Lishi Zhang

Volumetric brain changes in females with fragile X-associated tremor/ataxia syndrome (FXTAS)

Background: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder occurring in male and rare female carriers of a premutation expansion (55 to 200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. Methods: Volumetric MRI studies, clinical staging, cognitive testing, and molecular analysis were conducted in 15 female premutation carriers affected by FXTAS (age 59.5 ± 10.3 years), 20 unaffected female carriers (43.3 ± 11.2 years), 11 genetically normal female controls (51.0 ± 10.3 years), 36 affected male carriers (65.0 ± 5.6 years), 25 unaffected male carriers (53.5 ± 12.5 years), and 39 male controls (58.0 ± 15.0 years). Female and male carriers with FXTAS were matched on duration of disease. Results: We found less pronounced reductions of cerebellar volume and a lower incidence of involvement (symmetric high T2 signal) of the middle cerebellar peduncles (MCP sign) in females affected by FXTAS (13%) compared with affected males (58%). We found reduced brain volumes and increased white matter disease associated with the presence of FXTAS in females compared with female controls. We also observed significant associations between reduced cerebellar volume and both increased severity of FXTAS symptoms and increased length of the CGG repeat expansion in male premutation carriers, but not in females. Conclusions: Females affected by fragile X-associated tremor/ataxia syndrome (FXTAS) demonstrated milder brain changes than affected males, although they showed a similar pattern of radiologic findings consistent with brain atrophy and white matter disease. FXTAS should be considered (by ordering fragile X DNA testing) in females who present with late-onset ataxia, action tremor, or neuropathy, particularly in those with a family history of mental retardation, autism, or premature ovarian failure.

FMR1 CGG repeat length predicts motor dysfunction in premutation carriers

Background: Fragile X–associated tremor/ataxia syndrome (FXTAS) is a recently described, underrecognized neurodegenerative disorder of aging fragile X mental retardation 1 (FMR1) premutation carriers, particularly men. Core motor features are action tremor, gait ataxia, and parkinsonism. Carriers have expanded CGG repeats (55 to 200); larger expansions cause fragile X syndrome, the most common heritable cause of mental retardation and autism. This study determines whether CGG repeat length correlates with severity and type of motor dysfunction in premutation carriers. Methods: Persons aged ≥50 years with a family history of fragile X syndrome underwent structured videotaping. Movement disorder neurologists, blinded to carrier status, scored the tapes using modified standardized rating scales. CGG repeat length analyses for women incorporated the activation ratio, which measures the percentage of normal active chromosome X alleles. Results: Male carriers (n = 54) had significantly worse total motor scores, especially in tremor and ataxia, than age-matched male noncarriers (n = 51). There was a trend toward a difference between women carriers (n = 82) and noncarriers (n = 39). In men, increasing CGG repeat correlated with greater impairment in all motor signs. In women, when activation ratio was considered, increasing CGG correlated with greater ataxia. Conclusions: CGG repeat size is significantly associated with overall motor impairment in premutation carriers. Whereas this association is most pronounced for men and covers overall motor impairment—tremor, ataxia, and parkinsonism—the association exists for ataxia among women carriers. This is the first report of a significant correlation between the premutation status and a motor feature of fragile X–associated tremor/ataxia syndrome in women. GLOSSARY: AR = activation ratio; FXTAS = fragile X-associated tremor/ataxia syndrome; MCP = middle cerebellar peduncle; mRNA = messenger RNA.

Cannulating the contraindicated: effect of low birth weight on mortality in neonates with congenital diaphragmatic hernia on extracorporeal membrane oxygenation

BACKGROUND/PURPOSEnRestrictions for ECMO in neonates include birth weight less than 2kg (BW <2kg) and/or gestational age less than 34weeks (GA <34weeks). We sought to describe their relationship on mortality.nnnMETHODSnNeonates with a primary diagnosis code of CDH were identified in the Extracorporeal Life Support Organization (ELSO) registry, and logistic regression models were used to examine the effect of BW <2kg and GA <34weeks on mortality.nnnRESULTSnWe identified 7564 neonates with CDH. The overall mortality was 50%. There was a significantly higher risk of death with unadjusted odds ratio (OR) 2.39 (95% confidence interval [CI]: 1.53-3.74; P<0.01) for BW <2kg neonates. The adjusted OR of death for BW <2kg neonates remained significantly high with over two-fold increase in the odds of mortality when adjusted for potential confounding variables (OR 2.11, 95% CI: 1.30-3.43; P<0.01). However, no difference in mortality was observed in neonates with GA <34weeks.nnnCONCLUSIONSnWhile mortality among CDH neonates with a BW <2kg was substantially increased, GA <34weeks was not significantly associated with mortality. Effort should be made to identify the best candidates for ECMO in this high-risk group and develop treatment strategies to optimize their survival.nnnTYPE OF STUDYnCase-Control Study, Retrospective Comparative Study.nnnLEVEL OF EVIDENCEnLevel III.

Antibiotic prophylaxis in clean-contaminated head and neck cases with microvascular free flap reconstruction: A systematic review and meta-analysis

Optimal antibiotic prophylaxis duration in head and neck clean‐contaminated free‐flap cases is unknown.

Are Electronic and Paper Questionnaires Equivalent to Assess Patients with Overactive Bladder

Purpose: Overactive bladder syndrome is defined as urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence in the absence of urinary tract infection or another obvious pathological condition. Electronic questionnaires have been used in a few specialties with the hope of improving treatment outcomes and patient satisfaction. However, they have not been widely used in the urological field. When treating overactive bladder, the main outcome is to improve patient quality of life. The primary objective of this study was to evaluate whether electronic questionnaires would be equally accepted as or preferred to paper questionnaires. The secondary objective was to look at the preference in relation to patient age, education and iPad® tablet familiarity. Materials and Methods: We prospectively evaluated the iList® electronic questionnaire application using a friendly iPad tablet in patients with overactive bladder who presented to the urology clinic at our institution. Each of the 80 patients who were recruited randomly completed the validated OABSS (Overactive Bladder Symptom Score) and the PPBC (Patient Perception of Bladder Condition) questionnaires in paper and electronic format on the tablet. Variables potentially associated with the outcomes of interest included demographic data, questionnaire method preference, patient response rate and iPad familiarity. We used the 2‐sided Z‐test to determine whether the proportion of patients who considered the tablet to be the same, better or much better than paper was significantly greater than 50%. The 2‐sided chi‐square test was applied to assess whether the intervention effect significantly differed among the demographic subgroups. Results: A total of 80 patients 21 to 87 years old were enrolled in the study from November 2015 to August 2016. Of the patients 53% were female and 49% were 65 years or younger. The incidence of those who considered the tablet to be the same or better than paper was 82.5% (95% CI 74.2–90.8, p <0.001). The incidence of patients who considered the tablet to be the same or better than paper ranged from 76% to 97% regardless of age, gender and education subgroup as well as in those with any familiarity with the tablet (each p <0.001). Of the 20 patients who were not familiar with the tablet 45% preferred the electronic questionnaire (p = 0.654). Conclusions: We found that the proportion of patients who considered electronic questionnaires to be equivalent to or better than paper versions was higher than those who preferred paper questionnaires regardless of age, gender or education level.

Effect of pump type on outcomes in neonates with congenital diaphragmatic hernia requiring ECMO

Purpose: With the exception of neonatal respiratory failure, most centers are now using centrifugal over roller-type pumps for the delivery of extracorporeal membrane oxygenation (ECMO). Evidence supporting the use of centrifugal pumps specifically in infants with congenital diaphragmatic hernia (CDH) remains lacking. We hypothesized that the use of centrifugal pumps in infants with CDH would not affect mortality or rates of severe neurologic injury (SNI). Methods: Infants with CDH were identified within the ELSO registry (2000-2016). Patients were then divided into those undergoing ECMO with rollertype pumps or centrifugal pumps. Patients were matched based on propensity score (PS) for the ECMO pump type based on pre-ECMO covariates. This was done for all infants and separately for each ECMO mode, venovenous (VV) and venoarterial (VA) ECMO. Results: We identified 4,367 infants who were treated with either roller or centrifugal pumps from 2000-2016. There was no difference in mortality or SNI between the two pump types in any of the groups (all infants, VA-ECMO infants, VV-ECMO infants). However, there was at least a six-fold increase in the odds of hemolysis for centrifugal pumps in all groups: all infants (odds ratio [OR] 6.99, p<0.001), VA-ECMO infants (OR 8.11, p<0.001 and VV-ECMO infants (OR 9.66, p<0.001). Conclusion: For neonates with CDH requiring ECMO, there is no survival advantage or difference in severe neurologic injury between those receiving roller or centrifugal pump ECMO. However, there is a significant increase in red blood cell hemolysis associated with centrifugal ECMO support.

Development and Validation of Prediction Scores for Early Mortality at Transition to Dialysis

Objective: To develop and validate a risk prediction model that would help individualize treatment and improve the shared decision‐making process between clinicians and patients. Patients and Methods: We developed a risk prediction tool for mortality during the first year of dialysis based on pre–end‐stage renal disease characteristics in a cohort of 35,878 US veterans with incident end‐stage renal disease who transitioned to dialysis treatment between October 1, 2007, and March 31, 2014 and then externally validated this tool among 4284 patients in the Kaiser Permanente Southern California (KPSC) health care system who transitioned to dialysis treatment between January 1, 2007, and September 30, 2015. Results: To ensure model goodness of fit, 2 separate models were selected for patients whose last estimated glomerular filtration rate (eGFR) before dialysis initiation was less than 15 mL/min per 1.73 m2 or 15 mL/min per 1.73 m2 or higher. Model discrimination in the internal validation cohort of veterans resulted in C statistics of 0.71 (95% CI, 0.70‐0.72) and 0.66 (95% CI, 0.65‐0.67) among patients with eGFR lower than 15 mL/min per 1.73 m2 and 15 mL/min per 1.73 m2 or higher, respectively. In the KPSC external validation cohort, the developed risk score exhibited C statistics of 0.77 (95% CI, 0.74‐0.79) in men and 0.74 (95% CI, 0.71‐0.76) in women with eGFR lower than 15 mL/min per 1.73 m2 and 0.71 (95% CI, 0.67‐0.74) in men and 0.67 (95% CI, 0.62‐0.72) in women with eGFR of 15 mL/min per 1.73 m2 or higher. Conclusion: A new risk prediction tool for mortality during the first year after transition to dialysis (available at www.DialysisScore.com) was developed in the large national Veterans Affairs cohort and validated with good performance in the racially, ethnically, and gender diverse KPSC cohort. This risk prediction tool will help identify high‐risk populations and guide management strategies at the transition to dialysis.

Outcomes of infants with congenital diaphragmatic hernia treated with venovenous versus venoarterial extracorporeal membrane oxygenation: A propensity score approach

PURPOSEnPrevious studies comparing extracorporeal membrane oxygenation (ECMO) modality for congenital diaphragmatic hernia (CDH) have not accounted for confounding by indication. We therefore hypothesized that using a propensity score (PS) approach to account for selection bias may identify outcome differences based on ECMO modality for infants with CDH.nnnMETHODSnWe utilized ELSO Registry data (2000-2016). Patients with CDH were divided to either venoarterial (VA) or venovenous (VV) ECMO. Patients were matched by PS to control for nonrandom treatment assignment. Subgroup analyses were conducted based on timing of CDH repair relative to ECMO. Primary analysis was the intent-to-treat cohort based on the initial ECMO mode. Mortality was the primary outcome, and severe neurologic injury (SNI) was a secondary outcome.nnnRESULTSnPS matching (3:1) identified 3304 infants (VAu202f=u202f2470, VVu202f=u202f834). In the main group, mortality was not different between VA and VV ECMO (ORu202f=u202f1.01, 95% CI: 0.86-1.18) and there was no difference in SNI between VA and VV (ORu202f=u202f0.80; 95% CI: 0.63-1.01). For the pre-ECMO CDH repair subgroup, 175 VA cases were matched to 70 VV. In these neonates, mortality was higher for VV compared to VA (ORu202f=u202f2.10, 95% CI: 1.19-3.69), without any difference in SNI (ORu202f=u202f1.48; 95% CI: 0.59-3.71). For the subgroup that did not have pre-ECMO CDH repair, 2030 VA cases were matched to 683 VV cases. In this subgroup, VV was associated with 27% lower risk of SNI relative to VA (ORu202f=u202f0.73, 95% CI: 0.56-0.95) without any difference in mortality (ORu202f=u202f0.94, 95% CI: 0.79-1.11).nnnCONCLUSIONnThis study revalidates that ECMO mode does not significantly affect mortality or SNI in infants with CDH. In the subset of infants who require pre-ECMO CDH repair, VA favors survival, whereas, in the subgroup of infants that did not have pre-ECMO CDH repair, VV favors lower rates of SNI. We conclude that neither mode appears consistently superior across all situations, and clinical judgment should remain a multifactorial decision.nnnLEVEL OF EVIDENCEnLevel III.

Development and Validation of Extracorporeal Membrane Oxygenation Mortality-Risk Models for Congenital Diaphragmatic Hernia

The purpose of our study was to develop and validate extracorporeal membrane oxygenation (ECMO)–specific mortality risk models for congenital diaphragmatic hernia (CDH). We utilized the data from the Extracorporeal Life Support Organization Registry (2000–2015). Prediction models were developed using multivariable logistic regression. We identified 4,374 neonates with CDH with an overall mortality of 52%. Predictive discrimination (C statistic) for pre-ECMO mortality model was C = 0.65 (95% confidence interval, 0.62–0.68). Within the highest risk group, based on the pre-ECMO risk score, mortality was 87% and 75% in the training and validation data sets, respectively. The pre-ECMO risk score included pre-ECMO ventilator settings, pH, prior diaphragmatic hernia repair, critical congenital heart disease, perinatal infection, and demographics. For the on-ECMO model, mortality prediction improved substantially: C = 0.73 (95% confidence interval, 0.71–0.76) with the addition of on-ECMO–associated complications. Within the highest risk group, defined by the on-ECMO risk score, mortality was 90% and 86% in the training and validation data sets, respectively. Mortality among neonates with CDH needing ECMO can be reliably predicted with validated clinical variables identified in this study. ECMO-specific mortality prediction tools can allow risk stratification to be used in research and quality improvement efforts, as well as with caution for individual case management.