Ataxia Telangiectasia Mutated and MSH2 Control Blunt DNA End Joining in Ig Class Switch Recombination.

Class-switch recombination (CSR) produces secondary Ig isotypes and requires activation-induced cytidine deaminase (AID)-dependent DNA deamination of intronic switch regions within the IgH (Igh) gene locus. Noncanonical repair of deaminated DNA by mismatch repair (MMR) or base excision repair (BER) creates DNA breaks that permit recombination between distal switch regions. Ataxia telangiectasia mutated (ATM)-dependent phosphorylation of AID at serine 38 (pS38-AID) promotes its interaction with apurinic/apyrimidinic endonuclease 1 (APE1), a BER protein, suggesting that ATM regulates CSR through BER. However, pS38-AID may also function in MMR during CSR, although the mechanism remains unknown. To examine whether ATM modulates BER- and/or MMR-dependent CSR, Atm-/- mice were bred to mice deficient for the MMR gene mutS homolog 2 (Msh2). Surprisingly, the predicted Mendelian frequencies of Atm-/-Msh2-/- adult mice were not obtained. To generate ATM and MSH2-deficient B cells, Atm was conditionally deleted on an Msh2-/- background using a floxed ATM allele (Atmf) and B cell-specific Cre recombinase expression (CD23-cre) to produce a deleted ATM allele (AtmD). As compared with AtmD/D and Msh2-/- mice and B cells, AtmD/DMsh2-/- mice and B cells display a reduced CSR phenotype. Interestingly, Sµ-Sγ1 junctions from AtmD/DMsh2-/- B cells that were induced to switch to IgG1 in vitro showed a significant loss of blunt end joins and an increase in insertions as compared with wild-type, AtmD/D, or Msh2-/- B cells. These data indicate that the absence of both ATM and MSH2 blocks nonhomologous end joining, leading to inefficient CSR. We propose a model whereby ATM and MSH2 function cooperatively to regulate end joining during CSR through pS38-AID.

A review of 92 obstetric patients with COVID-19 in the Bronx, New York and their peripartum anaesthetic management.

INTRODUCTION: The Bronx is a borough of New York City that has been profoundly affected by the COVID-19 pandemic. Limited reports exist discussing the anaesthetic management of obstetric patients infected with COVID-19. We review a cohort of obstetric patients in the Bronx with COVID-19 and report their delivery data, anaesthetic management, and maternal-fetal outcomes. MATERIAL AND METHODS: We reviewed 92 pregnant patients with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who delivered between 1 February 2020 and 1 May 2020. Medical records were reviewed for patient characteristics, anaesthetic management, and clinical outcomes. Patients were stratified by mode of delivery and COVID-19 disease severity. RESULTS: Of the 92 deliveries, 49 (53%) were vaginal, 14 (15%) were scheduled caesareans, and 29 (32%) were unscheduled caesareans. 64 patients (70%) were asymptomatic for COVID-19 (mild disease: 18 patients [19%], moderate disease: 7 patients [8%], severe disease: 2 patients [2%], critical disease: 1 patient [1%]). 83 patients (90%) received neuraxial analgesia and/or anaesthesia, with combined spinal-epidural (CSE) and dural puncture epidural (DPE) as the most common techniques. 5 patients (5%) required general anaesthesia (GA) for caesarean delivery, 3 (3%) of whom were intubated for severe or critical COVID-19 disease. CONCLUSIONS: Given the risks associated with SARS-CoV-2 aerosol transmission, GA was avoided in all but the most critically ill patients. CSE and DPE were optimal for minimizing catheter failure rates and risk of conversion to GA. SARS-CoV-2 infection in obstetric patients may be associated with an increased risk for adverse outcomes including preeclampsia, preterm delivery, unscheduled caesarean delivery, and mechanical ventilation.