The incidence of hypersensitivity reactions to hyaluronic acid dermal fillers is between 0.3 and 4.25%, mediated by T‐lymphocytes. Flu‐like illness can trigger immunogenic reactions at the site of ...filler placement. Cases of SARS‐CoV‐2 are significant and pose a possible risk of inducing hypersensitivity. This case report is of a delayed‐type hypersensitivity after hyaluronic acid dermal filler treatment of the nose and subsequent infection with SARS‐CoV‐2. Risk factors for the development of such symptoms were identified as the presence of hyaluronic acid combined with flu‐like illness and repeated treatment of one area. The case resolved without intervention. Clinicians should be mindful of the risk posed by the interaction of hyaluronic acid dermal filler with SARS‐CoV‐2 in light of the pandemic.
Nitric oxide (NO) is a key signalling molecule in the regulation of cerebral blood flow. This review summarises current evidence regarding the role of NO in the regulation of cerebral blood flow at ...rest, under physiological conditions, and after brain injury, focusing on subarachnoid haemorrhage, traumatic brain injury, and ischaemic stroke and following cardiac arrest. We also review the role of NO in the response to hypoxic insult in the developing brain. NO depletion in ischaemic brain tissue plays a pivotal role in the development of subsequent morbidity and mortality through microcirculatory disturbance and disordered blood flow regulation. NO derived from endothelial nitric oxide synthase (eNOS) appears to have neuroprotective properties. However NO derived from inducible nitric oxide synthase (iNOS) may have neurotoxic effects. Cerebral NO donor agents, for example sodium nitrite, appear to replicate the effects of eNOS derived NO, and therefore have neuroprotective properties. This is true in both the adult and immature brain. We conclude that these agents should be further investigated as targeted pharmacotherapy to protect against secondary brain injury.
•The nitric oxide synthase pathway plays a pivotal role in brain blood flow regulation.•Disruption to this pathway occurs after injury, and contributes to secondary insult.•Nitric oxide donor agents show promise as therapy for secondary brain injury.
Despite improvements in the clinical management of aneurysmal subarachnoid haemorrhage over the last decade, delayed cerebral ischaemia (DCI) remains the single most important cause of morbidity and ...mortality in those patients who survive the initial bleed. The pathological mechanisms underlying DCI are still unclear and the calcium channel blocker nimodipine remains the only therapeutic intervention proven to improve functional outcomes after SAH. The recent failure of the drug clazosentan to improve functional outcomes despite reducing vasoconstriction has moved the focus of research into DCI away from cerebral artery constriction towards a more multifactorial aetiology. Novel pathological mechanisms have been suggested, including damage to cerebral tissue in the first 72 h after aneurysm rupture (‘early brain injury’), cortical spreading depression, and microthrombosis. A greater understanding of the significance of these pathophysiological mechanisms and potential genetic risk factors is required, if new approaches to the prophylaxis, diagnosis, and treatment of DCI are to be developed. Furthermore, objective and reliable biomarkers are needed for the diagnosis of DCI in poor grade SAH patients requiring sedation and to assess the efficacy of new therapeutic interventions. The purpose of this article is to appraise these recent advances in research into DCI, relate them to current clinical practice, and suggest potential novel avenues for future research.
Metastatic colorectal cancer (mCRC) that harbours a BRAF V600E mutation (BRAF MT) is associated with poorer outcomes. However, whether this mutation is predictive of treatment benefit from ...anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) is uncertain.
We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) published up to July 2014 that evaluated the effect of BRAF MT on the treatment benefit from anti-EGFR mAbs for mCRC.
Seven RCTs met the inclusion criteria for assessment of overall survival (OS), whereas eight RCTs met the inclusion criteria for assessment of progression-free survival (PFS). For RAS WT/BRAF MT tumours, the hazard ratio for OS benefit with anti-EGFR mAbs was 0.97 (95% CI; 0.67-1.41), whereas the hazard ratio was 0.81 (95% CI; 0.70-0.95) for RAS WT/BRAF WT tumours. However, the test of interaction (P=0.43) was not statistically significant, highlighting that the observed differences in the effect of anti-EGFR mAbs on OS according to the BRAF mutation status may be due to chance alone. Regarding PFS benefit with anti-EGFR mAbs, the hazard ratio was 0.86 (95% CI; 0.61-1.21) for RAS WT/BRAF MT tumours as compared with 0.62 (95% CI; 0.50-0.77) for RAS WT/BRAF WT tumours (test of interaction, P=0.07).
This meta-analysis demonstrates that there is insufficient evidence to definitively state that RAS WT/BRAF MT individuals attain a different treatment benefit from anti-EGFR mAbs for mCRC compared with RAS WT/BRAF WT individuals. As such, there are insufficient data to justify the exclusion of anti-EGFR mAb therapy for patients with RAS WT/BRAF MT mCRC.
Monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) prolong survival in metastatic colorectal cancer (mCRC) Kirsten rat sarcoma viral oncogene (KRAS) exon 2 wild-type ...tumors. Recent evidence has suggested that other RAS mutations (in exons 3 and 4 of KRAS and exons 2, 3 and 4 of a related gene, NRAS) may also be predictive of resistance.
Systematic review and meta-analysis of randomized, controlled trials (RCTs) evaluating anti-EGFR mAbs that have assessed tumors for new RAS mutations. Tumors with the new RAS mutations were compared with both tumors without any RAS mutations and tumors with KRAS exon 2 mutations with respect to anti-EGFR treatment progression-free survival (PFS) and overall survival (OS) benefit.
Nine RCTs comprising a total of 5948 participants evaluated for both KRAS exon 2 and new RAS mutations met the inclusion criteria. Approximately 20% of KRAS exon 2 wild-type tumors harbored one of the new RAS mutations. Tumors without any RAS mutations (either KRAS exon 2 or new RAS mutations) were found to have significantly superior anti-EGFR mAb PFS (P < 0.001) and OS (P = 0.008) treatment effect compared with tumors with any of the new RAS mutations. No difference in PFS or OS benefit was evident between tumors with KRAS exon 2 mutations and tumors with the new RAS mutations. Results were consistent between different anti-EGFR agents, lines of therapy and chemotherapy partners. Anti-EGFR mAb therapy significantly improved both PFS {hazard ratio 0.62 95% confidence interval (CI) 0.50–0.76} and OS hazard ratio 0.87 (95% CI 0.77–0.99) for tumors without any RAS mutations. No PFS or OS benefit was evident with use of anti-EGFR mAbs for tumors harboring any RAS mutation (P > 0.05).
Tumors harboring one of the new RAS mutations are unlikely to significantly benefit from anti-EGFR mAb therapy in mCRC.
Porcine reproductive and respiratory syndrome (PRRS) causes decreased reproductive performance in breeding animals and increased respiratory problems in growing animals, which result in significant ...economic losses in the swine industry. Vaccination has generally not been effective in the prevention of PRRS, partially because of the rapid mutation rate and evolution of the virus. The objective of the current study was to discover the genetic basis of host resistance or susceptibility to the PRRS virus through a genome-wide association study using data from the PRRS Host Genetics Consortium PRRS-CAP project. Three groups of approximately 190 commercial crossbred pigs from 1 breeding company were infected with PRRS virus between 18 and 28 d of age. Blood samples and BW were collected up to 42 d post infection (DPI). Pigs were genotyped with the Illumina Porcine 60k Beadchip. Whole-genome analysis focused on viremia at each day blood was collected and BW gains from 0 to 21 DPI (WG21) or 42 DPI (WG42). Viral load (VL) was quantified as area under the curve from 0 to 21 DPI. Heritabilities for WG42 and VL were moderate at 0.30 and litter accounted for an additional 14% of phenotypic variation. Genomic regions associated with VL were found on chromosomes 4 and X and on 1, 4, 7, and 17 for WG42. The 1-Mb region identified on chromosome 4 influenced both WG and VL, exhibited strong linkage disequilibrium, and explained 15.7% of the genetic variance for VL and 11.2% for WG42. Despite a genetic correlation of -0.46 between VL and WG42, genomic EBV for this region were favorably and nearly perfectly correlated. The favorable allele for the most significant SNP in this region had a frequency of 0.16 and estimated allele substitution effects were significant (P < 0.01) for each group when the SNP was fitted as a fixed covariate in a model that included random polygenic effects with overall estimates of -4.1 units for VL (phenotypic SD = 6.9) and 2.0 kg (phenotypic SD = 3 kg) for WG42. Candidate genes in this region on SSC4 include the interferon induced guanylate-binding protein gene family. In conclusion, host response to experimental PRRS virus challenge has a strong genetic component, and a QTL on chromosome 4 explains a substantial proportion of the genetic variance in the studied population. These results could have a major impact in the swine industry by enabling marker-assisted selection to reduce the impact of PRRS but need to be validated in additional populations.
Rifting of the continents leading to plate rupture occurs by a combination of mechanical deformation and magma intrusion, yet the spatial and temporal scales over which these alternate mechanisms ...localize extensional strain remain controversial. Here we quantify anisotropy of the upper crust across the volcanically active Afar Triple Junction using shear-wave splitting from local earthquakes to evaluate the distribution and orientation of strain in a region of continental breakup. The pattern of S-wave splitting in Afar is best explained by anisotropy from deformation-related structures, with the dramatic change in splitting parameters into the rift axis from the increased density of dyke-induced faulting combined with a contribution from oriented melt pockets near volcanic centres. The lack of rift-perpendicular anisotropy in the lithosphere, and corroborating geoscientific evidence of extension dominated by dyking, provide strong evidence that magma intrusion achieves the majority of plate opening in this zone of incipient plate rupture.
BACKGROUND Clinical and ultrasound experience has revealed that after soft tissue injections of the lateral cheek, the filler may displace from the zygoma to the caudal temporal area. OBJECTIVE To ...obtain more data to provide insight into product distribution when soft tissue fillers are injected in the zygomatic region. METHODS Two hundred patients were examined with facial ultrasound imaging of the zygomatic and temporal region. Inclusion criteria were simply a positive response on the screening questionnaire as to whether or not they had filler injections placed in their lateral cheek. Control injections were also performed to the zygomatic regions of a body donor and in 10 patients ultrasound-guided. RESULTS A correlation was found between the layers in which filler was detected on the zygoma and where it was ultimately found in the temples. Four different redistribution patterns were observed: (1) migration of filler within the superficial muscular aponeurotic system (SMAS) on the zygoma into the superficial temporal fascia. Migration of filler from the lateral suborbicularis oculi fat to (2) the deep interfacial plane of the temple or (3) to the superficial temporal fat pad; (4) migration from the supraperiosteal layer of the zygoma to the superficial temporal fat pad. Body donor and patients: filler deposits injected on the zygoma were witnessed to shift during injection into the caudal part of the temple. CONCLUSION Soft tissue filler aliquots may be redistributed into the temples after injections of the lateral side of the zygomatic arch. The displacement follows a distinct pattern depending on the initial layer of injection.
Summary
Infectious diseases are costly to the swine industry; porcine reproductive and respiratory syndrome (PRRS) is the most devastating. In earlier work, a quantitative trait locus associated with ...resistance/susceptibility to PRRS virus was identified on Sus scrofa chromosome 4 using approximately 560 experimentally infected animals from a commercial cross. The favorable genotype was associated with decreased virus load and increased weight gain (WG). The objective here was to validate and further characterize the association of the chromosome 4 region with PRRS resistance using data from two unrelated commercial crossbred populations. The validation populations consisted of two trials each of approximately 200 pigs sourced from different breeding companies that were infected with PRRS virus and followed for 42 days post‐infection. Across all five trials, heritability estimates were 0.39 and 0.34 for viral load (VL; area under the curve of log‐transformed viremia from 0 to 21 days post‐infection) and WG to 42 days post‐infection respectively. Effect estimates of SNP WUR10000125 in the chromosome 4 region were in the same directions and of similar magnitudes in the two new trials as had been observed in the first three trials. Across all five trials, the 1‐Mb region on chromosome 4 explained 15 percent of genetic variance for VL and 11 percent for WG. The effect of the favorable minor allele at SNP WUR10000125 was dominant. Ordered genotypes for SNP WUR10000125 showed that the effect was present irrespective of whether the favorable allele was paternally or maternally inherited. These results demonstrate that selection for host response to PRRS virus infection could reduce the economic impact of PRRS.
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