Topic: Congenital

Abstract
<div><h4>Trial of Selective Early Treatment of Patent Ductus Arteriosus with Ibuprofen.</h4><i>Gupta S, Subhedar NV, Bell JL, Field D, ... Juszczak E, Baby-OSCAR Collaborative Group</i><br /><b>Background</b><br />The cyclooxygenase inhibitor ibuprofen may be used to treat patent ductus arteriosus (PDA) in preterm infants. Whether selective early treatment of large PDAs with ibuprofen would improve short-term outcomes is not known.<br /><b>Methods</b><br />We conducted a multicenter, randomized, double-blind, placebo-controlled trial evaluating early treatment (≤72 hours after birth) with ibuprofen for a large PDA (diameter of ≥1.5 mm with pulsatile flow) in extremely preterm infants (born between 23 weeks 0 days\' and 28 weeks 6 days\' gestation). The primary outcome was a composite of death or moderate or severe bronchopulmonary dysplasia evaluated at 36 weeks of postmenstrual age.<br /><b>Results</b><br />A total of 326 infants were assigned to receive ibuprofen and 327 to receive placebo; 324 and 322, respectively, had data available for outcome analyses. A primary-outcome event occurred in 220 of 318 infants (69.2%) in the ibuprofen group and 202 of 318 infants (63.5%) in the placebo group (adjusted risk ratio, 1.09; 95% confidence interval [CI], 0.98 to 1.20; P = 0.10). A total of 44 of 323 infants (13.6%) in the ibuprofen group and 33 of 321 infants (10.3%) in the placebo group died (adjusted risk ratio, 1.32; 95% CI, 0.92 to 1.90). Among the infants who survived to 36 weeks of postmenstrual age, moderate or severe bronchopulmonary dysplasia occurred in 176 of 274 (64.2%) in the ibuprofen group and 169 of 285 (59.3%) in the placebo group (adjusted risk ratio, 1.09; 95% CI, 0.96 to 1.23). Two unforeseeable serious adverse events occurred that were possibly related to ibuprofen.<br /><b>Conclusions</b><br />The risk of death or moderate or severe bronchopulmonary dysplasia at 36 weeks of postmenstrual age was not significantly lower among infants who received early treatment with ibuprofen than among those who received placebo. (Funded by the National Institute for Health Research Health Technology Assessment Programme; Baby-OSCAR ISRCTN Registry number, ISRCTN84264977.).<br /><br />Copyright © 2024 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 25 Jan 2024; 390:314-325</small></div>
Gupta S, Subhedar NV, Bell JL, Field D, ... Juszczak E, Baby-OSCAR Collaborative Group
N Engl J Med: 25 Jan 2024; 390:314-325 | PMID: 38265644
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Abstract
<div><h4>Affinity-optimizing enhancer variants disrupt development.</h4><i>Lim F, Solvason JJ, Ryan GE, Le SH, ... Jandu SK, Farley EK</i><br /><AbstractText>Enhancers control the location and timing of gene expression and contain the majority of variants associated with disease<sup>1-3</sup>. The ZRS is arguably the most well-studied vertebrate enhancer and mediates the expression of Shh in the developing limb<sup>4</sup>. Thirty-one human single-nucleotide variants (SNVs) within the ZRS are associated with polydactyly<sup>4-6</sup>. However, how this enhancer encodes tissue-specific activity, and the mechanisms by which SNVs alter the number of digits, are poorly understood. Here we show that the ETS sites within the ZRS are low affinity, and identify a functional ETS site, ETS-A, with extremely low affinity. Two human SNVs and a synthetic variant optimize the binding affinity of ETS-A subtly from 15% to around 25% relative to the strongest ETS binding sequence, and cause polydactyly with the same penetrance and severity. A greater increase in affinity results in phenotypes that are more penetrant and more severe. Affinity-optimizing SNVs in other ETS sites in the ZRS, as well as in ETS, interferon regulatory factor (IRF), HOX and activator protein 1 (AP-1) sites within a wide variety of enhancers, cause gain-of-function gene expression. The prevalence of binding sites with suboptimal affinity in enhancers creates a vulnerability in genomes whereby SNVs that optimize affinity, even slightly, can be pathogenic. Searching for affinity-optimizing SNVs in genomes could provide a mechanistic approach to identify causal variants that underlie enhanceropathies.</AbstractText><br /><br />© 2024. The Author(s).<br /><br /><small>Nature: 17 Jan 2024; epub ahead of print</small></div>
Lim F, Solvason JJ, Ryan GE, Le SH, ... Jandu SK, Farley EK
Nature: 17 Jan 2024; epub ahead of print | PMID: 38233525
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Abstract
<div><h4>AAV1-hOTOF gene therapy for autosomal recessive deafness 9: a single-arm trial.</h4><i>Lv J, Wang H, Cheng X, Chen Y, ... Li H, Shu Y</i><br /><b>Background</b><br />Autosomal recessive deafness 9, caused by mutations of the OTOF gene, is characterised by congenital or prelingual, severe-to-complete, bilateral hearing loss. However, no pharmacological treatment is currently available for congenital deafness. In this Article, we report the safety and efficacy of gene therapy with an adeno-associated virus (AAV) serotype 1 carrying a human OTOF transgene (AAV1-hOTOF) as a treatment for children with autosomal recessive deafness 9.<br /><b>Methods</b><br />This single-arm, single-centre trial enrolled children (aged 1-18 years) with severe-to-complete hearing loss and confirmed mutations in both alleles of OTOF, and without bilateral cochlear implants. A single injection of AAV1-hOTOF was administered into the cochlea through the round window. The primary endpoint was dose-limiting toxicity at 6 weeks after injection. Auditory function and speech were assessed by appropriate auditory perception evaluation tools. All analyses were done according to the intention-to-treat principle. This trial is registered with Chinese Clinical Trial Registry, ChiCTR2200063181, and is ongoing.<br /><b>Findings</b><br />Between Oct 19, 2022, and June 9, 2023, we screened 425 participants for eligibility and enrolled six children for AAV1-hOTOF gene therapy (one received a dose of 9 × 10<sup>11</sup> vector genomes [vg] and five received 1·5 × 10<sup>12</sup> vg). All participants completed follow-up visits up to week 26. No dose-limiting toxicity or serious adverse events occurred. In total, 48 adverse events were observed; 46 (96%) were grade 1-2 and two (4%) were grade 3 (decreased neutrophil count in one participant). Five children had hearing recovery, shown by a 40-57 dB reduction in the average auditory brainstem response (ABR) thresholds at 0·5-4·0 kHz. In the participant who received the 9 × 10<sup>11</sup> vg dose, the average ABR threshold was improved from greater than 95 dB at baseline to 68 dB at 4 weeks, 53 dB at 13 weeks, and 45 dB at 26 weeks. In those who received 1·5 × 10<sup>12</sup> AAV1-hOTOF, the average ABR thresholds changed from greater than 95 dB at baseline to 48 dB, 38 dB, 40 dB, and 55 dB in four children with hearing recovery at 26 weeks. Speech perception was improved in participants who had hearing recovery.<br /><b>Interpretation</b><br />AAV1-hOTOF gene therapy is safe and efficacious as a novel treatment for children with autosomal recessive deafness 9.<br /><b>Funding</b><br />National Natural Science Foundation of China, National Key R&D Program of China, Science and Technology Commission of Shanghai Municipality, and Shanghai Refreshgene Therapeutics.<br /><br />Copyright © 2024 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 24 Jan 2024; epub ahead of print</small></div>
Lv J, Wang H, Cheng X, Chen Y, ... Li H, Shu Y
Lancet: 24 Jan 2024; epub ahead of print | PMID: 38280389
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Abstract
<div><h4>Clot or Not? Reviewing the Reciprocal Regulation Between Lipids and Blood Clotting.</h4><i>Zhang Z, Rodriguez M, Zheng Z</i><br /><AbstractText>Both hyperlipidemia and thrombosis contribute to the risks of atherosclerotic cardiovascular diseases, which are the leading cause of death and reduced quality of life in survivors worldwide. The accumulation of lipid-rich plaques on arterial walls eventually leads to the rupture or erosion of vulnerable lesions, triggering excessive blood clotting and leading to adverse thrombotic events. Lipoproteins are highly dynamic particles that circulate in blood, carry insoluble lipids, and are associated with proteins, many of which are involved in blood clotting. A growing body of evidence suggests a reciprocal regulatory relationship between blood clotting and lipid metabolism. In this review article, we summarize the observations that lipoproteins and lipids impact the hemostatic system, and the clotting-related proteins influence lipid metabolism. We also highlight the gaps that need to be filled in this area of research.</AbstractText><br /><br /><br /><br /><small>Arterioscler Thromb Vasc Biol: 18 Jan 2024; epub ahead of print</small></div>
Zhang Z, Rodriguez M, Zheng Z
Arterioscler Thromb Vasc Biol: 18 Jan 2024; epub ahead of print | PMID: 38235555
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Abstract
<div><h4>Management of pregnancy and delivery in congenital fibrinogen disorders: Communication from the ISTH SSC Subcommittee on Factor XIII and Fibrinogen.</h4><i>Casini A, Kadir RA, Abdelwahab M, Manco-Johnson MJ, ... Santoro C, Acharya S</i><br /><AbstractText>Congenital fibrinogen disorders (CFDs) are a heterogeneous group of rare congenital quantitative and / or qualitative fibrinogen deficiency. The spectrum of molecular anomalies is broad, leading to several subtypes of fibrinogen disorders (i.e., afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, hypodysfibrinogenemia). Pregnancy in women with CFDs is a high-risk clinical situation, with an increased tendency to miscarriages, bleeding, and thrombosis. Even though it is well established that management of such pregnancies requires a multidisciplinary approach involving specialists (hematologists and maternal / fetal medicine experts with expertise in the management of inherited bleeding disorders), specific guidelines are lacking. In this ISTH SSC communication, we aim to propose an expert consensus opinion with literature evidence where available on the strategy for management of pregnancy, delivery, and puerperium in CFDs.</AbstractText><br /><br />Copyright © 2024. Published by Elsevier Inc.<br /><br /><small>J Thromb Haemost: 22 Jan 2024; epub ahead of print</small></div>
Casini A, Kadir RA, Abdelwahab M, Manco-Johnson MJ, ... Santoro C, Acharya S
J Thromb Haemost: 22 Jan 2024; epub ahead of print | PMID: 38266678
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<div><h4>Pediatric pulmonary thromboembolism: a 3-year Canadian Pediatric Surveillance Program Study.</h4><i>Krmpotic K, Ramsay L, McMullen S, Chan AK, Plint AC, Moorehead P</i><br /><b>Background</b><br />Pediatric pulmonary embolism (PE) is a rare event associated with significant morbidity and mortality. Awareness of clinical presentation and practices unique to children may aid clinicians in prompt identification and treatment.<br /><b>Objectives</b><br />To describe the incidence, risk factors, clinical presentation, diagnostic and therapeutic practices, and short-term outcomes of pediatric PE.<br /><b>Methods</b><br />We conducted a 3-year national surveillance study through the Canadian Pediatric Surveillance Program. Over 2,800 pediatric specialists and sub-specialists were contacted monthly from 2020 to 2022 and requested to report all new cases of PE in patients up to 18 years of age. Case-specific data were obtained through voluntary completion of a detailed questionnaire.<br /><b>Results</b><br />58 cases (78% female, n=45) were reported (2.4 cases per million children), with rates highest in adolescents 15 to 18 years (6.6 cases per million). Detailed information, available for 31 (53%) cases, documented at least 1 risk factor in 28 (90%) cases; 24 (77%) patients presented with 2 or more symptoms. Computed tomography pulmonary angiography was used for diagnostic confirmation in 25 (81%) cases. Anticoagulation was initiated in 24 (77%) of 31 cases; fewer than 5 patients underwent thrombolysis or surgical interventions. Of 28 patients who received therapeutic interventions, 8 (29%) experienced treatment-related complications. Fewer than 5 mortalities were reported.<br /><b>Conclusions</b><br />Pediatric PE is a rare event, with female adolescents at highest risk. Although presentation is often non-specific, clinicians should maintain a high index of suspicion, particularly in patients with risk factors and when other diagnoses that may explain symptoms have been excluded.<br /><br />Copyright © 2024. Published by Elsevier Inc.<br /><br /><small>J Thromb Haemost: 22 Jan 2024; epub ahead of print</small></div>
Krmpotic K, Ramsay L, McMullen S, Chan AK, Plint AC, Moorehead P
J Thromb Haemost: 22 Jan 2024; epub ahead of print | PMID: 38266677
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Abstract
<div><h4>Clinical prediction tool to identify children at risk of pulmonary embolism.</h4><i>Tiratrakoonseree T, Charoenpichitnun S, Natesirinilkul R, Songthawee N, ... Vaewpanich J, Sirachainan N</i><br /><b>Introduction</b><br />The diagnosis of pediatric pulmonary embolism (PE) is often delayed due to non-specific symptoms, and clinical prediction tools designed for adults are unsuitable for children. This study aimed to create a PE predictive model and to evaluate the reported tools in the Thai pediatric population.<br /><b>Materials and methods</b><br />A multi-center retrospective study from 4 university hospitals included children ≤18 years of age undergoing computed tomography pulmonary angiogram from 2000 to 2020 with the suspicion of PE. Patients\' clinical presentations and risk factors of venous thromboembolism (VTE) were compared between the PE-positive and PE-negative groups. Significant risk factors from univariate and multivariate logistic regression were included to create a clinical prediction tool. The performance of the model was demonstrated by sensitivity, specificity, area under the curve (AUC), Hosmer Lemeshow test, ratio of observed and expected outcomes and bootstrapping.<br /><b>Results</b><br />Of the 104 patients included, 43 (41.3 %) were grouped as PE-positive and 61 (58.7 %) as PE-negative. Five parameters, including congenital heart disease/pulmonary surgery, known thrombophilia, previous VTE, nephrotic syndrome and chest pain showed significant differences between the two groups. Score ≥ 2 yielded a 74.4 % sensitivity and a 75.4 % specificity with an AUC of the model of 0.809. The model performance and validation results were within satisfactory ranges.<br /><b>Conclusion</b><br />The study created a clinical prediction tool indicating the likelihood of PE among Thai children. A score ≥2 was suggestive of PE.<br /><br />Copyright © 2024 Faculty of Medicine Ramathibodi Hospital, Mahidol University. Published by Elsevier Ltd.. All rights reserved.<br /><br /><small>Thromb Res: 12 Jan 2024; 234:151-157</small></div>
Tiratrakoonseree T, Charoenpichitnun S, Natesirinilkul R, Songthawee N, ... Vaewpanich J, Sirachainan N
Thromb Res: 12 Jan 2024; 234:151-157 | PMID: 38241765
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Abstract
<div><h4>DQB1 Antigen Matching Improves Rejection-Free Survival in Pediatric Heart Transplant Recipients.</h4><i>Wright LK, Gajarski RJ, Hayes E, Parekh H, Yester JW, Nandi D</i><br /><b>Introduction</b><br />Presence of donor-specific antibodies (DSAs), particularly to class II antigens, remains a major challenge in pediatric heart transplantation. Donor-recipient human leukocyte antigen (HLA) matching is a potential strategy to mitigate poor outcomes associated with DSAs. We evaluated the hypothesis that antigen mismatching at the DQB1 locus is associated with worse rejection-free survival.<br /><b>Methods</b><br />Data was collected from Scientific Registry of Transplant Recipients for all pediatric heart transplant recipients 2010-2021. Only transplants with complete HLA typing at the DQB1 locus for recipient and donor were included. Primary outcome was rejection-free graft survival through 5 years.<br /><b>Results</b><br />Of 5,115 children, 4,135 had complete DQB1 typing and were included. Of those, 503 (12%) had 0 DQB1 donor-recipient mismatches, 2,203 (53%) had 1, and 1,429 (35%) had 2. Rejection-free survival through 5 years trended higher for children with 0 DQB1 mismatches (68%), compared to those with 1 (62%) or 2 (63%) mismatches (pairwise p=0.08 for both). In multivariable analysis, 0 DQB1 mismatches remained significantly associated with improved rejection-free graft survival compared to 2 mismatches, while 1 DQB1 mismatch was not. Subgroup analysis showed the strongest effect in non-Hispanic Black children and those undergoing retransplant.<br /><b>Conclusion</b><br />Matching at the DQB1 locus is associated with improved rejection-free survival after pediatric heart transplant, particularly in Black children, and those undergoing retransplant. Assessing high-resolution donor typing at the time of allocation may further corroborate and refine this association. DQB1 matching may improve long-term outcomes in children stabilized either with optimal pharmacotherapy or supported with durable devices able to await ideal donors.<br /><br />Copyright © 2024. Published by Elsevier Inc.<br /><br /><small>J Heart Lung Transplant: 15 Jan 2024; epub ahead of print</small></div>
Wright LK, Gajarski RJ, Hayes E, Parekh H, Yester JW, Nandi D
J Heart Lung Transplant: 15 Jan 2024; epub ahead of print | PMID: 38232791
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<div><h4>Association of Periodic Limb Movements and Obstructive Sleep Apnea With Risk of Cardiovascular Disease and Mortality.</h4><i>Zinchuk A, Srivali N, Qin L, Jeon S, ... Koo B, Yaggi HK</i><br /><b>Background</b><br />Obstructive sleep apnea is a well-established risk factor for cardiovascular disease (CVD). Recent studies have also linked periodic limb movements during sleep to CVD. We aimed to determine whether periodic limb movements during sleep and obstructive sleep apnea are independent or synergistic factors for CVD events or death.<br /><b>Methods and results</b><br />We examined data from 1049 US veterans with an apnea-hypopnea index (AHI) <30 events/hour. The primary outcome was incident CVD or death. Cox proportional hazards regression assessed the relationships between the AHI, periodic limb movement index (PLMI), and the AHI×PLMI interaction with the primary outcome. We then examined whether AHI and PLMI were associated with primary outcome after adjustment for age, sex, race and ethnicity, obesity, baseline risk of mortality, and Charlson Comorbidity Index. During a median follow-up of 5.1 years, 237 of 1049 participants developed incident CVD or died. Unadjusted analyses showed an increased risk of the primary outcome with every 10-event/hour increase in PLMI (hazard ratio [HR], 1.08 [95% CI, 1.05-1.13]) and AHI (HR, 1.17 [95% CI, 1.01- 1.37]). Assessment associations of AHI and PLMI and their interaction with the primary outcome revealed no significant interaction between PLMI and AHI. In fully adjusted analyses, PLMI, but not AHI, was associated with an increased risk of primary outcome: HR of 1.05 (95% CI, 1.00-1.09) per every 10 events/hour. Results were similar after adjusting with Framingham risk score.<br /><b>Conclusions</b><br />Our study revealed periodic limb movements during sleep as a risk factor for incident CVD or death among those who had AHI <30 events/hour, without synergistic association between periodic limb movements during sleep and obstructive sleep apnea.<br /><br /><br /><br /><small>J Am Heart Assoc: 19 Jan 2024:e031630; epub ahead of print</small></div>
Zinchuk A, Srivali N, Qin L, Jeon S, ... Koo B, Yaggi HK
J Am Heart Assoc: 19 Jan 2024:e031630; epub ahead of print | PMID: 38240208
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This program is still in alpha version.