12 results on '"Knightly C"'
Search Results
2. The Philadelphia story: The 22q11.2 deletion: Report on 250 patients
- Author
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Donna McDonald-McGinn, Kirschner, R., Goldmuntz, E., Sullivan, K., Eicher, P., Gerdes, M., Moss, E., Solot, C., Wang, P., Jacobs, I., Handler, S., Knightly, C., Heher, K., Wilson, M., Ming, J. E., Grace, K., Driscoll, D., Pasquariello, P., Randall, P., Larossa, D., Emanuel, B. S., and Zackai, E. H.
- Subjects
Adult ,Heart Defects, Congenital ,Male ,Philadelphia ,Velopharyngeal Insufficiency ,Adolescent ,Chromosomes, Human, Pair 22 ,Infant, Newborn ,Facies ,Infant ,Genetic Counseling ,Cohort Studies ,Diagnosis, Differential ,Phenotype ,Child, Preschool ,DiGeorge Syndrome ,Humans ,Abnormalities, Multiple ,Female ,Chromosome Deletion ,Child - Abstract
A submicroscopic deletion of chromosome 22q11.2 has been identified in the majority of patients with the DiGeorge, velocardiofacial, and conotruncal anomaly face syndromes, and in some patients with the Opitz G/BBB and Cayler cardiofacial syndromes. We have been involved in the analysis of DiGeorge syndrome and related diagnoses since 1982 and have evaluated a large number of patients with the deletion. We describe our cohort of 250 patients whose clinical findings help to define the extremely variable phenotype associated with the 22q11.2 deletion and may assist clinicians in providing genetic counseling and guidelines for clinical management based on these findings.
3. Safety and Immunogenicity of a Messenger RNA-Based Cytomegalovirus Vaccine in Healthy Adults: Results From a Phase 1 Randomized Clinical Trial.
- Author
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Fierro C, Brune D, Shaw M, Schwartz H, Knightly C, Lin J, Carfi A, Natenshon A, Kalidindi S, Reuter C, Miller J, and Panther L
- Subjects
- Humans, Female, Adult, Male, Middle Aged, Young Adult, Healthy Volunteers, Antibodies, Neutralizing blood, Immunogenicity, Vaccine, Double-Blind Method, Cytomegalovirus Vaccines immunology, Cytomegalovirus Vaccines administration & dosage, Cytomegalovirus Infections prevention & control, Cytomegalovirus Infections immunology, Antibodies, Viral blood, Cytomegalovirus immunology, Cytomegalovirus genetics, RNA, Messenger genetics
- Abstract
Background: This phase 1 trial evaluated the safety, reactogenicity, and immunogenicity of mRNA-1647, a messenger RNA (mRNA)-based cytomegalovirus (CMV) vaccine, in CMV-seronegative and -seropositive adults., Methods: Participants were randomly assigned to receive 30, 90, 180, or 300 µg of mRNA-1647 or placebo on a 0-, 2-, and 6-month schedule and followed for 12 months after the last dose., Results: A total of 154 (80 CMV-seronegative and 74 CMV-seropositive) participants were enrolled; 118 participants were randomized to mRNA-1647 and 36 to placebo. Mean (standard deviation) age was 32.5 (8.6) and 35.1 (8.9) years in the placebo and mRNA-1647 groups, respectively, in phase B (63% and 64% female) and 42.5 (6.2) and 33.3 (8.7) years, respectively, in phase C (2% and 16% female). No deaths, related serious adverse events, or adverse events of special interest were reported. Most adverse reactions were grade ≤2 severity. Increased neutralizing antibody, binding antibody, and antigen-specific cell-mediated responses were observed across mRNA-1647 treatment groups, regardless of CMV serostatus., Conclusions: This phase 1, first-in-human trial demonstrated that mRNA-1647 has an acceptable safety profile in adults and elicits humoral and cellular immune responses. Clinical Trials Registration. NCT03382405., Competing Interests: Potential conflicts of interest. C. K., J. L., A. C., A. N., S. K., C. R., J. M., and L. P. are employees of Moderna, Inc, and hold stock/stock options in the company. C. F., D. B., M. S., and H. S. have no conflicts of interest to disclose. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
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- 2024
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4. A phase 1, randomized, placebo-controlled, dose-ranging study to evaluate the safety and immunogenicity of an mRNA-based chikungunya virus vaccine in healthy adults.
- Author
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Shaw CA, August A, Bart S, Booth PJ, Knightly C, Brasel T, Weaver SC, Zhou H, and Panther L
- Subjects
- Humans, Adult, Vaccines, Synthetic, Antibodies, Neutralizing, Antibodies, Viral, Immunogenicity, Vaccine, Double-Blind Method, mRNA Vaccines, Chikungunya virus, Chikungunya Fever prevention & control
- Abstract
Background: Chikungunya, a mosquito-borne viral disease caused by the chikungunya virus (CHIKV), causes a significant global health burden, and there is currently no approved vaccine to prevent chikungunya disease. In this study, the safety and immunogenicity of a CHIKV mRNA vaccine candidate (mRNA-1388) were evaluated in healthy participants in a CHIKV-nonendemic region., Methods: This phase 1, first-in-human, randomized, placebo-controlled, dose-ranging study enrolled healthy adults (ages 18-49 years) between July 2017 and March 2019 in the United States. Participants were randomly assigned (3:1) to receive 2 intramuscular injections 28 days apart with mRNA-1388 in 3 dose-level groups (25 μg, 50 μg, and 100 μg) or placebo and were followed for up to 1 year. Safety (unsolicited adverse events [AEs]), tolerability (local and systemic reactogenicity; solicited AEs), and immunogenicity (geometric mean titers [GMTs] of CHIKV neutralizing and binding antibodies) of mRNA-1388 versus placebo were evaluated., Results: Sixty participants were randomized and received ≥ 1 vaccination; 54 (90 %) completed the study. mRNA-1388 demonstrated favorable safety and reactogenicity profiles at all dose levels. Immunization with mRNA-1388 induced substantial and persistent humoral responses. Dose-dependent increases in neutralizing antibody titers were observed; GMTs (95 % confidence intervals [CIs]) at 28 days after dose 2 were 6.2 (5.1-7.6) for mRNA-1388 25 μg, 53.8 (26.8-108.1) for mRNA-1388 50 μg, 92.8 (43.6-197.6) for mRNA-1388 100 μg, and 5.0 (not estimable) for placebo. Persistent humoral responses were observed up to 1 year after vaccination and remained higher than placebo in the 2 higher mRNA-1388 dose groups. The development of CHIKV-binding antibodies followed a similar trend as that observed with neutralizing antibodies., Conclusions: mRNA-1388, the first mRNA vaccine against CHIKV, was well tolerated and elicited substantial and long-lasting neutralizing antibody responses in healthy adult participants in a nonendemic region., Clinicaltrials: gov: NCT03325075., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A.A., C.A.S., C.K., H.Z., and L.P. are employees of Moderna, Inc., and may hold stock/stock options in the company. S.B., P.-G.J.B., T.B., and S.W. have no relevant or material financial interests that relate to the research described in this article., (Copyright © 2023. Published by Elsevier Ltd.)
- Published
- 2023
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5. Safety and Immunogenicity of an mRNA-Based Human Metapneumovirus and Parainfluenza Virus Type 3 Combined Vaccine in Healthy Adults.
- Author
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August A, Shaw CA, Lee H, Knightly C, Kalidindia S, Chu L, Essink BJ, Seger W, Zaks T, Smolenov I, and Panther L
- Abstract
Background: Human metapneumovirus (hMPV) and parainfluenza virus type 3 (PIV3) cause respiratory tract illness in children and the elderly. No licensed vaccines are available., Methods: In this phase 1, randomized, dose-ranging, first-in-human study, the safety, reactogenicity, and humoral immunogenicity of an investigational mRNA-based hMPV and PIV3 combination vaccine, mRNA-1653, were evaluated in healthy adults aged 18-49 years. Sentinel participants (n = 20) received 2 doses of mRNA-1653 (25, 75, 150, or 300 μg) in the dose escalation phase, and participants (n = 104) received 2 doses of mRNA-1653 (75, 150, or 300 μg) or placebo in the dose selection phase; injections were 28 days apart., Results: The most common solicited reactogenicity events were injection site pain, headache, fatigue, and myalgia, the majority of which were grade 1 or 2. A single mRNA-1653 dose increased neutralization titers against hMPV and PIV3 1 month after vaccination compared with baseline. No notable increases in neutralizing antibody titers were observed with escalating dose levels after mRNA-1653, although no statistical inferences were made; a second mRNA-1653 dose had little observable impact on antibody titers. Neutralizing titers through 1 year remained above baseline for hMPV and returned to baseline for PIV3., Conclusions: mRNA-1653 was well tolerated, with an acceptable safety profile and increased hMPV and PIV3 neutralization titers in healthy adults., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
- Published
- 2022
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6. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine.
- Author
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Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, Diemert D, Spector SA, Rouphael N, Creech CB, McGettigan J, Khetan S, Segall N, Solis J, Brosz A, Fierro C, Schwartz H, Neuzil K, Corey L, Gilbert P, Janes H, Follmann D, Marovich M, Mascola J, Polakowski L, Ledgerwood J, Graham BS, Bennett H, Pajon R, Knightly C, Leav B, Deng W, Zhou H, Han S, Ivarsson M, Miller J, and Zaks T
- Subjects
- 2019-nCoV Vaccine mRNA-1273, Adolescent, Adult, Aged, COVID-19 diagnosis, COVID-19 immunology, Female, Humans, Incidence, Male, Middle Aged, Patient Acuity, Single-Blind Method, Spike Glycoprotein, Coronavirus, Treatment Outcome, Young Adult, COVID-19 prevention & control, COVID-19 Vaccines adverse effects, COVID-19 Vaccines immunology, SARS-CoV-2
- Abstract
Background: Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle-encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19., Methods: This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2., Results: The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups., Conclusions: The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.)., (Copyright © 2020 Massachusetts Medical Society.)
- Published
- 2021
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7. Hearing Loss after Cardiac Surgery in Infancy: An Unintended Consequence of Life-Saving Care.
- Author
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Grasty MA, Ittenbach RF, Knightly C, Solot CB, Gerdes M, Bernbaum JC, Wernovsky G, Spray TL, Nicolson SC, Clancy RR, Licht DJ, Zackai E, Gaynor JW, and Burnham NB
- Subjects
- Child Development, Child, Preschool, Female, Follow-Up Studies, Hearing Loss diagnosis, Hearing Loss epidemiology, Humans, Infant, Infant, Newborn, Male, Postoperative Complications diagnosis, Postoperative Complications epidemiology, Prevalence, Prospective Studies, Risk Factors, Hearing Loss etiology, Heart Defects, Congenital surgery, Postoperative Complications etiology
- Abstract
Objectives: To investigate the prevalence of hearing loss after cardiac surgery in infancy, patient and operative factors associated with hearing loss, and the relationship of hearing loss to neurodevelopmental outcomes., Study Design: Audiologic and neurodevelopmental evaluations were conducted on 348 children who underwent repair of congenital heart disease at the Children's Hospital of Philadelphia as part of a prospective study evaluating neurodevelopmental outcomes at 4 years of age. A prevalence estimate was calculated based on presence and type of hearing loss. Potential risk factors and the impact of hearing loss on neurodevelopmental outcomes were evaluated., Results: The prevalence of hearing loss was 21.6% (95% CI, 17.2-25.9). The prevalence of conductive hearing loss, sensorineural hearing loss, and indeterminate hearing loss were 12.4% (95% CI, 8.8-16.0), 6.9% (95% CI, 4.1-9.7), and 2.3% (95% CI, 0.6-4.0), respectively. Only 18 of 348 subjects (5.2%) had screened positive for hearing loss before this study and 10 used a hearing aid. After adjusting for patient and operative covariates, younger gestational age, longer postoperative duration of stay, and a confirmed genetic anomaly were associated with hearing loss (all P < .01). The presence of hearing loss was associated with worse language, cognition and attention (P <.01)., Conclusions: These findings suggest that the prevalence of hearing loss in preschool children after heart surgery in infancy may be 20-fold higher than in the 1% prevalence seen in the general population. Younger gestational age, presence of a genetic anomaly, and longer postoperative duration of stay were associated with hearing loss. Hearing loss was associated with worse neurodevelopmental outcomes., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2018
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8. Phase-I study MEDI-534, of a live, attenuated intranasal vaccine against respiratory syncytial virus and parainfluenza-3 virus in seropositive children.
- Author
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Gomez M, Mufson MA, Dubovsky F, Knightly C, Zeng W, and Losonsky G
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- Administration, Intranasal, Child, Child, Preschool, Feces virology, Female, Human Experimentation, Humans, Infant, Male, Parainfluenza Vaccines administration & dosage, Parainfluenza Vaccines adverse effects, Placebos administration & dosage, Respiratory Syncytial Virus Vaccines administration & dosage, Respiratory Syncytial Virus Vaccines adverse effects, Vaccines, Attenuated administration & dosage, Vaccines, Attenuated adverse effects, Vaccines, Attenuated immunology, Virus Shedding, Parainfluenza Vaccines immunology, Parainfluenza Virus 3, Human immunology, Paramyxoviridae Infections prevention & control, Respiratory Syncytial Virus Infections prevention & control, Respiratory Syncytial Virus Vaccines immunology, Respiratory Syncytial Viruses immunology
- Abstract
A live, attenuated respiratory syncytial virus and parainfluenza virus type 3 vaccine was evaluated in healthy respiratory syncytial virus/parainfluenza virus type 3 seropositive children aged 1 to 9 years. Three cohorts of 40 children were randomized 1:1 to receive 10, 10, or 10 median tissue culture infectious dose50 MEDI-534 vaccine or placebo. The vaccine's safety profile was similar to placebo, no viral shedding was detected, and the vaccine was minimally immunogenic.
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- 2009
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9. Muenke syndrome (FGFR3-related craniosynostosis): expansion of the phenotype and review of the literature.
- Author
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Doherty ES, Lacbawan F, Hadley DW, Brewer C, Zalewski C, Kim HJ, Solomon B, Rosenbaum K, Domingo DL, Hart TC, Brooks BP, Immken L, Lowry RB, Kimonis V, Shanske AL, Jehee FS, Bueno MR, Knightly C, McDonald-McGinn D, Zackai EH, and Muenke M
- Subjects
- Adult, Aged, Audiometry methods, Child, Preschool, Developmental Disabilities diagnosis, Developmental Disabilities genetics, Female, Hearing Loss, Sensorineural diagnosis, Humans, Infant, Male, Mutation, Pedigree, Phenotype, Sex Factors, Speech Disorders diagnosis, Speech Disorders genetics, Syndrome, Tomography, X-Ray Computed methods, Craniosynostoses diagnosis, Craniosynostoses genetics, Hearing Loss, Sensorineural genetics, Receptor, Fibroblast Growth Factor, Type 3 genetics
- Abstract
Muenke syndrome is an autosomal dominant disorder characterized by coronal suture craniosynostosis, hearing loss, developmental delay, carpal and tarsal fusions, and the presence of the Pro250Arg mutation in the FGFR3 gene. Reduced penetrance and variable expressivity contribute to the wide spectrum of clinical findings in Muenke syndrome. To better define the clinical features of this syndrome, we initiated a study of the natural history of Muenke syndrome. To date, we have conducted a standardized evaluation of nine patients with a confirmed Pro250Arg mutation in FGFR3. We reviewed audiograms from an additional 13 patients with Muenke syndrome. A majority of the patients (95%) demonstrated a mild-to-moderate, low frequency sensorineural hearing loss. This pattern of hearing loss was not previously recognized as characteristic of Muenke syndrome. We also report on feeding and swallowing difficulties in children with Muenke syndrome. Combining 312 reported cases of Muenke syndrome with data from the nine NIH patients, we found that females with the Pro250Arg mutation were significantly more likely to be reported with craniosynostosis than males (P < 0.01). Based on our findings, we propose that the clinical management should include audiometric and developmental assessment in addition to standard clinical care and appropriate genetic counseling., ((c) 2007 Wiley-Liss, Inc.)
- Published
- 2007
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10. The Philadelphia story: the 22q11.2 deletion: report on 250 patients.
- Author
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McDonald-McGinn DM, Kirschner R, Goldmuntz E, Sullivan K, Eicher P, Gerdes M, Moss E, Solot C, Wang P, Jacobs I, Handler S, Knightly C, Heher K, Wilson M, Ming JE, Grace K, Driscoll D, Pasquariello P, Randall P, Larossa D, Emanuel BS, and Zackai EH
- Subjects
- Abnormalities, Multiple diagnosis, Adolescent, Adult, Child, Child, Preschool, Cohort Studies, DiGeorge Syndrome diagnosis, Diagnosis, Differential, Facies, Female, Genetic Counseling, Heart Defects, Congenital diagnosis, Heart Defects, Congenital genetics, Humans, Infant, Infant, Newborn, Male, Phenotype, Philadelphia, Velopharyngeal Insufficiency diagnosis, Abnormalities, Multiple genetics, Chromosome Deletion, Chromosomes, Human, Pair 22, DiGeorge Syndrome genetics, Velopharyngeal Insufficiency genetics
- Abstract
A submicroscopic deletion of chromosome 22q11.2 has been identified in the majority of patients with the DiGeorge, velocardiofacial, and conotruncal anomaly face syndromes, and in some patients with the Opitz G/BBB and Cayler cardiofacial syndromes. We have been involved in the analysis of DiGeorge syndrome and related diagnoses since 1982 and have evaluated a large number of patients with the deletion. We describe our cohort of 250 patients whose clinical findings help to define the extremely variable phenotype associated with the 22q11.2 deletion and may assist clinicians in providing genetic counseling and guidelines for clinical management based on these findings.
- Published
- 1999
11. Delayed-onset hearing loss in respiratory distress syndrome: case reports.
- Author
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Konkle DF and Knightly CA
- Subjects
- Audiometry, Pure-Tone, Auditory Perception, Child, Child, Preschool, Evoked Potentials, Auditory, Brain Stem, Female, Hearing Aids, Hearing Loss, Sensorineural diagnosis, Hearing Loss, Sensorineural rehabilitation, Humans, Infant, Newborn, Speech Disorders etiology, Hearing Loss, Sensorineural etiology, Respiratory Distress Syndrome, Newborn complications
- Abstract
The pre-, peri-, and postnatal histories for two infants who suffered respiratory distress syndrome (RDS) are presented. Each infant was diagnosed with RDS within 24 hours after birth, placed on high-frequency jet ventilation, and passed auditory brainstem response (ABR) screening prior to hospital discharge. Both infants were enrolled in a neonatal follow-up program with no report of hearing loss during the first year of life. At 2.5 years of age, each infant was found to have severe-to-profound sensorineural hearing loss. Neither infant suffered kidney failure, rubella, cytomegalovirus, or genetic involvement. Audiologic monitoring after hospital discharge was not performed because each infant passed the ABR screen. Thus, the date of onset and/or progression of hearing loss are unknown. Until additional research findings are available, we recommend that the hearing of any infant diagnosed with RDS be monitored frequently until 3 years of age.
- Published
- 1993
12. Auditory Brain Stem Responses Recorded With Uncushioned Earphones.
- Author
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Marsh RR and Knightly CA
- Abstract
Although the cushion is essential to accurate pure-tone audiometry with conventional earphones, it may interfere with the auditory brain stem response (ABR) testing of small infants because of its size and the risk of ear canal collapse. To determine the consequences of ABR testing with an uncushioned earphone, adults were tested with and without the cushion, and probe-tube sound measurements were made. Although removing the cushion results in substantial signal attenuation below 1 kHz, there is little effect on the click-elicited ABR.
- Published
- 1992
- Full Text
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