In this randomized, double-blinded, parallel-group study, we compared the efficacy of tramadol and morphine administered IV for the management of pain in trauma patients in the prehospital situation. ...One-hundred-five patients were randomly allocated to receive tramadol (Group T) or morphine (Group M). The initial dose was 100 mg tramadol in Group T and 5 mg morphine (body weight < or = 70 kg) or 10 mg morphine (body weight >70 kg) in Group M; this could be increased to 200 mg in Group T and 15 or 20 mg in Group M if necessary. Pain intensity was assessed with four-point verbal rating scales. Sedation, physiologic data, and adverse events were also recorded. Analgesia was similar in both groups; the 95% confidence interval for the difference between the decrease in pain intensity observed with tramadol or morphine was -0.26 to 0.30, which was within the predefined equivalence range (-0.50 to 0.50). Neither sedation scores nor physiologic data differed between groups. Tramadol is an acceptable alternative to morphine in the prehospital trauma setting.
We present the SEDs of a hard X-ray selected sample containing 136 sources with FSUB2-10keV/SUB>10SUP-14/SUP erg cmSUP-2/SUP sSUP-1/SUP 132 are AGNs. The sources are detected in a 1 degSUP2/SUP area ...of the XMM-Newton Medium Deep Survey where optical data from the VVDS and CFHTLS and infrared data from the SWIRE survey are available. Based on a SED fitting technique we derive photometric redshifts with sigma(1+z)=0.11 and 6% of outliers and identify AGN signatures in 83% of the objects. This fraction is higher than derived when a spectroscopic classification is available. The remaining 17SUP+9/SUPSUB-6/SUB% of AGNs show star-forming galaxy SEDs (SF class). The sources with AGN signatures are divided in two classes, AGN1 (33SUP+6/SUPSUB-1/SUB%) and AGN2 (50SUP+6/SUPSUB-11/SUB%). The AGN1 and AGN2 classes include sources whose SEDs are fitted by type 1 and type 2 AGN templates, respectively. On average, AGN1s show soft X-ray spectra, consistent with being unabsorbed, while AGN2s and SFs show hard X-ray spectra, consistent with being absorbed. The analysis of the average SEDs as a function of X-ray luminosity shows a reddening of the infrared SEDs, consistent with a decreasing contribution from the host galaxy at higher luminosities. The AGNs in the SF classes are likely obscured in the mid-infrared, as suggested by their low LSUB3-20mum/SUB/LSUPcorr/SUPSUB0.5-10keV/SUB ratios. We confirm the previously found correlation for AGNs between the radio luminosity and the X-ray and the mid-infrared luminosities. The X-ray-radio correlation can be used to identify heavily absorbed AGNs. However, the estimated radio fluxes for the missing AGN population responsible for the bulk of the background at E>10 keV are too faint to be detected even in the deepest current radio surveys.
We report a retrospective analysis of 115 elderly patients over 70 years of age who underwent laparoscopic cholecystectomy for symptomatic lithiasis between January 1990 and January 1996. This ...technique is perfectly adapted to elderly patients. Complications are less frequent and better tolerated than for conventional open surgery. In this series, the success rate was 97.39% with technique-related complications at 2.7%. None of these complications required reoperation.
Summary
Background
Bimekizumab is a monoclonal antibody that selectively inhibits both interleukin (IL)‐17A and IL‐17F, which is currently under investigation for treatment of moderate‐to‐severe ...plaque psoriasis. Maintenance dosing every 4 weeks is well established with IL‐17 inhibitors for psoriasis.
Objectives
To investigate the possible dosing interval during bimekizumab maintenance therapy to maintain clear skin, to inform phase III studies.
Methods
Forty‐nine patients with moderate‐to‐severe plaque psoriasis received bimekizumab 320 mg at weeks 0/4, followed at week 16 by bimekizumab 320 mg (n = 17) or placebo (n = 32). Efficacy, safety, pharmacokinetics, immunogenicity and biopsy transcriptomic analyses were assessed to week 28.
Results
At week 8, 47% of patients achieved a 100% improvement from baseline in Psoriasis Area and Severity Index (PASI 100), increasing to 57% at week 12 (8 weeks after the second dose) before decreasing. In those who received bimekizumab at week 16, PASI 100 rate increased to comparable peak levels at week 20, but reduced by week 28 to 41% (12 weeks after the third dose). The week 8 transcriptional signature observed in lesional psoriatic skin rapidly normalized to levels consistent with nonlesional skin, resulting in molecular remission. Keratinocyte‐related gene products such as CXCL1 (C‐X‐C motif chemokine ligand 1), IL‐8 (encoded by the CXCL8 gene), CCL20 (C‐C motif chemokine 20), IL‐36γ and IL‐17C were profoundly normalized to levels associated with nonlesional skin.
Conclusions
Here, inhibition of IL‐17F in addition to IL‐17A resulted in rapid, deep clinical responses. Additionally, profound normalization of keratinocyte biology and the psoriatic transcriptome was observed, including normalization of both IL17 and IL23 gene expression by week 8. These data provide evidence to support evaluation of bimekizumab maintenance dosing both every 8 and every 4 weeks in phase III clinical trials.
What is already known about this topic?
Strong clinical responses have been demonstrated with biologics that inhibit interleukin (IL)‐17A, and inhibition of this cytokine has been shown to affect the transcriptome of patients with psoriasis.
Prolonged maintenance dosing intervals are preferred by patients, with sustainable clinical responses key to improvements in quality of life.
Maintenance dosing every 4 weeks is well established with IL‐17A inhibitors in psoriasis.
What does this study add?
A first assessment of the effects of a monoclonal antibody that selectively inhibits both IL‐17A and IL‐17F on the transcriptome of patients with moderate‐to‐severe plaque psoriasis shows rapid normalization of the transcriptional signature in lesional psoriatic skin after 8 weeks.
These data provide evidence to support further evaluation of bimekizumab maintenance dosing both every 8 weeks and every 4 weeks in psoriasis in phase III studies.
Linked Comment: S. Gerdes and J. Albrecht. Br J Dermatol 2022; 186:603–604.
Plain language summary available online
Summary
Background
The interleukin (IL)‐23/IL‐17 immune axis is of central importance in psoriasis. However, the impact of IL‐17 family cytokines other than IL‐17A in psoriasis has not been fully ...established.
Objectives
To elucidate the contribution of IL‐17 family cytokines in psoriasis.
Methods
To address the expression and localization of IL‐17 family cytokines, lesional and nonlesional skin samples from patients with psoriasis were analysed by several complementary methods, including quantitative polymerase chain reaction, immunoassays, in situ hybridization and immunohistochemistry. Mechanistic studies assessing the functional activity of IL‐17 family cytokines were performed using ex vivo cultured human skin biopsies and primary human keratinocytes.
Results
We demonstrated that IL‐17A, IL‐17F, IL‐17A/F and IL‐17C are expressed at increased levels in psoriasis lesional skin and induce overlapping gene expression responses in ex vivo cultured human skin that correlate with the transcriptomic signature of psoriasis skin. Furthermore, we showed that brodalumab, in contrast to ixekizumab, normalizes gene expression responses induced by the combination of IL‐17A, IL‐17F, IL‐17A/F and IL‐17C in human keratinocytes.
Conclusions
Several IL‐17 ligands signalling through IL‐17RA are overexpressed in psoriasis skin and induce similar psoriasis‐related inflammatory pathways demonstrating their relevance in relation to therapeutic intervention in psoriasis.
What is already known about this topic?
The key role of interleukin (IL)‐17A in psoriasis is well established.
Previous studies have shown that IL‐17A, IL‐17F and IL‐17C are overexpressed in psoriasis skin, whereas contradictory results have been published for IL‐17E.
IL‐17 family cytokines induce secretion of inflammatory mediators such as antimicrobial peptides, chemokines and cytokines involved in the pathophysiology of psoriasis.
What does this study add?
Levels of IL‐17A/F are increased in lesional psoriasis skin but markedly lower than IL‐17A and IL‐17F.
In ex vivo cultured human skin, a physiologically relevant model, IL‐17A, IL‐17F, IL‐17A/F and IL‐17C show functional redundancy in shaping the psoriasis transcriptome.
IL‐17RA antagonism normalizes expression of psoriasis‐related genes in keratinocytes induced by the combination of IL‐17 family cytokines.
What is the translational message?
Overexpression and functional redundancy of IL‐17 family cytokines in psoriasis may explain why some patients with psoriasis with primary or secondary failure of response to secukinumab or ixekizumab achieve a clinical response after switching to brodalumab.
Linked Comment: M. Sugaya. Br J Dermatol 2021; 185:483.
We present the X-ray pipeline developed for the purpose of the cluster search in the XMM Large-Scale Structure (XMM-LSS) survey. It is based on a two-stage procedure via a dedicated handling of the ...Poisson nature of the signal: (i) source detection on multiresolution wavelet filtered images and (ii) source analysis by means of a maximum likelihood fit to the photon images. The source detection efficiency and characterization are studied through extensive Monte Carlo simulations. This led us to define two samples of extended sources: the C1 class that is uncontaminated, and the less restrictive C2 class that allows for 50 per cent contamination. The resulting predicted selection function is presented and the comparison to the current XMM-LSS confirmed cluster sample shows very good agreement. We arrive at average predicted source densities of about seven C1 and 12 C2 per deg2, which is higher than any available wide field X-ray survey. We finally note a substantial deviation of the predicted redshift distribution for our samples from the one obtained using the usual assumption of a flux-limited sample.
Aim
To assess progressive learning of root canal shaping in order to define the number of simulated canals in resin blocks needed to reach a level of learning beyond which no further improvement in ...performance is observed.
Methodology
A total of 216 simulated canals in resin blocks were instrumented by 18 operators without experience in Endodontics and by 18 Endodontists. The R25 file of the Reciproc system (VDW, Munich, Germany) was used to prepare the canals. The blocks were photographed before and after instrumentation. An analysis was made of the variations in the dimensions of the canals at 6 locations and of the instrumentation time. A Student's t‐test was used to analyse the data (P < 0.05).
Results
The group without experience were associated with significant differences in instrumentation time between the first canal and the subsequent canals (P < 0.05) but differences in canal dimensions were not significant (P > 0.05). In the group with experience, the instrumentation time did not differ significantly after the fifth canal, and no significant variations in canal dimensions were observed (P > 0.05).
Conclusions
When conducting studies on root canal shaping or educating students with new instruments, a simulated canal sample size of 6 was appropriate to achieve competence.
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