Search

To reduce treatment burden and optimise patient outcomes in diabetic macular oedema, we present 1-year results from two phase 3 trials of faricimab, a novel angiopoietin-2 and vascular endothelial growth factor-A bispecific antibody.YOSEMITE and RHINE were randomised, double-masked, non-inferiority trials across 353 sites worldwide. Adults with vision loss due to centre-involving diabetic macular oedema were randomly assigned (1:1:1) to intravitreal faricimab 6·0 mg every 8 weeks, faricimab 6·0 mg per personalised treatment interval (PTI), or aflibercept 2·0 mg every 8 weeks up to week 100. PTI dosing intervals were extended, maintained, or reduced (every 4 weeks up to every 16 weeks) based on disease activity at active dosing visits. The primary endpoint was mean change in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Efficacy analyses included the intention-to-treat population (non-inferiority margin 4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); safety analyses included patients with at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (YOSEMITE NCT03622580 and RHINE NCT03622593).3247 patients were screened for eligibility in YOSEMITE (n=1532) and RHINE (n=1715). After exclusions, 940 patients were enrolled into YOSEMITE between Sept 5, 2018, and Sept 19, 2019, and 951 patients were enrolled into RHINE between Oct 9, 2018, and Sept 20, 2019. These 1891 patients were randomly assigned to faricimab every 8 weeks (YOSEMITE n=315, RHINE n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Non-inferiority for the primary endpoint was achieved with faricimab every 8 weeks (adjusted mean vs aflibercept every 8 weeks in YOSEMITE 10·7 ETDRS letters [97·52% CI 9·4 to 12·0] vs 10·9 ETDRS letters [9·6 to 12·2], difference -0·2 ETDRS letters [-2·0 to 1·6]; RHINE 11·8 ETDRS letters [10·6 to 13·0] vs 10·3 ETDRS letters [9·1 to 11·4] letters, difference 1·5 ETDRS letters [-0·1 to 3·2]) and faricimab PTI (YOSEMITE 11·6 ETDRS letters [10·3 to 12·9], difference 0·7 ETDRS letters [-1·1 to 2·5]; RHINE 10·8 ETDRS letters [9·6 to 11·9], difference 0·5 ETDRS letters [-1·1 to 2·1]). Incidence of ocular adverse events was comparable between faricimab every 8 weeks (YOSEMITE n=98 [31%], RHINE n=137 [43%]), faricimab PTI (n=106 [34%], n=119 [37%]), and aflibercept every 8 weeks (n=102 [33%], n=113 [36%]).Robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for faricimab to extend the durability of treatment for patients with diabetic macular oedema.F Hoffmann-La Roche.

Faricimab is a bispecific antibody that acts through dual inhibition of both angiopoietin-2 and vascular endothelial growth factor A. We report primary results of two phase 3 trials evaluating intravitreal faricimab with extension up to every 16 weeks for neovascular age-related macular degeneration (nAMD).TENAYA and LUCERNE were randomised, double-masked, non-inferiority trials across 271 sites worldwide. Treatment-naive patients with nAMD aged 50 years or older were randomly assigned (1:1) to intravitreal faricimab 6·0 mg up to every 16 weeks, based on protocol-defined disease activity assessments at weeks 20 and 24, or aflibercept 2·0 mg every 8 weeks. Randomisation was performed through an interactive voice or web-based response system using a stratified permuted block randomisation method. Patients, investigators, those assessing outcomes, and the funder were masked to group assignments. The primary endpoint was mean change in best-corrected visual acuity (BCVA) from baseline averaged over weeks 40, 44, and 48 (prespecified non-inferiority margin of four letters), in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (TENAYA NCT03823287 and LUCERNE NCT03823300).Across the two trials, 1329 patients were randomly assigned between Feb 19 and Nov 19, 2019 (TENAYA n=334 faricimab and n=337 aflibercept), and between March 11 and Nov 1, 2019 (LUCERNE n=331 faricimab and n=327 aflibercept). BCVA change from baseline with faricimab was non-inferior to aflibercept in both TENAYA (adjusted mean change 5·8 letters [95% CI 4·6 to 7·1] and 5·1 letters [3·9 to 6·4]; treatment difference 0·7 letters [-1·1 to 2·5]) and LUCERNE (6·6 letters [5·3 to 7·8] and 6·6 letters [5·3 to 7·8]; treatment difference 0·0 letters [-1·7 to 1·8]). Rates of ocular adverse events were comparable between faricimab and aflibercept (TENAYA n=121 [36·3%] vs n=128 [38·1%], and LUCERNE n=133 [40·2%] vs n=118 [36·2%]).Visual benefits with faricimab given at up to 16-week intervals demonstrates its potential to meaningfully extend the time between treatments with sustained efficacy, thereby reducing treatment burden in patients with nAMD.F Hoffmann-La Roche.

Cigarette smoking in patients with asthma leads to poor symptom control. As patients who are current smokers have been excluded from enrollment in many clinical trials on asthma, there are few reports on the treatment in current smokers with asthma. In this study, we aimed to assess how respiratory physicians manage asthma in current smokers in Japan.Respiratory physicians in 16 Japanese hospitals answered a questionnaire on treatment for patients with asthma between December 2014 and February 2015. Medical records were reviewed for 1756 patients with asthma.The mean patient age was 61.1 years, and 62.9% of the patients were female. A total of 102 patients (5.8%) were current smokers, and 546 patients (31.1%) were former smokers. Long-acting muscarinic antagonists (LAMA) were prescribed more frequently for current smokers with asthma than for former smokers and never smokers with asthma (10.8% vs 4.6%, p = 0.01, 10.8% vs 3.8%, p0.01). In contrast, macrolides were prescribed more frequently for former smokers and never smokers with asthma than for current smokers with asthma (7.7% vs 1.0%, p = 0.01, 6.4% vs 1.0%, p = 0.03). Triple therapy, i.e., inhaled corticosteroids, long-acting beta agonists, and LAMA concomitantly, was prescribed for current smokers with asthma more frequently than for former smokers and never smokers with asthma (9.8% vs 4.0%, p = 0.01, 9.8% vs 3.3%, p0.01).According to this survey, current smokers with asthma received more intensive therapy, including LAMA, than did former smokers with asthma.

Plants are constantly exposed to pathogens in their immediate environment. Plants sense the invasion of pathogens by recognizing the components including peptide fragments derived from pathogens, known as pathogen-associated molecular patterns (PAMPs). Plants also produce immunogenic peptides called phytocytokines that regulate immune responses. These molecules are recognized by pattern recognition receptors (PRRs) at plasma membrane. Activated PRRs induce a variety of immune responses including production of reactive oxygen species (ROS), induction of Ca2+ influx and activation of mitogen activated protein kinases (MAPKs). Pattern-triggered immunity (PTI) wards off microbes and pests. In this review, we summarize recent our advances in understanding how the peptide fragments are generated and perceived by plant PRRs at cell surface, and the activated PRRs transduce the downstream immune signaling.

SummaryThe nucleotide-binding domain and leucine-rich repeat-containing (NLR) family proteins recognize pathogen-derived molecules and trigger immune responses in both plants and animals. In plants, the direct or indirect recognition of specific pathogen effectors by NLRs culminates in a hypersensitive response (HR) and the production of reactive oxygen species (ROS), key components of the plant defense response. However, the molecules activated by NLRs and how they induce immune responses are largely unknown. We found that the rice GTPase OsRac1 at the plasma membrane interacts directly with Pit, an NLR protein that confers resistance to the rice blast fungus. OsRac1 contributes to Pit-mediated ROS production as well as the HR and is required for Pit-mediated disease resistance in rice. Furthermore, the active form of Pit induces the activation of OsRac1 at the plasma membrane. Thus, OsRac1 is activated by Pit during pathogen attack and plays a critical role in Pit-mediated immunity in rice.

Objective To describe a technique for suturing a luxated intraocular lens (IOL) in the vitreous cavity to the ciliary sulcus using intraocular cow hitch (girth) knots without IOL extraction. Design Noncomparative interventional case series. Participants Five patients with a luxated IOL in the vitreous cavity. Intervention All patients underwent surgery to fixate the IOL using this technique. Methods A three-port vitrectomy was performed in all five cases. A needle with looped 10-0 polypropylene was introduced into the vitreous cavity through a sclerotomy incision, and only the needle was passed out of the eye, guided by a bent 27-gauge needle from the 3-o’clock position 1.5 mm from the limbus. A cow hitch (girth) knot at the end of the loop was made outside the globe, grasped with a straight intravitreal forceps, and introduced into the vitreous cavity. Hooking the cow hitch (girth) knot around the haptics of the IOL in the vitreous cavity, the 10-0 polypropylene was pulled so that the IOL haptic was fixated onto the sulcus. After the opposite haptic was brought into the anterior chamber, the 10-0 polypropylene was looped around the haptics of the IOL and manipulated with a push-and-pull hook in the anterior chamber through the two corneal side ports to make a cow hitch (girth) knot outside the anterior chamber. By pulling up the suture, the knot was brought back and tied in the anterior chamber. It was then fixated to the ciliary sulcus at the 9-o’clock position. Main outcome measures Patients were evaluated for visual acuity, refraction, and surgical complications associated with the procedure. Results In all five cases, the IOL fixated stably and remained well positioned. No significant intraoperative or postoperative complications occurred. Conclusions This technique enables secure fixation of the luxated IOL in the vitreous without extracting it.

Purpose: To determine the usefulness of fluorescein angiography in studying Takayasu disease. Methods: We examined 31 eyes in 16 patients with Takayasu disease using indirect ophthalmoscopy, color photography, and fluorescein angiography. Ophthalmoscopic and fluorescein angiographic findings were compared. Results: Fluorescein angiography revealed no additional retinal changes in 10 eyes that had no retinal vein dilatation as seen by indirect ophthalmoscopy. Seven (33%) of 21 eyes that had dilated retinal veins also had additional abnormal findings, such as microaneurysms, arteriovenous shunts, retinal neovascularization, and avascular areas. Some differences in grading the stages of retinopathy were noted with these newly found retinal changes, as compared with the classifications determined by ophthalmoscopy alone. Conclusions: In Takayasu disease, studying the fundus of patients with fluorescein angiography is particularly important in correctly classifying the stages of retinopathy when the retinal vein appears dilated in ophthalmoscopic observation.

This study describes the effect of starch-synthesizing enzymes on biosynthesis of storage starch in rice amylose-extender mutants, which contain branched D-glucans with abnormal structures. Western blot analysis indicated that two out of five amylose-extender mutant lines lacked an isoform of starch branching enzyme, termed RBE3, although the levels of granule-bound starch synthase and a major form of branching enzyme, RBE1, were normal in these two mutants. Proteins corresponding to the 87-kDa RBE3 molecule were present in the three other amylose-extender mutants as well as in the wild type. However, the level of branching enzyme activity significantly decreased in all amylose-extender mutants, suggesting that the 87-kDa proteins in these three mutants are inactive forms of RBE3. Therefore, we conclude that formation of the abnormal branched glucans in the amylose-extender mutant of rice is due to the lack of the RBE3 activity. The cDNA clones encoding RBE3 have been identified from a normal rice seed cDNA library in lambda gt11, using a synthetic oligonucleotide as a probe. The deduced amino acid sequence of RBE3 indicates that this protein is initially synthesized as a precursor of 825 amino acids, including a 65-residue transit peptide at the NH2 terminus. The sequences of the catalytic regions in amylolytic enzymes are highly conserved in the sequence of RBE3. Thus, the branching enzyme isoform belongs to a family of the amylolytic enzymes. RBE3 also shares a noticeable degree of sequence identity with RBE1, especially at the central portion of the protein molecule. However, RBE3 possesses an approximately 70-residue extra sequence at the NH2 terminus and lacks a COOH-terminal sequence of almost 50 residues as compared with RBE1. The structural differences at both termini may explain the distinct role in starch synthesis for RBE1 and RBE3.

PURPOSE: To describe a technique for suturing a dislocated intraocular lens (IOL) using an intraocular cowhitch knot without IOL extraction. METHODS: Through the sideports of paracentesis, a cowhitch knot is made outside of the anterior chamber by looping 10-0 Prolene around the haptics of the IOL. The knot is then tied in the anterior chamber by pulling up the suture. After repeating this for the opposite side, the cowhitch knots are fixated to the ciliary sulcus. RESULTS: In 4 cases treated this way, the IOL remained well positioned. CONCLUSION: This technique enables secure fixation of the IOL haptics.

A general review of both classical and recent research on hydroxyapatite chromatography is presented, with the main purpose of establishing the specific mechanism involved in this type of chromatography. The deductions were confirmed with the aid of a crystallographic study of hydroxyapatite, adsorption experiments and quantitative analysis on the basis of a general theory of gradient chromatography. The mutual separation of proteins and other biomacromolecules with subtle structural differences is highly specific to hydroxyapatite chromatography.

By using several types of hydroxyapatite (HA) with different external shapes and surface structures, adsorption and the high-performance liquid chromatographic experiments for several proteins were carried out in parallel. Direct confirmation was obtained that two types of adsorbing surface, the a (or b ) and the c crystal surface, generally appear on the HA particle. During the chromatographic process on the column, acidic proteins with isoelectric points lower than about 7 (and also nucleic acids including other nucleotides) are mainly adsorbed on the a (or b ) surface, basic proteins with isoelectric points higher than about 7 are mainly adsorbed onto the c surface, and these occur independently of the external crystal shape of HA that is used. It is highly probable that the surface of a domain on the HA crystal on which the molecular adsorption takes place is smooth, and that the size of the domain under consideration is larger than the size of the proteins that have been applied, i.e. , larger than 100–200 A, at least with respect to the HAs that have been examined. Multilayers of protein molecules may be formed on the HA surface when the molarity of the phosphate buffer in the mobile phase is much lower than the molarity that is needed for the migration of the molecules on the column.

A theory for the general analytical calculations of chromatogram for mixtures of rod-like molecules with the same dimensions and the same shape is proposed for the case when the elution is carried out with a linear molarity gradient of competing ions. Most of the theory is valid, however, for molecules other than those with rod-like shapes. If the adsorption occurs on C crystal sites of hydroxyapatite, in many instances all of the theory is valid for molecules of any shape. The theory is based on the classical theory of adsorption chromatography, but the physical meanings of the basic assumptions in the classical theory are necessarily reconsidered. It is shown that the differential equation originally proposed by Wilson for the description of the chromatographic process on the column is generally valid in gradient elution, assuming that there is no longitudinal diffusion of molecules on the column, while the equations that was modified by DeVault is not valid except for some extreme cases. In stepwise elution, however, it is DeVault's equation and not Wilson's equation that is generally valid.

In an earlier paper, the energy of adsorption of nucleoside phosphates oχ to a C site of hydroxyapatite was estimated. In this pape, the theory of chromatography developed for rigid molecules in earlier papers is extended to the case of flexible molecules, and the experimental chromatogram obtained by Bernardi for a low-molecular-weight poly- l -lysine is analysed by using a method similar to that applied to nucleoside phosphates. It is estimated that the energy of adsorption on to a P site for an e-amino group of the side-chain of poly- l -lysine is 2–.2 kcal/mole. It it probable that the feature of interaction among competing or sodium ions near the crystal surface of hydroxyapatite is different from that which occurs in the usual bulk solution. On the basis of a crystallographic study, it can also be deduced that a P site is constructed with six oxygen ions belonging to three crystal phosphates and that P sites are arranged hexagonally on the (a, b) crystal surface of hydroxyapatite with a minimal distance of 9.42 A. The manner of the adsorption of poly- l -lysine on an array of P sites is discussed by using space-filling models for both poly- l -lysine and the crystal surface, the latter being constructed on the surface of the plasticine, which is compared with the results obtained from the analysis of the chromatographic data. The chromatographic data for lysozyme and cytochrome c discussed in an earlier paper are again discussed on the basis of several parameters obtained in this paper.

Taves and Reedy postulated that phosphate ions are adsorbed at hydroxyl positions on the surface of hydroxyapatite, and proposed a model for the adsorption of tripolyphosphate on the crystal surface. On the basis of this model and the hypothesis that a hydroxyl position on the crystal corresponds to a chromatographic C site, the experimental chromatogram for a mixture of AMP, ADP, ATP and adenosine tetraphosphate obtained by Bernardi was analysed by using the theory developed in an earlier paper in this series. It was estimated that the energy of adsorption on a C site for a univalent phosphate group on the polyphosphate chain of nucloside polyphosphate is 0.9–1 kcal/mole and that the adenosine group of the molecule covers at most only one crystal site. Some other experimental parameters were lso evaluated. The reasonable results obtained in the calculation strongly support the hypothesis of the one-to-one correspondence between a hydroxyl position and a chromatographic C site and the model of Taves and Reedy.

Chromatography of a number of water-soluble homo- and heteropolypeptides on hydroxyapatite columns has shown that only those containing carboxyl groups (poly- l -aspartate, poly- l -glutamate and their copolymers) are adsorbed by hydroxyapatite. The presence of urea or salt in the eluting buffer does not modify the elution molarity of poly- l -glutamate. It is likely that in the case of proteins, too, the chemical groups responsible for the interaction with hydroxyapatite are the carboxyl groups. A special case is that of phosphoproteins where a very strong interaction with hydroxyapatite is due to the presence of the protein-phosphate groups. Denaturation of proteins reduces their affinity for hydroxyapatite probably by reducing the number of carboxyl groups available for the interaction and by destroying the clusters of carboxyl groups present on the surface of native proteins and responsible for the interaction.