Subcutaneous Infliximab (CT-P13) as Maintenance Therapy for Inflammatory Bowel Disease: 2 Randomized Phase 3 Trials.

BACKGROUND & AIMS: CT-P13 subcutaneous (SC), an SC formulation of the intravenous (IV) infliximab biosimilar CT-P13 IV, creates a unique exposure profile. We aimed to demonstrate superiority of CT-P13 SC vs placebo as maintenance therapy in patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: Two randomized, placebo-controlled, double-blind studies were conducted in patients with moderately to severely active CD or UC and inadequate response or intolerance to corticosteroids and immunomodulators. All patients received open-label CT-P13 IV 5 mg/kg at weeks 0, 2, and 6. At week 10, clinical responders were randomized (2:1) to CT-P13 SC 120 mg or placebo every 2 weeks until week 54 (maintenance phase) using prefilled syringes. Co-primary end points were clinical remission and endoscopic response (CD) and clinical remission (UC) at week 54 (all-randomized population). RESULTS: Overall, 396 patients with CD and 548 patients with UC received induction treatment. At week 54 in the CD study, statistically significant higher proportions of CT-P13 SC-treated patients vs placebo-treated patients achieved clinical remission (62.3% vs 32.1%; P < .0001) and endoscopic response (51.1% vs 17.9%; P < .0001). In the UC study, clinical remission rates at week 54 were statistically significantly higher with CT-P13 SC vs placebo (43.2% vs 20.8%; P < .0001). Achievement of key secondary end points was significantly higher with CT-P13 SC vs placebo across both studies. CT-P13 SC was well tolerated, with no new safety signals identified. CONCLUSIONS: CT-P13 SC was more effective than placebo as maintenance therapy and was well tolerated in patients with moderately to severely active CD or UC who responded to CT-P13 IV induction. CLINICALTRIALS: gov, Numbers: NCT03945019 (CD) and NCT04205643 (UC).

Potential Antioxidant and Anti-Inflammatory Properties of Polyphenolic Compounds from Cirsium japonicum Extract.

Cirsium japonicum is a medicinal plant that has been used due to its beneficial properties. However, extensive information regarding its therapeutic potential is scarce in the scientific literature. The antioxidant and anti-inflammatory potential of polyphenols derived from the Cirsium japonicum extracts (CJE) was systematically analyzed. High-performance liquid chromatography (HPLC) with mass spectrometry (MS) was used to examine the compounds in CJE. A total of six peaks of polyphenol compounds were identified in the extract, and their MS data were also confirmed. These bioactive compounds were subjected to ultrafiltration with LC analysis to assess their potential for targeting cyclooxygenase-2 (COX2) and DPPH. The outcomes showed which primary compounds had the highest affinity for binding both COX2 and DPPH. This suggests that components that showed excellent binding ability to DPPH and COX2 can be considered significant active substances. Additionally, in vitro analysis of CJE was carried out in macrophage cells after inducing inflammation with lipopolysaccharide (LPS). As a result, it downregulated the expression of two critical pro-inflammatory cytokines, COX2 and inducible nitric oxide synthase (iNOS). In addition, we found a solid binding ability through the molecular docking analysis of the selected compounds with inflammatory mediators. In conclusion, we identified polyphenolic compounds in CJE extract and confirmed their potential antioxidant and anti-inflammatory effects. These results may provide primary data for the application of CJE in the food and pharmaceutical industries with further analysis.

Accelerated settling velocity of airborne particulate matter on hairy plant leaves.

Phytoremediation has emerged as an ecofriendly technique to reduce hazardous particulate matter (PM) in the air. Although previous studies have conducted statistical analyses to reveal PM removal capabilities of various plant species according to their leaf characteristics, the underlying physical mechanism of PM adsorption of plants remains unclear. Conventional methodologies for measuring PM accumulation usually require long-term field tests and provide limited understanding on PM removal effects of individual leaf traits of various plants. In this study, we propose a novel methodology which can compare the electrostatic interactions between PMs and plant leaves according to their trichome structures by using digital in-line holographic microscopy (DIHM). Surface characteristics of Perilla frutescens and Capsicum annuum leaves are measured to examine electrostatic effects according to the morphological features of trichomes. 3D settling motions of PMs near the microstructures of trichomes of the two plant species are compared in detail. To validate the PM removal effect of the hairy microstructures, a polydimethylsiloxane (PDMS) replica model of a P. frutescens leaf is fabricated to demonstrate accelerated settling velocities of PMs near trichome-like microstructures. The size and electric charge distributions of PMs with irregular shapes are analyzed using DIHM. Numerical simulation of the PM deposition near a trichome-like structure is conducted to verify the empirical results. As a result, the settling velocities of PMs on P. frutescens leaves and a PDMS replica sample are 12.11 ± 1.88% and 34.06 ± 4.19% faster than those on C. annuum leaves and a flat PDMS sample, respectively. These findings indicate that the curved microstructures of hairy trichomes of plant leaves increase the ability to capture PMs by enhancing the electric field intensity just near trichomes. Compared with conventional methods, the proposed methodology can quantitatively evaluate the settling velocity of PMs on various plant leaves according to the morphological structure and density of trichomes within a short period of time. The present research findings would be widely utilized in the selection of suitable air-purifying plants for sustainable removal of harmful air pollutants in urban and indoor environments.

Rod photoreceptor clearance due to misfolded rhodopsin is linked to a DAMP-immune checkpoint switch.

Chronic endoplasmic reticulum stress resulting from misfolding of the visual pigment rhodopsin (RHO) can lead to loss of rod photoreceptors, which initiates retinitis pigmentosa, characterized initially by diminished nighttime and peripheral vision. Cone photoreceptors depend on rods for glucose transport, which the neurons use for assembly of visual pigment-rich structures; as such, loss of rods also leads to a secondary loss of cone function, diminishing high-resolution color vision utilized for tasks including reading, driving, and facial recognition. If dysfunctional rods could be maintained to continue to serve this secondary cone preservation function, it might benefit patients with retinitis pigmentosa, but the mechanisms by which rods are removed are not fully established. Using pigs expressing mutant RHO, we find that induction of a danger-associated molecular pattern (DAMP) "eat me" signal on the surface of mutant rods is correlated with targeting the live cells for (PrCR) by retinal myeloid cells. Glucocorticoid therapy leads to replacement of this DAMP with a "don't eat me" immune checkpoint on the rod surface and inhibition of PrCR. Surviving rods then continue to promote glucose transport to cones, maintaining their viability.

Randomized Controlled Trial: Subcutaneous vs Intravenous Infliximab CT-P13 Maintenance in Inflammatory Bowel Disease.

BACKGROUND & AIMS: This study compared pharmacokinetics, symptomatic and endoscopic efficacy, safety, and immunogenicity of a subcutaneous formulation of the infliximab biosimilar CT-P13 (CT-P13 SC) vs intravenous CT-P13 (CT-P13 IV) in patients with inflammatory bowel disease (IBD). METHODS: This randomized, multicenter, open-label, parallel-group, phase 1 study enrolled tumor necrosis factor inhibitor-naïve patients with active ulcerative colitis (total Mayo score 6-12 points with endoscopic subscore ≥2) or Crohn's disease (Crohn's Disease Activity Index 220-450 points) at 50 centers. After CT-P13 IV induction at Week (W) 0/W2, patients were randomized (1:1) to receive CT-P13 SC every 2 weeks (q2w) from W6 to W54 or CT-P13 IV every 8 weeks from W6 to W22. At W30, all patients receiving CT-P13 IV switched to CT-P13 SC q2w until W54. The primary endpoint was noninferiority of CT-P13 SC to CT-P13 IV for observed predose CT-P13 concentration at W22 (Ctrough,W22), concluded if the lower bound of the 2-sided 90% confidence interval (CI) for the ratio of geometric least-squares means exceeded 80%. RESULTS: Overall, 66 and 65 patients were randomized to CT-P13 SC and CT-P13 IV, respectively. The primary endpoint of noninferiority was met with a geometric least-squares means ratio for Ctrough,W22 of 1154.17% (90% CI 786.37-1694.00; n = 59 [CT-P13 SC]; n = 57 [CT-P13 IV]). W30/W54 clinical remission rates were comparable between arms. Other efficacy, safety, and immunogenicity assessments were also broadly comparable between arms, including after switching. CONCLUSIONS: The pharmacokinetic noninferiority of CT-P13 SC to CT-P13 IV, and the comparable efficacy, safety, and immunogenicity profiles, support the potential suitability of CT-P13 SC treatment in IBD. ClinicalTrials.gov ID: NCT02883452.

Efficacy and safety of switching from reference adalimumab to CT-P17 (100 mg/ml): 52-week randomized, double-blind study in rheumatoid arthritis.

OBJECTIVE: To compare the safety and efficacy of switching from reference adalimumab to adalimumab biosimilar CT-P17 with continuing reference adalimumab/CT-P17 in active RA. METHODS: This double-blind, phase III study randomized (1:1) subjects with active RA to receive 40 mg (100 mg/ml) CT-P17 or European Union-sourced reference adalimumab subcutaneously every 2 weeks (Q2W) until week (W) 24 [treatment period (TP) 1]. Thereafter, subjects receiving reference adalimumab were randomized (1:1) to continue reference adalimumab or switch to CT-P17 from W26 (both Q2W until W48; TP2). Subjects receiving CT-P17 in TP1 continued CT-P17. W0-W24 results were previously reported; we present W26-W52 findings. End points were efficacy (including joint damage progression), pharmacokinetics, safety and immunogenicity. RESULTS: Of 607 subjects who initiated TP2 treatment, 303 continued CT-P17, 153 continued reference adalimumab and 151 switched to CT-P17. Efficacy improvements up to W24 were maintained during TP2; efficacy was comparable among groups. At W52, 20% improvement in ACR response rates were 80.5% (continued CT-P17), 77.8% (continued reference adalimumab) and 82.2% (switched to CT-P17). Joint damage progression was minimal. Mean trough serum adalimumab concentrations were similar among groups. CT-P17 and reference adalimumab safety profiles were numerically similar and switching did not affect immunogenicity. At W52, 28.4% (continued CT-P17), 27.0% (continued reference adalimumab) and 28.3% (switched to CT-P17) of subjects were anti-drug antibody-positive. CONCLUSION: Efficacy, pharmacokinetics, safety and immunogenicity of CT-P17 and reference adalimumab were comparable after 1 year of treatment, including after switching from reference adalimumab to CT-P17. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT03789292.

Association between ARID2 and RAS-MAPK pathway in intellectual disability and short stature.

BACKGROUND: ARID2 belongs to the Switch/sucrose non-fermenting complex, in which the genetic defects have been found in patients with dysmorphism, short stature and intellectual disability (ID). As the phenotypes of patients with ARID2 mutations partially overlap with those of RASopathy, this study evaluated the biochemical association between ARID2 and RAS-MAPK pathway. METHODS: The phenotypes of 22 patients with either an ARID2 heterozygous mutation or haploinsufficiency were reviewed. Comprehensive molecular analyses were performed using somatic and induced pluripotent stem cells (iPSCs) of a patient with ARID2 haploinsufficiency as well as using the mouse model of Arid2 haploinsufficiency by CRISPR/Cas9 gene editing. RESULTS: The phenotypic characteristics of ARID2 deficiency include RASopathy, Coffin-Lowy syndrome or Coffin-Siris syndrome or undefined syndromic ID. Transient ARID2 knockout HeLa cells using an shRNA increased ERK1 and ERK2 phosphorylation. Impaired neuronal differentiation with enhanced RAS-MAPK activity was observed in patient-iPSCs. In addition, Arid2 haploinsufficient mice exhibited reduced body size and learning/memory deficit. ARID2 haploinsufficiency was associated with reduced IFITM1 expression, which interacts with caveolin-1 (CAV-1) and inhibits ERK activation. DISCUSSION: ARID2 haploinsufficiency is associated with enhanced RAS-MAPK activity, leading to reduced IFITM1 and CAV-1 expression, thereby increasing ERK activity. This altered interaction might lead to abnormal neuronal development and a short stature.

Nicotine Affects Murine Aortic Stiffness and Fatigue Response During Supraphysiological Cycling.

Nicotine exposure is a major risk factor for several cardiovascular diseases. Although the deleterious effects of nicotine on aortic remodeling processes have been studied to some extent, the biophysical consequences are not fully elucidated. In this investigation, we applied quasi-static and dynamic loading to quantify ways in which exposure to nicotine affects the mechanical behavior of murine arterial tissue. Segments of thoracic aortas from C57BL/6 mice exposed to 25 mg/kg/day of subcutaneous nicotine for 28 days were subjected to uniaxial tensile loading in an open-circumferential configuration. Comparing aorta segments from nicotine-treated mice relative to an equal number of control counterparts, stiffness in the circumferential direction was nearly twofold higher (377 kPa ± 165 kPa versus 191 kPa ± 65 kPa, n = 5, p = 0.03) at 50% strain. Using a degradative power-law fit to fatigue data at supraphysiological loading, we observed that nicotine-treated aortas exhibited significantly higher peak stress, greater loss of tension, and wider oscillation band than control aortas (p ≤ 0.01 for all three variables). Compared to simple stress relaxation tests, fatigue cycling is shown to be more sensitive and versatile in discerning nicotine-induced changes in mechanical behavior over many cycles. Supraphysiological fatigue cycling thus may have broader potential to reveal subtle changes in vascular mechanics caused by other exogenous toxins or pathological conditions.

Long-term efficacy and safety of CT-P6 versus trastuzumab in patients with HER2-positive early breast cancer: final results from a randomized phase III trial.

PURPOSE: Equivalent efficacy was demonstrated for the biosimilar CT-P6 and trastuzumab following neoadjuvant therapy for patients with human epidermal growth factor receptor-2 (HER2)-positive early breast cancer. Following adjuvant treatment, efficacy and safety were comparable between treatments. We report updated safety and efficacy data after up to 3 years' follow-up. METHODS: Following neoadjuvant chemotherapy with CT-P6/trastuzumab, patients underwent surgery and continued receiving adjuvant CT-P6/trastuzumab. The primary endpoint (previously reported) was pathological complete response. Time-to-event analyses (disease-free survival [DFS], progression-free survival [PFS], and overall survival [OS]), study drug-related and cardiac adverse events, and immunogenicity were assessed during post-treatment follow-up. RESULTS: Most patients entered the follow-up period (CT-P6: 259 [95.6%]; trastuzumab: 269 [96.8%]). After a median follow-up of 38.7 (CT-P6) and 39.6 (trastuzumab) months, medians were not reached for time-to-event parameters; estimated hazard ratios (HRs) and 3-year survival rates were similar between groups. Estimated HRs (95% confidence intervals) for CT-P6 versus trastuzumab were 1.23 (0.78-1.93) for DFS, 1.31 (0.86-2.01) for PFS, and 1.10 (0.57-2.13) for OS (intention-to-treat population). Safety findings were comparable between groups for the overall study and follow-up period, including study drug-related cardiac disorders (CT-P6: 22 [8.1%] patients; trastuzumab: 24 [8.6%] patients [overall]) and decreases in left ventricular ejection fraction. Immunogenicity was similar between groups. CONCLUSION: The similarity of the time-to-event analyses between CT-P6 and trastuzumab supports the equivalence in terms of efficacy established for the primary endpoint. CT-P6 was well tolerated, with comparable safety and immunogenicity to trastuzumab. ClinicalTrials.gov: NCT02162667 (registered June 13, 2014).

Domino-like water transport on Tillandsia through flexible trichome wings.

Tillandsia usneoides in epiphytic bromeliads takes up water through absorptive trichomes on the shoot surface under extreme environmental conditions. Although previous studies revealed the way by which T. usneoides absorbs water and prevents water loss, its water transport remains unclear. We characterized structures of trichome wings of T. usneoides. Wing length-to-thickness ratio of 136 and trichome interval (d)-to-wing length (l) ratio (d/l) smaller than 1 caused the water film to flatten the wings sequentially, resulting in domino-like water transport. A hinge-like linkage between wing and outer ring cells and the wing size longer than the elastocapillary length (LEC ) brought about this unique reconfiguration, which is the flattening and recovery of wings. Tillandsia usneoides transported water rapidly on the surface as the water film propagated on the exterior trichomes with flexible wings and the transport distance at the macroscopic scale grew as tx with x = 0.68 ± 0.04, unlike the conventional scaling of t0.5 . Empirical and theoretical investigations proved our assumption that external water transport with the domino-like effect predominated over internal vascular transport. Biomimetic trichome wings simulated the domino-like water transport, highlighting the important role of flexible wing arrays.

Efficacy, pharmacokinetics and safety of subcutaneous versus intravenous CT-P13 in rheumatoid arthritis: a randomized phase I/III trial.

OBJECTIVE: To assess non-inferiority of s.c. to i.v. CT-P13 in RA. METHODS: Patients with active RA and inadequate response to MTX participated in this phase I/III double-blind study at 76 sites. Patients received CT-P13 i.v. 3 mg/kg [week (W) 0 and W2] before randomization (1:1) at W6 to CT-P13 s.c. via pre-filled syringe (PFS) 120 mg biweekly until W28, or CT-P13 i.v. 3 mg/kg every 8 weeks until W22. Randomization was stratified by country, W2 serum CRP and W6 body weight. From W30, all patients received CT-P13 s.c. In a usability sub-study, patients received CT-P13 s.c. via auto-injector (W46-54) then PFS (W56-64). The primary endpoint was change (decrease) from baseline in disease activity score in 28 joints (DAS28)-CRP at W22 (non-inferiority margin: -0.6). RESULTS: Of 357 patients enrolled, 343 were randomized to CT-P13 s.c. (n = 167) or CT-P13 i.v. (n = 176) at W6. The least-squares mean change (decrease) from baseline (standard error) in DAS28-CRP at W22 was 2.21 (0.22) for CT-P13 s.c. (n = 162) and 1.94 (0.21) for CT-P13 i.v. [n = 168; difference 0.27 (95% CI: 0.02, 0.52)], establishing non-inferiority. Efficacy findings were similar between arms at W54. Safety was similar between arms throughout: 92 (54.8%; CT-P13 s.c.) and 117 (66.9%; CT-P13 i.v.) patients experienced treatment-emergent adverse events (from W6). There were no treatment-related deaths or new safety findings. Usability was similar for CT-P13 s.c. via auto-injector or PFS. CONCLUSION: CT-P13 s.c. was non-inferior to CT-P13 i.v. in active RA. The convenience of s.c. administration could benefit patients. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT03147248.

Randomised, phase I pharmacokinetic study of adalimumab biosimilar CT-P17 (40 mg/0.4 mL) by autoinjector and prefilled syringe in healthy subjects.

AIMS: To evaluate pharmacokinetic equivalence and preliminary safety of the adalimumab biosimilar CT-P17 administered via autoinjector (CT-P17 AI) or prefilled syringe (CT-P17 PFS) in healthy subjects. METHODS: This phase I, open-label study (ClinicalTrials.gov: NCT04295356) randomised subjects (1:1) to receive a single 40-mg (100 mg/mL) dose of CT-P17 AI or CT-P17 PFS. Primary endpoint was pharmacokinetic equivalence of CT-P17 AI to CT-P17 PFS for: area under the concentration-time curve from time zero to infinity (AUC0-inf ); area under the concentration-time curve from time zero to the last quantifiable concentration (AUC0-last ); maximum serum concentration (Cmax ). Equivalence was determined if the 90% confidence interval for the geometric least-squares mean ratio was within the 80-125% equivalence margin. Additional pharmacokinetic endpoints, safety and immunogenicity were evaluated. RESULTS: Of 193 subjects who were randomised (98 CT-P17 AI; 95 CT-P17 PFS), 180 received study drug. Pharmacokinetic equivalence was demonstrated: 90% confidence intervals were within the 80-125% equivalence margin (AUC0-inf : 93.98-114.29; AUC0-last : 91.09-121.86; Cmax : 94.08-111.90). Mean serum CT-P17 concentrations, secondary pharmacokinetic parameters and numbers of subjects with antidrug antibodies (ADAs) or neutralising ADAs were comparable between groups. AUC0-inf , AUC0-last and Cmax were numerically lower for ADA-positive than for ADA-negative subjects (both groups); pharmacokinetic equivalence was also demonstrated among ADA-positive subjects. CT-P17 AI and CT-P17 PFS were well tolerated, with comparable overall safety profiles. CONCLUSIONS: CT-P17 AI and CT-P17 PFS were pharmacokinetically equivalent. Overall safety and immunogenicity were comparable between the 2 delivery devices.

INFECTIOUS ENDOPHTHALMITIS AFTER SCLERAL FIXATION OF AN INTRAOCULAR LENS.

PURPOSE: To determine the mechanism of infection, clinical features, and risk factors of endophthalmitis after scleral fixation of an intraocular lens. METHODS: We included 15 patients with infectious endophthalmitis after scleral fixation of an intraocular lens between April 2004 and December 2017, as well as four patients found through a literature search. Thus, a total of 19 patients were analyzed. RESULTS: Among 19 eyes, infectious endophthalmitis developed at a mean of 23 months (range: 1 day-10 years) after scleral fixation surgery. Nine eyes (47.4%) had early-onset endophthalmitis (≤6 weeks), and 10 eyes (52.6%) had delayed-onset endophthalmitis (>6 weeks). Eleven eyes (57.9%) had presumed microbial influx due to suture exposure. Those with delayed-onset endophthalmitis showed a higher rate of suture-related infection (80.0% vs. 33.3%) and culture of gram-negative bacteria (70.0% vs. 12.5%) than did those with early-onset endophthalmitis. CONCLUSIONS: Infectious endophthalmitis can develop late after scleral fixation of an intraocular lens, usually related to the exposed sutures, and the visual prognosis is poor. Eyes that have sutured scleral fixation should be monitored regularly, and preventive measures should be performed if an exposed suture is found.

Title: efficacy of intravitreal dexamethasone implant on hard exudate in diabetic macular edema.

BACKGROUND: To investigate the effect of intravitreal dexamethasone implant (DEX implant) on hard exudate (HE) accompanying diabetic macular edema (DME). METHODS: This study was a non-comparative non-randomized 1-year prospective interventional study. Patients with DME and HE were treated using DEX implant two or three times. Color fundus photography and optical coherence tomography (OCT) were performed at every visit. HE area was measured semi-automatically from the fundus photographs. RESULTS: Thirty-five patients completed the study. Eleven patients (31.4%) received two injections, while the remaining received three times. HE area (primary outcome) significantly decreased from 1.404±2.094 mm2 (baseline) to 0.212±0.592 mm2 (last visit), which was 24% of the baseline HE area (P<0.001). HE1500 (HE within 1500 µm from the fovea) area also decreased significantly from 0.382±0.467 mm2 to 0.066±0.126 mm2 (P<0.001). Furthermore, anaverage best corrected visual acuity (BCVA) improvement of 4.4 Early Treatment Diabetic Retinopathy Study (ETDRS) letters was observed (from 49.9±18.3 to 54.3±20.4 letters) (P= 0.008). Central macular thickness (CMT) decreased from 455.8±23.6 µm to 366.8±31.1 µm (P=0.009). Repetitive measurements for entire study duration was analyzed using generalized estimating equations (GEE), where BCVA was related to age, CMT, and HE1500 area in multivariate analyses. CONCLUSION: DEX implant could reduce and suppress HE in DME for one year with two or three injections. And centrally located HE area (HE1500 area) is related to vision. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02399657 , Registered 26 March 2015.

Effectual removal of indoor ultrafine PM using submicron water droplets.

Exposure to ultrafine airborne particulate matter (PM1.0) poses a significant risk to human health and well-being. Examining the effect of submicron water droplets on the removal of ultrafine PM is timely and important for mitigating indoor ultrafine PM, which is difficult to filter out from incoming air. In this study, submicron water droplets were made by using a nanoporous membrane and an ultrasonic module of a commercial household ultrasonic humidifier (UH) for effectual ultrafine PM removal. The effect of water droplet size on indoor PM removal was experimentally investigated. Variations in the normalized PM concentration, removal efficiency and deposition constants were evaluated by analyzing the temporal variation in PM concentration inside a test chamber. The measured PM deposition constants were compared with the results of other previous studies. As a result, submicron water droplets of 800 nm in mean diameter were generated by ultrasonic module combined passive nanoporous membrane, and PM1.0 concentration decreased by 30% in the initial 30 min. Compared with micron-sized water droplets, PM1.0 removal efficiency improved by approximately two times higher. Moreover, the substitution of the experimental results into a theoretical model ascertained that PM collection efficiency is increased by approximately 103 levels as the size of water droplets decreases. These results would be utilized in the development and implementation of effective strategies for indoor PM removal.

Efficacy and safety of biosimilar CT-P13 compared with originator infliximab in patients with active Crohn's disease: an international, randomised, double-blind, phase 3 non-inferiority study.

BACKGROUND: The infliximab biosimilar CT-P13 was approved for use in Crohn's disease after clinical comparison with originator infliximab in ankylosing spondylitis and rheumatoid arthritis; however, concerns about such indication extrapolation have been expressed. This study investigated whether CT-P13 is non-inferior to infliximab in patients with Crohn's disease who were naive to biological therapy. METHODS: In this randomised, multicentre, double-blind, phase 3 non-inferiority study, we enrolled patients with active Crohn's disease who had not responded to, or were intolerant to, non-biological treatments. Patients were randomly assigned (1:1:1:1) to receive CT-P13 then CT-P13, CT-P13 then infliximab, infliximab then infliximab, or infliximab then CT-P13, with switching occurring at week 30. Patients received 5 mg/kg CT-P13 or infliximab at weeks 0, 2, 6, and then every 8 weeks up to week 54. The primary endpoint was the proportion of patients with a decrease of 70 points or more in Crohn's Disease Activity Index (CDAI) from baseline to week 6. A non-inferiority margin of -20% was set (CT-P13 was non-inferior to infliximab if the lower limit of the two-sided 95% CI for the treatment difference was greater than -20). This trial is registered with ClinicalTrials.gov, number NCT02096861, and is completed. FINDINGS: Between Aug 20, 2014, and Feb 15, 2017, 308 patients were assessed for eligibility, and 220 patients were enrolled: 111 were randomly assigned to initiate CT-P13 (56 to the CT-P13-CT-P13 group and 55 to the CT-P13-infliximab group) and 109 to initiate infliximab (54 to the infliximab-infliximab group and 55 to the infliximab-CT-P13 group). CDAI-70 response rates at week 6 were similar for CT-P13 (77 [69·4%, 95% CI 59·9 to 77·8] of 111) and infliximab (81 [74·3%, 95% CI 65·1 to 82·2] of 109; difference -4·9% [95% CI -16·9 to 7·3]), thereby establishing non-inferiority. Over the total study period, 147 (67%) patients experienced at least one treatment-emergent adverse event (36 [64%] in the CT-P13-CT-P13 group, 34 [62%] in the CT-P13-infliximab group, 37 [69%] in the infliximab-infliximab group, and 40 [73%] in the infliximab-CT-P13 group). INTERPRETATION: This study showed non-inferiority of CT-P13 to infliximab in patients with active Crohn's disease. Biosimilar CT-P13 could be a new option for the treatment of active Crohn's disease. FUNDING: Celltrion, Pfizer.

Nanoscale element behavior in a continuum.

Patterns in materials are not just decoration but also important for function. In view of this, the dynamics of patterning procedures in materials has been investigated as an important developmental procedure. In this study, nanoscale components in a continuum are traced in terms of natural patterning procedures. Externally applied compressive or extensive forces to an elastic thin sheet commonly induce an orientated lateral line pattern. From a nanoscale element point of view, the dynamics of natural arrangements, forming anisotropic patterns in preference to isotropy, still remains unclear. In this study, new developmental procedures for line patterns are suggested by stimuli-responsive viscoelastic nanocomposite network model systems. Forces originating from an internal source without directional orientation generate lines in preference to isotropic patterns. With repeated, non-oriented (or isotropic) and self-modulated strain variations, stress is accumulated to drive anisotropic orientations and further lines. The anisotropic elemental arrangement is justified by the equilibrium between the short-range attraction and long-range repulsion from a bottom-up viewpoint. This study suggests a new material design methodology that is useful for electrical devices, biomedical devices and other patterned soft condensed matter in conjunction with line patterns typically generated in a broad range of viscoelastic materials.

Some thoughts on the QR method for analytical similarity evaluation.

As indicated in a recent published draft guidance on comparative analytical assessment, the United States (US) Food and Drug Administration (FDA) seems to suggest the use of quality range (QR) method for analytical similarity evaluation. It is a concern that the use of QR method for analytical similarity evaluation could potentially approve biological products which are not deemed biosimilar to the reference biological products. In this article, the limitations and potential risk for the use of the QR method for analytical similarity evaluation are discussed. Alternatively, two modified versions of the QR method, which are referred to as effect size (ES) mQR and plausibility interval (PI) mQR methods are suggested. The performance and statistical properties of the mQR methods are evaluated via extensive clinical trial simulation under various scenarios. The results indicate that the modified versions of the QR method not only overcome the limitations of the QR method for analytical similarity evaluation, but also can potentially help in detecting reference product changes during manufacturing process.

One-Year Results of Treatment of Diabetic Macular Edema with Aflibercept Using the Treat-and-Extend Dosing Regimen: the VIBIM Study.

INTRODUCTION: The purpose of this study was to report the one-year results of treatment of diabetic macular edema (DME) with aflibercept using a treat-and-extend regimen (TER). METHODS: This was a prospective, multicenter, single-arm study planned for 2 years. The eyes received 5 consecutive intravitreal injections of 2 mg of aflibercept every 4 weeks, and the interval between injections was then adjusted by 2 weeks based on changes in the central subfield macular thickness (CSMT). If the CSMT was worse, stable, or better, the interval was shortened, extended, or maintained, respectively. The primary outcome measure was the change in best-corrected visual acuity (BCVA) from baseline to 104 weeks, and the secondary outcome was the change in BCVA from baseline to 52 weeks. RESULTS: Of the 48 patients enrolled, 46 completed a 1-year visit. BCVA improved significantly by 9.1 letters (95% confidence interval: 5.3-13.0 letters) from 56.2 letters at baseline (p < 0.001), and CSMT decreased by -171.7 µm from 489.4 to 317.7 µm (p < 0.001). The proportion of eyes having 20/40 or better vision increased from 17.4 to 41.3%, and the proportion of eyes that gained ≥15 letters was 28.3%. The mean number of injections was 8.5 times for 52 weeks. Worsening of macular edema did not occur in 76.1% of eyes during the extension period, and the interval between injections was extended to 12 weeks in 73.9% of eyes at 52 weeks. CONCLUSIONS: The TER showed 1-year efficacy comparable to that of the fixed dosing regimen of pivotal trials, and its flexible dosing would prevent overtreatment.

Use of 3D Human Liver Organoids to Predict Drug-Induced Phospholipidosis.

Drug-induced phospholipidosis (PL) is a storage disorder caused by the formation of phospholipid-drug complexes in lysosomes. Because of the diversity of PL between species, human cell-based assays have been used to predict drug-induced PL in humans. We established three-dimensional (3D) human liver organoids as described previously and investigated their liver characteristics through multiple analyses. Drug-induced PL was initiated in these organoids and in monolayer HepG2 cultures, and cellular changes were systemically examined. Organoids that underwent differentiation showed characteristics of hepatocytes rather than HepG2 cells. The organoids also survived under PL-inducing drug conditions for 48 h and maintained a more stable albumin secretion level than the HepG2 cells. More cytoplasmic vacuoles were observed in organoids and HepG2 cells treated with more potent PL-induced drugs, but to a greater extent in organoids than in HepG2 cells. Lysosome-associated membrane protein 2, a marker of lysosome membranes, showed a stronger immunohistochemical signal in the organoids. PL-distinctive lamellar bodies were observed only in amiodarone-treated organoids by transmission electron microscopy. Human liver organoids are thus more sensitive to drug-induced PL and less affected by cytotoxicity than HepG2 cells. Since PL is a chronic condition, these results indicate that organoids better reflect metabolite-mediated hepatotoxicity in vivo and could be a valuable system for evaluating the phospholipidogenic effects of different compounds during drug development.