Blinded Treatment Research Articles

Effect of Concurrent Use of Memantine on The Efficacy of Masupirdine (SUVN‐502): A Post‐hoc Analysis of a Phase‐2 Randomized Placebo‐Controlled Study

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disorder manifested by progressive deterioration in cognition, memory and activities of daily living. The commonly used treatments in the management of cognitive and memory deficits associated with AD are either minimally effective, provide temporary relief or limited to use in a highly selected population. Selective blockade of serotonin‐6 (5‐HT6) receptors, which are exclusively localized in the central nervous system, is reported to play an important role in learning and memory. Masupirdine is a potent and selective 5‐HT6 receptor antagonist with pro‐cognitive properties in animal models of cognition.MethodThe efficacy and safety of masupirdine were evaluated in patients with moderate AD concurrently treated with donepezil and memantine. A total of 564 patients were randomized in a 1:1:1 ratio, using permuted blocked randomization. The study consisted of a 2 to 4‐week screening period, a 26‐week double blind treatment period, and a 4‐week washout period. The primary efficacy outcome was the 11‐item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS‐Cog 11). In post‐hoc analyses, patients were subdivided based on the use of memantine dosage form and memantine plasma concentrations to assess the impact of memantine on the efficacy of masupirdine.ResultIn this exploratory post‐hoc analysis, less worsening of cognition (ADAS‐Cog 11 scores) was observed with masupirdine treatment as compared to placebo in subjects whose trough memantine plasma concentrations were ≤100 ng/mL.ConclusionThese exploratory and thought provoking observations merit better understanding and further possible investigations of masupirdine effects and its role as a potential future drug in the AD pharmaceutical armamentarium.

Characterization of the activity and the mechanism of action of a new toluquinol derivative with improved potential as an antiangiogenic drug

The inhibition of sustained angiogenesis is an attractive approach for the treatment of cancer, blindness and other angiogenesis-dependent diseases. Encouraged by our previous finding that toluquinol, a methyl hydroquinone isolated from a marine fungus, exhibited an interesting antiangiogenic activity, we further explored structural modifications of this natural compound in order to develop improved drug candidates. Our results indicate that although the methyl group plays a relevant role in the cytotoxic activity of toluquinol, some derivatives in which this methyl was replaced by another substituent, could keep the antiangiogenic activity, whereas exhibiting a lower cytotoxicity in vitro. This is the case of (E)− 2-(3-methoxyprop-1-en-1-yl) benzene-1,4-diol, which exhibits a decreased toxicity, whereas maintaining or even improving the antiangiogenic activity of toluquinol, as demonstrated by a number of in vitro (endothelial cells proliferation, migration and tube formation) and in vivo (chick embryo chrorioallantoic membrane vascularization and murine corneal neovascularization) experimental approaches. Our results point to a mechanism of action that could be related to an induction of apoptosis, as well as to an increase in the reactive oxygen species levels, a reduction of the redox capacity and the inhibition of the VEGFR2, Akt and ERK phosphorylation in VEGF-activated endothelial cells. The biological activity of this new angiogenesis inhibitor, along with its lower undesired toxicity, suggests that it is a promising drug candidate with improved potential for the treatment of angiogenesis-related diseases.

Management and Treatment Outcomes of High-Risk Corneal Transplantations.

Corneal transplantation is the most effective treatment for corneal blindness. Standard planned keratoplasties have a high success rate. Conditions such as active inflammation at the time of surgery, the presence of ocular surface disease, previous graft disease, or neovascularization make them more susceptible to rejection. These are so-called high-risk corneal transplantations. In our study, we selected 52 patients with a higher risk of graft rejection. A total of 78 procedures were performed. The main indications for the first keratoplasty were infections (59.6%) and traumas (21.2%). Visual acuity (VA) significantly improved from 2.05 logMAR on the day of keratoplasty to 1.66 logMAR in the latest examination (p = 0.003). An analysis of the graft survival showed a 1-year survival of 54% and a 5-year survival of 19.8% of grafts. The mean observation time without complications after the first, second, and third surgery was 23, 13, and 14 months, respectively. The best results were noted among patients with infectious indications for keratoplasty (p = 0.001). Among them, those with bacterial infection had the best visual outcomes (p = 0.047).

ICG-mediated photodisruption of the inner limiting membrane enhances retinal drug delivery.

Many groundbreaking therapies for the treatment of blindness require delivery of biologics or cells to the inner retina by intravitreal injection. Unfortunately, the advancement of these therapies is greatly hampered by delivery difficulties where obstruction of the therapeutics at the inner limiting membrane (ILM) represents the dominant bottleneck. In this proof-of-principle study, we explore an innovative light-based approach to locally ablate the ILM in a minimally invasive and highly controlled manner, thus making the ILM more permeable for therapeutics. More specifically, we demonstrate that pulsed laser irradiation of ILM-bound indocyanine green (ICG), a clinically applied ILM dye, results in the formation of vapor nanobubbles which can disrupt the bovine ILM as well as the extraordinary thick human ILM. We have observed that this photodisruption allows for highly successful retinal delivery of model nanoparticles which are otherwise blocked by the intact ILM. Strikingly, this treatment is furthermore able of enhancing the efficacy of mRNA-loaded lipid nanoparticles within the bovine retina by a factor of 5. In conclusion, this study provides evidence for a light-based approach to overcome the ILM which has the potential to improve the efficacy of all retinal therapies hampered by this delivery barrier.

Titanium Powder 3D-Printing Technology for a Novel Keratoprosthesis in Alkali-Burned Rabbits.

PurposeTo evaluate the surgical technique, clinical performance, and biocompatibility of a novel keratoprosthesis (KPro) named KPro of Brazil (KoBra) in an alkali-burned rabbit model.MethodsTwo-piece three-dimensional-printed titanium powder and polymethyl methacrylate KPros were implanted into 14 alkali-burned corneas of 14 rabbits using an autologous full-thickness corneal graft as the KPro carrier. Rabbits were examined weekly for 12 months to evaluate retention and postoperative complications. Anterior segment optical coherence tomography (AS-OCT) and scanning electron microscopy (SEM) were performed at the end of the experiment to evaluate the relationship between the KoBra and the carrier graft.ResultsAll surgeries were performed without intraoperative complications, and the immediate postoperative period was uneventful. In 12 eyes (85.7%), the implanted KPros integrated into the operated eyes and maintained clear optics without extrusion or further complications over 12 months. Two eyes presented late postoperative complications that progressed to KPro extrusion: one had a presumed infectious keratitis, and the other had sterile stromal necrosis. AS-OCT demonstrated the correct relationship of the device and carrier graft in all remaining animals at the final follow-up. SEM findings indicate the integration of the porous structure of the back plate into the surrounding tissue.ConclusionsClinical evaluations, AS-OCT, and SEM findings indicate good biointegr-ation of the implanted device into the corneal carrier graft. KoBra has the advantage of using recipients’ own corneas as the prosthesis supporter, and its surgical procedure is relatively simple and safe.Translational RelevanceTitanium three-dimensional-printed technology used in an animal limbal stem-cell deficiency model holds great promise for the treatment of corneal blindness in humans.

Human (but not animal) motion can be recognized at first sight – After treatment for congenital blindness

The long-standing nativist vs. empiricist debate asks a foundational question in epistemology – does our knowledge arise through experience or is it available innately? Studies that probe the sensitivity of newborns and patients recovering from congenital blindness are central in informing this dialogue.One of the most robust sensitivities our visual system possesses is to ‘biological motion’ – the movement patterns of humans and other vertebrates. Various biological motion perception skills (such as distinguishing between movement of human and non-human animals, or between upright and inverted human movement) become evident within the first months of life. The mechanisms of acquiring these capabilities, and specifically the contribution of visual experience to their development, are still under debate.We had the opportunity to directly examine the role of visual experience in biological motion perception, by testing what level of sensitivity is present immediately upon onset of sight following years of congenital visual deprivation. Two congenitally blind patients who underwent sight-restorative cataract-removal surgery late in life (at the ages of 7 and 20 years) were tested before and after sight restoration. The patients were shown displays of walking humans, pigeons, and cats, and asked to describe what they saw.Visual recognition of movement patterns emerged immediately upon eye-opening following surgery, when the patients spontaneously began to identify human, but not animal, biological motion. This recognition ability was evident contemporaneously for upright and inverted human displays.These findings suggest that visual recognition of human motion patterns may not critically depend on visual experience, as it was evident upon first exposure to un-obstructed sight in patients with very limited prior visual exposure, and furthermore, was not limited to the typical (upright) orientation of humans in real-life settings.

Trial-level characteristics associate with treatment effect estimates: a systematic review of meta-epidemiological studies

BackgroundTo summarize the up-to-date empirical evidence on trial-level characteristics of randomized controlled trials associated with treatment effect estimates.MethodsA systematic review searched three databases up to August 2020. Meta-epidemiological (ME) studies of randomized controlled trials on intervention effect were eligible. We assessed the methodological quality of ME studies using a self-developed criterion. Associations between treatment effect estimates and trial-level characteristics were presented using forest plots.ResultsEighty ME studies were included, with 25/80 (31%) being published after 2015. Less than one-third ME studies critically appraised the included studies (26/80, 33%), published a protocol (23/80, 29%), and provided a list of excluded studies with justifications (12/80, 15%). Trials with high or unclear (versus low) risk of bias on sequence generation (3/14 for binary outcome and 1/6 for continuous outcome), allocation concealment (11/18 and 1/6), double blinding (5/15 and 2/4) and smaller sample size (4/5 and 2/2) significantly associated with larger treatment effect estimates. Associations between high or unclear risk of bias on allocation concealment (5/6 for binary outcome and 1/3 for continuous outcome), double blinding (4/5 and 1/3) and larger treatment effect estimates were more frequently observed for subjective outcomes. The associations between treatment effect estimates and non-blinding of outcome assessors were removed in trials using multiple observers to reach consensus for both binary and continuous outcomes. Some trial characteristics in the Cochrane risk-of-bias (RoB2) tool have not been covered by the included ME studies, including using validated method for outcome measures and selection of the reported results from multiple outcome measures or multiple analysis based on results (e.g., significance of the results).ConclusionsConsistently significant associations between larger treatment effect estimates and high or unclear risk of bias on sequence generation, allocation concealment, double blinding and smaller sample size were found. The impact of allocation concealment and double blinding were more consistent for subjective outcomes. The methodological and reporting quality of included ME studies were dissatisfactory. Future ME studies should follow the corresponding reporting guideline. Specific guidelines for conducting and critically appraising ME studies are needed.

The research progress of mesenchymal stem cell induction and differentiation into corneal tissue

Keratopathy is one of the most important blinding eye diseases in the world. Corneal opacity caused by keratopathy can seriously damage visual function. For example, corneal ulcer can lead to perforation and even loss of the eyeball. Although corneal transplantation is a routine treatment in clinical practice, there are not only a serious shortage of corneal donors in our country, but also various complications after keratoplasty that can not be avoided. In recent years, with the rapid development of regenerative medicine, it has been found that mesenchymal stem cells can differentiate into a variety of functional cells including corneal tissue under suitable induction conditions, which has a broad prospect of clinical application. This finding provides new ideas and methods for the treatment of keratopathy and corneal blindness in many aspects. This article reviews the research status of induction methods of mesenchymal stem cells in various specialties, particularly in the corneal subspecialty.

Current estimates of the economic burden of blindness and visual impairment in India: A cost of illness study

Purpose:Currently, there are an estimated 4.95 million blind persons and 70 million vision impaired persons in India, out of which 0.24 million are blind children. Early detection and treatment of the leading causes of blindness such as cataract are important in reducing the prevalence of blindness and vision impairment. There are significant developments in the field of blindness prevention, management, and control since the “Vision 2020: The right to sight” initiative. Very few studies have analyzed the cost of blindness at the population level. This study was undertaken to update the information on the economic burden of blindness and visual impairment in India based on the prevalence of blindness in India. We used secondary and publicly available data and a few assumptions for our estimations.Methods:We used gross national income (GNI), disability weights, and loss of productivity metrics to calculate the economic burden of blindness and vision impairment based on the “cost of illness” methodology.Results:The estimated net loss of GNI due to blindness in India is INR 845 billion (Int$ 38.4 billion), with a per capita loss of GNI per blind person of INR 170,624 (Int$ 7,756). The cumulative loss of GNI due to avoidable blindness in India is INR 11,778.6 billion (Int$ 535 billion). The cumulative loss of GNI due to blindness increased almost three times in the past two decades. The potential loss of productivity due to vision impairment is INR 646 billion (Int$ 29.4 billion).Conclusion:These estimates provide adequate information for budgetary allocation and will help advocate the need for accelerated adoption of all four strategies of integrated people-centered eye care (IPCEC). Early detection and treatment of blindness, especially among children, is very important in reducing the economic burden; thus, there is a need for integrating primary eye care horizontally with all levels of primary healthcare.

031 Long-term efficacy of ocrelizumab in primary progressive multiple sclerosis: 6.5-study years

BackgroundEfficacy/safety of ocrelizumab in primary progressive multiple sclerosis were demonstrated in the ORATORIO (NCT01194570) double-blind period (DBP). Here we assessed the efficacy of switching to, or earlier initiation of, ocrelizumab after 6.5-study years (312 weeks), in the open-label extension (OLE).MethodsDuring the DBP, patients were randomised to ocrelizumab or placebo for ≥120 weeks until a prespecified number of confirmed disability progression (CDP) events occurred. Patients continued blinded treatment until the outcome was ascertained (extended controlled period [ECP]). At OLE initia- tion, patients continued ocrelizumab (OCR-OCR) or switched from placebo to ocrelizumab (PBO-OCR). Time to onset of 24-week-CDP and time-to-wheelchair-confinement (Expanded Disability Status Scale≥7.0) were analysed.ResultsDuring the DBP, ocrelizumab reduced the risk of 24-week-CDP by 25% (p=0.037) vs placebo. At Week 168 (12 weeks after the first patients entered the OLE), the proportion of patients with 24-week-CDP in PBO-OCR and OCR-OCR was 44.7% vs 33.3% (Δ=11.4%; p=0.005), and at Week 312 was 64.8% vs 51.7% (Δ=13.1%; p=0.002), respectively. During DBP+ECP+OLE, risk of wheelchair confinement was 42% lower (p=0.011) and of 24-week-CDP was 28% lower (p=0.002) in OCR-OCR vs PBO-OCR.ConclusionsCompared with PBO-OCR, initiating ocrelizumab 3–5 years earlier significantly reduced the risk of wheelchair confinement and 24-week-CDP.k.schmierer@qmul.ac.uk

Remodelling 3D printed GelMA-HA corneal scaffolds by cornea stromal cells

Engineering scaffolds with a structure mimicking that of native cornea allows for addressing the severe donor shortage for the corneal blindness treatment, which, however, remains challenging. In the light that corneal stromal (CS) cells can play a key role in corneal stroma formation, in this study we incorporated CS cells into three-dimensional (3D) scaffolds printed from hyaluronic acid-modified gelatin-methacrylate (GelMA-HA) scaffolds and characterized the scaffolds in terms of remodeled extracellular matrix (ECM) in vitro. Our results illustrated that the modification of GelMA by HA allowed for 3D printing of corneal scaffolds and further improved the characteristics of primary rabbit-derived corneal stromal cells for remodelling scaffolds. After 60 days, we decellularized the remodeled corneal scaffolds and examined their optical properties; and our results demonstrated that the 3D printed corneal scaffolds provided CS cells with cues that guided them toward the directional and spatial organization and facilitated the ECM remodelling.

Readmission Rates in Patients With Multiple Sclerosis: A Nationwide Cohort Study.

Multiple sclerosis (MS) is an inflammatory central nervous system demyelinating disorder resulting in neurologic decline. Patients predominantly have a relapsing and remitting disease course requiring multiple hospitalizations and, occasionally, rehospitalizations. Hospitalization readmission rates are important metrics that have direct financial implications for hospitals and serve as an indicator of disease burden on patients and society. We sought to analyze hospital readmissions of patients with MS and identify the subsequent predictive characteristics/comorbidities for readmission. All hospital admissions due to MS were queried using the 2017 Nationwide Readmissions Database. All patients with nonelective rehospitalization within 30 days of discharge were examined. The 30-day readmission rate for MS is 10.6% (range, 10.4%-10.8%). Female sex has a protective role in readmission rates, and age has no effect. Comorbidities, including heart failure, acute kidney injury, chronic obstructive pulmonary disease, chronic kidney disease, respiratory failure, substance abuse, diabetes, hypertension, peripheral artery disease, liver failure, anemia, coagulation disorders, cancer, depression, and infections, are predictive of readmissions, whereas sleep apnea is protective. No effect is seen with neurologic blindness, plasma exchange, or intravenous immunoglobulin treatment. Several medical comorbidities are predictive of hospital readmission of patients with MS. Most rehospitalizations are due to infectious and neurologic etiologies; thus, targeted interventions may lead to lower readmission rates.

FC054: Voclosporin for Lupus Nephritis: Results of the Two-Year Aurora 2 Continuation Study

Abstract BACKGROUND AND AIMS Voclosporin, a novel calcineurin inhibitor, was approved in the USA in January 2021 for the treatment of adult patients with active lupus nephritis in combination with background immunosuppressive therapy. Voclosporin has a favorable metabolic profile and a consistent dose-concentration relationship, eliminating the need for therapeutic drug monitoring. Previously reported results from the Phase 2 AURA-LV and Phase 3 AURORA 1 studies showed that the addition of voclosporin to mycophenolate mofetil (MMF) and low-dose steroids in patients with lupus nephritis significantly increased rates of complete renal response at 48 weeks (AURA-LV) and 52 weeks (AURORA 1). Here we report the results of the completed continuation study, AURORA 2, which assessed the long-term safety and tolerability of voclosporin compared with placebo in patients with lupus nephritis receiving treatment for an additional 24 months following completion of the AURORA 1 study. METHOD Key inclusion criteria for the parent AURORA 1 study included a diagnosis of biopsy-proven active lupus nephritis (Class III, IV, or V ± III/IV), proteinuria ≥ 1.5 mg/mg (≥2 mg/mg for Class V) and estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2. Patients who completed AURORA 1 were eligible to enroll in AURORA 2 and continued with the same blinded treatment of voclosporin (23.7 mg BID) or placebo in combination with MMF (target dose 2 g/day) and low-dose oral steroids. Safety and tolerability were evaluated by monitoring adverse events and laboratory assessments including eGFR; changes in urine protein creatinine ratio (UPCR) were also assessed. RESULTS In total, 116 patients in the voclosporin arm and 100 patients in the control arm enrolled in AURORA 2, with 92 (79.3%) and 73 (73.0%) patients in each respective arm completing treatment to the end of AURORA 2. There were no new or unexpected safety signals detected in patients who continued on treatment with voclosporin compared to control-treated patients. Rates of serious adverse events in the voclosporin (19.0%) and control arms (24.0%) were similar, with eight serious adverse events of infection in each arm. Estimated glomerular filtration rate remained stable through the end of AURORA 2 (Figure 1). The slopes of the least-squares (LS) mean change in corrected eGFR from AURORA 2 baseline to end of study were –0.2 [95% confidence interval (CI) –3.0 to 2.7' in the voclosporin arm and –5.4 (95% CI –8.4 to –2.3) in the control arm. There were no deaths in the voclosporin arm during AURORA 2; four deaths were reported in the control arm due to pulmonary embolism (n = 1) and coronavirus infection (n = 3). The LS mean reductions in UPCR observed in AURORA 1 were maintained in AURORA 2 with no increase in UPCR noted at the follow-up visit 4 weeks after study drug discontinuation (Figure 2). CONCLUSION Voclosporin was well-tolerated over three years of treatment with a similar safety profile to control and no unexpected safety signals detected. Further, the significant and meaningful reductions in proteinuria initially achieved in AURORA 1 were maintained throughout AURORA 2. These data provide evidence of a long-term treatment benefit of voclosporin in patients with lupus nephritis.

OA34 Post-hoc analysis of spinal MRI SPARCC inflammation scores in patients with radiographic axial spondyloarthritis treated with ixekizumab: results from the COAST-V study at week 16

Abstract Background/Aims Ixekizumab, an interleukin-17A inhibitor, has demonstrated efficacy in radiographic axial spondyloarthritis (r-axSpA) irrespective of baseline local inflammation as measured by spinal magnetic resonance imaging (MRI) Spondyloarthritis Research Consortium of Canada (SPARCC) inflammation scores. This post-hoc analysis assessed the efficacy of ixekizumab in patients with r-axSpA categorized by MRI SPARCC score at baseline and 16-week change from baseline (CFB). Methods COAST-V (NCT02696785) was a phase 3, randomized, controlled trial enrolling patients with active r-axSpA naïve to biologic disease-modifying antirheumatic drugs, randomized 1:1:1:1 to 80-mg ixekizumab every 2 weeks, 80-mg ixekizumab every 4 weeks (Q4W), adalimumab, or placebo for the 16-week blinded treatment period. Three categories were defined according to spinal MRI SPARCC inflammation score at baseline and CFB (based on published minimally important change): 1) low baseline (baseline SPARCC score <5.0 points), 2) low responder (baseline SPARCC score ≥5.0 points and CFB <5.0 points), 3) high responder (baseline SPARCC score ≥5.0 points and CFB ≥5.0 points). Proportions of patients achieving Assessment in SpondyloArthritis international Society 40% (ASAS40), Ankylosing Spondylitis Disease Activity Score (ASDAS) <2.1, and BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) 50 were determined. Means at baseline and week-16 least squares means of CFBs were calculated for ASDAS, BASDAI, Spinal Pain, Bath Ankylosing Spondylitis Functional Index (BASFI), and 36-item Short Form Health Survey Physical Component Summary (SF-36 PCS). Non-responder imputation and modified baseline observation carried forward were used for missing week-16 data in discrete and continuous variables, respectively. Results Of 78 patients receiving ixekizumab Q4W, 35 (44.9%), 11 (14.1%), and 32 (41.0%), were MRI SPARCC low baseline, low responders, and high responders, respectively. Similar proportions of ixekizumab-treated patients in all categories achieved ASAS40, ASDAS<2.1, and BASDAI50 week-16 responses; week-16 improvements in other efficacy endpoints were broadly similar, with high responders showing greater improvements in ASAS40 and ASDAS CFB (Table). In adalimumab-treated patients, week-16 improvements were less pronounced in the low baseline and low responder categories. Conclusion Patients with r-axSpA receiving ixekizumab Q4W showed broadly similar reduction in the signs and symptoms of r-axSpA irrespective of their spinal MRI SPARCC inflammation score category at week 16. Disclosure H. Marzo-Ortega: Honoraria; Abbvie, Celgene, Eli Lilly and Company, Janssen, Novartis, Pfizer, Takeda, UCB, Biogen. Grants/research support; Janssen, Novartis. W. Tsai: Consultancies; Abbvie, Pfizer, Roche. H. Kameda: Consultancies; Abbvie, Asahikasei Pharma, Bristol-Myers Squibb, Eisai, Eli Lilly and Company, Janssen, Mitsubishi Tanabe Pharma, Novartis, Chugai, Pfizer. Member of speakers’ bureau; Abbvie, Asahikasei Pharma, Bristol-Myers Squibb, Eisai, Eli Lilly and Company, Janssen, Mitsubishi Tanabe Pharma, Novartis, Chugai, Pfizer. A. Konomi: Shareholder/stock ownership; Eli Lilly and Company. Other; Employment - Eli Lilly and Company. A.J. Bradley: Shareholder/stock ownership; Eli Lilly and Company. Other; Employment - Eli Lilly and Company. K. Ng: Shareholder/stock ownership; Eli Lilly and Company. Other; Employment - Eli Lilly and Company. Y. Schymura: Shareholder/stock ownership; Eli Lilly and Company. Other; Employment - Eli Lilly and Company. S. Liu-Leage: Shareholder/stock ownership; Eli Lilly and Company. Other; Employment - Eli Lilly and Company. W.P. Maksymowych: Corporate appointments; CARE Arthritis Limited. Consultancies; Abbvie, Boehringer Ingelheim, Celgene, Eli Lilly and Company, Galapagos, Janssen, Novartis, Pfizer, UCB. Member of speakers’ bureau; Abbvie, Janssen, Novartis, Pfizer, UCB. Grants/research support; Abbvie, Novartis, Pfizer, UCB. M. Østergaard: Consultancies; Abbvie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly and Company, Hospira, Janssen, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, UCB. Member of speakers’ bureau; Abbvie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly and Company, Hospira, Janssen, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, UCB. Grants/research support; Abbvie, Celgene, Centocor, Merck, Novartis.

Green Bean Juice (Phaseolus radiatus linn) Decrease Total Cholesterol Levels In Women With Hypercholesterolemia

Cholesterol total level is a risk factor for cardiovascular disease. Mung beans contain soluble fiber and isoflavones that decrease cholesterol levels. The aim of this research is to find out the potency of mung beans juice to decrease total cholesterol total level of hypercholesterol woman. Research design was quasi experimental with pretest - posttest control group. The subjects were 34 women with hypercholesterolemia, and divided into two groups ie 17 womens in Penarukan Village which is treatment group and 17 womens in Ketapang Village which is control groups. All the subjects have met the inclusion criteria. The treatment group consumed juice of 300 ml/day for 14 days while the control group did not get juice. It was a single blind treatment. Cholesterol total level measurement used Electrode Based Biosensor and CHOD-PAP methods. The mean of cholesterol total level of control group before and after was increasing 5,7% ie 240,1 mg/dl and 253,9 mg/dl, but intervention group was decreasing 11% ie 220 mg/dl and 195,7 mg/dl. Paired t-test result shows that there is a significant difference between total cholesterol levels before and after in the treatment group and control group (p= 0.000). The conclusion of this research is the provision of mung beans juice 300 ml/day for 14 days reduce total cholesterol levels.
 Keywords : Hypercholesterolemia Women; Mung beans Juice; Total Cholesterol Level;

Comprehensive chemical profile and quantitative analysis of the Shabyar tablet, a traditional ethnic medicine prescription, by ultra-high-performance liquid chromatography with quadrupole-orbitrap high-resolution mass spectrometry.

The Shabyar tablet is commonly used as a traditional ethnic medicine prescription for the treatment of night blindness, poor vision, and headaches. However, the chemical components of the Shabyar tablet have not been holistically explored, which seriously hinders the discovery of the activity. This study qualitatively and quantitatively investigated the overall chemical profile of the Shabyar tablet using ultra-high-performance liquid chromatography hyphenated with quadrupole-orbitrap high-resolution mass spectrometry. Altogether, 170 chemical components, including 59 flavonoids, 78 organic acids, 12 anthranones, three anthraquinones, one naphthalene, and 17 other compounds were tentatively identified and attributed, with 40 among these being unambiguously characterized in comparison with their corresponding authentic standards. To further determine the major representative constituents of the Shabyar tablet, a quantitative method was used for the simultaneous analysis of 33 characteristic components in Shabyar samples. The results were validated in terms of linearity, precision, repeatability, stability, and recovery. This newly developed approach could be successfully employed for evaluating the holistic quality of crude extracts and Chinese medicines in the Shabyar compound tablet and provide a solid chemical foundation for additional investigations on in vivo pharmacodynamics and therapeutic mechanisms to identify the potential effective components of traditional medicines.

Ultra-minimally Invasive Sonographically-guided Trigger Digit Release: An External Pilot Study.

ObjectivesThe most common surgical option for releasing the first annular pulley in trigger digit (TD) is classic open surgery followed by blind percutaneous release. However, they have been related to major complications and incomplete releases, respectively. Intrasheath sonographically-guided first annular pulley release has recently been shown to be safe and effective in every digit. The objectives of this pilot study were to preliminary compare clinically an intrasheath sonographically-guided first annular pulley release versus a classic open technique and to evaluate the feasibility of a future clinical trial in patients with TDs.MethodsThirty patients were randomized 1:1 in an external pilot study comparing the two surgical techniques: a percutaneous sonographically-guided release performed through a 1 mm incision using a hook knife versus a classic open surgery with a 1 cm incision. Inclusion criteria were primary TD grade III (Froimson). We defined success if primary (safety and efficacy) and secondary (recruitment rates, compliance, completion, treatment blinding, personnel resources, and sample size calculation for the clinical trial) objectives could be matched. We registered the grip strength, the QuickDASH score and a set of postoperative clinical variables at one, three, and six weeks and at three months. We calculated the sample size for the clinical trial using the QuickDASH at the end of the follow-up. Outcomes assessors were blinded.ResultsAll patients in both groups showed resolution of their symptoms with no associated complications or relapses. Secondary feasibility objectives were matched: 76.9% of eligible patients were included in the study, 3.3% refused randomization, 20 patients per month were recruited, 100% received blinded treatment, 98.5% showed compliance, and 100% completed the study. The sample size for a future clinical trial was 84 patients. There were no differences in grip strength. The intrasheath sonographically-guided first annular pulley release showed significantly better QuickDASH scores, until the sixth postoperative week.ConclusionsThe intrasheath sonographically-guided first annular pulley release is safe and efficacious, and shows a trend toward clinical superiority versus the classic open procedure, which should be confirmed with a clinical trial. Our study shows that a randomized clinical trial is feasible.

Reply to: Challenging the paradigm.

Inhaled corticosteroids should be targeted to those with documented airway eosinophilia, not prescribed indiscriminately to all who wheeze. Blind steroid treatment without regard to underlying pathophysiology is not 21st century standard of care. https://bit.ly/34lyaJG

Bio-fabrication of stem-cell-incorporated corneal epithelial and stromal equivalents from silk fibroin and gelatin-based biomaterial for canine corneal regeneration.

Corneal grafts are the imperative clinical treatment for canine corneal blindness. To serve the growing demand, this study aimed to generate tissue-engineered canine cornea in part of the corneal epithelium and underlying stroma based on canine limbal epithelial stem cells (cLESCs) seeded silk fibroin/gelatin (SF/G) film and canine corneal stromal stem cells (cCSSCs) seeded SF/G scaffold, respectively. Both cell types were successfully isolated by collagenase I. SF/G corneal films and stromal scaffolds served as the prospective substrates for cLESCs and cCSSCs by promoting cell adhesion, cell viability, and cell proliferation. The results revealed the upregulation of tumor protein P63 (P63) and ATP-binding cassette super-family G member 2 (Abcg2) of cLESCs as well as Keratocan (Kera), Lumican (Lum), aldehyde dehydrogenase 3 family member A1 (Aldh3a1) and Aquaporin 1 (Aqp1) of differentiated keratocytes. Moreover, immunohistochemistry illustrated the positive staining of tumor protein P63 (P63), aldehyde dehydrogenase 3 family member A1 (Aldh3a1), lumican (Lum) and collagen I (Col-I), which are considerable for native cornea. This study manifested a feasible platform to construct tissue-engineered canine cornea for functional grafts and positively contributed to the body of knowledge related to canine corneal stem cells.

MIRIKIZUMAB REDUCES ABDOMINAL PAIN IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE CROHN’S DISEASE

Abstract BACKGROUND Mirikizumab (miri), an anti-IL-23p19 inhibitor, has demonstrated efficacy in patients with ulcerative colitis and moderately to severely active Crohn’s disease (CD) in a Phase 2, randomised, double-blind, placebo-controlled study (NCT02891226). This analysis evaluated the effect of miri versus placebo (PBO) on worst abdominal pain (AP) utilising an 11-point AP Numeric Reporting Scale (AP NRS). METHODS During induction, patients were randomised 2:1:1:2 to receive PBO, 200mg, 600mg, or 1000mg miri administered intravenously (IV) every four weeks (Q4W). At week (W)12, patients entered a blinded maintenance treatment. Patients who received miri during induction and achieved ≥1 point improvement in Simple Endoscopic Score for Crohn’s Disease (SES-CD) at W12 were randomised 1:1 to either continue induction treatment (IV 200mg, 600mg, 1000mg miri Q4W) or receive 300mg miri Q4W administered subcutaneously (SC) for 40W (maintenance). Because of small patient numbers, the randomised maintenance groups results were combined for those who continued the same IV induction treatment (All IV-C) and those who were randomised to SC treatment (All SC). SES-CD non-improvers (NI/1000mg IV Miri) and patients who received PBO (PBO/1000mg IV Miri) during induction received 1000mg miri IV Q4W during maintenance. Patients recorded “worst AP in the past 24 hours” each day using an 11-point AP NRS (0=no pain to 10=worst possible pain) on an electronic diary. The Pain NRS is a valid, reliable, and responsive patient reported outcome that can be used to assess pain among patients with CD. Weekly average score was calculated and compared to placebo using a mixed model for repeated measures (MMRM) for visits in the induction period. Observed change in Pain NRS is presented for maintenance. RESULTS Significant reduction in AP NRS was reported by patients treated with 600mg miri compared to patients treated with placebo at W8 (least square mean difference ± standard error [95% confidence interval]: -1.01 ± 0.4 [-1.87, -0.14], p=0.02) (Table 1) and in all miri treatment groups: 200mg (-0.92 ± 0.4 [-1.80, -0.03], p=0.04), 600mg (-1.23 ± 0.4 [-2.11, -0.36], p=0.006) and 1000mg (-0.86 ± 0.4 [-1.57, -0.15], p=0.02) miri versus PBO at W12 (Table 1). Patients who received miri during induction continued to show improvements at W52 (Table 1). Patients treated with PBO/1000mg IV during maintenance reported similar improvements to patients who received miri from W0-52 (Table 1). CONCLUSION Using an 11-point Abdominal Pain Numeric Reporting Scale, mirikizumab treatment was associated with statistically significant improvements in abdominal pain when compared to placebo after 12 weeks in patients with moderately to severely active Crohn’s disease. Additional numeric reductions in abdominal pain were observed through 52 weeks in all mirikizumab treated patient groups.