Sociodemographic and Clinical Factors Associated With Clinical Outcome in Neuroinfectious Diseases: A Multicenter Retrospective Cohort Study.

Objective: To evaluate sociodemographic and clinical factors associated with clinical outcomes in patients hospitalized with neuroinfectious diseases at three tertiary care centers in New York City. Methods: This retrospective cohort study was conducted at three large urban tertiary care centers between January 1, 2010 and December 31, 2017. Poor clinical outcome was defined as length of hospital stay (LOS) ≥2 weeks and/or discharge to a location other than home. Sociodemographic and clinical factors were obtained from electronic medical records and descriptively analyzed. Multivariate logistic regression analysis investigated relationships between sociodemographic and clinical factors, and outcomes. Results: Among 205 patients with definitive neuroinfectious diagnoses, older patients were more likely to have a LOS ≥2 weeks (odds ratio [OR]: 1.03; 95% confidence interval [CI]: 1.01-1.05) and less likely to be discharged home (OR: 0.96; 95% CI: 0.94-0.98) than younger patients. Patients with an immunocompromised state were more likely to have a LOS ≥2 weeks (OR: 2.80; 95% CI: 1.17-6.69). Additionally, patients admitted to the intensive care unit (ICU) were more likely to have a LOS ≥2 weeks (OR: 4.65; 95% CI: 2.13-10.16) and less likely to be discharged home (OR: 0.14; 95% CI: 0.06-0.34). There were no statistically significant associations between sex, race, ethnicity, English proficiency, substance use, or poverty index, and clinical outcome. Conclusions: In this multicenter cohort of hospitalized neuroinfectious diseases, older age, history of immunocompromised state, and admission to the ICU were significantly associated with poor clinical outcome.

Contraceptive Care in the Rheumatic Diseases: A Review.

ABSTRACT: Contraception can help individuals with rheumatic and musculoskeletal diseases (RMDs) to avoid undesired pregnancies and improve reproductive outcomes. Despite the importance of contraception in the care of females with RMDs, evidence suggests that many of these individuals do not receive consistent or disease-specific counseling regarding contraceptive options. This includes female patients receiving teratogenic prescriptions as part of the management of their RMDs, or who have severe disease activity that might culminate in adverse pregnancy and perinatal outcomes. Contraceptive counseling can help females with RMDs who wish to prevent pregnancy to select a contraceptive method that is best for them.We conducted a narrative review of the primary literature addressing reversible, prescription-based contraception for females with RMDs, framed by published guidelines on contraceptive safety. Many safe and effective contraceptive options are available for females with RMDs. Special considerations must be given to individuals with systemic lupus erythematosus, whose disease activity may be exacerbated by exogenous estrogen. Females with positive antiphospholipid antibodies should avoid estrogen-containing contraception due to an unacceptable risk of thrombosis and should conditionally avoid depot medroxyprogesterone acetate, which appears to have a prothrombotic signature. Limited contraceptive options are available to male patients. Contraceptive care for adolescents with RMDs can be extrapolated from guidelines written for adult patients, with the additional consideration of barrier protection for individuals at risk for sexually transmitted infections. Future research is needed to assess the effects of contraception use on rheumatic disease activity and side effects.

Delays in Diagnosis and Treatment of Bacterial Meningitis in NYC: Retrospective Cohort Analysis.

Community-acquired bacterial meningitis (CABM) morbidity and mortality remains high in those infected. Rapid diagnosis and treatment is paramount to reducing mortality and improving outcome. This retrospective cohort study aims to assess the time from presentation to diagnosis and treatment of vaccine preventable CABM as well as identify possible factors associated with delays in diagnosis and antibiotic administration. A retrospective chart review was conducted of individuals who presented to Columbia University Irving Medical Center (CUIMC), Children's Hospital of New York (CHONY), Mount Sinai Medical Center, and Weill Cornell Medical Center with BM due to Haemophilus influenzae type B, Streptococcus pneumoniae, and Neisseria meningitidis between January 1, 2012 and December 31, 2017. Diagnosis was delayed by more than 8 hours in 13 patients (36.1%) and 5 individuals (13.9%) had a delay of 4 hours or more from presentation to the administration of antibiotics with appropriate CNS coverage. All of these patients were also initially misdiagnosed at an outpatient clinic, outside hospital, or emergency department. This retrospective study identified febrile and/or viral infections not otherwise specified and otitis media as the most common misdiagnoses underlying delays from presentation to diagnosis and to antibiotic treatment in those with BM.

Clinical and electrographic features of persistent seizures and status epilepticus associated with anti-NMDA receptor encephalitis (anti-NMDARE).

Based on a multicenter cohort of people with anti-NMDA receptor encephalitis (anti-NMDARE), we describe seizure phenotypes, electroencephalographic (EEG) findings, and anti-seizure treatment strategies. We also investigated whether specific electrographic features are associated with persistent seizures or status epilepticus after acute presentation. In this retrospective cohort study, we reviewed records of children and adults with anti-NMDARE between 2010 and 2014 who were included in the Rare Epilepsy of New York City database, which included the text of physician notes from five academic medical centers. Clinical history (e.g., seizure semiology) and EEG features (e.g., background organization, slowing, epileptiform activity, seizures, sleep architecture, extreme delta brush) were abstracted. We compared clinical features associated with persistent seizures (ongoing seizures after one month from presentation) and status epilepticus, using bivariate and multivariable analyses. Among the 38 individuals with definite anti-NMDARE, 32 (84%) had seizures and 29 (76%) had seizures captured on EEG. Electrographic-only seizures were identified in five (13%) individuals. Seizures started at a median of four days after initial symptoms (IQR: 3-6 days). Frontal lobe-onset focal seizures were most common (n=12; 32%). Most individuals (31/38; 82%) were refractory to anti-seizure medications. Status epilepticus was associated with younger age (15 years [9-20] vs. 23 years [18-27]; p=0.04) and Hispanic ethnicity (30 [80%] vs. 8 [36%]; p=0.04). Persistent seizures (ongoing seizures after one month from presentation) were associated with younger age (nine years [3-14] vs. 22 years [15-28]; p<0.01). Measured electrographic features were not associated with persistent seizures. Seizures associated with anti-NMDARE are primarily focal seizures originating in the frontal lobes. Younger patients may be at increased risk of epileptogenesis and status epilepticus. Continuous EEG monitoring helps identify subclinical seizures, but specific EEG findings may not predict the severity or persistence of seizures during hospitalization.

Spatiotemporal Gradient of Cortical Neuron Death Contributes to Microcephaly in Knock-In Mouse Model of Ligase 4 Syndrome.

Cells of the developing central nervous system are particularly susceptible to formation of double-stranded DNA breaks (DSBs) arising from physiological and/or environmental insults. Therefore, efficient repair of DSBs is especially vital for maintaining cellular health and proper functioning in the developing brain. Here, increased expression of DSB initiating and nonhomologous end joining repair machinery in newborn neurons in the developing brains of both mouse and human are demonstrated. In parallel, the first characterization is provided of the brain phenotype in the Lig4R278H/R278H (Lig4R/R) mouse model of DNA Ligase 4 (LIG4) syndrome, in which a hypomorphic Lig4 mutation, originally identified in patients, impedes nonhomologous end joining. It is shown that Lig4R/R mice develop nonprogressive microcephaly, resulting primarily from apoptotic death of newborn neurons that is both spatially and temporally specific during peak cortical neurogenesis. This apoptosis leads to a reduction in neurons throughout the postnatal cerebral cortex, but with a more prominent impact on those of the lower cortical layers. Together, these findings begin to uncover the pathogenesis of microcephaly in LIG4 syndrome and open avenues to more focused investigations on the critical roles of DSB formation and repair in vulnerable neuronal populations of the brain.

EXTL3 mutations cause skeletal dysplasia, immune deficiency, and developmental delay.

We studied three patients with severe skeletal dysplasia, T cell immunodeficiency, and developmental delay. Whole-exome sequencing revealed homozygous missense mutations affecting exostosin-like 3 (EXTL3), a glycosyltransferase involved in heparan sulfate (HS) biosynthesis. Patient-derived fibroblasts showed abnormal HS composition and altered fibroblast growth factor 2 signaling, which was rescued by overexpression of wild-type EXTL3 cDNA. Interleukin-2-mediated STAT5 phosphorylation in patients' lymphocytes was markedly reduced. Interbreeding of the extl3-mutant zebrafish (box) with Tg(rag2:green fluorescent protein) transgenic zebrafish revealed defective thymopoiesis, which was rescued by injection of wild-type human EXTL3 RNA. Targeted differentiation of patient-derived induced pluripotent stem cells showed a reduced expansion of lymphohematopoietic progenitor cells and defects of thymic epithelial progenitor cell differentiation. These data identify EXTL3 mutations as a novel cause of severe immune deficiency with skeletal dysplasia and developmental delay and underline a crucial role of HS in thymopoiesis and skeletal and brain development.