Nationwide Outcomes After Thoracoscopic Versus Open Resection of Congenital Pulmonary Airway Malformations in Newborns.

Purpose: Elective resection of congenital pulmonary airway malformations (CPAM) has been debated for decades and varies significantly between individual surgeons. However, few studies have compared outcomes and costs associated with thoracoscopic and open thoracotomy approaches on a national level. This study sought to compare nationwide outcomes and resource utilization in infants undergoing elective lung resection for CPAM. Materials and Methods: The Nationwide Readmission Database was queried from 2010 to 2014 for newborns who underwent elective surgical resection of CPAM. Patients were stratified by operative approach (thoracoscopic versus open). Demographics, hospital characteristics, and outcomes were analyzed using standard statistical tests. Results: A total of 1716 newborns with CPAM were identified. Elective readmission for pulmonary resection was performed in 12% (n = 198), with 63% of resections completed at a different hospital than the newborn stay. Most resections were thoracoscopic (75%), compared to only 25% via thoracotomy. Infants treated with thoracoscopic resection were more often male (78% versus 62% open, P = .040) and were older at the time of resection. Patients who had an open thoracotomy experienced a higher rate of serious complications (40% versus 10% thoracoscopic, P < .001), including postoperative hemorrhage, tension pneumothorax, and pulmonary collapse. Readmission costs were higher for infants treated via thoracotomy (P < .001). Conclusion: Thoracoscopic lung resection for CPAM is associated with lower cost and fewer postoperative complications than thoracotomy. Most resections are performed at different hospitals than the place of birth, which may affect long-term outcomes from single institutional studies. These findings may be used to address costs and improve future evaluations of elective CPAM resections.

Nationwide management of perforated pediatric appendicitis: Interval versus same-admission appendectomy.

PURPOSE: Although conservative management followed by readmission for interval appendectomy is commonly used to manage perforated appendicitis, many studies are limited to individual or noncompeting pediatric hospitals. This study sought to compare national outcomes following interval or same-admission appendectomy in children with perforated appendicitis. METHODS: The Nationwide Readmission Database was queried (2010-2014) for patients <18 years old with perforated appendicitis who underwent appendectomy using ICD9-CM Diagnosis codes. A propensity score-matched analysis (PSMA) utilizing 33 covariates between those with (Interval Appendectomy) and without a prior admission (Same-Admission Appendectomy) was performed to examine postoperative outcomes. RESULTS: There were 63,627 pediatric patients with perforated appendicitis. 1014 (1%) had a prior admission for perforated appendicitis within one calendar year undergoing interval appendectomy compared to 62,613 (99%) Same-Admission appendectomy patients. The Interval Appendectomy group was more likely to receive a laparoscopic (87% vs. 78% same-admission) than open (13% vs. 22% same-admission; p < 0.001) operation. Patients receiving interval appendectomy were more likely to have their laparoscopic procedure converted to open (5% vs. 3%) and receive more concomitant procedures. PSMA demonstrated a higher rate of small bowel obstruction in those receiving Same-Admission appendectomy while all other complications were similar. Although those receiving Interval Appendectomy had a shorter index length of stay (LOS) and lower admission costs, they incurred an additional $8044 [$5341-$13,190] from their prior admission. CONCLUSION: Patients treated with interval appendectomy experienced more concomitant procedures and incurred higher combined hospitalization costs while still having a similar postoperative complication profile compared to those receiving same-admission appendectomy for perforated appendicitis. LEVEL OF EVIDENCE: III. TYPE OF STUDY: Retrospective Comparative Study.

Difference between SARS-CoV-2, seasonal coronavirus, influenza, and respiratory syncytial virus infection in solid organ transplant recipients.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been raging since the end of 2019 and has shown worse outcomes in solid organ transplant (SOT) recipients. The clinical differences as well as outcomes between respiratory viruses have not been well defined in this population. METHODS: This is a retrospective cohort study of adult SOT recipients with nasopharyngeal swab or bronchoalveolar lavage PCR positive for either SARS-CoV-2, seasonal coronavirus, respiratory syncytial virus (RSV) or influenza virus from January 2017 to October 2020. The follow up period was 3 months. Clinical characteristics and outcomes were evaluated. RESULTS: A total of 377 recipients including 157 SARS-CoV-2, 70 seasonal coronavirus, 50 RSV and 100 influenza infections were identified. The most common transplanted organ was kidney 224/377 (59.4%). Lower respiratory tract infection (LRTI) was found in 210/377 (55.7%) and the risk factors identified with multivariable analysis were SARS-CoV-2 infection, steroid use, and older age. Co- and secondary infections were seen in 77/377 (20.4%) recipients with bacterial pathogens as dominant. Hospital admission was seen in 266/377 (67.7%) recipients without significant statistical difference among viruses, however, ICU admission, mechanical ventilation and mortality were higher with SARS-CoV-2 infection. In the multivariable model, the risk factors for mortality were SARS-CoV-2 infection and older age. CONCLUSIONS: We found higher incidence of ICU admission, mechanical ventilation, and mortality among SARS-CoV-2 infected recipients. Older age was found to be the risk factor for lower respiratory tract infection and mortality for SARS-CoV-2, coronaviruses, RSV and influenza virus groups.

Outcomes of Gastrostomy Tubes in Newborns With Congenital Heart Disease and Comparison of Techniques.

INTRODUCTION: Gastrostomy tube (GT) placement for enteral access is one of the most common procedures for infants with numerous conditions such as congenital heart disease (CHD). Discrepancies in the literature exist regarding outcomes of newborns with CHD undergoing GT placement. This study sought to characterize postoperative outcomes and readmission complications in this patient population. METHODS: The Nationwide Readmission Database was queried from 2010 to 2014 for all newborns who underwent GT placement during their index hospitalization. Newborns with or without CHD other than an isolated atrial or ventricular septal defect were compared using standard statistical tests. A propensity score-matched analysis was performed among newborns with or without CHD using > 100 covariates. RESULTS: Seven thousand seven hundred thirty six patients underwent GT placement. Newborns with CHD (27%) more frequently underwent open GT (59% versus 55%) and less frequently underwent laparoscopic (17% versus 19%) or percutaneous (24% versus 26%) GT placement compared to those without CHD, P = 0.043. GT-related complications on index admission were similar between groups (7% versus 7%, P = 0.770). Newborns with CHD had higher overall readmission rates (39% versus 31%), more GT-related readmission complications (7% versus 3%), and higher readmission costs ($35,787 versus $20,073) compared to newborns without CHD, all P < 0.001. Laparoscopic GT was associated with the lowest rate of GT-related complications (0%) and overall readmission rates (27%) compared to open or percutaneous endoscopic gastrostomy (all P < 0.001). CONCLUSIONS: Compared to newborns without CHD, newborns with CHD had higher rates of overall readmissions, readmission costs, and GT-related complications on readmission. The laparoscopic GT approach was underused despite fewer complications and readmissions.

Reinfection with SARS-CoV-2 in solid-organ transplant recipients: Incidence density and convalescent immunity prior to reinfection.

BACKGROUND: Long-term protective immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains poorly characterized, particularly in solid organ transplant (SOT) patients. METHOD: We determined the incidence density of SARS-CoV-2 reinfection in a cohort of adult SOT recipients initially infected between March 1st, 2020 and March 30th, 2021 and included those with initial infection before or after transplantation. Incidence density was the total cases divided by total days after initial diagnosis with active graft. RESULTS: Of 210 infected recipients, five (2.4%) developed reinfection, including two who had received full mRNA vaccination, but none developed hypoxia. The incidence density for reinfection was 9.4 (95% confidence interval [CI] 3.9-22.6) and for primary infection the density was 9.1 (95% CI 7.9-10.5) cases/100,000 patient days. Two recipients had immunity evaluated in the weeks prior to reinfection, by measuring immunoglobulin-G (IgG) antibody titer to the SARS-CoV-2 receptor binding domain and virus-specific CD4+ and CD8+ T-cell reactivity following stimulation with SARS-CoV-2 peptide pools. Both mounted virus specific CD4 T-cell responses prior to reinfection (1.19% and 0.28% of total CD4 T cells) and both had reactive IgG testing (1.30 and 4.99 signal/cut off ratio). CONCLUSIONS: This suggests that SOT recipients infected with SARS-CoV-2 remain at high risk for reinfection even after generating cellular and humoral immune responses.

A CADM3 variant causes Charcot-Marie-Tooth disease with marked upper limb involvement.

The CADM family of proteins consists of four neuronal specific adhesion molecules (CADM1, CADM2, CADM3 and CADM4) that mediate the direct contact and interaction between axons and glia. In the peripheral nerve, axon-Schwann cell interaction is essential for the structural organization of myelinated fibres and is primarily mediated by the binding of CADM3, expressed in axons, to CADM4, expressed by myelinating Schwann cells. We have identified-by whole exome sequencing-three unrelated families, including one de novo patient, with axonal Charcot-Marie-Tooth disease (CMT2) sharing the same private variant in CADM3, Tyr172Cys. This variant is absent in 230 000 control chromosomes from gnomAD and predicted to be pathogenic. Most CADM3 patients share a similar phenotype consisting of autosomal dominant CMT2 with marked upper limb involvement. High resolution mass spectrometry analysis detected a newly created disulphide bond in the mutant CADM3 potentially modifying the native protein conformation. Our data support a retention of the mutant protein in the endoplasmic reticulum and reduced cell surface expression in vitro. Stochastic optical reconstruction microscopy imaging revealed decreased co-localization of the mutant with CADM4 at intercellular contact sites. Mice carrying the corresponding human mutation (Cadm3Y170C) showed reduced expression of the mutant protein in axons. Cadm3Y170C mice showed normal nerve conduction and myelin morphology, but exhibited abnormal axonal organization, including abnormal distribution of Kv1.2 channels and Caspr along myelinated axons. Our findings indicate the involvement of abnormal axon-glia interaction as a disease-causing mechanism in CMT patients with CADM3 mutations.

Assessing non-Mendelian inheritance in inherited axonopathies.

PURPOSE: Inherited axonopathies (IA) are rare, clinically and genetically heterogeneous diseases that lead to length-dependent degeneration of the long axons in central (hereditary spastic paraplegia [HSP]) and peripheral (Charcot-Marie-Tooth type 2 [CMT2]) nervous systems. Mendelian high-penetrance alleles in over 100 different genes have been shown to cause IA; however, about 50% of IA cases do not receive a genetic diagnosis. A more comprehensive spectrum of causative genes and alleles is warranted, including causative and risk alleles, as well as oligogenic multilocus inheritance. METHODS: Through international collaboration, IA exome studies are beginning to be sufficiently powered to perform a pilot rare variant burden analysis. After extensive quality control, our cohort contained 343 CMT cases, 515 HSP cases, and 935 non-neurological controls. We assessed the cumulative mutational burden across disease genes, explored the evidence for multilocus inheritance, and performed an exome-wide rare variant burden analysis. RESULTS: We replicated the previously described mutational burden in a much larger cohort of CMT cases, and observed the same effect in HSP cases. We identified a preliminary risk allele for CMT in the EXOC4 gene (p value= 6.9 × 10-6, odds ratio [OR] = 2.1) and explored the possibility of multilocus inheritance in IA. CONCLUSION: Our results support the continuing emergence of complex inheritance mechanisms in historically Mendelian disorders.

Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes.

Here we report biallelic mutations in the sorbitol dehydrogenase gene (SORD) as the most frequent recessive form of hereditary neuropathy. We identified 45 individuals from 38 families across multiple ancestries carrying the nonsense c.757delG (p.Ala253GlnfsTer27) variant in SORD, in either a homozygous or compound heterozygous state. SORD is an enzyme that converts sorbitol into fructose in the two-step polyol pathway previously implicated in diabetic neuropathy. In patient-derived fibroblasts, we found a complete loss of SORD protein and increased intracellular sorbitol. Furthermore, the serum fasting sorbitol levels in patients were dramatically increased. In Drosophila, loss of SORD orthologs caused synaptic degeneration and progressive motor impairment. Reducing the polyol influx by treatment with aldose reductase inhibitors normalized intracellular sorbitol levels in patient-derived fibroblasts and in Drosophila, and also dramatically ameliorated motor and eye phenotypes. Together, these findings establish a novel and potentially treatable cause of neuropathy and may contribute to a better understanding of the pathophysiology of diabetes.

Author Correction: Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Truncating Mutations in UBAP1 Cause Hereditary Spastic Paraplegia.

The diagnostic gap for rare neurodegenerative diseases is still considerable, despite continuous advances in gene identification. Many novel Mendelian genes have only been identified in a few families worldwide. Here we report the identification of an autosomal-dominant gene for hereditary spastic paraplegia (HSP) in 10 families that are of diverse geographic origin and whose affected members all carry unique truncating changes in a circumscript region of UBAP1 (ubiquitin-associated protein 1). HSP is a neurodegenerative disease characterized by progressive lower-limb spasticity and weakness, as well as frequent bladder dysfunction. At least 40% of affected persons are currently undiagnosed after exome sequencing. We identified pathological truncating variants in UBAP1 in affected persons from Iran, USA, Germany, Canada, Spain, and Bulgarian Roma. The genetic support ranges from linkage in the largest family (LOD = 8.3) to three confirmed de novo mutations. We show that mRNA in the fibroblasts of affected individuals escapes nonsense-mediated decay and thus leads to the expression of truncated proteins; in addition, concentrations of the full-length protein are reduced in comparison to those in controls. This suggests either a dominant-negative effect or haploinsufficiency. UBAP1 links endosomal trafficking to the ubiquitination machinery pathways that have been previously implicated in HSPs, and UBAP1 provides a bridge toward a more unified pathophysiology.

POLG mutations presenting as Charcot-Marie-Tooth disease.

We report on two patients, with different POLG mutations, in whom axonal neuropathy dominated the clinical picture. One patient presented with late onset sensory axonal neuropathy caused by a homozygous c.2243G>C (p.Trp748Ser) mutation that resulted from uniparental disomy of the long arm of chromosome 15. The other patient had a complex phenotype that included early onset axonal Charcot-Marie-Tooth disease (CMT) caused by compound heterozygous c.926G>A (p.Arg309His) and c.2209G>C (p.Gly737Arg) mutations.

A novel MFN2 mutation causes variable clinical severity in a multi-generational CMT2 family.

Dominant mutations in MFN2 cause a range of phenotypes, including severe, early-onset axonal neuropathy, "classical CMT2", and late-onset axonal neuropathy. We found a novel MFN2 mutation - c.283A>G (p.Arg95Gly) - that results in an axonal neuropathy with variable clinical severity in a multigenerational family. In affected family members, electromyography showed moderate to severe, chronic denervation in distal muscles. Such variable clinical severity highlights the need to do careful assessments of at risk individuals when assessing MFN2 variants.

Identification of a new SYT2 variant validates an unusual distal motor neuropathy phenotype.

OBJECTIVE: To report a new SYT2 missense mutation causing distal hereditary motor neuropathy and presynaptic neuromuscular junction (NMJ) transmission dysfunction. METHODS: We report a multigenerational family with a new missense mutation, c. 1112T>A (p. Ile371Lys), in the C2B domain of SYT2, describe the clinical and electrophysiologic phenotype associated with this variant, and validate its pathogenicity in a Drosophila model. RESULTS: Both proband and her mother present a similar clinical phenotype characterized by a slowly progressive, predominantly motor neuropathy and clear evidence of presynaptic NMJ dysfunction on nerve conduction studies. Validation of this new variant was accomplished by characterization of the mutation homologous to the human c. 1112T>A variant in Drosophila, confirming its dominant-negative effect on neurotransmitter release. CONCLUSIONS: This report provides further confirmation of the role of SYT2 in human disease and corroborates the resultant unique clinical phenotype consistent with heriditary distal motor neuropathy. SYT2-related motor neuropathy is a rare disease but should be suspected in patients presenting with a combination of presynaptic NMJ dysfunction (resembling Lambert-Eaton myasthenic syndrome) and a predominantly motor neuropathy, especially in the context of a positive family history.

Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2.

Although mutations in more than 90 genes are known to cause CMT, the underlying genetic cause of CMT remains unknown in more than 50% of affected individuals. The discovery of additional genes that harbor CMT2-causing mutations increasingly depends on sharing sequence data on a global level. In this way-by combining data from seven countries on four continents-we were able to define mutations in ATP1A1, which encodes the alpha1 subunit of the Na+,K+-ATPase, as a cause of autosomal-dominant CMT2. Seven missense changes were identified that segregated within individual pedigrees: c.143T>G (p.Leu48Arg), c.1775T>C (p.Ile592Thr), c.1789G>A (p.Ala597Thr), c.1801_1802delinsTT (p.Asp601Phe), c.1798C>G (p.Pro600Ala), c.1798C>A (p.Pro600Thr), and c.2432A>C (p.Asp811Ala). Immunostaining peripheral nerve axons localized ATP1A1 to the axolemma of myelinated sensory and motor axons and to Schmidt-Lanterman incisures of myelin sheaths. Two-electrode voltage clamp measurements on Xenopus oocytes demonstrated significant reduction in Na+ current activity in some, but not all, ouabain-insensitive ATP1A1 mutants, suggesting a loss-of-function defect of the Na+,K+ pump. Five mutants fall into a remarkably narrow motif within the helical linker region that couples the nucleotide-binding and phosphorylation domains. These findings identify a CMT pathway and a potential target for therapy development in degenerative diseases of peripheral nerve axons.