a critical look into stapedotomy learning curve influence of patient characteristics and different criteria defining success

Purpose: To evaluate stapedotomy learning curve with cumulative summation methodology using different success criteria (ie, air-bone gap [ABG] ≤10 dB, ABG ≤15 dB, restoration of interaural symmetry, or hearing threshold gain >20 dB), and to assess patient characteristics influencing or modifying the learning curve. Methods: Retrospective chart review of primary and revision stapedotomy cases performed by surgeon 1 (S1, n = 78) and surgeon 2 (S2, n = 85). Results: Using the classic criterion for a successful stapedotomy (ABG ≤10 dB), patients with preoperative ABG >34 dB were associated with unsuccessful procedures (S1 P = .02; S2 P = .07). Revision surgery was associated with unsuccessful outcomes (S1 P = .005; S2 P = .0012). Cumulative summation plots using different criteria did not show a linear trend of association between stapedotomy success and number of operations, but preoperative characteristics of the patients who underwent stapedotomy significantly influenced the plots. Cumulative summation plots showed an initial increasing tendency with improving results, but when ear surgeons got more skilled, they operated on more complex cases (ie, patients with higher preoperative ABG or revision stapedotomy) and they could not meet the success criteria. Conclusions: Cumulative summation plots do not seem useful to evaluate the stapedotomy learning curve, as they do not correctly deal with heterogeneous case series. The increasing complexity of the stapedotomy patients during the surgeons' career impacts on the outcome of stapedotomy and confounds the evaluation of the growing skills of the surgeon. Stapedotomy audiological success rates are strongly influenced by the success criteria used

Gene-expression of metastasized versus non-metastasized primary head and neck squamous cell carcinomas: A pathway-based analysis

Background: Regional lymph node metastasis is an important prognostic factor in head and neck squamous cell carcinoma (HNSCC) and plays a decisive role in the choice of treatment. Here, we present an independent gene expression validation study of metastasized versus non-metastasized HNSCC. Methods: We used a dataset recently published by Roepman et al. as reference dataset and an independent gene expression dataset of 11 metastasized and 11 non-metastasized HNSCC tumors as validation dataset. Reference and validation studies were performed on different microarray platforms with different probe sets and probe content. In addition to a supervised gene-based analysis, a supervised pathway-based analysis was performed, evaluating differences in gene expression for predefined tumorigenesis- and metastasis related gene sets. Results: The gene-based analysis showed 26 significant differentially expressed genes in the reference dataset, 21 of which were present on the microarray platform used in the validation study. 7 of these genes appeared to be significantly expressed in the validation dataset, but failed to pass the correction for multiple testing. The pathway-based analysis revealed 23 significant differentially expressed gene sets, 7 of which were statistically validated. These gene sets are involved in extracellular matrix remodeling (MMPs, MMP regulating pathways and the uPA system), hypoxia and angiogenesis (HIF1α regulated angiogenic factors and HIF1α regulated invasion). Conclusion: Pathways that are differentially expressed between metastasized and non-metastasized HNSCC are involved in the processes of extracellular matrix remodeling, hypoxia and angiogenesis. A supervised pathway-based analysis enhances the understanding of the biological context of the results, the comparability of results across different microarray studies, and reduces multiple testing problems by focusing on a limited number of pathways of interest instead of analyzing the large number of probes available on the microarray

Cochlear-optimized treatment planning in photon and proton radiosurgery for vestibular schwannoma patients

Objective: To investigate the potential to reduce the cochlear dose with robotic photon radiosurgery or intensity-modulated proton therapy planning for vestibular schwannomas. Materials and Methods: Clinically delivered photon radiosurgery treatment plans were compared to five cochlear-optimized plans: one photon and four proton plans (total of 120). A 1x12 Gy dose was prescribed. Photon plans were generated with Precision (Cyberknife, Accuray) with no PTV margin for set-up errors. Proton plans were generated using an in-house automated multi-criterial planning system with three or nine-beam arrangements, and applying 0 or 3 mm robustness for set-up errors during plan optimization and evaluation (and 3 % range robustness). The sample size was calculated based on a reduction of cochlear Dmean &gt; 1.5 Gy(RBE) from the clinical plans, and resulted in 24 patients. Results: Compared to the clinical photon plans, a reduction of cochlear Dmean &gt; 1.5 Gy(RBE) could be achieved in 11/24 cochlear-optimized photon plans, 4/24 and 6/24 cochlear-optimized proton plans without set-up robustness for three and nine-beam arrangement, respectively, and in 0/24 proton plans with set-up robustness. The cochlea could best be spared in cases with a distance between tumor and cochlea. Using nine proton beams resulted in a reduced dose to most organs at risk. Conclusion: Cochlear dose reduction is possible in vestibular schwannoma radiosurgery while maintaining tumor coverage, especially when the tumor is not adjacent to the cochlea. With current set-up robustness, proton therapy is capable of providing lower dose to organs at risk located distant to the tumor, but not for organs adjacent to it. Consequently, photon plans provided better cochlear sparing than proton plans.</p

Similar gene expression profiles of sporadic, PGL2-, and SDHD-linked paragangliomas suggest a common pathway to tumorigenesis

Contains fulltext : 81540.pdf (publisher's version ) (Open Access)BACKGROUND: Paragangliomas of the head and neck are highly vascular and usually clinically benign tumors arising in the paraganglia of the autonomic nervous system. A significant number of cases (10-50%) are proven to be familial. Multiple genes encoding subunits of the mitochondrial succinate-dehydrogenase (SDH) complex are associated with hereditary paraganglioma: SDHB, SDHC and SDHD. Furthermore, a hereditary paraganglioma family has been identified with linkage to the PGL2 locus on 11q13. No SDH genes are known to be located in the 11q13 region, and the exact gene defect has not yet been identified in this family. METHODS: We have performed a RNA expression microarray study in sporadic, SDHD- and PGL2-linked head and neck paragangliomas in order to identify potential differences in gene expression leading to tumorigenesis in these genetically defined paraganglioma subgroups. We have focused our analysis on pathways and functional gene-groups that are known to be associated with SDH function and paraganglioma tumorigenesis, i.e. metabolism, hypoxia, and angiogenesis related pathways. We also evaluated gene clusters of interest on chromosome 11 (i.e. the PGL2 locus on 11q13 and the imprinted region 11p15). RESULTS: We found remarkable similarity in overall gene expression profiles of SDHD -linked, PGL2-linked and sporadic paraganglioma. The supervised analysis on pathways implicated in PGL tumor formation also did not reveal significant differences in gene expression between these paraganglioma subgroups. Moreover, we were not able to detect differences in gene-expression of chromosome 11 regions of interest (i.e. 11q23, 11q13, 11p15). CONCLUSION: The similarity in gene-expression profiles suggests that PGL2, like SDHD, is involved in the functionality of the SDH complex, and that tumor formation in these subgroups involves the same pathways as in SDH linked paragangliomas. We were not able to clarify the exact identity of PGL2 on 11q13. The lack of differential gene-expression of chromosome 11 genes might indicate that chromosome 11 loss, as demonstrated in SDHD-linked paragangliomas, is an important feature in the formation of paragangliomas regardless of their genetic background.1 p

Recent advances in the genetics of SDH-related paraganglioma and pheochromocytoma

The last 10 years have seen enormous progress in the field of paraganglioma and pheochromocytoma genetics. The identification of the first gene related to paraganglioma, SDHD, encoding a subunit of mitochondrial succinate dehydrogenase (SDH), was quickly followed by the identification of mutations in SDHC and SDHB. Very recently several new SDH-related genes have been discovered. The SDHAF2 gene encodes an SDH co-factor related to the function of the SDHA subunit, and is currently exclusively associated with head and neck paragangliomas. SDHA itself has now also been identified as a paraganglioma gene, with the recent identification of the first mutation in a patient with extra-adrenal paraganglioma. Another SDH-related co-factor, SDHAF1, is not currently known to be a tumor suppressor, but may shed some light on the mechanisms of tumorigenesis. An entirely novel gene associated with adrenal pheochromocytoma, TMEM127, suggests that other new paraganglioma susceptibility genes may await discovery. In addition to these recent discoveries, new techniques related to mutation analysis, including genetic analysis algorithms, SDHB immunohistochemistry, and deletion analysis by MLPA have improved the efficiency and accuracy of genetic analysis. However, many intriguing questions remain, such as the striking differences in the clinical phenotype of genes that encode proteins with an apparently very close functional relationship, and the lack of expression of SDHD and SDHAF2 mutations when inherited via the maternal line. Little is still known of the origins and causes of truly sporadic tumors, and the role of oxygen in the relationships between high-altitude, familial and truly sporadic paragangliomas remains to be elucidated

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Cochlear Implantation in Adults with Asymmetric Hearing Loss: Benefits of Bimodal Stimulation

Objective: This study addresses the outcome of cochlear implantation in addition to hearing aid use in patients with asymmetric sensorineural hearing loss. Study Design: Prospective longitudinal study. Setting: Tertiary referral center. Patients: Seven adults with asymmetric sensorineural hearing loss, i.e., less than 30% aided speech recognition in their worst hearing ear and 60 to 85% speech recognition in their best hearing ear. All patients had a postlingual onset of their hearing loss and less than 20 years of auditory deprivation of their worst hearing ear. Intervention: Cochlear implantation in the functionally deaf ear. Main Outcome Measures: Speech recognition in quiet, speech recognition in noise, spatial speech recognition, localization abilities, music appreciation, and quality of life. Measurements were performed before cochlear implantation and 3, 6, and 12 months after cochlear implantation. Results: Before cochlear implantation, the average speech recognition of the ear fitted with a hearing aid was 74%. Cochlear implantation eventually resulted in an average speech recognition of 75%. Bimodal stimulation yielded speech recognition scores of 82, 86, and 88% after 3, 6, and 12 months, respectively. At all time intervals, bimodal stimulation resulted in a significantly better speech recognition as compared with stimulation with only hearing aid or only cochlear implant (CI). Speech recognition in noise and spatial speech recognition significantly improved as well as the ability to localize sounds and the quality of life. Conclusion: This study demonstrated that patients are able to successfully integrate electrical stimulation with contralateral acoustic amplification and benefit from bimodal stimulation. Therefore, we think that cochlear implantation should be considered in this particular group of patients, even in the presence of substantial residual hearing on the contralateral side

Chemisorption working capacity and kinetics of CO2 and H2O of hydrotalcite-based adsorbents for sorption-enhanced water-gas-shift applications

The adsorption behavior of carbon dioxide and water on a K-promoted hydrotalcite based adsorbent has been studied by thermogravimetric analysis with the aim to better understand the kinetic behavior and mechanism of such material in sorption enhanced water-gas shift reactions. The cyclic adsorption capacity was measured as a function of temperature (300–500 °C), pressure (0–8 bar) and the cycle time. Both species interact at elevated temperatures with the adsorbent. The history of the adsorbent (pretreatment/desorption conditions) has a profound influence on its sorption capacity. Slow desorption kinetics determine the sorption capacity during cyclic operation, where a high temperature during the desorption and long half-cycle times can increase the cyclic working capacity for both CO2 and H2O significantly. Accounting for the sorbent history and the definition of adsorption capacity are very important features when comparing sorption capacities to values reported in literature. The adsorbent shows very high capacities for H2O compared to CO2 which has not been reported in the literature up to now. The mechanism for H2O and CO2 adsorption seems to be a different one. Whereas H2O adsorption seems to follow the principles of a simple physisorption mechanism, CO2 adsorption can only be explained by a chemical reaction with the adsorbent. Working isotherms (cyclic working capacity at isothermal conditions at different pressures) of both CO2 and H2O were measured up to 8 bar total pressure. Higher partial pressures increase the cyclic working capacity of the adsorbent up to 0.47 mmol/g for CO2View the MathML source(PCO2=8bar) and 1.06 mmol/g for H2O (View the MathML sourcePH2O=4.2bar) at 400 °C after 30 min of adsorption followed by 30 min of dry regeneration with N2