Interleukin-17A (IL-17A) is involved in antibody specificity to conformational epitopes.

The specificity of antibodies (Ab) is essential for the precise recognition of foreign or dangerous molecules. We have shown that mice infected with non-pathogenic Lactate Dehydrogenase Elevating Virus (LDV) inoculated with human growth hormone (hGH) or Ovalbumin (OVA), exhibit modified specificity of anti-hGH or anti-OVA Ab associated with the secretion of IFN-γ, IL-13, and IL-17. Cytokines are directly or indirectly involved in the isotypes, specificity, and affinity of Ab. Accordingly, here we investigated the effect of IL-17 neutralization on Ab specificities to OVA and Diphtheria Toxoid (DTx) in a mouse model of viral infection. Thereby, we employed an anti-cytokine "auto-vaccination" with an OVA/IL-17A complex or a Monoclonal Ab (MAb) anti-IL-17A (MM17/F3). Competitive ELISA assays were used to estimate the quality of the humoral immune response and the amount of Abs to conformational versus linear antigenic determinants. Results indicated that the OVA/IL-17A complex increased Abs levels to conformational epitopes of OVA, while LDV prolonged antibodies for a longer period. Mice treated with MM17F3 MAb showed an increase in Abs to conformational epitopes of OVA. A similar effect, confirmed by a competitive Western-blot assay, was produced by LDV. Moreover, an increased level of IgM, IgG1, and IgG2a was found in infected animals. Similarly, MAb anti-IL-17A treatment increased the proportion of Ab to conformational epitopes of DTx in uninfected mice, while LDV decreased this parameter. In conclusion, our findings demonstrate a correlation between IL-17A neutralization and a change in Ab specificity to OVA or DTx, presenting a novel strategy for obtaining Abs with higher specificity.

The LD-V: An innovative formula for latissimus dorsi flap volume assessment.

BACKGROUND: Latissimus Dorsi (LD) flap is at present among the best techniques for autologous breast reconstruction. A reliable pre-operatory estimation of flap volume would enhance surgical planning, thus improving the aesthetic outcomes of the reconstruction and reducing the need of secondary revision procedures. The study was aimed at providing a simple and reproducible formula to predict LD flap volume pre-operatively. METHODS: 61 patients (66 flaps) who underwent breast reconstruction with LD flap at Policlinico Tor Vergata were prospectively enroled in the study. Anthropometric data and flap measurements were collected pre-operatively. LD flap volume was determined intraoperatively utilising a water displacement technique. A multivariate regression analysis was performed to analyse the collected data and to obtain the mathematical model that most accurately predicts flap volume. RESULTS: The mean actual LD flap volume calculated through water displacement was 213.14 cc (SD 64.56). Performing a multivariate regression analysis BMI and skin paddle width emerged as the most accurate predictors of Latissimus Dorsi flap volume. The mean predicted LD flap volume (LD-V) using the LD-V formula was 213.19 cc (SD 54.59), with a strong Pearson correlation (r = 0.845; R2 =0.715) with the volume calculated through the water displacement technique. CONCLUSIONS: The LD-V formula is an easy and reliable tool for LD flap volume assessment, available as 3.0 WebApp at www.braflap.com, that can be used as a valuable adjunct to surgeon's subjective evaluation to optimise breast reconstruction with the LD flap. LEVEL OF EVIDENCE: II.

Coupled membranes: a mechanism of frequency filtering and transmission in the field cricket ear evidenced by micro-computed tomography, laser Doppler vibrometry and finite element analysis.

Many animals employ a second frequency filter beyond the initial filtering of the eardrum (or tympanal membrane). In the field cricket ear, both the filtering mechanism and the transmission path from the posterior tympanal membrane (PTM) have remained unclear. A mismatch between PTM vibrations and sensilla tuning has prompted speculations of a second filter. PTM coupling to the tracheal branches is suggested to support a transmission pathway. Here, we present three independent lines of evidence converging on the same conclusion: the existence of a series of linked membranes with distinct resonant frequencies serving both filtering and transmission functions. Micro-computed tomography (µ-CT) highlighted the 'dividing membrane (DivM)', separating the tracheal branches and connected to the PTM via the dorsal membrane of the posterior tracheal branch (DM-PTB). Thickness analysis showed the DivM to share significant thinness similarity with the PTM. Laser Doppler vibrometry indicated the first of two PTM vibrational peaks, at 6 and 14 kHz, originates not from the PTM but from the coupled DM-PTB. This result was corroborated by µ-CT-based finite element analysis. These findings clarify further the biophysical source of neuroethological pathways in what is an important model of behavioural neuroscience. Tuned microscale coupled membranes may also hold biomimetic relevance.

Characterization and apportionment of carbonaceous aerosol emission factors from light-duty and heavy-duty vehicle fleets in Maharashtra, India.

This study aims to investigate the characteristics of carbonaceous aerosols and estimate emission factor (EF) based on roadway tunnel measurements, from two distinct vehicular fleets: an all light-duty vehicle (LDV) fleet, and a mixed fleet of 80% LDV and 20% heavy-duty vehicle (HDV). Carbonaceous content (organic carbon: OC and elemental carbon: EC) in total fine particles (PM2.5) accounted for 41% ± 6.8% in LDV fleet and 48% ± 7.2% in mixed fleet. While higher volatile OC dominated in the LDV fleet emissions, in mixed fleet, lower volatile OC and EC emissions dominated due to the presence of higher HDV and super-emitter (SE) fractions which led to significantly higher optically active absorbing aerosols. Reconstructed HDV fleet EF was higher than LDV fleet by 36 times (PM2.5), 19 times (OC) and 51 times (EC). Our findings emphasize the significance of implementing vehicle inspection and maintenance programs, coupled with decarbonization of HDVs to mitigate on-road vehicular emissions in India.

Safety and efficacy of cataract surgery performed with a low-energy femtosecond laser compared with conventional phacoemulsification in Chinese patients: a randomized clinical trial.

BACKGROUND: To compare the safety and efficacy of femtosecond laser-assisted cataract surgery (FLACS) performed with the low-energy FEMTO LDV Z8 (Ziemer Ophthalmic Systems AG, Port, Switzerland) laser compared with conventional phacoemulsification (CP) in Chinese patients. METHODS: This prospective, multicenter, interventional study included 126 patients who were randomized (1:1) to undergo either FLACS or CP followed by intraocular lens (IOL) implantation between January 2019 and April 2020. The primary endpoint included the comparison of the endothelial cell loss (ECL) between the two groups at 3 months. Secondary endpoints included the comparison of cumulative dissipated energy (CDE), change in central corneal thickness (CCT) from baseline, and postoperative uncorrected and corrected distance visual acuities (UDVA and CDVA) in the two groups. RESULTS: At all postoperative time points, the FLACS group was found to be non-inferior to CP for the mean ECL (- 409.3 versus - 436.9 cells/mm2 at 3 months) and mean CDE (4.1 versus 4.5 percent-seconds). The increase in CCT was significantly lower in the FLACS group compared with the CP group at Day 7 (4.9 versus 9.2 µm; P = 0.04); however, the difference was not statistically significant at 1 and 3 months. Postoperatively, mean UDVA and CDVA were comparable between the two groups. No intraoperative complications occurred. CONCLUSIONS: Cataract surgery performed with a low-energy femtosecond laser was non-inferior to CP; however, the FLACS group had a statistically significantly lower increase in CCT at Day 7 compared with CP. Trial registration This trial is registered at ClinicalTrials.gov on May 15, 2019, with trial registration number: NCT03953053.

Intracochlear pressure and temporal bone motion interaction under bone conduction stimulation.

BACKGROUND: Under bone conduction (BC) stimulation, the otic capsule, and surrounding temporal bone, undergoes a complex 3-dimentional (3D) motion that depends on the frequency, location and coupling of the stimulation. The correlation between the resultant intracochlear pressure difference across the cochlear partition and the 3D motion of the otic capsule is not yet known and is to be investigated. METHODS: Experiments were conducted in 3 fresh frozen cadaver heads, individually on each temporal bone, resulting in a total of 6 samples. The skull bone was stimulated, via the actuator of a BC hearing aid (BCHA), in the frequency range of 0.1-20 kHz. Stimulation was applied at the ipsilateral mastoid and the classical BAHA location via a conventional transcutaneous (5-N steel headband) and percutaneous coupling, sequentially. Three-dimensional motions were measured across the lateral and medial (intracranial) surfaces of the skull, the ipsilateral temporal bone, the skull base, as well as the promontory and stapes. Each measurement consisted of 130-200 measurement points (∼5-10 mm pitch) across the measured skull surface. Additionally, intracochlear pressure in the scala tympani and scala vestibuli was measured via a custom-made intracochlear acoustic receiver. RESULTS: While there were limited differences in the magnitude of the motion across the skull base, there were major differences in the deformation of different sections of the skull. Specifically, the bone near the otic capsule remained primarily rigid across all test frequency (above 10 kHz), in contrast to the skull base, which deformed above 1-2 kHz. Above 1 kHz, the ratio, between the differential intracochlear pressure and the promontory motion, was relatively independent of coupling and stimulation location. Similarly, the stimulation direction appears to have no influence on the cochlear response, above 1 kHz. CONCLUSIONS: The area around the otic capsule appears rigid up to significantly higher frequencies than the rest of the skull surface, resulting in primarily inertial loading of the cochlear fluid. Further work should be focused at the investigation of the solid-fluid interaction between the bony walls of the otic capsule and the cochlear contents.

Lead Zirconate Titanate Transducers Embedded in Composite Laminates: The Influence of the Integration Method on Ultrasound Transduction.

In the context of an embedded structural health monitoring (SHM) system, two methods of transducer integration into the core of a laminate carbon fiber-reinforced polymer (CFRP) are tested: cut-out and between two plies. This study focuses on the effect of integration methods on Lamb wave generation. For this purpose, plates with an embedded lead zirconate titanate (PZT) transducer are cured in an autoclave. The embedded PZT insulation, integrity, and ability to generate Lamb waves are checked with electromechanical impedance, X-rays, and laser Doppler vibrometry (LDV) measurements. Lamb wave dispersion curves are computed by LDV using two-dimensional fast Fourier transform (Bi-FFT) to study the quasi-antisymmetric mode (qA0) excitability in generation with the embedded PZT in the frequency range of 30 to 200 kHz. The embedded PZT is able to generate Lamb waves, which validate the integration procedure. The first minimum frequency of the embedded PZT shifts to lower frequencies and its amplitude is reduced compared to a surface-mounted PZT.

Single-Point and Surface Quality Assessment Algorithm in Continuous Production with the Use of 3D Laser Doppler Scanning Vibrometry System.

In the current economic situation of many companies, the need to reduce production time is a critical element. However, this cannot usually be carried out with a decrease in the quality of the final product. This article presents a possible solution for reducing the time needed for quality management. With the use of modern solutions such as optical measurement systems, quality control can be performed without additional stoppage time. In the case of single-point measurement with the Laser Doppler Vibrometer, the measurement can be performed quickly in a matter of milliseconds for each product. This article presents an example of such quality assurance measurements, with the use of fully non-contact methods, together with a proposed evaluation criterion for quality assessment. The proposed quality assurance algorithm allows the comparison of each of the products' modal responses with the ideal template and stores this information in the cloud, e.g., in the company's supervisory system. This makes the presented 3D Laser Vibrometry System an advanced instrumentation and data acquisition system which is the perfect application in the case of a factory quality management system based on the Industry 4.0 concept.

Efficacy of a new fragmentation pattern in femtosecond laser-assisted cataract surgery with the Ziemer FEMTO LDV Z8.

PURPOSE: To determine the efficacy of different fragmentation patterns in femtosecond laser-assisted cataract surgery (FLACS) using Ziemer FEMTO LDV Z8. METHODS: We compared three different types of surgery: conventional cataract surgery (CCS), FLACS with conventional radial slices (named No-Spiderweb), and FLACS with a novel fragmentation pattern (radial slices combined with one or two rings) called "Spiderweb." Visual acuity (VA), nuclear opacity (NO) according to the Lens Opacities Classification System (LOCS lll), effective phacoemulsification time (EPT) and vacuum time were obtained for 845 eyes. RESULTS: Using FLACS (Spiderweb + No-Spiderweb), EPT was significantly reduced by 26% compared to CCS (FLACS: 2.46 ± 2.60 s; CCS: 3.34 ± 2.89 s; ΔM = - 0.88 s, p < .001). Furthermore, EPT as a function of progression of lens opacity was found to be not only lower in Spiderweb compared to CCS, but also in comparison with No-Spiderweb. At NO3, a significant reduction of 65% in EPT was observed by using Spiderweb compared to CCS (Spiderweb: 0.68 ± 1.23 s; CCS: 1.96 ± 1.53 s; ΔM = - 1.28 s, p <.001). Interestingly, EPT at NO3 was also significantly reduced by 57% in Spiderweb compared to No-Spiderweb (Spiderweb: 0.68 ± 1.23 s; No-Spiderweb: 1.57 ± 1 .59 s; ΔM = - 0.90 s, p <.001). The use of Spiderweb only marginally extends the vacuum time compared to No-Spiderweb by 11 s (Spiderweb: 209.13 ± 35.83 s; No-Spiderweb: 198.35 ± 36.84 s; p = .003) and the postoperative improved VA showed no significant difference among the different types of surgery (all ps ≥ .05). CONCLUSION: FLACS significantly reduces EPT compared to CCS. Furthermore, the novel Spiderweb pattern significantly reduces EPT in patients with a cataract of NO3 compared to CCS, but also to FLACS with the existing radial pattern (No-Spiderweb).

Patient-reported outcomes with direct-acting antiviral treatment for hepatitis C in West and Central Africa (TAC ANRS 12311 trial).

Background & Aims: Patient-reported outcomes (PROs) are poorly documented for patients with chronic hepatitis C on direct-acting antiviral (DAA) treatment in low-to-middle-income countries. We documented PROs during and after DAA treatment in participants of the TAC ANRS 12311 trial (West and Central Africa). Methods: Trial participants received a 12-week regimen containing either sofosbuvir plus ribavirin (HCV genotype 2, n = 40), or sofosbuvir plus ledipasvir (HCV genotypes 1 and 4, n = 80). Health-related quality of life (SF-12), fatigue (Piper Fatigue scale), and self-reported symptoms (35-symptom list) were assessed at enrolment (Week (W) 0), during treatment (W2, W4, W8 and W12) and after treatment (W24 and W36). These PROs were compared between W0 and W36 (Wilcoxon signed-rank or McNemar tests). Mixed-effects linear regression models helped identify correlates of physical and mental quality of life component summaries (PCS and MCS) in a longitudinal analysis. Results: Most PROs were significantly improved 24 weeks after treatment end (W36), without significant differences between treatment groups. For the post-treatment period, multivariable analysis showed significant increases in PCS for patients with cirrhosis and in MCS for patients in the sofosbuvir plus ribavirin group. A higher number of self-reported symptoms at W0 was associated with lower PCS and MCS, older age and cirrhosis with lower PCS, and male sex and HCV cure with higher PCS. Conclusions: Sofosbuvir-based DAA therapy was associated with a significant improvement in PROs 6 months after treatment end in patients with chronic HCV infection from Central and West Africa. These findings may guide HCV treatment providers in low-to-middle-income countries to deliver pre-treatment information concerning the benefits of DAAs beyond viral eradication. ClinicalTrialsgov Identifier: NCT02405013. Impact and implications: Perceptions and experiences (i.e. "patient-reported outcomes") of patients with chronic hepatitis C receiving direct-acting antivirals (DAAs) are poorly documented in the African setting. This study shows significant improvements in health-related quality of life, fatigue, and self-reported symptoms 24 weeks after the end of a 12-week sofosbuvir-based DAA regimen in 120 patients from Central and West Africa. These findings substantially add to the body of knowledge about DAA therapy in the African setting. Treatment providers should be encouraged to inform patients of the benefits of DAAs beyond viral eradication, to increase treatment adherence and retention in care.

Effect of freezing and embalming of human cadaveric whole head specimens on bone conduction.

BACKGROUND AND AIMS: Conserved specimens do not decay and therefore permit long-term experiments thereby overcoming limited access to fresh (frozen) temporal bones for studies on middle ear mechanics. We used a Thiel conservation method which is mainly based on a watery solution of salts. In contrast to pure Formalin, Thiel conservation aims to preserve the mechanical proprieties of human tissue. The aim of this study is to examine the effect of Thiel conservation on bone conduction in the same specimen before and after conservation. METHODS: Nine ears of five defrosted whole heads were stimulated with a direct, electrically driven, bone anchored hearing system (Baha, Baha SuperPower). The motion produced by bone conduction stimulation was measured with a single point laser Doppler vibrometer (LDV) at the promontory, the ossicular chain, and the round window through a posterior tympanotomy. After the initial experiments, the entire whole heads were placed in Thiel solution. In order to enable direct comparison between fresh frozen and Thiel specimens, our Thiel conservation did not include intravascular and intrathecal perfusion. The measurements were repeated 3 and 12 months later. To determine the effect of freezing, defrosting, and embalming on the whole heads, CT scans were performed at different stages of the experimental procedure. Additionally, three extracted temporal bones were stimulated a Baha, motion of the promontory measured by LDV and embalmed in Thiel solution to investigate the direct impact of Thiel solution on the bone. RESULTS: The averaged magnitude of motion on the promontory increased in whole head specimens by a mean of 10.3 dB after 3 months of Thiel embalming and stayed stable after 12 months. A similar effect was observed for motion at the tympanic membrane (+7.2 dB), the stapes (+9.5 dB), and the round window (+4.0 dB). In contrast to the whole head specimens, the motion of the extracted temporal bones did not change after 3 months of Thiel embalming (-0.04 dB in average). CT scans of the whole heads after conservation showed a notable brain volume loss mostly >50% as well as a remarkable change in the consistency and structure of the brain. Partial changes could already be observed before the Thiel embalming but after 1-2 days of defrosting. In an additional experiment, a substitution of brain mass and weight by Thiel fluid did not lead to new deterioration in sound transmission. In contrast, a frozen (non-defrosted) whole head showed a distinctively reduced magnitude of promontory motion before defrosting. DISCUSSION: For our setup, the vibration of the ear due to bone conduction in the same whole head specimens significantly increased after Thiel conservation. Such an increase was not observed in extracted temporal bone specimens. Due to brain changes in the CT scans, we investigated the consequences of the brain volume changes and structure loss on the frozen brain before defrosting. The loss of brain volume alone could not explain the increase of ear vibrations, as we did not observe a difference when the volume was replaced with Thiel fluid. However, freezing and defrosting of the entire brain seems to have a major influence. Beside the destructive effect of freezing on the brain, the modified conservation method without perfusion changed the brain structure. In conclusion, bone conduction in whole heads depends on the physical condition of the brain, rather than on the conservation.

A comparative study on micelles, liposomes and solid lipid nanoparticles for paclitaxel delivery.

The purpose of this work was to compare the in vitro and in vivo characteristics of LDV-targeted lipid-based micelles, liposomes and solid lipid nanoparticles (SLN) to provide further insights into their therapeutic potential for clinical development. Micelles, liposomes and SLN were prepared using LDV peptide amphiphiles and palmitic acid-derived lipids using solvent evaporation, thin-film hydration and microfluidic mixing respectively. Nanocarriers were characterized for their physicochemical properties, paclitaxel loading efficiency, in vitro release behavior, stability in biological media as well as in vivo antitumor efficacy in melanoma xenograft model. TEM and DLS results confirmed the presence of paclitaxel-loaded nanosized micelles (6 to 12 nm), liposomes (123.31 ± 5.87 nm) and SLN (80.53 ± 5.37 nm). SLN demonstrated the slowest paclitaxel release rate and the highest stability in biological media compared to micelles and liposomes. Paclitaxel-loaded SLN demonstrated a statistically significant delay in tumor growth compared to mice treated with paclitaxel-loaded liposomes and paclitaxel-loaded micelles (p < 0.05). The results obtained in this study indicate the potential of SLN as drug delivery vehicles for anticancer therapy.

Comparison of ultrasound energy consumption between low-energy femtosecond laser-assisted cataract surgery and conventional phacoemulsification cataract surgery in patients with different cataract densities.

PURPOSE: Femtosecond laser-assisted cataract surgery (FLACS)'s effect on reducing ultrasound energy, accumulated with cumulative dispersed energy (CDE) units, still remains controversial. This study aims to evaluate the effect of low-energy FLACS on CDE with that of conventional phacoemulsification surgery (CPS) in different cataract densities from multiple surgeons. METHODS: It was a retrospective case-control study. Total 629 eyes receiving either low-energy FLACS (performed with Ziemer LDV Z8 platform) or CPS were divided into two groups according to preoperative grading of Lens Opacity Classification System III (LOCSIII): milder and harder cataract group. The mean CDE were compared in different cataract densities and surgeons. A linear regression analysis was performed to evaluate the effect of using low-energy FLACS on CDE in harder cataract cases. RESULTS: We found overall CDE had no significant difference between two surgeries. However, low-energy FLACS led to a significantly lower CDE in patients with harder cataracts than CPS (18.47 ± 4.32 vs. 12.96 ± 2.34; p < 0.001). Similar results were observed in the three surgeon subgroups and in linear regression analysis and no significant difference of the effect accounting for surgeons. Moreover, low-energy FLACS results in a reduction of energy consumption comparing to CPS and has endothelial sparring effect in patients with harder cataracts. CONCLUSIONS: The reduced energy consumption was observed by using low-energy FLACS irrespective of surgeons' experience or the approaches adopted in patients with harder cataracts. Therefore, we can have more confidence to suggest this innovative platform to the patients in such cases.

The effectiveness and safety of direct-acting antivirals for hepatitis C virus treatment: A single-center experience in Saudi Arabia.

Background: The introduction of direct-acting antivirals (DAA) to treat the hepatitis C virus (HCV) overcame many drawbacks of interferon-based therapy. DAA achieved sustained viral response (SVR) rates above 90% and overcame many drawbacks of pegylated interferon regimens.The HCV genotype (GT) distribution varies by geographical area, with GT-4 being most prevalent in the Middle East region, including Saudi Arabia. Yet, the real-world evidence about using DAAs in the Saudi population is limited.Thus, the aim of this study to investigate the effectiveness and safety of DAAs in Saudi patients with HCV infection. Methods: A retrospective cohort study included patients treated with DAAs from 2015 to 2017 at a tertiary care hospital in Riyadh, Saudi Arabia. All patients with HCV treated with either ledipasvir plus sofosbuvir (LDS/SOF) ± ribavarin (RBV) or ombitasvir-paritaprevir-ritonavir (OBV/PTV/r) ± dasabuvir (DSV) ± RBV were included. Using a per-protocol analysis, the effectiveness outcome was the end-of-treatment response (EOTr) and Sustained virologic reponce12 weeks after competing the regimen (SVR12). The secondary safety outcome was the adverse event related to the therapy reported by the patients. Results: A total of 97 patients were included; with the majority infected with GT-4 (64 %), followed by GT-1 (18 %), in addition to 8 % having a mixed GT (1 + 4). The EOTr and SVR12 rates were 98 % and 96 %, respectively. SVR12 was 94.4 % within the LDS/SOF ± RBV group and 97.7 % within the OBV/PTV/r ± DSV ± RBV group. Only 4 % had a response failure due to relapse or breakthrough, and all were infected with mixed GT1 + 4. Medications were well tolerated with minimal side effects, including vomiting, nausea, and weakness. Conclusion: DAAs regimens are associated with high rates of SVR12 and are well tolerated with a good safety profile in Saudi HCV-infected patients.

Intracochlear pressure as an objective measure for perceived loudness with bone conduction implants.

BACKGROUND: The generally accepted method to assess the functionality of novel bone conduction implants in a preclinical stage is to experimentally measure the vibratory response of the cochlear promontory. Yet, bone conduction of sound is a complex propagation phenomenon, depending on both frequency and amplitude, involving different conduction pathways. OBJECTIVES: The aim of this study is to validate the use of intracochlear sound pressure (ICP) as an objective indicator for perceived loudness for bone conduction stimulation. It is investigated whether a correlation exists between intracochlear sound pressure measurements in cadaveric temporal bones and clinically obtained results using the outcome of a loudness balancing experiment. METHODS: Ten normal hearing subjects were asked to balance the perceived loudness between air conducted (AC) sound and bone conducted (BC) sound by changing the AC stimulus. Mean balanced thresholds were calculated and used as stimulation levels in a cadaver trial (N = 4) where intracochlear sound pressure was measured during AC and BC stimulation to assess the correlation with the measured clinical data. The intracochlear pressure was measured at the relatively low stimulation amplitude of 80 dBHL using a lock-in amplification technique. RESULTS: Applying AC and BC stimulation at equal perceived loudness on cadaveric heads yield a similar differential intracochlear pressure, with differences between AC and BC falling within the range of variability of normal hearing test subjects. CONCLUSION: Comparing the perceived loudness at 80 dB HL for both AC and BC validates intracochlear pressure as an objective indicator of the cochlear drive. The measurement setup is more time-intensive than measuring the vibratory response of the cochlear promontory, yet it provides direct information on the level of the cochlear scalae.

Effect of Sofosbuvir/Ledipasvir and Glecaprevir/Pibrentasvir on Serum Creatinine.

Background & objectives: There are reports of worsening renal functions with sofosbuvir, but there are no comparative data of different direct-acting antivirals (DAAs) on serum creatinine. In this retrospective cohort analysis, we examined the treatment effect of two commonly used regimens, sofosbuvir/ledipasvir (SOF/LDV) and glecaprevir/pibrentasvir (GLE/PIB), on serum creatinine. Methods: We included all patients treated with SOF/LDV (n = 825) and GLE/PIB (n = 116) between December 1, 2014, and December 31, 2018. An increase of serum creatinine ≥0.3 mg/dL was considered clinically significant. The change of creatinine values from pretreatment to posttreatment between two treatment groups was tested in unadjusted and adjusted generalized linear model, and risk factors associated with creatinine change were assessed. In addition, GLE/PIB-treated patients were matched 1:2 to SOF/LDV-treated patients using propensity scores, and then serum creatinine changes were compared. Results: The mean baseline creatinine was higher in the GLE/PIB group vs. SOF/LDV group (1.39 ± 1.86 vs. 0.91 ± 0.24, P = 0.007). When compared to baseline, serum creatinine at posttreatment week 4 was significantly higher in SOF/LDV group (0.97 ± 0.4 vs.0.91 ± 0.24, P < 0.001), but there was no significant change in the GLE/PIB group (1.41 ± 1.73 vs. 1.39 ± 1.86, P = 0.52). Overall, there was no significant change in serum creatinine between posttreatment week 4 and week 24 (P = 0.6). Clinically significant increase in serum creatinine was seen in 6% (46/825) of SOF/LDV and 7% (8/116) of GLE/PIB (P = 0.6). The unadjusted and adjusted models indicated that the changes in creatinine from baseline to posttreatment week 4 and week 24 were not associated with the type of DAA combination. Conclusion: Treatment of chronic hepatitis C infection with both SOF/LDV and GLE/PIB regimens may result in an increase of creatinine, and 6-7% will have an increase in serum creatinine of ≥0.3 mg/dL. The increase in creatinine, however, is unrelated to the type of DAA combination.

Stable and direct coating of fibronectin-derived Leu-Asp-Val peptide on ePTFE using one-pot tyrosine oxidation for endothelial cell adhesion.

Expanded polytetrafluoroethylene (ePTFE) is widely used in clinical applications, such as in the manufacture of blood-contacting implantable devices, owing to its flexibility, biostability, and non-adhesiveness. Modification with peptides is an effective strategy to further improve the ePTFE function. However, the chemical stability of PTFE makes it difficult to modify with peptides. In this study, we reported a simple method for the dense and stable coating of biofunctional peptides on the ePTFE surface through the anchor sequence, Tyr-Lys-Tyr-Lys-Tyr-Lys (YK3). A peptide (YK3-LDV) incorporating the YK3 anchor and a ligand sequence for α4ß1 integrin, Leu-Asp-Val (LDV), was successfully coated on ePTFE grafts through one-pot oxidation. The peptide layer constructed via YK3-LDV coating on ePTFE was stable and resistant to extensive washing by aqueous solutions of highly concentrated salts and surfactants. YK3-LDV coating promoted the in vitro adhesion of endothelial cells to ePTFE. Furthermore, YK3-LDV coating accelerated the in vivo formation of neointima-like tissue in a rat model with an ePTFE patch implanted into the carotid artery.

Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals.

Background & Aims: Direct-acting antiviral (DAA) regimens provide a cure in >95% of patients with chronic HCV infection. However, in some patients in whom therapy fails, resistance-associated substitutions (RASs) can develop, limiting retreatment options and risking onward resistant virus transmission. In this study, we evaluated RAS prevalence and distribution, including novel NS5A RASs and clinical factors associated with RAS selection, among patients who experienced DAA treatment failure. Methods: SHARED is an international consortium of clinicians and scientists studying HCV drug resistance. HCV sequence linked metadata from 3,355 patients were collected from 22 countries. NS3, NS5A, and NS5B RASs in virologic failures, including novel NS5A substitutions, were examined. Associations of clinical and demographic characteristics with RAS selection were investigated. Results: The frequency of RASs increased from its natural prevalence following DAA exposure: 37% to 60% in NS3, 29% to 80% in NS5A, 15% to 22% in NS5B for sofosbuvir, and 24% to 37% in NS5B for dasabuvir. Among 730 virologic failures, most were treated with first-generation DAAs, 94% had drug resistance in ≥1 DAA class: 31% single-class resistance, 42% dual-class resistance (predominantly against protease and NS5A inhibitors), and 21% triple-class resistance. Distinct patterns containing ≥2 highly resistant RASs were common. New potential NS5A RASs and adaptive changes were identified in genotypes 1a, 3, and 4. Following DAA failure, RAS selection was more frequent in older people with cirrhosis and those infected with genotypes 1b and 4. Conclusions: Drug resistance in HCV is frequent after DAA treatment failure. Previously unrecognized substitutions continue to emerge and remain uncharacterized. Lay summary: Although direct-acting antiviral medications effectively cure hepatitis C in most patients, sometimes treatment selects for resistant viruses, causing antiviral drugs to be either ineffective or only partially effective. Multidrug resistance is common in patients for whom DAA treatment fails. Older patients and patients with advanced liver diseases are more likely to select drug-resistant viruses. Collective efforts from international communities and governments are needed to develop an optimal approach to managing drug resistance and preventing the transmission of resistant viruses.

Intracochlear pressure in cadaver heads under bone conduction and intracranial fluid stimulation.

BACKGROUND: The frequency dependent contributions of the various bone conduction pathways are poorly understood, especially the fluid pathway. The aim of this work is to measure and investigate sound pressure propagation from the intracranial space to the cochlear fluid. METHODS: Stimulation was provided sequentially to the bone (BC) or directly to the intracranial contents (hydrodynamic conduction, or HC) in four cadaver heads, where each ear was tested individually, for a total of 8 samples. Intracranial pressure was generated and monitored via commercial hydrophones, while the intracochlear sound pressure (ICSP) levels were monitored via custom-made intracochlear acoustic receivers (ICAR). In parallel, measurements of the 3D motion of the cochlear promontory and stapes were made via 3D Laser Doppler Vibrometer (3D LDV). RESULTS: Reliability of the intracochlear sound pressure measurements depends on the immobilization of the ICAR relative to the otic capsule. Regardless of the significant differences in absolute stapes and promontory motion, the ratios between the otic capsule velocity, the stapes volume velocity (relative to the cochlea), and the intracochlear pressure were very similar under BC and HC stimulus. Under HC, the cochlear fluid appears be activated by an osseous pathway, rather than a direct non-osseous pathway from the cerebrospinal fluid (CSF), however, the osseous pathway itself is activated by the CSF pressure. CONCLUSIONS: Data suggests that the skull bone surrounding the brain and CSF could play a role in the interaction between the two CSF and the cochlea, under both stimulation conditions, at high frequencies, while inertia is dominant factor at low frequencies. Further work should be focused on the investigation of the solid-fluid interaction between the skull bone walls and the intracranial content.

Degenerative Myelopathy and Neuropathy in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) Mice Caused by Lactate Dehydrogenase-Elevating Virus (LDV).

Following implantation of patient-derived xenograft (PDX) breast carcinomas from three separate individuals, 33/51 female NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice presented with progressive, unilateral to bilateral, ascending hindlimb paresis to paralysis. Mice were mildly dehydrated, in thin to poor body condition, with reduced to absent hindlimb withdrawal reflex and deep pain sensation. Microscopically, there was variable axonal swelling, vacuolation, and dilation of myelin sheaths within the ventral spinal cord and spinal nerve roots of the thoracolumbar and sacral spinal cord, as well as within corresponding sciatic nerves. Results of PCR screening of PDX samples obtained at necropsy and pooled environmental swabs from the racks housing affected animals were positive for lactate dehydrogenase-elevating virus (LDV). LDV is transmitted through animal-animal contact or commonly as a contaminant of biologic materials of mouse origin. Infection is associated with progressive degenerative myelopathy and neuropathy in strains of mice harboring endogenous retrovirus (AKR, C58), or in immunosuppressed strains (NOD-SCID, Foxn1nu), and can interfere with normal immune responses and alter engraftment and growth of xenograft tumors in immunosuppressed mice. This is the first reported series of LDV-induced poliomyelitis in NSG mice and should be recognized as a potentially significant confounder to biomedical studies utilizing immunodeficient xenograft models.