APOE genotype dictates lipidomic signatures in primary human hepatocytes.

Apolipoprotein E (APOE) genetic variants are most notably known for their divergent impact on the risk of developing Alzheimer's disease. While APOE genotype has been consistently shown to modulate lipid metabolism in a variety of cellular contexts, the effect of APOE alleles on the lipidome in hepatocytes is unknown. In this study, we investigated the contribution of APOE alleles to lipidomic profiles of donor-derived primary human hepatocytes from 77 subjects. Lipidomic data obtained by liquid chromatography-mass spectrometry were analyzed across ε2/ε3, ε3/ε3, and ε3/ε4 genotypes to reveal how APOE modulates lipid relative levels over age and between groups. Hepatic APOE concentration, measured by ELISA, was assessed for correlation with lipid abundance in subjects grouped as per APOE genotype and sex. APOE genotype-specific differential lipidomic signatures associated with age for multiple lipid classes but did not differ between sexes. Compared to ε2/ε3, ε3/ε4 hepatocytes had higher abundance of acylcarnitines (AC) and acylphosphatidylglycerol (AcylPG) as a class, as well as higher medium and long-chain ACs, AcylPG, phosphatidylglycerol (PG), bis(monoacylglycerol)phosphate (BMP), monoacylglycerol (MG) and diacylglycerol (DG) species. The ε3/ε4 hepatocytes also exhibited a higher abundance of medium and long-chain ACs compared to the ε3/ε3 hepatocytes. Only in the ε3/ε4 hepatocytes, APOE concentration was lower and showed a negative correlation with BMP levels, specifically in females. APOE genotype dictates a differential lipidome in primary human hepatocytes. The lipids involved suggest mitochondrial dysfunction with accompanying alterations in neutral lipid storage, reflective of a general disturbance of free fatty acid metabolism in human hepatocytes with the ε4 allele.

Diversity and host specificity of Borrelia burgdorferi's outer surface protein C (ospC) alleles in synanthropic mammals, with a notable ospC allele U absence from mixed infections.

Interactions among pathogen genotypes that vary in host specificity may affect overall transmission dynamics in multi-host systems. Borrelia burgdorferi, a bacterium that causes Lyme disease, is typically transmitted among wildlife by Ixodes ticks. Despite the existence of many alleles of B. burgdorferi's sensu stricto outer surface protein C (ospC) gene, most human infections are caused by a small number of ospC alleles ["human infectious alleles" (HIAs)], suggesting variation in host specificity associated with ospC. To characterize the wildlife host association of B. burgdorferi's ospC alleles, we used metagenomics to sequence ospC alleles from 68 infected individuals belonging to eight mammalian species trapped at three sites in suburban New Brunswick, New Jersey (USA). We found that multiple allele ("mixed") infections were common. HIAs were most common in mice (Peromyscus spp.) and only one HIA was detected at a site where mice were rarely captured. ospC allele U was exclusively found in chipmunks (Tamias striatus), and although a significant number of different alleles were observed in chipmunks, including HIAs, allele U never co-occurred with other alleles in mixed infections. Our results suggest that allele U may be excluding other alleles, thereby reducing the capacity of chipmunks to act as reservoirs for HIAs.

Novel genes and sex differences in COVID-19 severity.

Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10-22 and P = 8.1 × 10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10-8) and ARHGAP33 (P = 1.3 × 10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.

Differential atrophy along the longitudinal hippocampal axis in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that primarily affects the hippocampus. Since hippocampal studies have highlighted a differential subregional regulation along its longitudinal axis, a more detailed analysis addressing subregional changes along the longitudinal hippocampal axis has the potential to provide new relevant biomarkers. This study included structural brain MRI data of 583 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cognitively normal (CN) subjects, mild cognitively impaired (MCI) subjects and AD patients were conveniently selected considering the age and sex match between clinical groups. Structural MRI acquisitions were pre-processed and analysed with a new longitudinal axis segmentation method, dividing the hippocampus in three subdivisions (anterior, intermediate, and posterior). When normalizing the volume of hippocampal sub-divisions to total hippocampus, the posterior hippocampus negatively correlates with age only in CN subjects (r = -.31). The longitudinal ratio of hippocampal atrophy (anterior sub-division divided by the posterior one) shows a significant increase with age only in CN (r = .25). Overall, in AD, the posterior hippocampus is predominantly atrophied early on. Consequently, the anterior/posterior hippocampal ratio is an AD differentiating metric at early disease stages with potential for diagnostic and prognostic applications.

Clinical Outcomes After Endoscopic Management of Low-Risk and High-Risk T1a Esophageal Adenocarcinoma: A Multicenter Study.

INTRODUCTION: Endoscopic eradication therapy (EET) is standard of care for T1a esophageal adenocarcinoma (EAC). However, data on outcomes in high-risk T1a EAC are limited. We assessed and compared outcomes after EET of low-risk and high-risk T1a EAC, including intraluminal EAC recurrence, extraesophageal metastases, and overall survival. METHODS: Patients who underwent EET for T1a EAC at 3 referral Barrett's esophagus endotherapy units between 1996 and 2022 were included. Patients with submucosal invasion, positive deep margins, or metastases at initial diagnosis were excluded. High-risk T1a EAC was defined as T1a EAC with poor differentiation and/or lymphovascular invasion, with low-risk disease being defined without these features. All pathology was systematically assessed by expert gastrointestinal pathologists. Baseline and follow-up endoscopy and pathology data were abstracted. Time-to-event analyses were performed to compare outcomes between groups. RESULTS: One hundred eighty-eight patients with T1a EAC were included (high risk, n = 45; low risk, n = 143) with a median age of 70 years, and 84% were men. Groups were comparable for age, sex, Barrett's esophagus length, lesion size, and EET technique. Rates of delayed extraesophageal metastases (11.1% vs 1.4%) were significantly higher in the high-risk group ( P = 0.02). There was no significant difference in the rates of intraluminal EAC recurrence ( P = 0.79) and overall survival ( P = 0.73) between the 2 groups. DISCUSSION: Patients with high-risk T1a EAC undergoing successful EET had a substantially higher rate of extraesophageal metastases compared with those with low-risk T1a EAC on long-term follow-up. These data should be factored into discussions with patients while selecting treatment approaches. Additional prospective data in this area are critical.

Multicenter Quantification of Radiation Exposure and Associated Risks for Prostatic Artery Embolization in 1476 Patients.

Background Prostatic artery embolization (PAE) is a safe, minimally invasive angiographic procedure that effectively treats benign prostatic hyperplasia; however, PAE-related patient radiation exposure and associated risks are not completely understood. Purpose To quantify radiation dose and assess radiation-related adverse events in patients who underwent PAE at multiple centers. Materials and Methods This retrospective study included patients undergoing PAE for any indication performed by experienced operators at 10 high-volume international centers from January 2014 to May 2021. Patient characteristics, procedural and radiation dose data, and radiation-related adverse events were collected. Procedural radiation effective doses were calculated by multiplying kerma-area product values by an established conversion factor for abdominopelvic fluoroscopy-guided procedures. Relationships between cumulative air kerma (CAK) or effective dose and patient body mass index (BMI), fluoroscopy time, or radiation field area were assessed with linear regression. Differences in radiation dose stemming from radiopaque prostheses or fluoroscopy unit type were assessed using two-sample t tests and Wilcoxon rank sum tests. Results A total of 1476 patients (mean age, 69.9 years ± 9.0 [SD]) were included, of whom 1345 (91.1%) and 131 (8.9%) underwent the procedure with fixed interventional or mobile fluoroscopy units, respectively. Median procedure effective dose was 17.8 mSv for fixed interventional units and 12.3 mSv for mobile units. CAK and effective dose both correlated positively with BMI (R2 = 0.15 and 0.17; P < .001) and fluoroscopy time (R2 = 0.16 and 0.08; P < .001). No radiation-related 90-day adverse events were reported. Patients with radiopaque implants versus those without implants had higher median CAK (1452 mGy [range, 900-2685 mGy] vs 1177 mGy [range, 700-1959 mGy], respectively; P = .01). Median effective dose was lower for mobile than for fixed interventional systems (12.3 mSv [range, 8.5-22.0 mSv] vs 20.4 mSv [range, 13.8-30.6 mSv], respectively; P < .001). Conclusion Patients who underwent PAE performed with fixed interventional or mobile fluoroscopy units were exposed to a median effective radiation dose of 17.8 mSv or 12.3 mSv, respectively. No radiation-related adverse events at 90 days were reported. © RSNA, 2024 See also the editorial by Mahesh in this issue.

Runs of homozygosity: windows into population history and trait architecture.

Long runs of homozygosity (ROH) arise when identical haplotypes are inherited from each parent and thus a long tract of genotypes is homozygous. Cousin marriage or inbreeding gives rise to such autozygosity; however, genome-wide data reveal that ROH are universally common in human genomes even among outbred individuals. The number and length of ROH reflect individual demographic history, while the homozygosity burden can be used to investigate the genetic architecture of complex disease. We discuss how to identify ROH in genome-wide microarray and sequence data, their distribution in human populations and their application to the understanding of inbreeding depression and disease risk.

Treatment Strategies for Bile Leak Following Pediatric Liver Transplantation.

There are no standard management protocols for the treatment of bile leak (BL) after liver transplantation. The objective of this study is to describe treatment options for BL after pediatric LT. METHODS: Retrospective analysis (January 2010-March 2023). VARIABLES STUDIED: preoperative data, status at diagnosis, and postoperative outcome. Four groups: observation (n = 9), percutaneous transhepatic cholangiography (PTC, n = 38), ERCP (2), and surgery (n = 27). RESULTS: Nine hundred and thirty-one pediatric liver transplantation (859 LDLT and 72 DDT); 78 (8.3%) patients had BL, all in LDLT. The median (IQR) peritoneal bilirubin (PB) level and fluid-to-serum bilirubin ratio (FSBR) at diagnosis was 14.40 mg/dL (8.5-29), and 10.7 (4.1-23.7). Patients who required surgery for treatment underwent the procedure earlier, at a median of 14 days (IQR: 7-19) versus 22 days for PTC (IQR: 15-27, p = 0.002). PB and FSBR were significantly lower in the observation group. In 11 cases, conservative management had resolution of the BL in an average time of 35 days, and 38 patients underwent PTC in a median time of 22 days (15-27). Twenty-seven (34.6%) patients were reoperated as initial treatment for BL in a median time of 17 days (1-108 days); 25 (33%) patients evolved with biliary stricture, 5 (18.5%) after surgery, and 20 (52.6%) after PTC (p = 0.01). CONCLUSION: Patients with BL who were observed presented significantly lower levels of PB and FSBR versus those who underwent PTC or surgery. Patients treated with PTC presented higher rates of biliary stricture during the follow-up.

Social norm complexity and past reputations in the evolution of cooperation.

Indirect reciprocity is the most elaborate and cognitively demanding of all known cooperation mechanisms, and is the most specifically human because it involves reputation and status. By helping someone, individuals may increase their reputation, which may change the predisposition of others to help them in future. The revision of an individual's reputation depends on the social norms that establish what characterizes a good or bad action and thus provide a basis for morality. Norms based on indirect reciprocity are often sufficiently complex that an individual's ability to follow subjective rules becomes important, even in models that disregard the past reputations of individuals, and reduce reputations to either 'good' or 'bad' and actions to binary decisions. Here we include past reputations in such a model and identify the key pattern in the associated norms that promotes cooperation. Of the norms that comply with this pattern, the one that leads to maximal cooperation (greater than 90 per cent) with minimum complexity does not discriminate on the basis of past reputation; the relative performance of this norm is particularly evident when we consider a 'complexity cost' in the decision process. This combination of high cooperation and low complexity suggests that simple moral principles can elicit cooperation even in complex environments.

Accelerated Corneal Crosslinking to Arrest Progression of Corneal Ectasia: A Prospective Multicenter Study.

OBJECTIVES: To report the results of epithelium-off accelerated corneal collagen crosslinking (accelerated corneal crosslinking [ACXL]) in patients with progressive keratoconus. METHODS: This prospective, nonrandomized, noncomparative, interventional, multicenter clinical study included all patients who underwent ACXL, either continuous (c-ACXL; 9 mW/cm 2 , 10', 5.4 J/cm 2 ) or pulsed (p-ACXL; 2″ON/1″OFF, 30 mW/cm 2 , 4.5', 5.4 J/cm 2 ) between January 2014 and May 2017. Best-corrected visual acuity, sphere, cylinder, spherical equivalent, and topographical keratometry data were collected preoperatively and at 1, 3, 6, 12, 18, and 24 months postoperatively. RESULTS: Ninety-six eyes of 78 patients were included. The mean age was 20.8±4.4 years (14-33) for c-ACXL and 26.7±7.7 years (12-37) for p-ACXL. The mean best-corrected visual acuity was 0.4±0.4 for c-ACXL and 0.01±0.1 for p-ACXL preoperatively, and 0.3±0.3 ( P =0.0014) and -0.01±0.1 ( P =0.1554), respectively, at the last follow-up. The subjective sphere and spherical equivalent did not show statistically significant differences between the time points ( P >0.05). The subjective cylinder showed significant differences ( P =0.0013 for c-ACXL; P =0.0358 for p-ACXL). Keratometric values (K steep , K flat , and SimK) remained stable, with no statistically significant differences ( P >0.05). No major complications were noted. CONCLUSIONS: Both c-ACXL and p-ACXL are equally safe and effective ACXL protocols in stabilizing the progression of keratoconus and can be considered alternatives to the conventional Dresden protocol.

Melatonin improves the viability and ultrastructure of bovine oocyte-granulosa complexes of in vitro cultured early antral follicles.

This study aims to investigate the effects of melatonin on follicular growth, viability and ultrastructure, as well as on the levels of mRNA for antioxidant enzymes, reactive oxygen species (ROS) and meiotic progression in oocytes from in vitro cultured bovine early antral follicles. To this end, isolated early antral follicles (500-600 µm) were cultured in TCM-199+ alone or supplemented with 10-6 , 10-7 or 10-8 M melatonin at 38.5°C with 5% CO2 for 8 days. Follicle diameters were evaluated at days 0, 4 and 8 of culture. At the end of culture, ultrastructure, chromatin configuration, viability (calcein-AM and ethidium homodimer-1 staining), and the levels of ROS and mRNA for catalase (CAT), superoxide dismutase (SOD) and peroxiredoxin 6 (PRDX6) and glutathione peroxidase (GPx) were investigated in oocyte-granulosa cell complexes (OGCs). The results showed that early antral follicles cultured with 10-6 and 10-8 M melatonin had a progressive and significant increase in their diameters throughout the culture period (p < .05). Additionally, oocytes from follicles cultured with 10-7 or 10-8 M melatonin had increased fluorescence for calcein-AM, while those cultured with 10-6 or 10-7 M had reduced fluorescence for ethidium homodimer-1. Different from follicles cultured in other treatments, those cultured with 10-8 M melatonin had well-preserved ultrastructure of oocyte and granulosa cells. Melatonin, however, did not influence the levels of ROS, the mitochondrial activity, oocyte meiotic resumption and expression mRNA for SOD, CAT, GPX1 and PRDX6. In conclusion, the presence of 10-8 M melatonin in culture medium improves viability and preserves the ultrastructure of oocyte and granulosa cells of early antral follicles cultured in vitro.

Classification of Corrosion Severity in SPCC Steels Using Eddy Current Testing and Supervised Machine Learning Models.

Steel Plate Cold-Rolled Commercial (SPCC) steel is known to have long-term durability. However, it still undergoes corrosion when exposed to corrosive environments. This paper proposes an evaluation method for assessing the corrosion level of SPCC steel samples using eddy current testing (ECT), along with two different machine learning approaches. The objective is to classify the corrosion of the samples into two states: a less corroded state (state-1) and a highly corroded state (state-2). Generative and discriminative models were implemented for classification. The generative classifier was based on the Gaussian mixture model (GMM), while the discriminative model was based on the logistic regression model. The features used in the classification models are the peaks of the perturbated magnetic fields at two different frequencies. The performance of the classifiers was evaluated using metrics such as absolute error, accuracy, precision, recall, and F1 score. The results indicate that the GMM model is more conducive to categorizing states with higher levels of corrosion, while the logistic regression model is helpful in estimating states with lower levels of corrosion. Meanwhile, high classification accuracy can be achieved based on both methods using eddy current testing.

Understanding the Chemomechanical Function of the Silver-Carbon Interlayer in Sheet-type All-Solid-State Lithium-Metal Batteries.

All-solid-state batteries with lithium metal anodes hold great potential for high-energy battery applications. However, forming and maintaining stable solid-solid contact between the lithium anode and solid electrolyte remains a major challenge. One promising solution is the use of a silver-carbon (Ag-C) interlayer, but its chemomechanical properties and impact on interface stabilities need to be comprehensively explored. Here, we examine the function of Ag-C interlayers in addressing interfacial challenges using various cell configurations. Experiments show that the interlayer improves interfacial mechanical contact, leading to a uniform current distribution and suppressing lithium dendrite growth. Furthermore, the interlayer regulates lithium deposition in the presence of Ag particles via improved Li diffusivity. The sheet-type cells with the interlayer achieve a high energy density of 514.3 Wh L-1 and an average Coulombic efficiency of 99.97% over 500 cycles. This work provides insights into the benefits of using Ag-C interlayers for enhancing the performance of all-solid-state batteries.

Graphene Nano-Optics in the Terahertz Gap.

Graphene nano-optics at terahertz (THz) frequencies (ν) is theoretically anticipated to feature extraordinary effects. However, interrogating such phenomena is nontrivial, since the atomically thin graphene dimensionally mismatches the THz radiation wavelength reaching hundreds of micrometers. Greater challenges happen in the THz gap (0.1-10 THz) wherein light sources are scarce. To surpass these barriers, we use a nanoscope illuminated by a highly brilliant and tunable free-electron laser to image the graphene nano-optical response from 1.5 to 6.0 THz. For ν < 2 THz, we observe a metal-like behavior of graphene, which screens optical fields akin to noble metals, since this excitation range approaches its charge relaxation frequency. At 3.8 THz, plasmonic resonances cause a field-enhancement effect (FEE) that improves the graphene imaging power. Moreover, we show that the metallic behavior and the FEE are tunable upon electrical doping, thus providing further control of these graphene nano-optical properties in the THz gap.

Lifelong exposure to high-altitude hypoxia in humans is associated with improved redox homeostasis and structural-functional adaptations of the neurovascular unit.

High-altitude (HA) hypoxia may alter the structural-functional integrity of the neurovascular unit (NVU). Herein, we compared male lowlanders (n = 9) at sea level (SL) and after 14 days acclimatization to 4300 m (chronic HA) in Cerro de Pasco (CdP), Péru (HA), against sex-, age- and body mass index-matched healthy highlanders (n = 9) native to CdP (lifelong HA). Venous blood was assayed for serum proteins reflecting NVU integrity, in addition to free radicals and nitric oxide (NO). Regional cerebral blood flow (CBF) was examined in conjunction with cerebral substrate delivery, dynamic cerebral autoregulation (dCA), cerebrovascular reactivity to carbon dioxide (CVRCO2 ) and neurovascular coupling (NVC). Psychomotor tests were employed to examine cognitive function. Compared to lowlanders at SL, highlanders exhibited elevated basal plasma and red blood cell NO bioavailability, improved anterior and posterior dCA, elevated anterior CVRCO2 and preserved cerebral substrate delivery, NVC and cognition. In highlanders, S100B, neurofilament light-chain (NF-L) and T-tau were consistently lower and cognition comparable to lowlanders following chronic-HA. These findings highlight novel integrated adaptations towards regulation of the NVU in highlanders that may represent a neuroprotective phenotype underpinning successful adaptation to the lifelong stress of HA hypoxia. KEY POINTS: High-altitude (HA) hypoxia has the potential to alter the structural-functional integrity of the neurovascular unit (NVU) in humans. For the first time, we examined to what extent chronic and lifelong hypoxia impacts multimodal biomarkers reflecting NVU structure and function in lowlanders and native Andean highlanders. Despite lowlanders presenting with a reduction in systemic oxidative-nitrosative stress and maintained cerebral bioenergetics and cerebrovascular function during chronic hypoxia, there was evidence for increased axonal injury and cognitive impairment. Compared to lowlanders at sea level, highlanders exhibited elevated vascular NO bioavailability, improved dynamic regulatory capacity and cerebrovascular reactivity, comparable cerebral substrate delivery and neurovascular coupling, and maintained cognition. Unlike lowlanders following chronic HA, highlanders presented with lower concentrations of S100B, neurofilament light chain and total tau. These findings highlight novel integrated adaptations towards the regulation of the NVU in highlanders that may represent a neuroprotective phenotype underpinning successful adaptation to the lifelong stress of HA hypoxia.

High-Altitude Erythrocytosis: Mechanisms of Adaptive and Maladaptive Responses.

Erythrocytosis, or increased production of red blood cells, is one of the most well-documented physiological traits that varies within and among in high-altitude populations. Although a modest increase in blood O2-carrying capacity may be beneficial for life in highland environments, erythrocytosis can also become excessive and lead to maladaptive syndromes such as chronic mountain sickness (CMS).

A meta-analysis on the effect of proximal landing zone location on stroke and mortality in thoracic endovascular aortic repair.

BACKGROUND: Thoracic endovascular aortic repair (TEVAR) involving the aortic arch may increase the opportunity for stroke owing to disruption of cerebral circulation and embolization. In this study, a systematic meta-analysis was performed to examine the impact of proximal landing zone location on stroke and 30-day mortality after TEVAR. METHODS: MEDLINE and Cochrane Library were searched for all original studies of TEVAR reporting outcomes of stroke or 30-day mortality for at least two adjacent proximal landing zones, based on the Ishimaru classification scheme. Forest plots were created using relative risks (RR) with 95% confidence intervals (CI). An I2 of <40% was regarded as minimal heterogeneity. A P value of <.05 was considered significant. RESULTS: Of the 57 studies examined, a total of 22,244 patients (male 73.1%, aged 71.9 ± 11.5 years) were included in the meta-analysis, with 1693 undergoing TEVAR with proximal landing zone 0, 1931 with zone 1, 5839 with zone 2, and 3089 with zone 3 and beyond. The overall risk of clinically evident stroke was 2.7% for zones ≥3, 6.6% for zone 2, 7.7% for zone 1, and 14.2% for zone 0. More proximal landing zones were associated with higher risks of stroke compared with distal (zone 2 vs ≥3: RR, 2.14; 95% CI, 1.43-3.20; P = .0002; I2 = 56%; zone 1 vs 2: RR, 1.48; 95% CI, 1.20-1.82; P = .0002; I2 = 0%; zone 0 vs 1: RR, 1.85; 95% CI, 1.52-2.24; P < .00001; I2 = 0%). Mortality at 30 days was 2.9% for zones ≥3, 2.4% for zone 2, 3.7% for zone 1, and 9.3% for zone 0. Zone 0 was associated with higher mortality compared with zone 1 (RR, 2.30; 95% CI, 1.75-3.03; P < .00001; I2 = 0%). No significant differences were found in 30-day mortality between zones 1 and 2 (P = .13) and between zone 2 and zones ≥3 (P = .87). CONCLUSIONS: The risk of stroke from TEVAR is lowest in zone 3 and beyond, increasing significantly as the landing zone is moved proximally. Furthermore, perioperative mortality is increased with zone 0 compared with zone 1. Therefore, risk of stent grafting in the proximal arch should be weighed against alternative surgical or nonoperative options. It is anticipated that the risk of stroke will improve with further development of stent graft technology and implantation technique.

Long-term outcomes following successful endoscopic treatment of T1 esophageal adenocarcinoma: a multicenter cohort study.

BACKGROUND AND AIMS: Endoscopic eradication therapy (EET) is guideline endorsed for management of early-stage (T1) esophageal adenocarcinoma (EAC). Patients with baseline high-grade dysplasia (HGD) and EAC are at highest risk of recurrence after successful EET, but limited data exist on long-term (>5 year) recurrence outcomes. Our aim was to assess the incidence and predictors of long-term recurrence in a multicenter cohort of patients with T1 EAC treated with EET. METHODS: Patients with T1 EAC achieving successful endoscopic cancer eradication with a minimum of 5 years' clinical follow-up were included. The primary outcome was neoplastic recurrence, defined as dysplasia or EAC, and it was characterized as early (<2 years), intermediate (2-5 years), or late (>5 years). Predictors of recurrence were assessed by time to event analysis. RESULTS: A total of 84 T1 EAC patients (75 T1a, 9 T1b) with a median 9.1 years (range, 5.1-18.3 years) of follow-up were included. The overall incidence of neoplastic recurrence was 2.0 per 100 person-years of follow-up. Seven recurrences (3 dysplasia, 4 EAC) occurred after 5 years of EAC remission. Overall, 88% of recurrences were treated successfully endoscopically. EAC recurrence-related mortality occurred in 3 patients at a median of 5.2 years from EAC remission. Complete eradication of intestinal metaplasia was independently associated with reduced recurrence (hazard ratio, .13). CONCLUSIONS: Following successful EET of T1 EAC, neoplastic recurrence occurred after 5 years in 8.3% of cases. Careful long-term surveillance should be continued in this patient population. Complete eradication of intestinal metaplasia should be the therapeutic end point for EET.

Behavioral effects induced by the cannabidiol analogs HU-502 and HU-556.

Cannabidiol is a phytocannabinoid that lacks the psychotomimetic properties of Δ9-tetrahydrocannabinol (THC), the main psychoactive Cannabis sativa component. Cannabidiol has several potential therapeutic properties, including anxiolytic, antidepressant, and antipsychotic; however, cannabidiol has low oral bioavailability, which can limit its clinical use. Here, we investigated if two cannabidiol analogs, HU-502 and HU-556, would be more potent than cannabidiol in behavioral tests predictive of anxiolytic, antidepressant, and antipsychotic effects. Different doses (0.01-3 mg/kg; intraperitoneally) of HU-556 and HU-502 were tested in male Swiss mice submitted to the elevated plus maze (EPM), forced swimming test (FST), and amphetamine-induced-prepulse inhibition (PPI) disruption and hyperlocomotion. Cannabidiol is effective in these tests at a dose range of 15-60 mg/kg in mice. We also investigated if higher doses of HU-556 (3 and 10 mg/kg) and HU-502 (10 mg/kg) produced the cannabinoid tetrad (hypolocomotion, catalepsy, hypothermia, and analgesia), which is induced by THC-like compounds. HU-556 (0.1 and 1 mg/kg) increased the percentage of open arm entries (but not time) in the EPM, decreased immobility time in the FST, and attenuated amphetamine-induced PPI disruption. HU-502 (1 and 3 mg/kg) decreased amphetamine-induced hyperlocomotion and PPI impairment. HU-556, at high doses, caused catalepsy and hypolocomotion, while HU-502 did not. These findings suggest that similar to cannabidiol, HU-556 could induce anxiolytic, antidepressant, and antipsychotic-like effects and that HU-502 has antipsychotic properties. These effects were found at a dose range devoid of cannabinoid tetrad effects.

Ceftriaxone Pharmacokinetics and Pharmacodynamics in 2 Pediatric Patients on Extracorporeal Membrane Oxygenation Therapy.

BACKGROUND: Critically ill patients with cardiac or respiratory failure may require extracorporeal membrane oxygenation (ECMO). Antibiotics are frequently administered when the suspected cause of organ failure is an infection. Ceftriaxone, a ß-lactam antibiotic, is commonly used in patients who are critically ill. Although studies in adults on ECMO have suggested minimal impact on ceftriaxone pharmacokinetics, limited research exists on ceftriaxone pharmacokinetics/pharmacodynamics (PK/PD) in pediatric ECMO patients. We report the PK profiles and target attainment of 2 pediatric patients on ECMO who received ceftriaxone. METHODS: Ceftriaxone concentrations were measured in 2 pediatric patients on ECMO using scavenged opportunistic sampling. PK profiles were generated and individual PK parameters were estimated using measured free ceftriaxone concentrations and a published population PK model in children who are critically ill, using Bayesian estimation. RESULTS: Patient 1, an 11-year-old boy on venovenous ECMO for respiratory failure received 2 doses of 52 mg/kg ceftriaxone 12 hours apart while on ECMO and additional doses every 12 hours off ECMO. On ECMO, ceftriaxone clearance was 13.0 L/h/70 kg compared with 7.6 L/h/70 kg off ECMO, whereas the model-predicted mean clearance in children who are critically ill without ECMO support was 6.54 L/h/70 kg. Patient 2, a 2-year-old boy on venoarterial ECMO due to cardiac arrest received 50 mg/kg ceftriaxone every 12 hours while on ECMO for >7 days. Only clearance while on ECMO could be estimated (9.1 L/h/70 kg). Trough concentrations in both patients were >1 mg/L (the breakpoint for Streptococcus pneumoniae ) while on ECMO. CONCLUSIONS: ECMO increased ceftriaxone clearance above the model-predicted clearances in the 2 pediatric patients studied. Twelve-hour dosing allowed concentrations to remain above the breakpoint for commonly targeted bacteria but not 4 times the breakpoint in one patient, suggesting that precision dosing may be beneficial to ensure target attainment in children on ECMO.