case study adapted from the IEEE 34-node distribution test feeder.
Most techniques for power system analysis model the grid by exact electrical circuits. For instance, in power flow study, state estimation, and voltage stability assessment, the use of admittance ...parameters (i.e., the nodal admittance matrix) and hybrid parameters is common. Moreover, network reduction techniques (e.g., Kron reduction) are often applied to decrease the size of large grid models (i.e., with hundreds or thousands of state variables), thereby alleviating the computational burden. However, researchers normally disregard the fact that the applicability of these methods is not generally guaranteed. In reality, the nodal admittance must satisfy certain properties in order for hybrid parameters to exist and Kron reduction to be feasible. Recently, this problem was solved for particular cases of monophase and balanced triphase grids. This paper investigates the general case of unbalanced polyphase grids. First, conditions determining the rank of the so-called compound nodal admittance matrix and its diagonal subblocks are deduced from the characteristics of the electrical components and the network graph. Second, the implications of these findings concerning the feasibility of Kron reduction and the existence of hybrid parameters are discussed. In this regard, this paper provides a rigorous theoretical foundation for various applications in power system analysis.
Radical cations of diamondoids, a fundamental class of highly stable cycloalkanes, are intermediates in functionalization reactions and possibly present in the interstellar medium. Herein, we ...characterize the structure of the radical cation of 1-amantadine (1-C10H15NH2 +, Ama+), the amino derivative of the parent adamantane (C10H16 +, Ada+), by infrared spectroscopy and density functional theory calculations. The structural isomers of Ama+ produced by electron ionization are probed by infrared photodissociation of cold Ar-tagged ions. In addition to the canonical nascent Ama+ isomer with an intact C10H15 cage, we identify two distonic bicyclic iminium isomers in which the adamantyl cage opens upon ionization, one of which is lower in energy than the cage isomer. The reaction profile with barriers and intermediates for this cage-opening reaction are determined. Comparison with Ada+ suggests that this type of ionization-induced cage-opening may be a common feature for diamondoids and important for their reactivity.
•Clinical trials suggest a COVID-19 vaccine effectiveness (VE) of >90% is achievable.•SARS-CoV-2 transmission is highly heterogeneous and exhibits random bursts in recorded cases.•This heterogeneity ...may introduce a strong positive random bias in early VE estimates.
Recently released interim numbers from advanced vaccine candidate clinical trials suggest that a COVID-19 vaccine effectiveness (VE) of >90% is achievable. However, SARS-CoV-2 transmission dynamics are highly heterogeneous and exhibit localized bursts of transmission, which may lead to sharp localized peaks in the number of new cases, often followed by longer periods of low incidence. Here we show that, for interim estimates of VE, these characteristic bursts in SARS-CoV-2 infection may introduce a strong positive bias in VE. Specifically, we generate null models of vaccine effectiveness, i.e., random models with bursts that over longer periods converge to zero VE but that for interim periods frequently produce apparent VE near 100%. As an example, by following the relevant clinical trial protocol, we can reproduce recently reported interim outcomes from an ongoing phase 3 clinical trial of an RNA-based vaccine candidate. Thus, to avoid potential random biases in VE, it is suggested that interim estimates on COVID-19 VE should control for the intrinsic inhomogeneity in both SARS-CoV-2 infection dynamics and reported cases.
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