Vital Dyes in Vitreomacular Surgery

Vital dyes contain complex molecules with chromophores that stain living tissues and have greatly enhanced identification and removal of transparent vitreoretinal tissues during surgery. Several “chromovitrectomy” dyes are frequently used by vitreoretinal specialists, including indocyanine green, trypan blue, brilliant blue G, and triamcinolone acetonide; other dyes are also under investigation. Trypan Blue was approved by the U.S. Food and Drug Administration (FDA) for epiretinal membrane removal, and preservative-free triamcinolone acetonide was approved by the FDA for intraocular use. However, currently available chromovitrectomy dyes have their limitations, and of particular concern for some of them is the possibility for acute and chronic toxicity to the neurosensory retina and retinal pigmented epithelium. The potentially irreversible acute toxicity and other limitations, such as lack of long-term safety profiles, highlight the need for further advancements

Characterizing New-Onset Exudation in the Randomized Phase 2 FILLY Trial of Complement Inhibitor Pegcetacoplan for Geographic Atrophy.

To evaluate clinical characteristics of eyes in which investigator-determined new-onset exudative age-related macular degeneration (eAMD) developed during the FILLY trial.Post hoc analysis of the phase 2 study of intravitreal pegcetacoplan in geographic atrophy (GA).Patients with GA secondary to age-related macular degeneration (AMD), n = 246.Either 15 mg intravitreal pegcetacoplan or sham given monthly or every other month for 12 months followed by a 6-month off-treatment period.Time of new eAMD onset in the study eye, history of eAMD in the fellow eye, presence of double-layer sign (DLS) on structural OCT in the study eye, changes in retinal anatomic features by structural OCT and fluorescein angiography (FA), and changes in visual acuity.Exudation was reported in 26 study eyes across treatment groups over 18 months. Mean time to eAMD diagnosis was 256 days (range, 31-555 days). Overall, a higher proportion of patients with a baseline history of eAMD in the fellow eye (P = 0.016) and a DLS in the study eye (P = 0.0001) demonstrated eAMD. Among study eyes in which eAMD developed, 18 of 26 (69%) had history of fellow-eye eAMD and 19 of 26 (73.1%) had DLS at baseline, compared with 76 of 217 study eyes (35%; P = 0.0007) and 70 of 215 study eyes (32.5%; P0.0001), respectively, in which eAMD did not develop. All 21 patients with structural OCT imaging at the time of eAMD diagnosis demonstrated subretinal fluid, intraretinal cysts, or both consistent with exudation. Among 17 patients who underwent FA at eAMD diagnosis, 10 showed detectable macular neovascularization (MNV), all occult lesions. Development of eAMD did not have an appreciable impact on visual acuity, and all patients responded to anti-vascular endothelial growth factor (VEGF) therapy.Intravitreal pegcetacoplan slowed the rate of GA growth and was associated with an unexpected dose-dependent increased incidence of eAMD with no temporal clustering of onset. Exudative AMD seemed to be associated with baseline eAMD in the contralateral eye and a DLS, suggestive of nonexudative MNV, in the study eye. The safety profile of pegcetacoplan was acceptable to proceed to phase 3 studies without adjustments to enrollment criteria

Characterization of Choroidal Layers in Normal Aging Eyes Using Enface Swept-Source Optical Coherence Tomography

Purpose To characterize qualitative and quantitative features of the choroid in normal eyes using enface swept-source optical coherence tomography (SS-OCT). Methods Fifty-two eyes of 26 consecutive normal subjects were prospectively recruited to obtain multiple three-dimensional 12x12mm volumetric scans using a long-wavelength high-speed SS-OCT prototype. A motion-correction algorithm merged multiple SS-OCT volumes to improve signal. Retinal pigment epithelium (RPE) was segmented as the reference and enface images were extracted at varying depths every 4.13 mu m intervals. Systematic analysis of the choroid at different depths was performed to qualitatively assess the morphology of the choroid and quantify the absolute thicknesses as well as the relative thicknesses of the choroidal vascular layers including the choroidal microvasculature (choriocapillaris, terminal arterioles and venules;CC) and choroidal vessels (CV) with respect to the subfoveal total choroidal thickness (TC). Subjects were divided into two age groups: younger (= 40 years). Results Mean age of subjects was 41.92 (24-66) years. Enface images at the level of the RPE, CC, CV, and choroidal-scleral interface were used to assess specific qualitative features. In the younger age group, the mean absolute thicknesses were: TC 379.4 mu m (SD +/- 75.7 mu m),CC 81.3 mu m (SD +/- 21.2 mu m) and CV 298.1 mu m (SD +/- 63.7 mu m). In the older group, the mean absolute thicknesses were: TC 305.0 mu m (SD +/- 50.9 mu m),CC 56.4 mu m (SD +/- 12.1 mu m) and CV 248.6 mu m (SD +/- 49.7 mu m). In the younger group, the relative thicknesses of the individual choroidal layers were: CC 21.5% (SD +/- 4.0%) and CV 78.4% (SD +/- 4.0%). In the older group, the relative thicknesses were: CC 18.9% (SD +/- 4.5%) and CV 81.1% (SD +/- 4.5%). The absolute thicknesses were smaller in the older age group for all choroidal layers (TC p=0.006, CC p=0.0003, CV p=0.03) while the relative thickness was smaller only for the CC (p=0.04). Conclusions Enface SS-OCT at 1050nm enables a precise qualitative and quantitative characterization of the individual choroidal layers in normal eyes. Only the CC is relatively thinner in the older eyes. In-vivo evaluation of the choroid at variable depths may be potentially valuable in understanding the natural history of age-related posterior segment disease

Decreased D2-40 and increased p16INK4A immunoreactivities correlate with higher grade of cervical intraepithelial neoplasia

<p>Abstract</p> <p>Background</p> <p>D2-40 has been shown a selective marker for lymphatic endothelium, but also shown in the benign cervical basal cells. However, the application of D2-40 immunoreactivity in the cervical basal cells for identifying the grade of cervical intraepithelial neoplasia (CIN) has not been evaluated.</p> <p>Methods</p> <p>In this study, the immunoreactive patterns of D2-40, compared with p16^INK4A, which is currently considered as the useful marker for cervical cancers and their precancerous diseases, were examined in total 125 cervical specimens including 32 of CIN1, 37 of CIN2, 35 of CIN3, and 21 of normal cervical tissue. D2-40 and p16^INK4Aimmunoreactivities were scored semiquantitatively according to the intensity and/or extent of the staining.</p> <p>Results</p> <p>Diffuse D2-40 expression with moderate-to-strong intensity was seen in all the normal cervical epithelia (21/21, 100%) and similar pattern of D2-40 immunoreactivity with weak-to-strong intensity was observed in CIN1 (31/32, 97.2%). However, negative and/or focal D2-40 expression was found in CIN2 (negative: 20/37, 54.1%; focal: 16/37, 43.2%) and CIN3 (negative: 22/35, 62.8%; focal: 12/35, 34.3%). On the other hand, diffuse immunostaining for p16^INK4Awas shown in 37.5% of CIN1, 64.9% of CIN2, and 80.0% of CIN3. However, the immunoreactive pattern of D2-40 was not associated with the p16^INK4Aimmunoreactivity.</p> <p>Conclusions</p> <p>Immunohistochemical analysis of D2-40 combined with p16^INK4Amay have a significant implication in clinical practice for better identifying the grade of cervical intraepithelial neoplasia, especially for distinguishing CIN1 from CIN2/3.</p

GA-based multi-objective optimization of active nonlinear quarter car suspension system—PID and fuzzy logic control

Background The primary function of a suspension system is to isolate the vehicle body from road irregularities thus providing the ride comfort and to support the vehicle and provide stability. The suspension system has to perform conflicting requirements; hence, a passive suspension system is replaced by the active suspension system which can supply force to the system. Active suspension supplies energy to respond dynamically and achieve relative motion between body and wheel and thus improves the performance of suspension system. Methods This study presents modelling and control optimization of a nonlinear quarter car suspension system. A mathematical model of nonlinear quarter car is developed and simulated for control and optimization in Matlab/Simulink® environment. Class C road is selected as input road condition with the vehicle traveling at 80 kmph. Active control of the suspension system is achieved using FLC and PID control actions. Instead of guessing and or trial and error method, genetic algorithm (GA)-based optimization algorithm is implemented to tune PID parameters and FLC membership functions’ range and scaling factors. The optimization function is modeled as a multi-objective problem comprising of frequency weighted RMS seat acceleration, Vibration dose value (VDV), RMS suspension space, and RMS tyre deflection. ISO 2631-1 standard is adopted to assess the ride and health criterion. Results The nonlinear quarter model along with the controller is modeled and simulated and optimized in a Matlab/Simulink environment. It is observed that GA-optimized FLC gives better control as compared to PID and passive suspension system. Further simulations are validated on suspension system with seat and human model. Parameters under observation are frequency-weighted RMS head acceleration, VDV at the head, crest factor, and amplitude ratios at the head and upper torso (AR_h and AR_ut). Simulation results are presented in time and frequency domain. Conclusion Simulation results show that GA-based FLC and PID controller gives better ride comfort and health criterion by reducing RMS head acceleration, VDV at the head, CF, and AR_h and AR_ut over passive suspension system

Ophthalmology

PURPOSE: To evaluate the 2-year efficacy, durability, and safety of dual angiopoietin-2/vascular endothelial growth factor (VEGF)-A pathway inhibition with intravitreal faricimab according to a personalized treat-and-extend-based regimen (T&E) with up to every-16-week (Q16W) dosing in the YOSEMITE/RHINE (NCT03622580/NCT03622593) phase 3 trials of diabetic macular edema (DME). DESIGN: Randomized, double-masked, noninferiority phase 3 trials. PARTICIPANTS: Adults with visual acuity loss due to center-involving DME. METHODS: Patients were randomized 1:1:1 to faricimab 6.0 mg Q8W, faricimab 6.0 mg T&E (previously referred to as personalized treatment interval), or aflibercept 2.0 mg Q8W. The T&E up to Q16W dosing regimen was based on central subfield thickness (CST) and best-corrected visual acuity (BCVA) change. MAIN OUTCOME MEASURES: Included changes from baseline in BCVA and CST, number of injections, durability, absence of fluid, and safety through week 100. RESULTS: In YOSEMITE/RHINE (N=940/951), noninferior year 1 visual acuity gains were maintained through year 2; mean BCVA change from baseline at 2 years (weeks 92/96/100 average) with faricimab Q8W (YOSEMITE/RHINE, +10.7/+10.9 letters) or T&E (+10.7/+10.1 letters) were comparable with aflibercept Q8W (+11.4/+9.4 letters). The median number of study drug injections was lower with faricimab T&E (YOSEMITE/RHINE, 10/11 injections) versus faricimab Q8W (15 injections) and aflibercept Q8W (14 injections) across both trials during the entire study. In the faricimab T&E arms, durability was further improved during year 2, with >60% of patients on Q16W dosing and ∼80% on ≥Q12W dosing at week 96. Almost 80% of patients who achieved Q16W dosing at week 52 maintained Q16W dosing without an interval reduction through week 96. Mean CST reductions were greater, and more patients achieved absence of DME (CST <325μm) and absence of intraretinal fluid with faricimab Q8W or T&E versus aflibercept Q8W through year 2. Overall, faricimab was well tolerated, with a safety profile comparable to aflibercept. CONCLUSIONS: Clinically meaningful visual acuity gains from baseline, anatomic improvements, and extended durability with intravitreal faricimab up to Q16W were maintained through year 2. Faricimab given as a personalized T&E-based dosing regimen supports the role of dual angiopoietin-2/VEGF-A inhibition to promote vascular stability and provide durable efficacy for patients with DME

On the orders of magnitude of epigenic dynamics and monoclonal antibody production

The hybridoma cell's maximum capacity for monoclonal antibody ( MAb ) production is estimated to be 2300–8000 MAb molecules/cell/s, using measured rates of transcription and translation, and the limitations imposed by the size of the polymerase molecule and the ribosome. Nearly all the production rates reported in the literature fall into or below this range of production rates. Data from batch cultures of hybridomas demonstrate a constant specific rate of MAb production until the time integral of the viable cell concentration reaches about 10 8 cells · h/cm 3 . At this point, some essential nutrients from the standard media are depleted, causing MAb production to decline.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47810/1/449_2004_Article_BF00369177.pd