Abstract Background Robot-assisted radical prostatectomy (RARP) remains controversial, and no improvement in cancer control outcomes has been demonstrated over open radical prostatectomy (ORP). ...Objective To examine population-based, comparative effectiveness of RARP versus ORP pertaining surgical margin status and use of additional cancer therapy. Design, setting, and participants This was a retrospective observational study of 5556 RARP and 7878 ORP cases from 2004 to 2009 from Surveillance Epidemiology and End Results–Medicare linked data. Intervention RARP versus ORP. Outcome measurements and statistical analysis Propensity-based analyses were performed to minimize treatment selection biases. Generalized linear regression models were computed for comparison of RP surgical margin status and use of additional cancer therapy (radiation therapy RT or androgen deprivation therapy ADT) by surgical approach. Results and limitations In the propensity-adjusted analysis, RARP was associated with fewer positive surgical margins (13.6% vs 18.3%; odds ratio OR: 0.70; 95% confidence interval CI, 0.66–0.75), largely because of fewer RARP positive margins for intermediate-risk (15.0% vs 21.0%; OR: 0.66; 95% CI, 0.59–0.75) and high-risk (15.1% vs 20.6%; OR: 0.70; 95% CI, 0.63–0.77) disease. In addition, RARP was associated with less use of additional cancer therapy within 6 mo (4.5% vs 6.2%; OR: 0.75; 95% CI, 0.69–0.81), 12 mo (OR: 0.73; 95% CI, 0.62–0.86), and 24 mo (OR: 0.67; 95% CI, 0.57–0.78) of surgery. Limitations include the retrospective nature of the study and the absence of prostate-specific antigen levels to determine biochemical recurrence. Conclusions RARP is associated with improved surgical margin status relative to ORP for intermediate- and high-risk disease and less use of postprostatectomy ADT and RT. This has important implications for quality of life, health care delivery, and costs. Patient summary Robot-assisted radical prostatectomy (RP) versus open RP is associated with fewer positive margins and better early cancer control because of less use of additional androgen deprivation and radiation therapy within 2 yr of surgery.
When amphibious fishes are on land, gill function is reduced or eliminated and the skin is hypothesized to act as a surrogate site of ionoregulation. Skin ionocytes are present in many fishes, ...particularly those with amphibious life histories. We used nine closely related killifishes spanning a range of amphibiousness to first test the hypothesis that amphibious killifishes have evolved constitutively increased skin ionocyte density to promote ionoregulation on land. We found that skin ionocyte densities were constitutively higher in five of seven amphibious species examined relative to exclusively water-breathing species when fish were prevented from leaving water, strongly supporting our hypothesis. Next, to examine the scope for plasticity, we tested the hypothesis that skin ionocyte density in amphibious fishes would respond plastically to air-exposure to promote ionoregulation in terrestrial environments. We found that air-exposure induced plasticity in skin ionocyte density only in the two species classified as highly amphibious, but not in moderately amphibious species. Specifically, skin ionocyte density significantly increased in
Anablepsoides hartii
(168%) and
Kryptolebias marmoratus
(37%) following a continuous air-exposure, and only in
K. marmoratus
(43%) following fluctuating air-exposure. Collectively, our data suggest that highly amphibious killifishes have evolved both increased skin ionocyte density as well as skin that is more responsive to air-exposure compared to exclusively water-breathing and less amphibious species. Our findings are consistent with the idea that gaining the capacity for cutaneous ionoregulation is a key evolutionary step that enables amphibious fishes to survive on land.
Abstract
This article reviews resistance to ceftazidime/avibactam as an aspect of its primary pharmacology, linked thematically with recent reviews of the basic in vitro and in vivo translational ...biology of the combination (J Antimicrob Chemother 2022; 77: 2321–40 and 2341–52). In Enterobacterales or Pseudomonas aeruginosa, single-step exposures to 8× MIC of ceftazidime/avibactam yielded frequencies of resistance from <∼0.5 × 10−9 to 2–8 × 10−9, depending on the host strain and the β-lactamase harboured. β-Lactamase structural gene mutations mostly affected the avibactam binding site through changes in the Ω-loop: e.g. Asp179Tyr (D179Y) in KPC-2. Other mutations included ones proposed to reduce the permeability to ceftazidime and/or avibactam through changes in outer membrane structure, up-regulated efflux, or both. The existence, or otherwise, of cross-resistance between ceftazidime/avibactam and other antibacterial agents was also reviewed as a key element of the preclinical primary pharmacology of the new agent. Cross-resistance between ceftazidime/avibactam and other β-lactam-based antibacterial agents was caused by MBLs. Mechanism-based cross-resistance was not observed between ceftazidime/avibactam and fluoroquinolones, aminoglycosides or colistin. A low level of general co-resistance to ceftazidime/avibactam was observed in MDR Enterobacterales and P. aeruginosa. For example, among 2821 MDR Klebsiella spp., 3.4% were resistant to ceftazidime/avibactam, in contrast to 0.07% of 8177 non-MDR isolates. Much of this was caused by possession of MBLs. Among 1151 MDR, XDR and pandrug-resistant isolates of P. aeruginosa from the USA, 11.1% were resistant to ceftazidime/avibactam, in contrast to 3.0% of 7452 unselected isolates. In this case, the decreased proportion susceptible was not due to MBLs.
The gills are the primary site of exchange in fishes. However, during early life-stages or in amphibious fishes, ionoregulation and gas-exchange may be primarily cutaneous. Given the similarities ...between larval and amphibious fishes, we hypothesized that cutaneous larval traits are continuously expressed in amphibious fishes across all life-stages to enable the skin to be a major site of exchange on land. Alternatively, we hypothesized that cutaneous larval traits disappear in juvenile stages and are re-expressed in amphibious species in later life-stages. We surveyed six species spanning a range of amphibiousness and characterized cutaneous ionocytes and neuroepithelial cells (NECs) as representative larval skin traits at up to five stages of development. We found that skin ionocyte density remained lower and constant in exclusively water-breathing, relative to amphibious species across development, whereas in amphibious species ionocyte density generally increased. Additionally, adults of the most amphibious species had the highest cutaneous ionocyte densities. Surprisingly, cutaneous NECs were only identified in the skin of one amphibious species (
Kryptolebias marmoratus
), suggesting that cutaneous NECs are not a ubiquitous larval or amphibious skin trait, at least among the species we studied. Our data broadly supports the continuous-expression hypothesis, as three of four amphibious experimental species expressed cutaneous ionocytes in all examined life-stages. Further, the increasing density of cutaneous ionocytes across development in amphibious species probably facilitates the prolonged occupation of terrestrial habitats.
The invasion of land required amphibious fishes to evolve new strategies to avoid toxic ammonia accumulation in the absence of water flow over the gills. We investigated amphibious behaviour and ...nitrogen excretion strategies in six phylogenetically diverse Aplocheiloid killifishes (
,
, and
) in order to determine if a common strategy evolved
All species voluntarily emersed (left water) over several days, and also in response to environmental stressors (low O
, high temperature). All species were ammoniotelic in water and released gaseous ammonia (NH
volatilization) during air exposure as the primary route for nitrogen excretion. Metabolic depression, urea synthesis, and/or ammonia accumulation during air exposure were not common strategies used by these species. Immunostaining revealed the presence of ammonia-transporting Rhesus proteins (Rhcg1 and Rhcg2) in the skin of all six species, indicating a shared mechanism for ammonia volatilization. We also found Rhcg in the skin of several other fully aquatic fishes, implying that cutaneous ammonia excretion is not exclusive to amphibious fishes. Overall, our results demonstrate that similar nitrogen excretion strategies while out of water were used by all killifish species tested; possibly the result of shared ancestral amphibious traits, phenotypic convergence, or a combination of both.
Previous reviews of ceftazidime/avibactam have focused on in vitro molecular enzymology and microbiology or the clinically associated properties of the combination. Here we take a different approach. ...We initiate a series of linked reviews that analyse research on the combination that built the primary pharmacology data required to support the clinical and business risk decisions to perform randomized controlled Phase 3 clinical trials, and the additional microbiological research that was added to the above, and the safety and chemical manufacturing and controls data, that constituted successful regulatory licensing applications for ceftazidime/avibactam in multiple countries, including the USA and the EU. The aim of the series is to provide both a source of reference for clinicians and microbiologists to be able to use ceftazidime/avibactam to its best advantage for patients, but also a case study of bringing a novel β-lactamase inhibitor (in combination with an established β-lactam) through the microbiological aspects of clinical development and regulatory applications, updated finally with a review of resistance occurring in patients under treatment. This first article reviews the biochemistry, structural biology and basic microbiology of the combination, showing that avibactam inhibits the great majority of serine-dependent β-lactamases in Enterobacterales and Pseudomonas aeruginosa to restore the in vitro antibacterial activity of ceftazidime. Translation to efficacy against infections in vivo is reviewed in the second co-published article, Nichols et al. (J Antimicrob Chemother 2022; dkac172).
Amphibious fishes on land encounter higher oxygen (O
) availability and novel energetic demands, which impacts metabolism. Previous work on the amphibious mangrove killifish (Kryptolebias marmoratus) ...has shown that cortisol becomes elevated in response to air exposure, suggesting a possible role in regulating metabolism as fish move into terrestrial environments. We tested the hypothesis that cortisol is the mechanism by which oxidative processes are upregulated during the transition to land in amphibious fishes. We used two groups of fish, treated fish (+metyrapone, a cortisol synthesis inhibitor) and control (-metyrapone), to determine the impact of cortisol during air exposure (0 and 1 h, 7 days) on O
consumption, terrestrial locomotion, the phenotype of red skeletal muscle, and muscle lipid concentration. Metyrapone-treated fish had an attenuated elevation in O
consumption rate during the water to air transition and an immediate reduction in terrestrial exercise performance relative to control fish. In contrast, we found no short- (0 h) or long-term (7 days) differences between treatments in the oxidative phenotype of red muscles, nor in muscle lipid concentrations. Our results suggest that cortisol stimulates the necessary increase in aerobic metabolism needed to fuel the physiological changes that amphibious fishes undergo during the acclimation to air, although further studies are required to determine specific mechanisms of cortisol regulation.
To celebrate its centenary year, Journal of Experimental Biology (JEB) commissioned a collection of articles examining the past, present and future of experimental biology. This Commentary closes the ...collection by considering the important research opportunities and challenges that await us in the future. We expect that researchers will harness the power of technological advances, such as '-omics' and gene editing, to probe resistance and resilience to environmental change as well as other organismal responses. The capacity to handle large data sets will allow high-resolution data to be collected for individual animals and to understand population, species and community responses. The availability of large data sets will also place greater emphasis on approaches such as modeling and simulations. Finally, the increasing sophistication of biologgers will allow more comprehensive data to be collected for individual animals in the wild. Collectively, these approaches will provide an unprecedented understanding of 'how animals work' as well as keys to safeguarding animals at a time when anthropogenic activities are degrading the natural environment.
In rainbow trout development, a switch occurs from high-affinity embryonic hemoglobin (Hb) and round, embryonic erythrocytes to lower-affinity adult Hb and oval, adult erythrocytes. Our study ...investigated the early ontogeny of rainbow trout blood properties and the hypoxia response. We hypothesized that hypoxia exposure would delay the ontogenetic turnover of Hb and erythrocytes because retention of high-affinity embryonic Hb would facilitate oxygen loading. To test this hypothesis we developed a method of efficiently extracting blood from individual embryos and larvae and optimized several techniques for measuring hematological parameters on microliter (0.5-2.0 μl) blood samples. In chronic hypoxia (30% of oxygen saturation), stage-matched embryos and larvae possessed half the Hb concentration, erythrocyte counts and hematocrit observed in normoxia. Hypoxia-reared larvae also had threefold to sixfold higher mRNA expression of the embryonic Hb α-1, β-1 and β-2 subunits relative to stage-matched normoxia-reared larvae. Furthermore, in hypoxia, the round embryonic erythrocytic shape persisted into later developmental stages. Despite these differences, Hb-oxygen affinity (P50), cooperativity and the Root effect were unaltered in hypoxia-reared O. mykiss. The data support our hypothesis that chronic hypoxia delays the ontogenetic turnover of Hb and erythrocytes, but without the predicted functional consequences (i.e. higher than expected P50). These results also suggest that the Hb-oxygen affinity is protected during development in chronic hypoxia to favor oxygen unloading at the tissues. We conclude that in early trout development, the blood-oxygen transport system responds very differently to chronic hypoxia relative to adults, possibly because respiration depends relatively more on oxygen diffusion than convection.
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