Recent advances in the diagnosis of drug-induced liver injury.

Drug-induced liver injury (DILI) is a major problem in the United States, commonly leading to hospital admission. Diagnosing DILI is difficult as it is a diagnosis of exclusion requiring a temporal relationship between drug exposure and liver injury and a thorough work up for other causes. In addition, DILI has a very variable clinical and histologic presentation that can mimic many different etiologies of liver disease. Objective scoring systems can assess the probability that a drug caused the liver injury but liver biopsy findings are not part of the criteria used in these systems. This review will address some of the recent updates to the scoring systems and the role of liver biopsy in the diagnosis of DILI.

Iron Deficiency Is Common after Restorative Proctocolectomy with Ileal Pouch-Anal Anastomosis in Patients with Ulcerative Colitis.

Background: Micronutrient deficiencies may occur after restorative proctocolectomy (RPC) with ileal pouch-anal anastomosis (IPAA) in patients with ulcerative colitis (UC), largely due to malabsorption and/or pouch inflammation. Objectives: The objective of this study was to report the frequency of iron deficiency in patients with UC who underwent RPC with IPAA and identify associated risk factors. Methods: We conducted a retrospective chart review of patients with UC or IBD-unclassified who underwent RPC with IPAA at Mount Sinai Hospital between 2008 and 2017. Patients younger than 18 years of age at the time of colectomy were excluded. Descriptive statistics were used to analyze baseline characteristics. Medians with interquartile range (IQR) were reported for continuous variables, and proportions were reported for categorical variables. Iron deficiency was defined by ferritin <30 ng/mL. Logistic regression was used to analyze unadjusted relationships between hypothesized risk factors and the outcome of iron deficiency. Results: A total of 143 patients had iron studies a median of 3.0 (IQR 1.7-5.6) years after final surgical stage, of whom 73 (51.0%) were men. The median age was 33.5 (IQR 22.7-44.3) years. Iron deficiency was diagnosed in 80 (55.9%) patients with a median hemoglobin of 12.4 g/dL (IQR 10.9-13.3), ferritin of 14 ng/mL (IQR 9.0-23.3), and iron value of 44 µg/dL (IQR 26.0-68.8). Of these, 29 (36.3%) had a pouchoscopy performed within 3 months of iron deficiency diagnosis. Pouchitis and cuffitis were separately noted in 4 (13.8%) and 13 (44.8%) patients, respectively, and concomitant pouchitis-cuffitis was noted in 9 (31.0%) patients. Age, sex, anastomosis type, pouch duration, and history of pouchitis and/or cuffitis were not associated with iron deficiency. Conclusion: Iron deficiency is common after RPC with IPAA in patients with UC. Cuffitis is seen in the majority of patients with iron deficiency; however, iron deficiency may occur even in the absence of inflammation.

Correlation of body mass index with recanalization risk after endovenous thermal ablation.

OBJECTIVE: Chronic venous insufficiency (CVI) has an increased prevalence among obese individuals with body mass indices (BMI) over 30. A safe, efficacious, and evidence-based recommended treatment for CVI due to superficial venous reflux (SVR) in great saphenous veins (GSVs), small saphenous veins (SSVs), accessory saphenous veins (ASVs), and reflux in the perforator veins (PVs) is endovenous thermal ablation (EVTA). We sought to identify if BMI is an independent risk factor for recanalization after EVTA. METHODS: All patients with CVI were initially managed conservatively, and those with pathologic SVR refractory to compression therapy were offered EVTAs depending on the site of reflux. Sonographic confirmation of SVR was defined as >500 milliseconds of reflux in the GSVs, SSVs, and ASVs and a diameter >4 mm. PV reflux was confirmed as >350 milliseconds of reflux and a diameter >2.5 mm. All patients received a follow-up duplex ultrasound 1 week after the procedure, every 3 months for the first year, and every 6 months thereafter. Multivariate analysis with logistic regression was performed regarding patients' age, ablation modality (laser vs radiofrequency ablation), vein location and laterality, BMI, and recanalization. RESULTS: From 2013 to 2018, 9739 endovenous ablations were performed on 3070 patients. Endovenous laser was used in 3862 procedures and radiofrequency ablation in 5831 procedures. Veins treated with EVTA were distributed as follows: 6182 GSVs, 2509 SSVs, 597 ASVs, and 451 PVs. The mean patient age was 61.1 years (15-99, standard deviation [SD] ±15.6) with a mean BMI of 31.2 kg/m2 (13.7-69.5, SD ±7.3). A total of 68.4% patients were women and 31.4% men. The mean follow-up was 25.8 months (0-65.9, SD ±12.9). Multivariate statistical analysis with logistic regression was used to determine potential statistical significance between BMI and vein recanalization after EVTA. Overall, obese patients experienced more recanalizations than nonobese patients (P = .032), with an average BMI of 33 kg/m2 for recanalizations. PVs were statistically more likely to recanalize than any other vein (P = .0001). A secondary analysis was performed with the exclusion of PVs, due to their five times increased risk of recanalization, and showed no significant difference of recanalization across all BMI subgroups (P = .127). CONCLUSIONS: BMI does not predict recanalization risk after EVTA, except for ablations performed on PVs.

Dyeless iliac vein stenting.

OBJECTIVE: Iliac vein stenting is increasingly being explored for the treatment of chronic venous insufficiency. While venography is considered the gold standard for assessing iliac veins, some have proposed that intravascular ultrasound should be utilized instead due to its greater sensitivity at detecting stenotic lesions. Routinely, our service uses both intravascular ultrasound and venography, but we have noted that some patients cannot tolerate dye due to allergy, renal insufficiency, or deemed high-risk by the interventionalist due to uncontrolled medical co-morbidities. This study aimed to investigate whether forgoing dye had an impact on iliac vein stent thrombosis. METHODS: From 2012 to 2016, 1482 iliac vein procedures (91 intravascular ultrasound-only and 1391 intravascular ultrasound plus venography) were performed on 992 patients who failed conservative treatment for chronic venous insufficiency. Our mean patient age was 65.8 years (range 21-99; SD ± 14.3) with 347 male and 645 female patients. The clinical presenting symptoms per clinical-etiology-anatomy-pathophysiology classification for the intravascular ultrasound-only cohort were C1:0, C2:3, C3:31, C433, C5:5, C6:20 and for the intravascular ultrasound plus venography cohort were C1:0, C2:24, C3:566, C4:583, C5:30, C6:188. Stent thrombi that developed within or at 30 days of stenting were categorized as early and greater than 30 days as late. Transcutaneous duplex ultrasound classified stent thrombi as either partial or occlusive. Our average follow-up time was 19.4 months (0-42, SD ± 12.5). RESULTS: A total of 2.2% intravascular ultrasound-only patients versus 2.75% intravascular ultrasound plus venogram patients developed early stent thrombosis, p = 0.35. Early partial stent thrombosis occurred in 1.1% of the intravascular ultrasound-only group versus 2.6% of the intravascular ultrasound plus venogram group, p = 0.38. Early occlusive stent thromboses occurred in 1.1% of intravascular ultrasound-only patients and 0.15% of intravascular ultrasound plus venogram patients, p = 0.06. Late stent thromboses developed in 4% of patients in the intravascular ultrasound-only cohort and 4% in the intravascular ultrasound plus venogram cohort, p = 0.97. Late partial stent thromboses occurred in 2.7% of intravascular ultrasound-only patients versus 2.6% in intravascular ultrasound plus venogram patients, p = 0.99. Late occlusive stent thromboses occurred in 1.3% of intravascular ultrasound-only patients versus 1.4% of intravascular ultrasound plus venogram patients, p = 0.95. Moreover, the formation of any stent was 6.2% in the intravascular ultrasound-only versus 6.75% in the intravascular ultrasound plus venogram group, p = 0.55. CONCLUSION: Results of our study show no significant difference in stent thrombosis between the intravascular ultrasound-only and intravascular ultrasound plus venogram cohorts. This concludes that using intravascular ultrasound alone is safe for iliac vein stenting.

Non-canonical activation of CREB mediates neuroprotection in a Caenorhabditis elegans model of excitotoxic necrosis.

Excitotoxicity, caused by exaggerated neuronal stimulation by Glutamate (Glu), is a major cause of neurodegeneration in brain ischemia. While we know that neurodegeneration is triggered by overstimulation of Glu-receptors (GluRs), the subsequent mechanisms that lead to cellular demise remain controversial. Surprisingly, signaling downstream of GluRs can also activate neuroprotective pathways. The strongest evidence involves activation of the transcription factor cAMP response element-binding protein (CREB), widely recognized for its importance in synaptic plasticity. Canonical views describe CREB as a phosphorylation-triggered transcription factor, where transcriptional activation involves CREB phosphorylation and association with CREB-binding protein. However, given CREB's ubiquitous cross-tissue expression, the multitude of cascades leading to CREB phosphorylation, and its ability to regulate thousands of genes, it remains unclear how CREB exerts closely tailored, differential neuroprotective responses in excitotoxicity. A non-canonical, alternative cascade for activation of CREB-mediated transcription involves the CREB co-factor cAMP-regulated transcriptional co-activator (CRTC), and may be independent of CREB phosphorylation. To identify cascades that activate CREB in excitotoxicity we used a Caenorhabditis elegans model of neurodegeneration by excitotoxic necrosis. We demonstrated that CREB's neuroprotective effect was conserved, and seemed most effective in neurons with moderate Glu exposure. We found that factors mediating canonical CREB activation were not involved. Instead, phosphorylation-independent CREB activation in nematode excitotoxic necrosis hinged on CRTC. CREB-mediated transcription that depends on CRTC, but not on CREB phosphorylation, might lead to expression of a specific subset of neuroprotective genes. Elucidating conserved mechanisms of excitotoxicity-specific CREB activation can help us focus on core neuroprotective programs in excitotoxicity. Cover Image for this issue: doi: 10.1111/jnc.14494.

Arrhythmia recognition and classification using combined linear and nonlinear features of ECG signals.

Arrhythmia is a cardiac condition caused by abnormal electrical activity of the heart, and an electrocardiogram (ECG) is the non-invasive method used to detect arrhythmias or heart abnormalities. Due to the presence of noise, the non-stationary nature of the ECG signal (i.e. the changing morphology of the ECG signal with respect to time) and the irregularity of the heartbeat, physicians face difficulties in the diagnosis of arrhythmias. The computer-aided analysis of ECG results assists physicians to detect cardiovascular diseases. The development of many existing arrhythmia systems has depended on the findings from linear experiments on ECG data which achieve high performance on noise-free data. However, nonlinear experiments characterize the ECG signal more effectively sense, extract hidden information in the ECG signal, and achieve good performance under noisy conditions. This paper investigates the representation ability of linear and nonlinear features and proposes a combination of such features in order to improve the classification of ECG data. In this study, five types of beat classes of arrhythmia as recommended by the Association for Advancement of Medical Instrumentation are analyzed: non-ectopic beats (N), supra-ventricular ectopic beats (S), ventricular ectopic beats (V), fusion beats (F) and unclassifiable and paced beats (U). The characterization ability of nonlinear features such as high order statistics and cumulants and nonlinear feature reduction methods such as independent component analysis are combined with linear features, namely, the principal component analysis of discrete wavelet transform coefficients. The features are tested for their ability to differentiate different classes of data using different classifiers, namely, the support vector machine and neural network methods with tenfold cross-validation. Our proposed method is able to classify the N, S, V, F and U arrhythmia classes with high accuracy (98.91%) using a combined support vector machine and radial basis function method.