Faculty Bibliography

De novo mutations arising on the paternal chromosome make the largest known contribution to autism risk, and correlate with paternal age at the time of conception. The recurrence risk for autism spectrum disorders is substantial, leading many families to decline future pregnancies, but the potential impact of assessing parental gonadal mosaicism has not been considered. We measured sperm mosaicism using deep-whole-genome sequencing, for variants both present in an offspring and evident only in father's sperm, and identified single-nucleotide, structural and short tandem-repeat variants. We found that mosaicism quantification can stratify autism spectrum disorders recurrence risk due to de novo mutations into a vast majority with near 0% recurrence and a small fraction with a substantially higher and quantifiable risk, and we identify novel mosaic variants at risk for transmission to a future offspring. This suggests, therefore, that genetic counseling would benefit from the addition of sperm mosaicism assessment.

BACKGROUND AND PURPOSE:Transcranial Doppler (TCD) criteria for cerebrovascular stenosis are only based on velocity with unsatisfactory positive predictive value (PPV) in previous studies. We refined a published scoring system that integrates several characteristics of TCD data in diagnosing middle cerebral artery (MCA) stenosis. METHODS:Using the TCD-digital subtraction angiography (DSA) database from Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) trial, velocity, spectrum pattern, diffuse ratio, and asymmetry ratio were assessed. The cutpoints were defined for each parameter and a point value was assigned to each category within that parameter. A summed score was calculated for each MCA. The accuracy was assessed for different cutpoints in predicting ≥50% MCA stenosis measured by DSA. Logistic regression and C-statistics were used for analysis. RESULTS:A total of 114 MCAs were included in vessel-based and 87 patients were included in patient-based analysis. Compared to the velocity-only cutpoints in SONIA, the score results in much improved PPV while negative predictive value (NPV) remains unchanged. The score based on mean velocity (score 0: <140 cm/s, score 3: ≥140 cm/s), spectrum pattern (score 0: no turbulence; score 1: mild turbulence; 2: significant turbulence), and asymmetry ratio (score 0: ratio <1.5, score 1: ratio 1.5-2; score 2: ratio ≥2.1) has the highest NPV while PPV remains favorable (PPV: 72% [95% CI 54-90%]; NPV: 84% [95% CI: 75-93%], area under curve [AUC]: .76 [95% CI: .66-.86]). CONCLUSIONS:The multiparameter scoring system incorporating several characteristics of TCD measures yielded higher PPV while maintaining high NPV compared with the single-parameter velocity criteria in diagnosing MCA ≥50% stenosis.

Background/UNASSIGNED:Spinal neurofibromas (SNFs) in neurofibromatosis type 1 (NF1) can cause progressive spinal cord compression and neurological dysfunction. The MEK inhibitor selumetinib shrinks the majority of plexiform neurofibromas (PNs) in patients with NF1. We assessed the effect of selumetinib on SNF. Methods/UNASSIGNED:/dose twice daily (max 50 mg b.i.d.; 1 cycle = 28 days). We qualitatively assessed the effect of selumetinib on SNF-related spinal canal distortion, cerebrospinal fluid distribution, and spinal cord deformity on MRI. Results/UNASSIGNED:Twenty-four patients (18 male), median age 16.9 years (range, 6.2-60.3), had SNF, 22 of which were associated with the same nerves as the target PN assessed on the clinical trial. Twenty patients had spinal cord deformity. Twenty-three patients completed at least 12 treatment cycles to date. Eighteen patients showed subtle to a marked improvement in SNF burden, 5 remained stable, and no worsening was observed during treatment. Conclusions/UNASSIGNED:This is the first study describing the effect of selumetinib on SNF. Of 24 patients, 18 exhibited some improvement of SNF burden on imaging. These findings suggest that selumetinib may prevent the worsening of cord compression, potentially reducing the need for surgical interventions in select patients or benefitting patients who do not have a surgical option. Prospective evaluation of the clinical benefit of selumetinib for SNF is warranted.

OBJECTIVE:To assay EEG signal quality recorded with tripolar concentric ring electrodes (TCREs) compared to regular EEG electrodes. METHODS:EEG segments were recorded simultaneously by TCREs and regular electrodes, low-pass filtered at 35 Hz (REG35) and 70 Hz (REG70). Clips were rated blindly by nine electroencephalographers for presence or absence of key EEG features, relative to the "gold-standard" of the clinical report. RESULTS:TCRE showed less EMG artifact (F = 15.4, p < 0.0001). Overall quality rankings were not significantly different. Focal slowing was better detected by TCRE and spikes were better detected by regular electrodes. Seizures (n = 85) were detected by TCRE in 64 cases (75.3%), by REG70 in 75 (88.2%) and REG35 in 69 (81.2%) electrodes. TCRE detected 9 (10.6%) seizures not detected by one of the other 2 methods. In contrast, 14 seizures (16.5%) were not detected by TCRE, but were by REG35 electrodes. Each electrode detected interictal spikes when the other did not. CONCLUSIONS:TCRE produced similar overall quality and confidence ratings versus regular electrodes, but less muscle artifact. TCRE recordings detected seizures in 7% of instances where regular electrodes did not. SIGNIFICANCE/CONCLUSIONS:The combination of the two types increased detection of epileptiform events compared to either alone.

BACKGROUND AND PURPOSE/OBJECTIVE:The current left atrial appendage (LAA) classification system (cLAA-CS) categorizes it into 4 morphologies: chicken wing (CW), windsock, cactus, and cauliflower, though there is limited data on either reliability or associations between different morphologies and stroke risk. We aimed to develop a simplified LAA classification system and to determine its relationship to embolic stroke subtypes. METHODS:Consecutive patients with ischemic stroke from a prospective stroke registry who previously underwent a clinically-indicated chest CT were included. Stroke subtype was determined and LAA morphology was classified using the traditional system (in which CW = low risk) and a new system (LAA-H/L, in which low risk morphology (LAA-L) was defined as an acute angle bend or fold from the proximal/middle portion of the LAA and high risk morphology (LAA-H) was defined as all others). As a proof of concept study, we determined reliability for the two classification systems, and we assessed the associations between both classification systems with stroke subtypes in our cohort and previous studies. RESULTS:We identified 329 ischemic stroke patients with a qualifying chest CT (126 cardioembolic subtype, 116 embolic stroke of undetermined source (ESUS), and 87 non-cardioembolic subtypes). Intra- and inter-rater agreements improved using the LAA-H/L (0.95 and 0.85, respectively) vs. cLAA-CS (0.50 and 0.40). The LAA-H/L led to classifying 69 LAA morphologies that met criteria for CW as LAA-H. In fully adjusted models, LAA-H was associated with cardioembolic stroke (OR 5.4, 95%CI 2.1-13.7) and ESUS (OR 2.8 95% CI 1.2-6.4). Non-CW morphology was also associated with embolic stroke subtypes, but the effect size was much less pronounced. Studies using the cLAA-CS yielded mixed results for inter- and intra-rater agreements but most showed an association between a non-CW morphology and stroke with no difference among the three non-CW subtypes. CONCLUSION/CONCLUSIONS:The LAA-H/L classification system is simple, has excellent intra and inter-rater agreements, and may help risk identify patients with cardioembolic stroke subtypes. Larger studies are needed to validate these findings.

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INTRODUCTION/BACKGROUND:Current management of ischemic priapism revolves around 3 principles: resolving the acute event, preserving erectile function, and reducing the risk of future recurrences. Although more conservative management options, such as aspiration, irrigation, and surgical shunts, are effective in many patients, those who are refractory to these interventions or have prolonged priapism may benefit from placement of a penile prosthesis (PP). AIM/OBJECTIVE:To provide a comprehensive overview of priapism management, highlight the current literature on the utility of penile implants for refractory priapism, and provide insight from a high-volume center on surgical decision making and technique. METHODS:A complete review of the current guidelines and associated literature was performed. Associated algorithms were evaluated, and our experience was overlaid on the data present in the literature. MAIN OUTCOME MEASURES/METHODS:The current management algorithm for priapism was evaluated. Subsequently, the data on acute and delayed PP placement were assessed. Rates of postoperative infection, erectile dysfunction, and patient satisfaction were also examined. RESULTS:Overall, both delayed and early PP implants are associated with higher rates of failure than routine PP implants. In patients with refractory or prolonged priapism, early implantation may be technically easier, with decreased loss of penile length and associated complications. CONCLUSION/CONCLUSIONS:Patients should be evaluated on an individual basis and counseled on the risks and benefits of PP implantation in early and delayed time frames. Although there is no definitive evidence at this time regarding the ideal device or timing of implantation, there are well-established pros and cons of malleable vs inflatable prostheses and of acute vs delayed implantation. Mishra K, Loeb A, Bukavina L, et al. Management of Priapism: A Contemporary Review. Sex Med Rev 2020;8:131-139.