Intraoperative round window electrocochleography and speech perception outcomes in pediatric cochlear implant recipients.

OBJECTIVES: The goal was to measure the magnitude of cochlear responses to sound in pediatric cochlear implant recipients at the time of implantation and to correlate this magnitude with subsequent speech perception outcomes. DESIGN: A longitudinal cohort study of pediatric cochlear implant recipients was undertaken. Intraoperative electrocochleographic (ECoG) recordings were obtained from the round window in response to a frequency series at 90 dB nHL in 77 children totaling 89 ears (12 were second side surgeries) just before device insertion. The increase in intraoperative time was approximately 10 min. An ECoG "total response" metric was derived from the summed magnitudes of significant responses to the first, second, and third harmonics across a series of frequencies. A subset of these children reached at least 9 months of implant use and were old enough for the phonetically balanced kindergarten (PB-k) word test to be administered (n = 26 subjects and 28 ears). PB-k scores were compared to the ECoG total response and other biologic and audiologic variables using univariate and multiple linear regression analyses. RESULTS: ECoG responses were measurable in almost all ears (87 of 89). The range of ECoG total response covered about 60 dB (from ~0.05 to 50 µV). Analyzing individual ECoG recordings in bilaterally implanted children revealed poor concordance between the measured response in the first versus second ear implanted (r = 0.21; p = 0.13; n = 12). In a univariate linear regression, the ECoG total response was significantly correlated with PB-k scores in the subset of 26 subjects who were able to be tested and accounted for 32% of the variance (p = 0.002, n = 28). Preoperative pure-tone average (PTA) accounted for slightly more of the variance (r = 0.37, p = 0.001). However, ECoG total response and PTA were significantly but only weakly correlated (r = 0.14, p = 0.001). Other significant predictors of speech performance included hearing stability (stable versus progressive) and age at testing (22 and 16% of the variance, respectively). In multivariate analyses with these four factors, the ECoG accounted for the most weight (ß = 0.36), followed by PTA (ß = 0.26). In a hierarchical multiple regression analysis, the most parsimonious models that best predicted speech perception outcomes included three variables: ECoG total response, and any two of preoperative PTA, age at testing, or hearing stability. The various three factor models each predicted approximately 50% of the variance in word scores. Without the ECoG total response, the other three factors predicted 36% of variance. CONCLUSIONS: Intraoperative round window ECoG recordings are reliably and easily obtained in pediatric cochlear implant recipients. The ECoG total response is significantly correlated with speech perception outcomes in pediatric implant recipients and can account for a comparable or greater proportion of variance in speech perception than other bio-audiologic factors. Intraoperative recordings can potentially provide useful prognostic information about acquisition of open set speech perception in implanted children.

The totality of evidence approach in the development of AVT02 (adalimumab), a biosimilar to Humira.

The development of a biosimilar is based on comparative structural, physicochemical, functional and clinical assessments. The sum of these analyses encompasses the 'totality of evidence', which demonstrates no clinically meaningful differences between the biosimilar and the reference product (RP). Once biosimilarity has been established, provided there is suitable scientific justification, clinical data may be extrapolated to other indications of the RP. AVT02 has been developed as a biosimilar to high-concentration, low-volume Humira (adalimumab), an anti-tumour necrosis factor-alpha monoclonal antibody approved for various chronic inflammatory indications. The totality of evidence for AVT02 is described, supporting its approval as an adalimumab biosimilar for all approved indications globally. Analytical similarity assessments using mass spectrometry methods demonstrated identical amino acid sequences for AVT02 and the RP, with high similarity in terms of primary structure, post-translational modifications and higher-order structural attributes. The mechanism of action was assessed by various cell-based potency assays and binding assays, and the results demonstrated that AVT02 is highly similar to the RP. No clinically meaningful differences in terms of purity, potency and safety were observed, and minor differences in a few physiochemical attributes did not impact the in vitro biologic activity and were not considered clinically relevant. Clinical similarity was demonstrated by comparing the pharmacokinetic, efficacy, safety and immunogenicity profiles of AVT02 with those of the RP. Clinical studies supported similar pharmacokinetic and comparable immunogenicity profiles between AVT02 and the RP in healthy participants and participants with moderate-to-severe chronic plaque psoriasis, with no new safety signals detected. The totality of evidence described demonstrates the biosimilarity of AVT02 to the RP, thereby fulfilling the scientific and regulatory requirements for AVT02 as a high-concentration biosimilar for the treatment of chronic plaque psoriasis and all approved indications of the RP.

Demonstrating the high similarity between the biosimilar AVT02 (adalimumab) and Humira, supporting AVT02 to be used to treat all conditions currently treated with Humira Biosimilars are drugs that have similar quality, effectiveness, and safety profiles to an already approved biological drug, which is referred to as the 'reference product (RP)'. Although biosimilars have identical amino acids (the building blocks that make up proteins) to the RPs, they are manufactured in living cells which leads to a small amount of natural variability. Therefore, extensive testing is required to confirm that a biosimilar is highly similar to the RP. The 'totality of evidence' is a set of tests to demonstrate that there are no meaningful differences between the biosimilar and the RP, in other words, that there is 'biosimilarity' between the biosimilar and RP. Once biosimilarity has been proven, the biosimilar may be used to treat all the diseases currently treated with the RP, without the need for separate clinical trials in each disease. AVT02 has been developed as a biosimilar to Humira, an antibody approved for various chronic inflammatory diseases such as chronic plaque psoriasis (PsO). A step-by-step approach was used to show biosimilarity of AVT02 to Humira. This included clinical studies (in healthy individuals and participants with moderate to severe chronic PsO) and non-clinical studies (comparisons of the chemistry of the drugs and how they work in the body). Clinical studies in healthy individuals and participants with PsO showed that AVT02 and Humira were taken up and degraded by the body in a similar way, peoples' immune response to the two drugs were similar, and both drugs had similar side effects. No clinically meaningful differences in the purity, effectiveness, and safety of AVT02 compared with Humira were seen. The evidence demonstrates the biosimilarity of AVT02 to Humira and supports the use of AVT02 to treat all conditions which are currently treated with Humira.

Effect of Cochlear Implantation on the Endocochlear Potential and Stria Vascularis.

HYPOTHESIS: Animals with cochlear implantation-induced hearing loss will have a lower endocochlear potential (EP) and decreased strial vascular density. BACKGROUND: The cause of residual hearing loss following cochlear implantation remains poorly understood. Recent work from our lab has shown a correlation between vascular changes in the cochlear lateral wall and postimplantation hearing loss, suggesting a role of the stria vascularis and EP. METHODS: Fourteen young, normal-hearing male albino guinea pigs underwent cochlear implantation using either a cochleostomy (CI-c, n = 9) or an extended round window (CI-eRW, n = 5) approach. Hearing sensitivity was assessed pre- and postoperatively using auditory brainstem response thresholds. Three weeks after implantation, EP measurements were obtained from the first and second turns. Hair cell counts and stria vascularis capillary density measurements were also obtained. RESULTS: The implanted group experienced significant threshold elevations at 8 to 24 kHz (mean threshold shift 9.1 ±â€Š1.1 dB), with a more robust threshold shift observed in the CI-eRW group compared to the CI-c group. Implanted animals had a significantly lower first turn EP (81.4 ±â€Š5.1 mV) compared with controls (87.9 ±â€Š6.1 mV). No differences were observed in the second turn (75.8 ±â€Š12.0 mV for implanted animals compared to 76.5 ±â€Š7.0 mV for controls). There were no significant correlations between turn-specific threshold shifts, EP measurements, or strial blood vessel density. CONCLUSIONS: Reliable EP measurements can be obtained in chronically implanted guinea pigs. Hearing loss after implantation is not explained by changes in strial vascular density or reductions in EP.

Stapes Surgery Outcomes in Patients With Concurrent Otosclerosis and Superior Semicircular Canal Dehiscence.

OBJECTIVE: To review outcomes of stapes surgery in patients with concurrent otosclerosis and superior semicircular canal dehiscence. STUDY DESIGN: Retrospective case series. SETTING: Tertiary referral center. PATIENTS: Patients with concurrent otosclerosis and superior canal dehiscence, confirmed by computed tomography (CT) imaging. INTERVENTION(S): Stapes surgery for conductive hearing loss. MAIN OUTCOME MEASURE(S): Postoperative air-bone gap (ABG), as well as the number of patients in whom surgery was deemed successful (postoperative ABG <10 dB HL). RESULTS: Five patients with superior canal dehiscence and concomitant otosclerosis who underwent surgical repair were identified. Mean preoperative ABG was 29.0 ±â€Š6.4 dB HL. Mean postoperative ABG was 13.0 ±â€Š13 dB HL. Three patients (60%) had a successful outcome, defined as postoperative ABG less than 10. One patient experienced unmasking of superior canal dehiscence vestibular symptoms. CONCLUSIONS: Patients with concurrent otosclerosis and superior canal dehiscence appear to have a lower likelihood of successful hearing restoration following stapes surgery. Patients should be counseled accordingly. Routine preoperative CT imaging before stapes surgery may be helpful to identify patients at risk for poor outcomes.

The 'totality-of-the-evidence' approach in the development of PF-06438179/GP1111, an infliximab biosimilar, and in support of its use in all indications of the reference product.

The 'totality-of-the-evidence' biosimilarity concept requires that sufficient structural, functional, nonclinical, and clinical data are acquired in a stepwise manner, to demonstrate that no clinically meaningful differences in quality, safety, or efficacy are observed compared with the reference product. We describe the totality of the evidence for PF-06438179/GP1111 (PF-SZ-IFX; IXIFI™ [infliximab-qbtx]/Zessly®) that supported its approval as an infliximab (IFX) biosimilar for all eligible indications of reference IFX (ref-IFX; Remicade®) in Europe and in the US. Analytical similarity involving in vitro assays capable of distinguishing structural or functional differences between PF-SZ-IFX and ref-IFX formed a foundation for the biosimilarity exercise. Differences identified in N-glycosylation and charge heterogeneity were found not to impact the results in in vitro biological assays reflective of the pharmacology underlying the mechanisms of action (tumor necrosis factor binding, reverse signaling, antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity) of IFX across disease indications. Similarity was assessed in a comparative clinical pharmacokinetic study and in a clinical efficacy and safety study in patients with rheumatoid arthritis, where therapeutic equivalence between PF-SZ-IFX and ref-IFX provided confirmatory evidence of biosimilarity, and, when coupled with the analytical similarity already established, supported extrapolation to all eligible disease indications of ref-IFX.

Small bowel obstruction after transoral robotic surgery.

BACKGROUND: Head and neck surgery is not often considered a risk factor for intestinal ileus and small bowel obstruction. However, many of these patients may have had prior abdominal surgery, a known risk factor for small bowel obstruction, and may be at risk for bowel obstruction after a surgical procedure of the head and neck. METHODS: We present a case describing a patient who, after undergoing transoral robotic surgery, experienced delayed postoperative ileus and eventual small bowel obstruction requiring exploratory laparotomy and bowel resection. RESULTS: Although the patient required total parenteral nutrition for several days, he eventually was able to resume tube feeds, and after several months was able to tolerate an oral diet. CONCLUSION: Although uncommon complications of head and neck surgery, intestinal ileus and small bowel obstruction can develop as the result of stress/inflammation, postoperative narcotic pain medication, and prior abdominal surgery.

A randomized study comparing the pharmacokinetics of the potential biosimilar PF-06438179/GP1111 with Remicade® (infliximab) in healthy subjects (REFLECTIONS B537-01).

BACKGROUND: To demonstrate pharmacokinetic (PK) similarity of PF-06438179/GP1111, a potential biosimilar to Remicade®, to Remicade® sourced from European Union (infliximab-EU) and United States (infliximab-US), and of infliximab-EU to infliximab-US. METHODS: In this phase I, parallel-group, three-arm trial, healthy adult subjects were randomized to receive a single 10-mg/kg intravenous infusion of PF-06438179/GP1111, infliximab-EU, or infliximab-US. PK, and safety and immunogenicity evaluations were performed over 8 and 12 weeks, respectively. PK similarity was established if the 90% confidence intervals (CIs) of the test-to-reference ratios for PK parameters, Cmax, AUCT, and AUCinf, were within the 80.00-125.00% pre-specified equivalence window. RESULTS: Of 151 subjects randomized, 146 received study treatment; 130 were eligible for PK similarity assessment. Serum concentration-time profiles were similar across the three treatments. The 90% CIs for test-to-reference ratios for Cmax, AUCT, and AUCinf were within 80.00-125.00% for comparison of PF-06438179/GP1111 to infliximab-EU and infliximab-US, and of infliximab-EU to infliximab-US. Similar numbers of subjects across treatment groups experienced adverse events. Anti-drug and neutralizing antibody profiles were largely similar among groups. CONCLUSIONS: This study demonstrated PK similarity of PF-06438179/GP1111 to infliximab-EU and infliximab-US, and of infliximab-EU to infliximab-US. All three products displayed comparable safety and immunogenicity profiles. TRIAL REGISTRATION: CT.gov identifier NCT01844804.

Development of biosimilars.

OBJECTIVE: To provide an overview of the underlying scientific principles and standards for developing a biosimilar product. METHODS: An Internet-based literature search through June 2015 was performed for information related to biosimilar manufacturing and development, including a review of regulatory guidelines and requirements. RESULTS: Biologics, both biosimilars and their corresponding reference products, are complex molecules produced by biotechnology in living systems. The development of biologics involves multiple levels of intricate, highly controlled manufacturing processes, combined with pre-clinical structural, functional, and biological assessments, as well as clinical efficacy and safety, including immunogenicity, analyses. In addition, to ensure a high degree of similarity, a biosimilar must undergo a comparability exercise at every step of its development, as outlined by regulatory agencies, to demonstrate that potential differences from the reference product are not clinically meaningful with regard to quality, safety, and efficacy [European Medicines Agency (EMA)] or safety, purity, and potency [US Food and Drug Administration (FDA)]. At the foundation of the biosimilar development process lays the establishment of a high degree of structural similarity with its reference product. State-of-the-art technologies must be employed to demonstrate a high degree of structural and functional similarity. Finally, clinical pharmacokinetic and pharmacodynamic as well as clinical efficacy and safety similarity must be confirmed between biosimilar and originator. Regulators, including the FDA and the EMA consider the totality of the evidence from this comprehensive step-wise comparative similarity exercise in its determination of biosimilarity for licensing. CONCLUSIONS: The rigorous and highly regulated processes required to develop a biosimilar have been designed as such to establish a high degree of biosimilarity with a reference product in terms of the structural, functional, biological, and clinical attributes.

Round window electrocochleography and speech perception outcomes in adult cochlear implant subjects: comparison with audiometric and biographical information.

HYPOTHESIS: Intraoperative round window (RW) electrocochleography (ECoG) can help predict speech perception outcomes in adult cochlear implant (CI) recipients. BACKGROUND: Speech perception outcomes using CIs are highly variable. Recent data demonstrated that intraoperative ECoG could account for nearly half the variance in postoperative word scores. The present study seeks to update this correlation with a larger sample size and determine if addition of clinical variables improves the prediction. METHODS: Intraoperative RW ECoG was performed in adult subjects undergoing CI. Amplitudes of the ongoing response to tone bursts of multiple frequencies at 85 to 95 dB HL were summed to obtain the total response (ECoG-TR). ECoG-TR was correlated with postoperative speech perception scores. Multiple linear regression was used to combine clinical factors with the ECoG-TR. RESULTS: The ECoG-TR accounted for 40% of the variance in CNC word scores (n = 32). The preoperative pure tone average (PTA) was the only clinical factor with a significant correlation (r² = 20%). The ability to predict word scores using ECoG-TR and PTA, or after addition of age and duration of hearing loss, was not significantly different from using ECoG-TR alone. For 2 outliers, ECoG-TR predicted a better word score than obtained. CONCLUSIONS: The measurement of cochlear physiology before CI, reduced to a single variable, is a better predictor of postoperative speech perception than common clinical factors. Additional analysis of the outliers showed that waveform morphology can provide distinct information in individual cases.

Triggering a cell shape change by exploiting preexisting actomyosin contractions.

Apical constriction changes cell shapes, driving critical morphogenetic events, including gastrulation in diverse organisms and neural tube closure in vertebrates. Apical constriction is thought to be triggered by contraction of apical actomyosin networks. We found that apical actomyosin contractions began before cell shape changes in both Caenorhabitis elegans and Drosophila. In C. elegans, actomyosin networks were initially dynamic, contracting and generating cortical tension without substantial shrinking of apical surfaces. Apical cell-cell contact zones and actomyosin only later moved increasingly in concert, with no detectable change in actomyosin dynamics or cortical tension. Thus, apical constriction appears to be triggered not by a change in cortical tension, but by dynamic linking of apical cell-cell contact zones to an already contractile apical cortex.

Parent and neutral loss monitoring on a quadrupole ion trap mass spectrometer: screening of acylcarnitines in complex mixtures.

A novel and practical technique for performing both parent and neutral loss (P&NL) monitoring experiments on a quadrupole ion trap mass spectrometer is presented. This technique is capable of performing scans analogous to the parent and neutral loss scans routinely applied on tandem-in-space instruments and allows for the screening of a sample to detect analytes of a specific compound class on a chromatographic time-scale. Acylcarnitines were chosen as the model compound class to demonstrate the analytical utility of P&NL monitoring because of their amenability to electrospray ionization (ESI), their unique and informative MS/MS fragmentation pattern, and their importance in biological functions. The [M + H]+ ions of all acylcarnitines dissociate to produce neutral losses of 59 and 161 amu and common product ions at m/z 60, 85, and 144. Both the neutral loss monitoring of 59 amu and the parent ion monitoring of m/z 85 are shown to be capable of identifying acylcarnitine [M + H]+ ions in a synthetic mixture and spiked pig plasma. The neutral loss monitoring of 59 amu is successful in detecting acylcarnitines in an unspiked pig plasma sample.

Effects of fragile ions on mass resolution and on isolation for tandem mass spectrometry in the quadrupole ion trap mass spectrometer.

In the quadrupole ion trap, it has been noted that factors other than an ion's mass and charge may affect its measured m/z, resulting in compound-dependent, or "chemical", mass shifts. We propose that ions can exhibit a chemical mass shift because they are "fragile" and may fragment during the application of resonance ejection during mass analysis; these effects were studied using ions that include protonated, deprotonated, and adduct ions of explosives, acylcarnitines, and macrolide antibiotics. Fragile ions affect mass resolution by causing broader peaks than nonfragile ions, especially at slower scan speeds, as the result of the application of resonance ejection. Fragile ions may also be fragmented by the application of the isolation waveform during selection of the parent ion for tandem mass spectrometry experiments, making it impossible to achieve unit isolation of a fragile ion. To obtain adequate isolation intensity, the isolation waveform notch width must be increased and the time period of isolation must be decreased. Fragile ions also require lower optimum collision energy to achieve efficient collision-induced dissociation. We have developed criteria for the determination of the degree of ion fragility based upon experimental results.

Influence of charge state on product ion mass spectra and the determination of 4S/6S sulfation sequence of chondroitin sulfate oligosaccharides.

Electrospray ionization-Fourier transform ion cyclotron resonance tandem mass spectrometry is used to study the influence of charge state on the product ion spectra of chondroitin sulfate oligosaccharides for determination of the sulfate position on N-acetylgalactosamine residues. Sustained off-resonance irradiation collision-induced dissociation and infrared multiphoton dissociation are investigated for tandem mass spectrometry of chondroitin sulfate. Product ion spectra were obtained for ions of varying charge states from (4,5)-unsaturated (delta-unsaturated), reduced delta-unsaturated, and saturated oligosaccharides from chondroitin sulfate A and chondroitin sulfate C, separately. It was observed that ions in which the charge (z) is less than the number of sulfates dissociate to produce predominantly even-numbered B(n), C(n), Y(n), and Z(n) ions, and that odd-numbered fragment ions are observed for ions that have z equal to the number of sulfates. Sulfate adducted ions were observed in the product ion spectra of singly charged tetramer and hexamer oligosaccharides. This sulfate adduction was determined to result from migration of neutral sulfate during excitation.

The measurement of extravascular lung density with SPECT imaging and its relationship with ventilatory abnormalities in patients with congestive heart failure.

BACKGROUND: Patients with congestive heart failure (CHF) have increased ventilatory equivalent for carbon dioxide (Ve/VCO(2)), which may contribute to the symptom of exercise-induced hyperpnea. We have developed a technique in which simultaneous blood volume single photon emission computed tomography imaging and transmission tomography are used to measure extravascular lung density (ELD). We investigated the correlation between Ve/VCO(2) and ELD in patients with CHF. METHODS AND RESULTS: Thirteen patients with stable CHF and eleven control subjects were studied. Attenuation-corrected blood volume emission tomography was acquired with simultaneous transmission tomography to measure pulmonary blood volume and total lung density, respectively. Seven CHF patients underwent maximal exercise treadmill testing with online respiratory gas analysis. ELD was calculated as total lung density minus pulmonary blood volume. SPECT and transmission tomography were repeated immediately after exercise. CHF patients had significantly higher total lung density and ELD compared with normal subjects. No differences in pulmonary blood volume were observed. There was a significant inverse correlation between ELD and left ventricular ejection fraction at rest in CHF patients (r = -0.77, P <.001). A strong correlation was also found between post-exercise ELD and Ve/VCO(2) at peak exercise (r = 0.74, P =.008) and at anaerobic threshold (r = 0.67, P =.024). CONCLUSION: Patients with chronic CHF have increased ELD. The correlation between ELD and Ve/VCO(2) suggests that increased lung water may contribute to the ventilatory abnormalities seen in patients with CHF.