Association of Clinical Rejection Versus Rejection on Protocol Biopsy With Cardiac Allograft Vasculopathy in Pediatric Heart Transplant Recipients.

BACKGROUND: Two or more early rejections (<1 y) or any late acute rejection (>1 y) have been associated with coronary artery vasculopathy (CAV) in pediatric heart transplant (HT) recipients. We hypothesized that clinical rejection defined by concurrent new-onset heart failure or left ventricular systolic dysfunction is more strongly associated with future CAV than rejection diagnosed on protocol biopsy. METHODS: We identified all subjects <21 years old who received first HT at Boston Children's Hospital during 1986-2015 with at least 1 post-HT coronary angiogram. CAV was diagnosed using 2010 International Society for Heart and Lung Transplantation guidelines. Time to CAV diagnosis was assessed using a Cox model with occurrence of clinical rejection analyzed as a time-varying covariate. RESULTS: Of 228 study subjects, 106 remained rejection-free, 77 had rejection diagnosed only on protocol biopsy (≥2R cellular or antibody-mediated), and 45 had a clinical rejection. Subjects with rejection diagnosed only on protocol biopsy were not at higher risk of CAV (hazard ratio [HR] 1.09, 95% confidence interval [CI]: 0.54-2.09). In contrast, clinical rejection was significantly associated with risk of CAV (HR 4.84, 95% CI: 2.99-7.83). Late rejection was associated with a higher risk of CAV (HR 4.27, 95% CI: 2.42-7.51) if it was clinical rejection but not if it was diagnosed on protocol biopsy (HR 0.83, 95% CI: 0.51-1.37). CONCLUSIONS: Clinical rejection poses a far greater risk for future CAV than rejection on protocol biopsy in pediatric HT recipients. Preventing CAV should therefore become the focus of medical management after initial treatment and resolution of clinical rejection.

CMR Guidance for Recanalization of Coronary Chronic Total Occlusion.

OBJECTIVES: This study explored whether cardiac magnetic resonance (CMR) could help select patients who could benefit from revascularization by identifying inducible myocardial ischemia and viability in the perfusion territory of the artery with chronic total occlusion (CTO). BACKGROUND: The benefit of revascularization using percutaneous coronary intervention (PCI) in CTO is controversial. CMR offers incomparable left ventricular (LV) systolic function assessment in addition to potent ischemic burden quantification and reliable myocardial viability analysis. Whether CMR guided CTO revascularization would be helpful to such patients has not yet been explored fully. METHODS: A prospective study of 50 consecutive CTO patients was conducted. Of 50 patients undergoing baseline stress CMR, 32 (64%) were selected for recanalization based on the presence of significant inducible perfusion deficit and myocardial viability within the CTO arterial territory. Patients were rescanned 3 months after successful CTO recanalization. RESULTS: At baseline, myocardial perfusion reserve (MPR) in the CTO territory was significantly reduced compared with the remote region (1.8 ± 0.72 vs. 2.2 ± 0.7; p = 0.01). MPR in the CTO region improved significantly after PCI (to 2.3 ± 0.9; p = 0.02 vs. baseline) with complete or near-complete resolution of CTO related perfusion defect in 90% of patients. Remote territory MPR was unchanged after PCI (2.5 ± 1.2; p = NS vs. baseline). The LV ejection fraction increased from 63 ± 13% to 67 ± 12% (p < 0.0001) and end-systolic volume decreased from 65 ± 38 to 56 ± 38 ml (p < 0.001) 3 months after CTO PCI. Importantly, despite minimal post-procedural infarction due to distal embolization and side branch occlusion in 8 of 32 patients (25%), the total Seattle Angina Questionnaire score improved from a median of 54 (range 45 to 74) at baseline to 89 (range 77 to 98) after CTO recanalization (p < 0.0001). CONCLUSIONS: In this small group of patients showing CMR evidence of significant myocardial inducible perfusion defect and viability, CTO recanalization reduces ischemic burden, favors reverse remodeling, and ameliorates quality of life.

Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency.

Inactivating mutations in chromodomain helicase DNA binding protein 7 (CHD7) cause CHARGE syndrome, a severe multiorgan system disorder of which Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a minor feature. Recent reports have described predominantly missense CHD7 alleles in IGD patients, but it is unclear if these alleles are relevant to causality or overall genetic burden of Kallmann syndrome (KS) and normosmic form of IGD. To address this question, we sequenced CHD7 in 783 well-phenotyped IGD patients lacking full CHARGE features; we identified nonsynonymous rare sequence variants in 5.2% of the IGD cohort (73% missense and 27% splice variants). Functional analyses in zebrafish using a surrogate otolith assay of a representative set of these CHD7 alleles showed that rare sequence variants observed in controls showed no altered function. In contrast, 75% of the IGD-associated alleles were deleterious and resulted in both KS and normosmic IGD. In two families, pathogenic mutations in CHD7 coexisted with mutations in other known IGD genes. Taken together, our data suggest that rare deleterious CHD7 alleles contribute to the mutational burden of patients with both KS and normosmic forms of IGD in the absence of full CHARGE syndrome. These findings (i) implicate a unique role or preferential sensitivity for CHD7 in the ontogeny of GnRH neurons, (ii) reiterate the emerging genetic complexity of this family of IGD disorders, and (iii) demonstrate how the coordinated use of well-phenotyped cohorts, families, and functional studies can inform genetic architecture and provide insights into the developmental biology of cellular systems.

Analysis of clinical negligence claims following tonsillectomy in England 1995 to 2010.

OBJECTIVES: We determined the characteristics of medical negligence claims following tonsillectomy. METHODS: Claims relating to tonsillectomy between 1995 and 2010 were obtained from the National Health Service Litigation Authority database. The number of open and closed claims was determined, and data were analyzed for primary injury claimed, outcome of claim, and associated costs. RESULTS: Over 15 years, there were 40 claims of clinical negligence related to tonsillectomy, representing 7.7% of all claims in otolaryngology. There were 34 closed claims, of which 32 (94%) resulted in payment of damages. Postoperative bleeding was the most common injury, with delayed recognition and treatment of bleeding alleged in most cases. Nasopharyngeal regurgitation as a result of soft palate fistulas or excessive tissue resection was the next-commonest cause of a claim. The other injuries claimed included dentoalveolar injury, bums, tonsillar remnants, and temporomandibular joint dysfunction. Inadequate informed consent was claimed in 5 cases. CONCLUSIONS: Clinical negligence claims following tonsillectomy have a high success rate. Although postoperative bleeding is the most common cause of negligence claims, a significant proportion of claims are due to rare complications of surgery. Informed consent should be tailored to the individual patient and should include a discussion of common and serious complications.

Toward safer practice in otology: a report on 15 years of clinical negligence claims.

OBJECTIVES/HYPOTHESIS: To determine the characteristics of medical negligence claims arising from otological practice. STUDY DESIGN: Retrospective analysis of medical negligence claims contained in the National Health Service Litigation Authority (NHSLA) database. METHODS: Claims relating to otology and neurotology between 1995 and 2010 were obtained from the NHSLA database and analyzed for cause of injury, type of injury, outcome of claim and costs. RESULTS: Over 15 years there were 137 claims in otology, representing 26% of all the claims in otolaryngology. Of these, 116 have been closed, and 84% of closed claims resulted in payment. Of the 97 successful claims, 63 were related to operative complications. This included six cases of wrong side/site surgery, and 15 cases of inadequate informed consent. The most common injuries claimed were hearing loss, facial paralysis, and additional/unnecessary surgery. Middle ear ventilation and mastoid surgery were the procedures most commonly associated with a successful claim. There were 15 successful claims of misdiagnosis/delayed diagnosis, with chronic suppurative otitis media the condition most frequently missed. There were nine successful claims related to outpatient procedures, of which seven were for aural toilet and six claims of medical mismanagement, including three cases of ototoxicity from topical medications. There were also four successful claims for morbidity due to delayed surgery. CONCLUSIONS: This is the first study to report outcomes of negligence claims in otology. Claims in otology are associated with a high success rate. A significant proportion of claims are not related to surgery and represent areas where safety should also be addressed.