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"Lewis, Andrew R."
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A secondary daily persistent headache from onset with underlying nutcracker physiology and spinal epidural venous congestion: case series with lumbar vein embolization as a therapeutic approach
The authors have published on a unique subset of patients whose headaches worsened in the Trendelenburg position and who on time-resolved MR angiography demonstrated left renal vein compression (nutcracker physiology) with retrograde left second lumbar vein (L2LV) flow and regional spinal epidural venous plexus (EVP) congestion. We hypothesized that the spinal EVP congestion subsequently causes a secondary congestion of the cerebral venous system, which then leads to an elevation of CSF pressure above that individuals CSF pressure set point. This results in a daily headache from onset. Thus, eliminating the spinal EVP could conceivably improve or eliminate the manifested headache syndrome. We now present a case series of four patients with long-term follow-up utilizing lumbar vein coil embolization as a new therapeutic approach. In each patient, the MR angiography findings were verified by catheter-based venography. Treatment consisted of endovascular embolization of the second lumbar vein. Four patients have had coil embolization of which three are 1 year or longer from their procedure while one is 10 months posttreatment. All patients were women. Duration of daily headache prior to embolization ranged from 4 to 8 years. Post-embolization: Three patients are either headache free or 90–95% improved with substantial pain free time. There were no procedure-related complications. Our results suggest that embolization of L2LV in a specific patient population with nutcracker physiology may substantially improve head pain issues. This is a minimally invasive outpatient technique with no apparent side effects.
Journal Article
Water Oxidation by a Cytochrome P450: Mechanism and Function of the Reaction
P450(cam) (CYP101A1) is a bacterial monooxygenase that is known to catalyze the oxidation of camphor, the first committed step in camphor degradation, with simultaneous reduction of oxygen (O2). We report that P450(cam) catalysis is controlled by oxygen levels: at high O2 concentration, P450(cam) catalyzes the known oxidation reaction, whereas at low O2 concentration the enzyme catalyzes the reduction of camphor to borneol. We confirmed, using (17)O and (2)H NMR, that the hydrogen atom added to camphor comes from water, which is oxidized to hydrogen peroxide (H2O2). This is the first time a cytochrome P450 has been observed to catalyze oxidation of water to H2O2, a difficult reaction to catalyze due to its high barrier. The reduction of camphor and simultaneous oxidation of water are likely catalyzed by the iron-oxo intermediate of P450(cam) , and we present a plausible mechanism that accounts for the 1:1 borneol:H2O2 stoichiometry we observed. This reaction has an adaptive value to bacteria that express this camphor catabolism pathway, which requires O2, for two reasons: 1) the borneol and H2O2 mixture generated is toxic to other bacteria and 2) borneol down-regulates the expression of P450(cam) and its electron transfer partners. Since the reaction described here only occurs under low O2 conditions, the down-regulation only occurs when O2 is scarce.
Journal Article
A direct NMR method for the measurement of competitive kinetic isotope effects
A new NMR method—requiring only milligram quantities of substrates—uses isotopically labeled neighbor atoms to directly and continuously report on KIEs at the reaction center. Application of the methodology defines a reaction coordinate for sialidase hydrolysis.
We present a technique that uses
13
C NMR spectroscopy to measure kinetic isotope effects on the second-order rate constant (
k
cat
/
K
m
) for enzyme-catalyzed reactions. Using only milligram quantities of isotopically labeled substrates, precise competitive KIEs can be determined while following the ongoing reaction directly in a NMR spectrometer. Our results for the
Vibrio cholerae
sialidase–catalyzed hydrolysis of natural substrate analogs support a concerted enzymatic transition state for these reactions.
Journal Article
Outcomes of Radiation Segmentectomy for Hepatocellular Carcinoma in Patients with Non-Alcoholic Fatty Liver Disease versus Chronic Viral Hepatitis
To compare the outcomes of radiation segmentectomy for early-stage hepatocellular carcinoma (HCC) in patients with non-alcoholic fatty liver disease (NAFLD) versus hepatitis C virus (HCV).
A retrospective analysis of consecutive patients with NAFLD- or HCV-related HCC treated with radiation segmentectomy from 01/2017-06/2022 was performed. Eligibility criteria included solitary tumor ≤8 cm or up to 3 HCC ≤3 cm, ECOG 0-1, and absence of vascular invasion or extrahepatic spread. Imaging best response was assessed per modified Response Evaluation Criteria in Solid Tumors. Target tumor and overall progression, time-to-progression (TTP), and overall survival (OS) were calculated. All outcomes were censored for liver transplantation (LT). Complete pathologic response (CPN) was assessed in patients who underwent LT.
Of 142 patients included (NAFLD: 61; HCV: 81), most had cirrhosis (NAFLD: 87%; HCV: 86%) and small tumors (median size NAFLD: 2.3 cm; HCV: 2.5 cm). Patients with NAFLD had higher BMI (p<0.001) and worse ALBI scores (p=0.003). Patients with HCV were younger (p<0.001) and had higher AFP levels (p=0.034). Median radiation dose (NAFLD: 508 Gy; HCV: 452 Gy) and specific activity (NAFLD: 700 Bq; HCV: 698 Bq) were similar between cohorts. Objective response was 100% and 97% in the NAFLD and HCV cohorts, respectively. Target tumor progression occurred in 1 (2%) NAFLD and 8 (10%) HCV patients. Target tumor TTP was not met for either cohort. Overall progression occurred in 23 (38%) NAFLD and 39 (48%) HCV patients. Overall TTP was 17.4 months (95% CI 13.5-22.2) in NAFLD and 13.5 months (95% CI 0.4-26.6) in HCV patients (p=0.86). LT was performed in 27 (44%) NAFLD and 33 (41%) HCV patients, with a CPN rate of 63% and 54%, respectively. OS was not met in the NAFLD cohort and was 53.9 months (95% CI 32.1-75.7) in the HCV cohort (p=0.15).
Although NAFLD and HCV are associated with different mechanisms of liver injury, patients with early-stage HCC treated with radiation segmentectomy achieve comparable outcomes.
Journal Article
Biochemical Safety of Ablative Yttrium-90 Radioembolization for Hepatocellular Carcinoma as a Function of Percent Liver Treated
Purpose: Transarterial radioembolization can serve as an ablative therapy for early-stage hepatocellular carcinoma (HCC). Given the volumetric variability of liver segments, this study aimed to characterize the safety of ablative radioembolization by determining percent liver treated (%LT) thresholds associated with biochemical toxicity. Patients and Methods: Patients with HCC receiving a single ablative radioembolization treatment using glass microspheres from 2017 through 2020 were reviewed. %LT was calculated as treatment angiosome volume divided by whole liver volume. Biochemical toxicities were defined as increases in Albumin-Bilirubin (ALBI) grade or Child-Pugh (CP) class compared to baseline and albumin or bilirubin adverse events (AEs) per the Common Terminology Criteria for Adverse Events. Receiver operating characteristic curves and multivariate logistic regression analyses were performed to assess the impact of %LT on toxicities. Results: Of 141 patients analyzed, 53% (n=75) were ALBI 1, 45% (n=64) ALBI 2, 79% (n=111) CP-A, and 21% (n=30) CP-B. A %LT ≥ 14.5% was associated with grade/class increases in ALBI 2 (p≤ 0.01) and CP-B patients (p=0.026). In multivariate analysis, a %LT ≥ 14.5% was an independent predictor of increases in the ALBI 2 and CP-B groups (p< 0.01). No significant %LT threshold was found for ALBI 1 and CP-A patients. No grade 3/4 albumin or bilirubin AEs were reported, while grade 2 AEs were related to an initial whole liver volume < 1.3 L (p≤ 0.01). Conclusion: Patients with ALBI 2 and CP-B liver function are less likely to have an increase in their respective grade/class when treating < 14.5% of the liver using glass microspheres. ALBI 1 and CP-A patients showed no definitive %LT threshold for biochemical toxicity within the range of this study.
Journal Article
Hepatocellular carcinoma radiation segmentectomy treatment intensification prior to liver transplantation increases rates of complete pathologic necrosis: an explant analysis of 75 tumors
Purpose
To verify the correlation between yttrium-90 glass microsphere radiation segmentectomy treatment intensification of hepatocellular carcinoma (HCC) and complete pathologic necrosis (CPN) at liver transplantation.
Methods
A retrospective, single center, analysis of patients with HCC who received radiation segmentectomy prior to liver transplantation from 2016 to 2021 was performed. The tumor treatment intensification cohort (
n
= 38) was prescribed radiation segmentectomy as per response recommendations identified in a previously published baseline cohort study (
n
= 37). Treatment intensification and baseline cohort treatment parameters were compared for rates of CPN. Both cohorts were then combined for an overall analysis of treatment parameter correlation with CPN.
Results
Sixty-three patients with a combined 75 tumors were analyzed. Specific activity, dose, and treatment activity were significantly higher in the treatment intensification cohort (all
p
< 0.01), while particles per cubic centimeter of treated liver were not. CPN was achieved in 76% (
n
= 29) of tumors in the treatment intensification cohort compared to 49% (
n
= 18) in the baseline cohort (
p
= 0.013). The combined cohort CPN rate was 63% (
n
= 47). ROC analysis showed that specific activity ≥ 327 Bq (AUC 0.75,
p
< 0.001), dose ≥ 446 Gy (AUC 0.69,
p
= 0.005), and treatment activity ≥ 2.55 Gbq (AUC 0.71,
p
= 0.002) were predictive of CPN. Multivariate logistic regression demonstrated that a specific activity ≥ 327 Bq was the sole independent predictor of CPN (
p
= 0.013).
Conclusion
Radiation segmentectomy treatment intensification for patients with HCC prior to liver transplantation increases rates of CPN. While dose strongly correlated with pathologic response, specific activity was the most significant independent radiation segmentectomy treatment parameter associated with CPN.
Journal Article
Which civil religion? Partisanship, Christian nationalism, and the dimensions of civil religion in the United States
Civil religion has been described as the “common elements of religious orientation that the great majority of Americans share”. In an age of partisan division, there have been calls for a revitalized civil religion, but the idea that civil religion can be unifying has been debated. In this paper, we investigate whether civil religion can be unifying, or is it fractured by partisanship? To address this, we use two strategies. First, we created a civil religion battery and deployed it on two different cross-sectional surveys. The results indicate that there are two dimensions to civil religion. These dimensions are distinct from Christian nationalism and structured along partisan lines. Second, we developed two survey experiments to understand the dimensions of civil religion and improve on the causal mechanisms that link civil religion to political behavior. Results indicate that, rather than promoting unity, civil religion is interpreted through partisan lenses.
Journal Article
Which Party Represents My Group? The Group Foundations of Partisan Choice and Polarization
While groups have been central to thinking about partisan identity and choices, there has been surprisingly little attention paid to the role of perceptions of the group composition of the parties. We explore this critical linking information in the context of religious groups, some of the chief pivots around which the parties have been sorting. Using three national samples, we show that perceptions of the religious group composition of the parties are often biased—evangelicals overestimate the presence of evangelicals within the Republican Party and the irreligious within the Democratic Party. The key finding is that individuals are far more likely to identify with the party in which they believe their group is well represented—a finding which clarifies the role of party image shifts in constructing partisanship, the limits of the culture war motif, and the importance of social perception in shaping beliefs about party representation.
Journal Article
