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1.
Am J Ophthalmol ; 263: 160-167, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38447598

ABSTRACT

PURPOSE: To compare the efficacy of botulinum toxin injections to strabismus surgery in children with acute, acquired, comitant esotropia (ACE), and to investigate factors predicting success. DESIGN: International, multi-center nonrandomized comparative study METHODS: Setting: Cloud-based survey. STUDY POPULATION: Children aged 2 to 17 years who underwent a single surgical intervention for ACE. INTERVENTIONS: Botulinum toxin injection ("chemodenervation" group) or strabismus surgery ("surgery" group). MAIN OUTCOME MEASURES: Primary measure: success rate at 6 months in propensity-matched cohort, defined as total horizontal deviation of 10 prism diopters or less with evidence of binocular single vision. Secondary measure: Risk factors for poor outcomes in the full cohort. RESULTS: Surgeons from 19 centers contributed. There were 74 patients in the chemodenervation group and 97 patients in the surgery group. In the propensity-matched data (n = 98), success rate was not significantly different at 6 months (70.2% vs 79.6%; P = .2) and 12 months (62.9% vs 77.8%; P = .2), but was significantly lower in the chemodenervation group at 24 months (52% vs 86.4%; P = .015). Irrespective of treatment modality, treatment delay was associated with lower success rates at 6 months, with median time from onset to intervention 4.5 months (interquartile range (IQR): 2.1, 6.7) in the success group and 7.7 months (IQR: 5.6, 10.1) in the failure group (P < .001). CONCLUSIONS: In children with ACE, success rate after chemodenervation was similar to that of surgery for up to 12 months but lower at 24 months. Those with prompt intervention and no amblyopia had the most favorable outcomes, regardless of treatment modality.


Subject(s)
Botulinum Toxins, Type A , Esotropia , Oculomotor Muscles , Ophthalmologic Surgical Procedures , Vision, Binocular , Humans , Child , Child, Preschool , Male , Esotropia/surgery , Esotropia/physiopathology , Female , Oculomotor Muscles/surgery , Oculomotor Muscles/physiopathology , Adolescent , Vision, Binocular/physiology , Treatment Outcome , Acute Disease , Botulinum Toxins, Type A/therapeutic use , Botulinum Toxins, Type A/administration & dosage , Injections, Intramuscular , Visual Acuity/physiology , Neuromuscular Agents/therapeutic use , Retrospective Studies , Follow-Up Studies
2.
Nat Commun ; 15(1): 285, 2024 Jan 04.
Article in English | MEDLINE | ID: mdl-38177144

ABSTRACT

Lassa virus (LASV) infection is expanding outside its traditionally endemic areas in West Africa, posing a pandemic biothreat. LASV-neutralizing antibodies, moreover, have proven difficult to elicit. To gain insight into LASV neutralization, here we develop a prefusion-stabilized LASV glycoprotein trimer (GPC), pan it against phage libraries comprising single-domain antibodies (nanobodies) from shark and camel, and identify one, D5, which neutralizes LASV. Cryo-EM analyses reveal D5 to recognize a cleavage-dependent site-of-vulnerability at the trimer apex. The recognized site appears specific to GPC intermediates, with protomers lacking full cleavage between GP1 and GP2 subunits. Guinea pig immunizations with the prefusion-stabilized cleavage-intermediate LASV GPC, first as trimer and then as a nanoparticle, induce neutralizing responses, targeting multiple epitopes including that of D5; we identify a neutralizing antibody (GP23) from the immunized guinea pigs. Collectively, our findings define a prefusion-stabilized GPC trimer, reveal an apex-situated site-of-vulnerability, and demonstrate elicitation of LASV-neutralizing responses by a cleavage-intermediate LASV trimer.


Subject(s)
Lassa Fever , Single-Domain Antibodies , Animals , Guinea Pigs , Lassa virus , Antibodies, Viral , Antibodies, Neutralizing
3.
J Clin Invest ; 133(22)2023 11 15.
Article in English | MEDLINE | ID: mdl-37966111

ABSTRACT

Prostate cancer is generally considered an immunologically "cold" tumor type that is insensitive to immunotherapy. Targeting surface antigens on tumors through cellular therapy can induce a potent antitumor immune response to "heat up" the tumor microenvironment. However, many antigens expressed on prostate tumor cells are also found on normal tissues, potentially causing on-target, off-tumor toxicities and a suboptimal therapeutic index. Our studies revealed that six-transmembrane epithelial antigen of prostate-2 (STEAP2) was a prevalent prostate cancer antigen that displayed high, homogeneous cell surface expression across all stages of disease with limited distal normal tissue expression, making it ideal for therapeutic targeting. A multifaceted lead generation approach enabled development of an armored STEAP2 chimeric antigen receptor T cell (CAR-T) therapeutic candidate, AZD0754. This CAR-T product was armored with a dominant-negative TGF-ß type II receptor, bolstering its activity in the TGF-ß-rich immunosuppressive environment of prostate cancer. AZD0754 demonstrated potent and specific cytotoxicity against antigen-expressing cells in vitro despite TGF-ß-rich conditions. Further, AZD0754 enforced robust, dose-dependent in vivo efficacy in STEAP2-expressing cancer cell line-derived and patient-derived xenograft mouse models, and exhibited encouraging preclinical safety. Together, these data underscore the therapeutic tractability of STEAP2 in prostate cancer as well as build confidence in the specificity, potency, and tolerability of this potentially first-in-class CAR-T therapy.


Subject(s)
Prostatic Neoplasms , Receptors, Chimeric Antigen , Male , Humans , Mice , Animals , Receptors, Chimeric Antigen/genetics , Receptors, Chimeric Antigen/metabolism , Immunotherapy, Adoptive , Prostatic Neoplasms/pathology , T-Lymphocytes , Transforming Growth Factor beta/metabolism , Xenograft Model Antitumor Assays , Cell Line, Tumor , Tumor Microenvironment , Oxidoreductases/metabolism
4.
J AAPOS ; 27(3): 139.e1-139.e5, 2023 06.
Article in English | MEDLINE | ID: mdl-37187405

ABSTRACT

PURPOSE: To describe the clinical and demographic characteristics of patients presenting with cataract at uveitis diagnosis treated at a single institution between 2005 and 2019 and to analyze postoperative outcomes following cataract surgery. METHODS: We retrospectively reviewed the medical records of children (<18 years of age) diagnosed with cataract at their initial uveitis presentation who subsequently underwent cataract extraction. Outcome measures were best-corrected visual acuity, number of uveitis flare-ups (cells ≥1+), and postoperative complications. RESULTS: A total of 14 children (17 eyes) were included. Mean patient age was 7.2 ± 3.9 years. Methotrexate was initiated preoperatively in 11 patients; adalimumab, in 3. Primary intraocular lens was implanted in 4 eyes. Best-corrected visual acuity improved from a mean of 0.90 ± 0.40 logMAR preoperatively to 0.50 ± 0.35 logMAR at 1 year and 0.57 ± 0.40 logMAR at mean of 6.3 ± 3.4 years postoperatively. Four eyes (24%) had a single episode of uveitis flare-up during the first postoperative year. Macular and/or disk edema was discovered in 6 eyes following cataract removal. Only 3 eyes (18%) had ocular hypertension in the first year, but glaucoma developed in subsequent years in 7 eyes (41%), 5 of which required surgery. CONCLUSIONS: In our study cohort, surgery for preexisting cataract at uveitis diagnosis resulted in improved visual acuity. Postoperative uveitis flare-ups were relatively uncommon, occurring in 4 of 17 eyes. Glaucoma was the main long-term complication.


Subject(s)
Cataract Extraction , Cataract , Glaucoma , Uveitis , Humans , Child , Child, Preschool , Retrospective Studies , Cataract Extraction/adverse effects , Cataract/complications , Cataract/diagnosis , Uveitis/complications , Uveitis/diagnosis , Uveitis/surgery , Glaucoma/surgery , Postoperative Complications/surgery
5.
J AAPOS ; 27(3): 151-153, 2023 06.
Article in English | MEDLINE | ID: mdl-37179002

ABSTRACT

We report the case of a 16-year-old girl admitted to hospital with multisystem inflammatory syndrome in children (MIS-C) secondary to COVID-19. Conjunctivitis-like symptoms prompted ocular examination, which demonstrated peripheral confluent corneal opacities and anterior uveitis. Uveitis laboratory investigations were negative, and with topical steroid treatment her signs and symptoms resolved completely. These features may be overlooked in the setting of MIS-C, where patients are systemically unwell and are typically examined at the bedside.


Subject(s)
COVID-19 , Keratitis , Uveitis , Child , Female , Humans , Adolescent , COVID-19/complications , Systemic Inflammatory Response Syndrome/complications , Systemic Inflammatory Response Syndrome/diagnosis , Uveitis/complications , Uveitis/diagnosis , Uveitis/drug therapy , Keratitis/diagnosis
6.
Sci Transl Med ; 15(692): eade4976, 2023 04 19.
Article in English | MEDLINE | ID: mdl-37075126

ABSTRACT

Current yearly seasonal influenza vaccines primarily induce an antibody response directed against the immunodominant but continually diversifying hemagglutinin (HA) head region. These antibody responses provide protection against the vaccinating strain but little cross-protection against other influenza strains or subtypes. To focus the immune response on subdominant but more conserved epitopes on the HA stem that might protect against a broad range of influenza strains, we developed a stabilized H1 stem immunogen lacking the immunodominant head displayed on a ferritin nanoparticle (H1ssF). Here, we evaluated the B cell response to H1ssF in healthy adults ages 18 to 70 in a phase 1 clinical trial (NCT03814720). We observed both a strong plasmablast response and sustained elicitation of cross-reactive HA stem-specific memory B cells after vaccination with H1ssF in individuals of all ages. The B cell response was focused on two conserved epitopes on the H1 stem, with a highly restricted immunoglobulin repertoire unique to each epitope. On average, two-thirds of the B cell and serological antibody response recognized a central epitope on the H1 stem and exhibited broad neutralization across group 1 influenza virus subtypes. The remaining third recognized an epitope near the viral membrane anchor and was largely limited to H1 strains. Together, we demonstrate that an H1 HA immunogen lacking the immunodominant HA head produces a robust and broadly neutralizing HA stem-directed B cell response.


Subject(s)
Influenza Vaccines , Influenza, Human , Adolescent , Adult , Aged , Humans , Middle Aged , Young Adult , Antibodies, Neutralizing , Antibodies, Viral , Epitopes , Hemagglutinin Glycoproteins, Influenza Virus , Hemagglutinins
7.
Immunity ; 55(12): 2405-2418.e7, 2022 12 13.
Article in English | MEDLINE | ID: mdl-36356572

ABSTRACT

Current influenza vaccines predominantly induce immunity to the hypervariable hemagglutinin (HA) head, requiring frequent vaccine reformulation. Conversely, the immunosubdominant yet conserved HA stem harbors a supersite that is targeted by broadly neutralizing antibodies (bnAbs), representing a prime target for universal vaccines. Here, we showed that the co-immunization of two HA stem immunogens derived from group 1 and 2 influenza A viruses elicits cross-group protective immunity and neutralizing antibody responses in mice, ferrets, and nonhuman primates (NHPs). Immunized mice were protected from multiple group 1 and 2 viruses, and all animal models showed broad serum-neutralizing activity. A bnAb isolated from an immunized NHP broadly neutralized and protected against diverse viruses, including H5N1 and H7N9. Genetic and structural analyses revealed strong homology between macaque and human bnAbs, illustrating common biophysical constraints for acquiring cross-group specificity. Vaccine elicitation of stem-directed cross-group-protective immunity represents a step toward the development of broadly protective influenza vaccines.


Subject(s)
Influenza A Virus, H5N1 Subtype , Influenza A Virus, H7N9 Subtype , Influenza Vaccines , Influenza, Human , Orthomyxoviridae Infections , Animals , Mice , Humans , Hemagglutinins , Broadly Neutralizing Antibodies , Hemagglutinin Glycoproteins, Influenza Virus , Antibodies, Viral , Ferrets , Antibodies, Neutralizing , Immunization
8.
Structure ; 30(7): 993-1003.e6, 2022 07 07.
Article in English | MEDLINE | ID: mdl-35489332

ABSTRACT

Several influenza antibodies with broad group 2 neutralization have recently been isolated. Here, we analyze the structure, class, and binding of one of these antibodies from an H7N9 vaccine trial, 315-19-1D12. The cryo-EM structure of 315-19-1D12 Fab in complex with the hemagglutinin (HA) trimer revealed the antibody to recognize the helix A region of the HA stem, at the supersite of vulnerability recognized by group 1-specific and by cross-group-neutralizing antibodies. 315-19-1D12 was derived from HV1-2 and KV2-28 genes and appeared to form a new antibody class. Bioinformatic analysis indicated its group 2 neutralization specificity to be a consequence of four key residue positions. We specifically tested the impact of the group 1-specific N33 glycan, which decreased but did not abolish group 2 binding of 315-19-1D12. Overall, this study highlights the recognition of a broad group 2-neutralizing antibody, revealing unexpected diversity in neutralization specificity for antibodies that recognize the HA stem supersite.


Subject(s)
Influenza A Virus, H7N9 Subtype , Influenza Vaccines , Influenza, Human , Antibodies, Neutralizing , Hemagglutinin Glycoproteins, Influenza Virus/metabolism , Hemagglutinins , Humans , Influenza A Virus, H7N9 Subtype/metabolism
9.
Nat Med ; 28(2): 373-382, 2022 02.
Article in English | MEDLINE | ID: mdl-35115707

ABSTRACT

Conserved epitopes on the influenza hemagglutinin (HA) stem are an attractive target for universal vaccine strategies as they elicit broadly neutralizing antibodies. Such antibody responses to stem-specific epitopes have been extensively characterized for HA subtypes H1 and H5 in humans. H2N2 influenza virus circulated 50 years ago and represents a pandemic threat due to the lack of widespread immunity, but, unlike H1 and H5, the H2 HA stem contains Phe45HA2 predicted to sterically clash with HA stem-binding antibodies characterized to date. To understand the effect of Phe45HA2, we compared the HA stem-specific B cell response in post hoc analyses of two phase 1 clinical trials, one testing vaccination with an H2 ferritin nanoparticle immunogen ( NCT03186781 ) and one with an inactivated H5N1 vaccine ( NCT01086657 ). In H2-naive individuals, the magnitude of the B cell response was equivalent, but H2-elicited HA stem-binding B cells displayed greater cross-reactivity than those elicited by H5. However, in individuals with childhood H2 exposure, H5-elicited HA stem-binding B cells also displayed high cross-reactivity, suggesting recall of memory B cells formed 50 years ago. Overall, we propose that a one-residue difference on an HA immunogen can alter establishment and expansion of broadly neutralizing memory B cells. These data have implications for stem-based universal influenza vaccination strategies.


Subject(s)
Influenza A Virus, H5N1 Subtype , Influenza Vaccines , Influenza, Human , Antibodies, Neutralizing , Antibodies, Viral , Child , Clinical Trials, Phase I as Topic , Epitopes , Hemagglutinin Glycoproteins, Influenza Virus , Hemagglutinins , Humans , Vaccination
10.
Front Immunol ; 12: 662909, 2021.
Article in English | MEDLINE | ID: mdl-34135892

ABSTRACT

Sequence signatures of multidonor broadly neutralizing influenza antibodies can be used to quantify the prevalence of B cells with virus-neutralizing potential to accelerate development of broadly protective vaccine strategies. Antibodies of the same class share similar recognition modes and developmental pathways, and several antibody classes have been identified that neutralize diverse group 1- and group 2-influenza A viruses and have been observed in multiple human donors. One such multidonor antibody class, the HV6-1-derived class, targets the stem region of hemagglutinin with extraordinary neutralization breadth. Here, we use an iterative process to combine informatics, biochemical, and structural analyses to delineate an improved sequence signature for HV6-1-class antibodies. Based on sequence and structure analyses of known HV6-1 class antibodies, we derived a more inclusive signature (version 1), which we used to search for matching B-cell transcripts from published next-generation sequencing datasets of influenza vaccination studies. We expressed selected antibodies, evaluated their function, and identified amino acid-level requirements from which to refine the sequence signature (version 2). The cryo-electron microscopy structure for one of the signature-identified antibodies in complex with hemagglutinin confirmed motif recognition to be similar to known HV6-1-class members, MEDI8852 and 56.a.09, despite differences in recognition-loop length. Threading indicated the refined signature to have increased accuracy, and signature-identified heavy chains, when paired with the light chain of MEDI8852, showed neutralization comparable to the most potent members of the class. Incorporating sequences of additional class members thus enables an improved sequence signature for HV6-1-class antibodies, which can identify class members with increased accuracy.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Influenza A virus/immunology , Influenza, Human/immunology , Influenza, Human/virology , Cross Reactions , Cryoelectron Microscopy , Epitopes/chemistry , Epitopes/immunology , Hemagglutinin Glycoproteins, Influenza Virus/chemistry , Hemagglutinin Glycoproteins, Influenza Virus/immunology , Humans , Influenza A virus/genetics , Models, Molecular , Neutralization Tests , Protein Binding , Protein Conformation , Structure-Activity Relationship
11.
Br J Ophthalmol ; 105(8): 1121-1126, 2021 08.
Article in English | MEDLINE | ID: mdl-32816790

ABSTRACT

PURPOSE: To compare ultra-wide-field colour fundus imaging (UWFI) to dilated fundus examination (DFE) for the screening of sickle cell retinopathy (SCR). DESIGN: This study is a prospective, blinded, multicentre case series. PARTICIPANTS: This study included two groups: an adult group (n=268 eyes) and a paediatric group (n=168 eyes). Sickle cell disease (SCD) types included haemoglobin S homozygous (HbSS), haemoglobin S and C (HbSC) and Hb S with ß-thalassaemia (HbSß-Thal). METHODS: Participants underwent DFE and UWFI. Each eye received three independent grades (1-4), documented by three graders: clinical grader, image grader 1 and image grader 2. Three clinically relevant diagnostic thresholds were determined. Based on these thresholds, the sensitivity, specificity, positive predictive value and negative predictive value for all three graders were calculated relative to each other as reference tests. RESULTS: HbSC was associated with the most advanced SCR grades. When compared to the clinical grader, image grader 1 and image grader 2 consistently detected more SCR and higher SCR grades in both adult and paediatric groups. In both groups, image grader 1 and image grader 2 identified twice as many cases of capillary occlusion/anastomosis than clinical grader. To detect the presence of any proliferative SCR, image grader 1 and image grader 2 had a sensitivity of 82%, 71% in the paediatrics group and 90% and 72% in the adult group. The clinical grader sensitivity was 52% in the paediatrics group and 53% in the adult group. CONCLUSION: The UWFI is a sensitive tool to screen for SCR. It is superior to DFE in detecting capillary occlusion or anastomosis.


Subject(s)
Anemia, Sickle Cell/diagnosis , Fluorescein Angiography , Retina/pathology , Retinal Diseases/diagnosis , Slit Lamp Microscopy , Adolescent , Adult , Aged , Child , Color , False Positive Reactions , Female , Fundus Oculi , Humans , Male , Middle Aged , Photography/methods , Predictive Value of Tests , Prospective Studies , Reproducibility of Results , Sensitivity and Specificity , Visual Fields/physiology , Young Adult
12.
Cell Rep ; 32(9): 108088, 2020 09 01.
Article in English | MEDLINE | ID: mdl-32877670

ABSTRACT

Multidonor antibodies are of interest for vaccine design because they can in principle be elicited in the general population by a common set of immunogens. For influenza, multidonor antibodies have been observed against the hemagglutinin (HA) stem, but not the immunodominant HA head. Here, we identify and characterize a multidonor antibody class (LPAF-a class) targeting the HA head. This class exhibits potent viral entry inhibition against H1N1 A/California/04/2009 (CA09) virus. LPAF-a class antibodies derive from the HV2-70 gene and contain a "Tyr-Gly-Asp"-motif, which occludes the HA-sialic acid binding site as revealed by a co-crystal structure with HA. Both germline-reverted and mature LPAF antibodies potently neutralize CA09 virus and have nanomolar affinities for CA09 HA. Moreover, increased frequencies for LPFA-a class antibodies are observed in humans after a single vaccination. Overall, this work highlights the identification of a multidonor class of head-directed influenza-neutralizing antibodies and delineates the mechanism of their recurrent elicitation in humans.


Subject(s)
Antibodies, Neutralizing/immunology , Influenza, Human/virology , Humans , Molecular Structure
13.
J AAPOS ; 24(2): 113-115, 2020 04.
Article in English | MEDLINE | ID: mdl-31982618

ABSTRACT

Lymphatic malformations are benign hamartomatous tumors present at birth but usually diagnosed in early childhood. We report a case of prenatal diagnosis of an isolated unilateral retrobulbar lymphatic malformation with fetal magnetic resonance imaging (MRI). This was first detected at 27 weeks' gestational age. Postnatal ocular examinations at 4 days and 5 weeks of age showed no signs of optic nerve compromise. Postnatal MRI at 18 days of age showed slight increase in size of the lesion, and no intracranial vascular malformations were detected.


Subject(s)
Prenatal Diagnosis , Ultrasonography, Prenatal , Female , Gestational Age , Humans , Infant, Newborn , Magnetic Resonance Imaging , Pregnancy
14.
Br J Ophthalmol ; 104(7): 938-942, 2020 07.
Article in English | MEDLINE | ID: mdl-31604701

ABSTRACT

BACKGROUND/AIMS: There is a paucity of large trials investigating the effect of management strategies for paediatric non-infectious uveitis on complications requiring surgery. The purpose of our study is to investigate whether earlier initiation of systemic immunosuppression in paediatric non-infectious uveitis is associated with fewer ophthalmic surgeries. METHODS: A retrospective review was conducted on 48 children with non-infectious uveitis assessed in 1998-2013. Patients were divided into uveitis diagnosed before December 2008 (group 1) and after January 2009 (group 2). Duration from uveitis onset to methotrexate initiation (U-MTX) and biological addition (U-Biologic) were reviewed. Follow-up visits with topical corticosteroids >3 times daily and active uveitis (≥1+ cells) during 3.5 years were documented. The main outcome measure was the need for ≥1 ophthalmic surgery at 3.5 years. RESULTS: In group 1, 69.5% of patients required ≥1 ophthalmic surgery at 3.5 years versus 26.9% in group 2 (p=0.005). U-MTX was 28.9±11.8 weeks and 14.2±10.0 weeks for groups 1 and 2 (p=0.028). U-Biologic was 134.6±46.0 weeks and 82.3±43.3 weeks for groups 1 and 2 (p=0.0016). Corticosteroid use >3 times daily was 85.9±52.7 weeks and 14.6±11.1 weeks for groups 1 and 2. Multivariate regression showed methotrexate initiation within 6 months of uveitis onset lowered the likelihood of needing ophthalmic surgery at 3.5 years (OR=6.2, 95% CI 1.2 to 33.4; p=0.033). Univariate regression demonstrated biological addition within 18 months of uveitis onset reduced the likelihood of requiring ophthalmic surgery (OR 12.57, 95% CI 1.28 to 123.48; p=0.030). CONCLUSION: Earlier control of uveitis by addition of immunosuppressive therapy reduced the need for ophthalmic surgery.


Subject(s)
Immunosuppressive Agents/therapeutic use , Methotrexate/therapeutic use , Ophthalmologic Surgical Procedures/statistics & numerical data , Uveitis, Anterior/drug therapy , Adalimumab/therapeutic use , Administration, Oral , Antirheumatic Agents/therapeutic use , Arthritis, Juvenile/drug therapy , Arthritis, Juvenile/physiopathology , Child , Child, Preschool , Eye Infections, Bacterial/drug therapy , Eye Infections, Bacterial/microbiology , Female , Glucocorticoids/administration & dosage , Humans , Immunosuppression Therapy , Infliximab/therapeutic use , Injections, Subcutaneous , Male , Retrospective Studies , Time Factors , Uveitis, Anterior/microbiology , Uveitis, Anterior/physiopathology , Visual Acuity/physiology
15.
Semin Ophthalmol ; 34(4): 293-302, 2019.
Article in English | MEDLINE | ID: mdl-31138081

ABSTRACT

Intraocular lens (IOL) implantation in pediatric eyes with insufficient capsular support is challenging and there are multiple IOL options. These include placement of an IOL within the capsular bag with a capsular tension ring, a scleral-fixated posterior-chamber IOL (PCIOL) with or without capsular tension segment or ring, an intra-scleral fixated IOL, an iris-sutured PCIOL, or an anterior chamber iris-fixated IOL. We reviewed 48 articles and 1 published abstract describing the surgical techniques, complications and visual outcomes of different IOL options in the management of aphakic pediatric eyes with insufficient capsular support. The present review found that the visual acuity outcomes of various IOLs are comparable. Furthermore, each IOL design and surgical technique has different rates of serious complications, including IOL dislocation or decentration, intraocular hemorrhage, glaucoma, endothelial cell loss, and endophthalmitis. An understanding of the risks and benefits of different IOL designs is important for counseling patients and families.


Subject(s)
Aphakia/surgery , Lens Capsule, Crystalline/physiology , Lens Implantation, Intraocular/methods , Lenses, Intraocular , Child , Humans , Iris/surgery , Lens Capsule, Crystalline/pathology , Sclera/surgery , Suture Techniques
16.
Sci Immunol ; 4(34)2019 04 19.
Article in English | MEDLINE | ID: mdl-31004012

ABSTRACT

Induction of an antibody response capable of recognizing highly diverse strains is a major obstacle to the development of vaccines for viruses such as HIV and influenza. Here, we report the dynamics of B cell expansion and evolution at the single-cell level after vaccination with a replication-competent adenovirus type 4 recombinant virus expressing influenza H5 hemagglutinin. Fluorescent H1 or H5 probes were used to quantitate and isolate peripheral blood B cells and their antigen receptors. We observed increases in H5-specific antibody somatic hypermutation and potency for several months beyond the period of active viral replication that was not detectable at the serum level. Individual broad and potent antibodies could be isolated, including one stem-specific antibody that is part of a new multidonor class. These results demonstrate prolonged evolution of the B cell response for months after vaccination and should be considered in efforts to evaluate or boost vaccine-induced immunity.


Subject(s)
Adenoviridae/genetics , B-Lymphocytes/immunology , Influenza A Virus, H5N1 Subtype/immunology , Influenza Vaccines/immunology , Influenza, Human/prevention & control , Adenoviridae/immunology , Administration, Oral , Adolescent , Adult , Antibodies, Viral/blood , Antibodies, Viral/genetics , Antibodies, Viral/immunology , Female , Genetic Vectors/genetics , Genetic Vectors/immunology , Hemagglutinin Glycoproteins, Influenza Virus/genetics , Hemagglutinin Glycoproteins, Influenza Virus/immunology , Humans , Immunogenicity, Vaccine , Influenza A Virus, H5N1 Subtype/genetics , Influenza Vaccines/administration & dosage , Influenza Vaccines/adverse effects , Influenza Vaccines/genetics , Influenza, Human/immunology , Influenza, Human/virology , Male , Middle Aged , Somatic Hypermutation, Immunoglobulin/immunology , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/adverse effects , Vaccines, Synthetic/genetics , Vaccines, Synthetic/immunology , Virus Replication/immunology , Young Adult
17.
Mol Ther ; 27(3): 673-680, 2019 03 06.
Article in English | MEDLINE | ID: mdl-30765323

ABSTRACT

Recombinant human growth hormone (GH) is commonly used to treat short stature in children. However, GH treatment has limited efficacy, particularly in severe, non-GH-deficient conditions such as chondrodysplasias, and potential off-target effects. Because short stature results from decreased growth plate chondrogenesis, we developed a cartilage-targeting single-chain human antibody fragment (CaAb) aiming to deliver therapeutic molecules to the growth plate, thereby increasing treatment efficacy while minimizing adverse effects on other tissues. To this end, we created fusion proteins of these CaAbs conjugated with insulin-like growth factor 1 (IGF-1), an endocrine and/or paracrine factor that positively regulates chondrogenesis. These CaAb-IGF-1 fusion proteins retained both cartilage binding and IGF-1 biological activity, and they were able to stimulate bone growth in an organ culture system. Using a GH-deficient (lit) mouse model, we found that subcutaneous injections of these CaAb-IGF-1 fusion proteins increased overall growth plate height without increasing proliferation in kidney cortical cells, suggesting on-target efficacy at the growth plate and less off-target effect on the kidney than IGF-1 alone. Alternate-day injections of these fusion proteins, unlike IGF-1 alone, were sufficient to produce a therapeutic effect. Our findings provide proof of principle that targeting therapeutics to growth plate cartilage can potentially improve treatment for childhood growth disorders.


Subject(s)
Insulin-Like Growth Factor I/pharmacology , Animals , Cartilage/drug effects , Cartilage/metabolism , Chondrogenesis/drug effects , Growth Plate/drug effects , Growth Plate/metabolism , Humans , MCF-7 Cells , Mice , Mice, Inbred C57BL , Mutation/genetics
18.
Nat Commun ; 10(1): 47, 2019 01 03.
Article in English | MEDLINE | ID: mdl-30604750

ABSTRACT

Diverse entry inhibitors targeting the gp120 subunit of the HIV-1 envelope (Env) trimer have been developed including BMS-626529, also called temsavir, a prodrug version of which is currently in phase III clinical trials. Here we report the characterization of a panel of small-molecule inhibitors including BMS-818251, which we show to be >10-fold more potent than temsavir on a cross-clade panel of 208-HIV-1 strains, as well as the engineering of a crystal lattice to enable structure determination of the interaction between these inhibitors and the HIV-1 Env trimer at higher resolution. By altering crystallization lattice chaperones, we identify a lattice with both improved diffraction and robust co-crystallization of HIV-1 Env trimers from different clades complexed to entry inhibitors with a range of binding affinities. The improved diffraction reveals BMS-818251 to utilize functional groups that interact with gp120 residues from the conserved ß20-ß21 hairpin to improve potency.


Subject(s)
Chemical Engineering/methods , HIV Envelope Protein gp120/antagonists & inhibitors , HIV Fusion Inhibitors/pharmacology , HIV-1/drug effects , Virus Internalization/drug effects , Crystallography, X-Ray , Drug Design , HIV Envelope Protein gp120/metabolism , HIV Fusion Inhibitors/chemistry , HIV-1/physiology , HeLa Cells , Humans , Molecular Docking Simulation , Nanoparticles/chemistry , Piperazines/chemistry , Piperazines/pharmacology , Protein Binding , Protein Conformation , Protein Multimerization , Triazoles/chemistry , Triazoles/pharmacology
19.
Can J Ophthalmol ; 53(4): 425-431, 2018 08.
Article in English | MEDLINE | ID: mdl-30119800

ABSTRACT

OBJECTIVE: To assess the clinical findings and microbiology investigations in patients with suspected infectious posterior segment uveitis (PSU). DESIGN: Retrospective case study. METHODS: Between January and December 2014, medical records of 270 patients with PSU were reviewed. Baseline ocular examination, presumed and final diagnoses, microbiology investigations from aqueous or vitreous fluid, and peripheral blood were reviewed. RESULTS: Infectious PSU was suspected in 28 patients among 270 PSU cases (10.4%, 28/270), and 11 cases were of infectious origin (4.1%, 11/270). Six patients were immunocompromised: 5 patients in the confirmed infectious PSU group (45.5%, 5/11) and 1 in the confirmed noninfectious group (5.9%, 1/17; p = 0.002). Initial visual acuity was 1.8 ± 0.35 logMAR and 0.9 ± 0.23 logMAR for patients with confirmed infectious and noninfectious PSU, respectively (p = 0.04). Anterior chamber reaction was worse in patients with confirmed infectious PSU (1.8 ± 0.49) than confirmed noninfectious cases (0.5 ± 0.1; p = 0.003). The frequency of chorioretinitis among patients with confirmed infectious and noninfectious PSU is 54.5% (6/11) and 11.8% (2/17; p = 0.03), respectively. Onset of confirmed infectious uveitis was more acute (≤6 weeks in duration) than noninfectious cases (p = 0.0015). Among the 11 patients with positive blood culture or serology, 6 had anterior and vitreous chamber fluid analysis. The rate of positive cultures and PCR is 16.7% (1/6) for aqueous humour and 50% (3/6) for vitreous samples. CONCLUSIONS: Clinical features more suggestive of infectious PSU include immunosuppression, worse initial visual acuity, acute onset, worse anterior chamber reaction, and chorioretinitis. Further studies are needed to enhance the diagnostic yields of aqueous and vitreous fluid analyses.


Subject(s)
Aqueous Humor/diagnostic imaging , Diagnostic Techniques, Ophthalmological , Eye Infections/diagnosis , Uveitis, Posterior/diagnosis , Visual Acuity , Vitreous Body/diagnostic imaging , Female , Follow-Up Studies , Humans , Male , Middle Aged , Retrospective Studies
20.
Can J Ophthalmol ; 52(2): 175-180, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28457287

ABSTRACT

OBJECTIVE: The aim of this study was to evaluate the visual outcome, uveitis control, and complications following cataract surgery for intraocular lens (IOL) implantation in patients with a known diagnosis of uveitis. DESIGN: The study was a retrospective interventional case series. PARTICIPANTS: We reviewed 98 patients (137 eyes) with adult uveitis undergoing cataract surgery with foldable acrylic posterior chamber IOL implantation between 2003 and 2013 in 2 uveitis practices. METHODS: Best-corrected visual acuity (BCVA) and uveitis grade (Standardized Uveitis Nomenclature criteria) were measured at 1 month preoperatively, at postoperative week 1, and at postoperative months 1, 6, and 12. The main outcome measures were mean change in postoperative BCVA, uveitis grade, and complications. RESULTS: Of the eyes studied, 84% had grade 0-0.5 anterior uveitis at postoperative week 1 and maintained uveitis control (77% grade 0; 19% grade 0.5 anterior uveitis) at 1 year postoperatively. None of the patients had active intermediate or posterior uveitis at any time point. Mean BCVA improved from 0.71 ± 0.38 logMAR preoperatively to 0.37 ± 0.36 at 6 months (p < 0.01) and to 0.30 ± 0.25 at 12 months (p = 0.01) postoperatively. Of the study participants, 30% had preoperative complications related to uveitis, including epiretinal membrane (12%), cystoid macular edema (12%), and glaucoma (5.8%); 46% of patients had small pupils as a result of posterior synechiae. Postoperative vision-limiting complications included posterior capsule opacification (18%), epiretinal membrane (9.0%), and cystoid macular edema (8.8%). Of the eyes studied, 5.8% underwent Nd:YAG capsulotomy. CONCLUSIONS: Cataract surgery with acrylic posterior-chamber IOL implantation is effective at improving visual acuity in patients with uveitis. Uveitis was well controlled in the majority of our study patients for 12 months after cataract surgery. The most frequent vision-limiting postoperative complication was posterior capsule opacification, which was treatable with Nd:YAG capsulotomy.


Subject(s)
Cataract/complications , Lens Implantation, Intraocular/methods , Phacoemulsification/methods , Uveitis/complications , Visual Acuity , Adolescent , Adult , Aged , Female , Follow-Up Studies , Humans , Male , Middle Aged , Retrospective Studies , Time Factors , Treatment Outcome , Uveitis/surgery , Young Adult
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