Summary Background Phase 1 studies have shown potential benefit of gene replacement in RPE65-mediated inherited retinal dystrophy. This phase 3 study assessed the efficacy and safety of voretigene neparvovec in participants whose inherited retinal dystrophy would otherwise progress to complete blindness. Methods In this open-label, randomised, controlled phase 3 trial done at two sites in the USA, individuals aged 3 years or older with, in each eye, best corrected visual acuity of 20/60 or worse, or visual field less than 20 degrees in any meridian, or both, with confirmed genetic diagnosis of biallelic RPE65 mutations, sufficient viable retina, and ability to perform standardised multi-luminance mobility testing (MLMT) within the luminance range evaluated, were eligible. Participants were randomly assigned (2:1) to intervention or control using a permuted block design, stratified by age (<10 years and ≥10 years) and baseline mobility testing passing level (pass at ≥125 lux vs <125 lux). Graders assessing primary outcome were masked to treatment group. Intervention was bilateral, subretinal injection of 1·5×1011 vector genomes of voretigene neparvovec in 0·3 mL total volume. The primary efficacy endpoint was 1-year change in MLMT performance, measuring functional vision at specified light levels. The intention-to-treat (ITT) and modified ITT populations were included in primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT00999609, and enrolment is complete. Findings Between Nov 15, 2012, and Nov 21, 2013, 31 individuals were enrolled and randomly assigned to intervention (n=21) or control (n=10). One participant from each group withdrew after consent, before intervention, leaving an mITT population of 20 intervention and nine control participants. At 1 year, mean bilateral MLMT change score was 1·8 (SD 1·1) light levels in the intervention group versus 0·2 (1·0) in the control group (difference of 1·6, 95% CI 0·72–2·41, p=0·0013). 13 (65%) of 20 intervention participants, but no control participants, passed MLMT at the lowest luminance level tested (1 lux), demonstrating maximum possible improvement. No product-related serious adverse events or deleterious immune responses occurred. Two intervention participants, one with a pre-existing complex seizure disorder and another who experienced oral surgery complications, had serious adverse events unrelated to study participation. Most ocular events were mild in severity. Interpretation Voretigene neparvovec gene replacement improved functional vision in RPE65-mediated inherited retinal dystrophy previously medically untreatable. Funding Spark Therapeutics.

Summary Background Gene therapy has the potential to reverse disease or prevent further deterioration of vision in patients with incurable inherited retinal degeneration. We therefore did a phase 1 trial to assess the effect of gene therapy on retinal and visual function in children and adults with Leber’s congenital amaurosis. Methods We assessed the retinal and visual function in 12 patients (aged 8–44 years) with RPE65-associated Leber’s congenital amaurosis given one subretinal injection of adeno-associated virus (AAV) containing a gene encoding a protein needed for the isomerohydrolase activity of the retinal pigment epithelium (AAV2-hRPE65v2) in the worst eye at low (1·5×1010 vector genomes), medium (4·8×1010 vector genomes), or high dose (1·5×1011 vector genomes) for up to 2 years. Findings AAV2-hRPE65v2 was well tolerated and all patients showed sustained improvement in subjective and objective measurements of vision (ie, dark adaptometry, pupillometry, electroretinography, nystagmus, and ambulatory behaviour). Patients had at least a 2 log unit increase in pupillary light responses, and an 8-year-old child had nearly the same level of light sensitivity as that in age-matched normal-sighted individuals. The greatest improvement was noted in children, all of whom gained ambulatory vision. The study is registered with ClinicalTrials.gov, number NCT00516477. Interpretation The safety, extent, and stability of improvement in vision in all patients support the use of AAV-mediated gene therapy for treatment of inherited retinal diseases, with early intervention resulting in the best potential gain. Funding Center for Cellular and Molecular Therapeutics at the Children’s Hospital of Philadelphia, Foundation Fighting Blindness, Telethon, Research to Prevent Blindness, F M Kirby Foundation, Mackall Foundation Trust, Regione Campania Convenzione, European Union, Associazione Italiana Amaurosi Congenita di Leber, Fund for Scientific Research, Fund for Research in Ophthalmology, and National Center for Research Resources.

This multicenter study demonstrates a dramatic increase in the diagnosis of VTE at children's hospitals from 2001 to 2007.

Background: Despite an increasing incidence of venous thromboembolism (VTE) in pediatric patients in tertiary care settings, relatively few pediatric physicians have experience with antithrombotic interventions. Objective: These guidelines of the American Society of Hematology (ASH), based on the best available evidence, are intended to support patients, clinicians, and other health care professionals in their decisions about management of pediatric VTE. Methods: ASH formed a multidisciplinary guideline panel that included 2 patient representatives and was balanced to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline-development process, including updating or performing systematic evidence reviews (up to April of 2017). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on 30 recommendations, covering symptomatic and asymptomatic deep vein thrombosis, with specific focus on management of central venous access device–associated VTE. The panel also addressed renal and portal vein thrombosis, cerebral sino venous thrombosis, and homozygous protein C deficiency. Conclusions: Although the panel offered many recommendations, additional research is required. Priorities include understanding the natural history of asymptomatic thrombosis, determining subgroup boundaries that enable risk stratification of children for escalation of treatment, and appropriate study of newer anticoagulant agents in children.

Background-The aim of this study was to estimate the impact of thrombophilia on risk of first childhood stroke through a meta-analysis of published observational studies. Methods and Results-A systematic search of electronic databases (Medline via PubMed, EMBASE, OVID, Web ofScience, The Cochrane Library) for studies published from 1970 to 2009 was conducted. Data on year of publication, study design, country of origin, number of patients/control subjects, ethnicity, stroke type (arterial ischemic stroke [AIS], cerebral venous sinus thrombosis [CSVT]) were abstracted. Publication bias indicator and heterogeneity across studies were evaluated, and summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with fixed-effects or random-effects models. Twenty-two of 185 references met inclusion criteria. Thus, 1764 patients (arterial ischemic stroke [AIS], 1526; cerebral sinus venous thrombosis [CSVT], 238) and 2799 control subjects (neonate to 18 years of age) were enrolled. No significant heterogeneity was discerned across studies, and no publication bias was detected. A statistically significant association with first stroke was demonstrated for each thrombophilia trait evaluated, with no difference found between AIS and CSVT. Summary ORs (fixed-effects model) were as follows: antithrombin deficiency, 7.06 (95% CI, 2.44 to 22.42); protein C deficiency, 8.76 (95% CI, 4.53 to 16.96); protein S deficiency, 3.20 (95% CI, 1.22 to 8.40), factor V G1691A, 3.26 (95% CI, 2.59 to 4.10); factor II G20210A, 2.43 (95% CI, 1.67 to 3.51); MTHFR C677T (AIS), 1.58 (95% CI, 1.20 to 2.08); antiphospholipid antibodies (AIS) [CSVT]) is estimated to be between 2.6 and 6.4 per 100 000 per year, reflecting a trend toward a higher frequency in more current literature. 1-3 Underlying conditions in children with symptomatic cerebrovascular accidents include congenital heart malformations, hemolytic anemias, and collagen vascular diseases, as well as some rare inborn metabolic disorders. 4 In addition, risk factors include trauma and infectious diseases. Apart from acquired thrombophilic risk factors such as the presence of antiphospholipid antibodies, 5,6 inherited thrombophilia, particularly antithrombin, protein C, and protein S deficiency, variants of coagulation factor V (G1691A) and factor II (G20210A), and elevated lipoprotein(a), have been found in small case series and case-control studies to be associated with AIS or CSVT in infants and children. Furthermore, an association of the thermolabile MTHFR C677T genotype with stroke is controversial in both adults and children. 5353 In fact, the increased likelihood of having a blood clot in the vasculature is related to elevated homocysteine levels, and mutations in the MTHFR gene only exploit their effect by contributing to the elevated homocysteine plasma level. Because adequate folate levels essentially cancel out the impaired regulation of homocysteine induced by MTHFR mutations, not all people will develop high homocysteine levels. [53][54][55][56] , Editori...

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is associated with thrombotic complications in adults, but the incidence of COVID-19 related thrombosis in children and adolescents is unclear. Most children with acute COVID-19 have mild disease, but coagulopathy has been associated with multisystem inflammatory syndrome in children (MIS-C), a post-infectious complication. We conducted a multicenter retrospective cohort study to determine the incidence of thrombosis in children hospitalized with COVID-19 or MIS-C and to evaluate associated risk factors. We classified patients into one of three groups for analysis: COVID-19, MIS-C, or asymptomatic SARS-CoV-2. Among a total of 853 admissions (426 COVID-19, 138 MIS-C, and 289 asymptomatic SARS-CoV-2) in 814 patients, there were 20 patients with thrombotic events (TE) (including 1 stroke). Patients with MIS-C had the highest incidence (6.5%, 9/138) versus COVID-19 (2.1%, 9/426) or asymptomatic SARS-CoV-2 (0.7%, 2/289). In patients with COVID-19 or MIS-C, the majority of thrombotic events (89%) occurred in patients ≥12 years. Patients &gt; 12 years with MIS-C had the highest rate of thrombosis at 19% (9/48). Notably, 71% of TE that were not present on admission occurred despite thromboprophylaxis. Multivariable analysis identified the following as significantly associated with thrombosis: age ≥12 years, cancer, presence of a central venous catheter, and MIS-C. In patients with COVID-19 or MIS-C, hospital mortality was 2.3% (13/564), but was 28% (5/18) in patients with thrombotic events. Our findings may help inform pediatric thromboprophylaxis strategies.

Background: Observational studies indicate that children hospitalized with COVID-19-related illness, like adults, are at increased risk for venous thromboembolism (VTE). A multicenter phase 2 clinical trial of anticoagulant thromboprophylaxis in

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