Contrasting model mechanisms of alanine aminotransferase (ALT) release from damaged and necrotic hepatocytes as an example of general biomarker mechanisms.

Interpretations of elevated blood levels of alanine aminotransferase (ALT) for drug-induced liver injury often assume that the biomarker is released passively from dying cells. However, the mechanisms driving that release have not been explored experimentally. The usefulness of ALT and related biomarkers will improve by developing mechanism-based explanations of elevated levels that can be expanded and elaborated incrementally. We provide the means to challenge the ability of closely related model mechanisms to generate patterns of simulated hepatic injury and ALT release that scale (or not) to be quantitatively similar to the wet-lab validation targets, which are elevated plasma ALT values following acetaminophen (APAP) exposure in mice. We build on a published model mechanism that helps explain the generation of characteristic spatiotemporal features of APAP hepatotoxicity within hepatic lobules. Discrete event and agent-oriented software methods are most prominent. We instantiate and leverage a small constellation of concrete model mechanisms. Their details during execution help bring into focus ways in which particular sources of uncertainty become entangled with cause-effect details within and across several levels. We scale ALT amounts in virtual mice directly to target plasma ALT values in individual mice. A virtual experiment comprises a set of Monte Carlo simulations. We challenge the sufficiency of four potentially explanatory theories for ALT release. The first of the tested model theories failed to achieve the initial validation target, but each of the three others succeeded. Results for one of the three model mechanisms matched all target ALT values quantitatively. It explains how ALT externalization is the combined consequence of lobular-location-dependent drug-induced cellular damage and hepatocyte death. Falsification of one (or more) of the model mechanisms provides new knowledge and incrementally shrinks the constellation of model mechanisms. The modularity and biomimicry of our explanatory models enable seamless transition from mice to humans.

A Model Mechanism-Based Explanation of an In Vitro-In Vivo Disconnect for Improving Extrapolation and Translation.

An improved understanding of in vivo-to-in vitro hepatocyte changes is crucial to interpreting in vitro data correctly and further improving hepatocyte-based in vitro-to-in vivo extrapolations to human targets. We demonstrate using virtual experiments as a means of helping to untangle plausible causes of inaccurate extrapolations. We start with virtual mice that use biomimetic software livers. Previously, using these mice, we discovered model mechanisms that enabled achieving quantitative validation targets while also providing plausible causal explanations for temporal characteristics of acetaminophen hepatotoxicity. We isolated virtual hepatocytes, created a virtual culture, and then conducted dose-response experiments in both culture and mice. We expected to see differences between the two dose-response curves but were somewhat surprised that they crossed because it evidenced that simulated acetaminophen metabolism and toxicity are different for virtual culture and mouse contexts even though individual hepatocyte mechanisms were unchanged. Differences in dose-response curves provide a virtual example of an in vivo-to-in vitro disconnect. We use detailed results of experiments to explain this disconnect. Individual hepatocytes contribute differently to system-level phenomena. In liver, hepatocytes are exposed to acetaminophen sequentially. Relative production of the reactive acetaminophen metabolite is largest (smallest) in pericentral (periportal) hepatocytes. Because that sequential exposure is absent in culture, hepatocytes from different lobular locations do not respond the same. A virtual culture-to-mouse translation can stand as a scientifically challengeable hypothesis explaining an in vivo-to-in vitro disconnect. It provides a framework to develop more reliable interpretations of in vitro observations, which then may be used to improve extrapolations.

Competing Mechanistic Hypotheses of Acetaminophen-Induced Hepatotoxicity Challenged by Virtual Experiments.

Acetaminophen-induced liver injury in mice is a model for drug-induced liver injury in humans. A precondition for improved strategies to disrupt and/or reverse the damage is a credible explanatory mechanism for how toxicity phenomena emerge and converge to cause hepatic necrosis. The Target Phenomenon in mice is that necrosis begins adjacent to the lobule's central vein (CV) and progresses outward. An explanatory mechanism remains elusive. Evidence supports that location dependent differences in NAPQI (the reactive metabolite) formation within hepatic lobules (NAPQI zonation) are necessary and sufficient prerequisites to account for that phenomenon. We call that the NZ-mechanism hypothesis. Challenging that hypothesis in mice is infeasible because 1) influential variables cannot be controlled, and 2) it would require sequential intracellular measurements at different lobular locations within the same mouse. Virtual hepatocytes use independently configured periportal-to-CV gradients to exhibit lobule-location dependent behaviors. Employing NZ-mechanism achieved quantitative validation targets for acetaminophen clearance and metabolism but failed to achieve the Target Phenomenon. We posited that, in order to do so, at least one additional feature must exhibit zonation by decreasing in the CV direction. We instantiated and explored two alternatives: 1) a glutathione depletion threshold diminishes in the CV direction; and 2) ability to repair mitochondrial damage diminishes in the CV direction. Inclusion of one or the other feature into NZ-mechanism failed to achieve the Target Phenomenon. However, inclusion of both features enabled successfully achieving the Target Phenomenon. The merged mechanism provides a multilevel, multiscale causal explanation of key temporal features of acetaminophen hepatotoxicity in mice. We discovered that variants of the merged mechanism provide plausible quantitative explanations for the considerable variation in 24-hour necrosis scores among 37 genetically diverse mouse strains following a single toxic acetaminophen dose.

Travel patterns of cancer surgery patients in a regionalized system.

BACKGROUND: Regionalization of complex surgeries has increased patient travel distances possibly leaving a substantial burden on those at risk for poorer surgical outcomes. To date, little is known about travel patterns of cancer surgery patients in regionalized settings. To inform this issue, we sought to assess travel patterns of those undergoing a major cancer surgery within a regionalized system. MATERIALS AND METHODS: We identified 4733 patients who underwent lung, esophageal, gastric, liver, pancreatic, and colorectal resections from 2002-2014 within a multihospital system in the Mid-Atlantic region of the United States. Patient age, race and/or ethnicity, and insurance status were extracted from electronic health records. We used Geographical Information System capabilities in R software to estimate travel distance and map patient addresses based on cancer surgery type and these characteristics. We used visual inspection, analysis of variance, and interaction analyses to assess the distribution of travel distances between patient populations. RESULTS: A total of 48.2% of patients were non-white, 49.9% were aged >65 y, and 54.9% had private insurance. Increased travel distance was associated with decreasing age and those undergoing pancreatic and esophageal resections. Also, black patients tend to travel shorter distances than other racial and/or ethnic groups. CONCLUSIONS: These maps offer a preliminary understanding into variations of geospatial travel patterns among patients receiving major cancer surgery in a Mid-Atlantic regionalized setting. Future research should focus on the impact of regionalization on timely delivery of surgical care and other quality metrics.

Prospective Study of Canaloplasty and Trabeculotomy Performed by Trainees.

Purpose: To evaluate outcomes of new adopters of the OMNI® Surgical System (Sight Sciences, Inc.) by prospectively evaluating intermediate-term outcomes of patients operated by trainees. Patients and Methods: This was a prospective study of surgeries performed by trainees on patients with open angle glaucoma undergoing simultaneous cataract surgery and ab interno canaloplasty and trabeculotomy using the OMNI Surgical System. Pre-operative intraocular pressure (IOP) and number of glaucoma medications were recorded. Only patients with a minimum of 6-month follow up were included. Baseline IOP was used to separate subjects into two groups: Group 1 (IOP ≥18 mmHg) and Group 2 (IOP <18 mmHg). Mean decrease in IOP and medications was calculated and compared with paired t-tests for the overall sample as well as the subgroups. Success was defined as those with a ≥20% reduction from pre-operative IOP or with an IOP ≤18 mmHg and ≥6 mmHg and on the same or fewer number of medications while not requiring additional surgery. Adverse events were also recorded. Results: Forty-two eyes of 31 patients were included. Mean pre-operative IOP was 17.2 ± 4.8 mmHg and mean number of medications was 2.4 ± 1.2. The primary endpoint was reached in 83.3% of patients at 12 months. IOP was reduced by 22.3% to 13.4 ± 2.4 (p<0.001). Mean number of medications decreased to 1.7 ± 1.6 (p<0.001). Group 1 mean IOP decreased 35.4% from 22.2 ± 4.6 mmHg to 14.3 ± 2.8 mmHg (p<0.001). Group 2 mean number of medications decreased from 2.3 ± 1.1 to 1.6 ± 1.5 (p<0.001). Conclusion: When operated on by the novice MIGS surgeon, the OMNI device provides effective IOP and glaucoma medication reduction with minimal adverse events. Efficacy and safety of the device in the hands of trainees was comparable to experienced glaucoma surgeons suggesting its ease of adoption.

Comparison of Superior versus Inferior Canaloplasty and Trabeculotomy Using the OMNI Surgical System.

Purpose: To compare outcomes of ab-interno canaloplasty and trabeculotomy of the superior versus inferior angle. Patients and methods: This was a prospective, non-randomized, interventional comparison study done at the Veteran Affairs Hospital in Long Beach, California. All patients underwent cataract surgery with intraocular lens implantation combined with ab-interno canaloplasty and trabeculotomy with the OMNI Surgical System (SightSciences, Menlo Park, CA, USA), either superiorly or inferiorly. Pre- and post-operative intraocular pressure using Goldmann applanation tonometry and best corrected visual acuity were obtained and compared using paired t-tests. Patients were excluded if they had any prior intraocular surgery or prior laser trabeculoplasty procedures. Results: 38 eyes from 29 patients were analyzed. 19 eyes were included in the superior group and 19 eyes in the inferior group. Mean pre-operative IOP in the superior group was 17.6 ± 5.2 mmHg and in the inferior group was 17.6 ± 4.6 mmHg (p > 0.99). At 12 months, mean postoperative IOP for the superior group decreased 24% to 13.3 ± 2.8 mmHg while the inferior group decreased 26% to 13.1 ± 2.2 mmHg (p = 0.92). Mean preoperative medications in the superior group were 2.2 ± 1.3 and in the inferior group was 2.4 ± 1.3 (p = 0.88). At 12 months, this decreased to 1.3 ± 1.5 post-operatively in the superior group and 2.2 ± 1.6 post-operatively in the inferior group (p = 0.64). Conclusion: There was no statistical difference in efficacy between superior versus inferior canaloplasty/trabeculotomy with OMNI. Therefore, surgeons can perform the procedure in the direction that is most comfortable for them without affecting outcomes.

Kynurenine aminotransferase II inhibition promotes sleep and rescues impairments induced by neurodevelopmental insult.

Dysregulated sleep is commonly reported in individuals with neuropsychiatric disorders, including schizophrenia (SCZ) and bipolar disorder (BPD). Physiology and pathogenesis of these disorders points to aberrant metabolism, during neurodevelopment and adulthood, of tryptophan via the kynurenine pathway (KP). Kynurenic acid (KYNA), a neuroactive KP metabolite derived from its precursor kynurenine by kynurenine aminotransferase II (KAT II), is increased in the brains of individuals with SCZ and BPD. We hypothesize that elevated KYNA, an inhibitor of glutamatergic and cholinergic neurotransmission, contributes to sleep dysfunction. Employing the embryonic kynurenine (EKyn) paradigm to elevate fetal brain KYNA, we presently examined pharmacological inhibition of KAT II to reduce KYNA in adulthood to improve sleep quality. Pregnant Wistar rats were fed either kynurenine (100 mg/day)(EKyn) or control (ECon) diet from embryonic day (ED) 15 to ED 22. Adult male (N = 24) and female (N = 23) offspring were implanted with devices to record electroencephalogram (EEG) and electromyogram (EMG) telemetrically for sleep-wake data acquisition. Each subject was treated with either vehicle or PF-04859989 (30 mg/kg, s.c.), an irreversible KAT II inhibitor, at zeitgeber time (ZT) 0 or ZT 12. KAT II inhibitor improved sleep architecture maintaining entrainment of the light-dark cycle; ZT 0 treatment with PF-04859989 induced transient improvements in rapid eye movement (REM) and non-REM (NREM) sleep during the immediate light phase, while the impact of ZT 12 treatment was delayed until the subsequent light phase. PF-04859989 administration at ZT 0 enhanced NREM delta spectral power and reduced activity and body temperature. In conclusion, reducing de novo KYNA production alleviated sleep disturbances and increased sleep quality in EKyn, while also improving sleep outcomes in ECon offspring. Our findings place attention on KAT II inhibition as a novel mechanistic approach to treating disrupted sleep behavior with potential translational implications for patients with neurodevelopmental and neuropsychiatric disorders.

The Incidence of Urgent Tube Shunt Surgery for Diabetic Neovascular Glaucoma at a Tertiary Academic Medical Center.

Background: Diabetic neovascular glaucoma is a secondary glaucoma that may require immediate correction of elevated intraocular pressure to control pain and protect the optic nerve. While there is a seasonal trend to glucose levels, it is unknown if a seasonal trend exists for diabetic neovascular glaucoma. Objective: This study evaluates the incidence of urgent glaucoma tube shunt implantation in diabetic neovascular glaucoma in a tertiary academic referral center in Southern California. Methods: Electronic medical records were queried for urgent glaucoma tube shunt surgery from 2014 to 2021. The number of cases were separated by month of occurrence, and average hemoglobin A1c values were calculated per month. Data were analyzed via ANOVA tests and one-tailed t-tests. Results: A total of 127 cases were identified. The months of March and April contained the most cases averaging 3 and 2.75 cases, respectively. April had statistically significant higher case numbers than that of other months (P = .041). ANOVA tests excluding April showed no statistically significant difference between the remaining months (P = .901). Average hemoglobin A1c values were highest in the months of April and March at 9.8 and 9.6%, respectively. Conclusion: Emergency glaucoma tube shunt surgery for diabetic neovascular glaucoma occurs most frequently in April. This observation may provide insight into disease prevention through diabetes management and help improve surgical operations such that staffing and resources are allocated accordingly.

A case report of cystoid macular edema, uveitis and vitreomacular traction in a patient taking Anastrozole.

PURPOSE: To report a case of cystoid macular edema, uveitis, and vitreomacular traction in a patient with a history of breast cancer and taking anastrozole. OBSERVATIONS: A 73-year-old female with a history of estrogen receptor-positive breast cancer and treatment with anastrozole presented with bilateral blurry vision, photophobia, and eye soreness. Optical coherence tomography (OCT) of both maculae revealed vitreomacular traction (VMT), an epiretinal membrane, cystoid macular edema (CME) in the right eye, and drusen without subretinal fluid bilaterally. Although later, macular OCT did show evidence of cystoid intraretinal spaces in the left eye as well. Fluorescein angiography showed bilateral petaloid leakage, bilateral slow disc leaking, as well as peripheral leakage in the right eye. Anastrozole was discontinued and, subsequent macular OCT showed release of VMT in the right eye, and eventual resolution of intraretinal cystoid spaces bilaterally. CONCLUSIONS AND IMPORTANCE: Stopping of anastrozole was associated in resolution of refractory CME in a patient on aromatase inhibitor therapy for breast cancer. It is therefore important to consider anastrozole and other aromatase inhibitor drugs as possible factors predisposing patients to the development of CME.

Utilizing virtual experiments to increase understanding of discrepancies involving in vitro-to-in vivo predictions of hepatic clearance.

Predictions of xenobiotic hepatic clearance in humans using in vitro-to-in vivo extrapolation methods are frequently inaccurate and problematic. Multiple strategies are being pursued to disentangle responsible mechanisms. The objective of this work is to evaluate the feasibility of using insights gained from independent virtual experiments on two model systems to begin unraveling responsible mechanisms. The virtual culture is a software analog of hepatocytes in vitro, and the virtual human maps to hepatocytes within a liver within an idealized model human. Mobile objects (virtual compounds) map to amounts of xenobiotics. Earlier versions of the two systems achieved quantitative validation targets for intrinsic clearance (virtual culture) and hepatic clearance (virtual human). The major difference between the two systems is the spatial organization of the virtual hepatocytes. For each pair of experiments (virtual culture, virtual human), hepatocytes are configured the same. Probabilistic rules govern virtual compound movements and interactions with other objects. We focus on highly permeable virtual compounds and fix their extracellular unbound fraction at one of seven values (0.05-1.0). Hepatocytes contain objects that can bind and remove compounds, analogous to metabolism. We require that, for a subset of compound properties, per-hepatocyte compound exposure and removal rates during culture experiments directly predict corresponding measures made during virtual human experiments. That requirement serves as a cross-system validation target; we identify compound properties that enable achieving it. We then change compound properties, ceteris paribus, and provide model mechanism-based explanations for when and why measures made during culture experiments under- (or over-) predict corresponding measures made during virtual human experiments. The results show that, from the perspective of compound removal, the organization of hepatocytes within virtual livers is more efficient than within cultures, and the greater the efficiency difference, the larger the underprediction. That relationship is noteworthy because most in vitro-to-in vivo extrapolation methods abstract away the structural organization of hepatocytes within a liver. More work is needed on multiple fronts, including the study of an expanded variety of virtual compound properties. Nevertheless, the results support the feasibility of the approach and plan.

Exploring ancestral phenotypes and evolutionary development of the mammalian middle ear based on Early Cretaceous Jehol mammals.

We report a new Cretaceous multituberculate mammal with 3D auditory bones preserved. Along with other fossil and extant mammals, the unequivocal auditory bones display features potentially representing ancestral phenotypes of the mammalian middle ear. These phenotypes show that the ectotympanic and the malleus-incus complex changed notably during their retreating from the dentary at various evolutionary stages and suggest convergent evolution of some features to extant mammals. In contrast, the incudomalleolar joint was conservative in having a braced hinge configuration, which narrows the morphological gap between the quadroarticular jaw joint of non-mammalian cynodonts and the incudomalleolar articulations of extant mammals. The saddle-shaped and abutting malleus-incus complexes in therians and monotremes, respectively, could have evolved from the braced hinge joint independently. The evolutionary changes recorded in the Mesozoic mammals are largely consistent with the middle ear morphogenesis during the ontogeny of extant mammals, supporting the relation between evolution and development.

The Relationship Between Plasma Tetrahydrocannabinol Levels and Intraocular Pressure in Healthy Adult Subjects.

BACKGROUND: Δ9-tetrahydrocannabinol (THC) has been shown to decreased intraocular pressure (IOP). This project aims to define the relationship between plasma THC levels and IOP in healthy adult subjects. METHODS: Eleven healthy subjects received a single dose of inhaled cannabis that was self-administered in negative pressure rooms. Measurements of IOP and plasma THC levels were taken at baseline and every 30 min for 1 h and afterwards every hour for 4 h. IOP reduction and percent change in IOP over time were calculated. Linear regression models were used to measure the relationship between IOP and plasma THC levels. Two line linear regression models with F-tests were used to detect change points in the regression. Then, Pearson correlations were computed based on the change point. RESULTS: Twenty-two eyes met inclusion criteria. The average peak percentage decrease in IOP was 16% at 60 min. Percent IOP reduction as well as total IOP reduction demonstrated a negative correlation with THC plasma levels showing r-values of -0.81 and -0.70, respectively. F-tests revealed a change point in the regression for plasma levels >20 ng/ml. For levels >20 ng/ml, the correlation coefficients changed significantly with r-values of 0.21 and 0.29 (p < 0.01). CONCLUSION: Plasma THC levels are significantly correlated with IOP reduction up to plasma levels of 20 ng/ml. Plasma levels >20 ng/ml were not correlated with further decrease in IOP. More research is needed to determine the efficacy of THC in reducing IOP for eyes with ocular hypertension and glaucoma.

Acquired Optic Pits Associated with Laser-assisted In Situ Keratomileusis: A Case Series.

PURPOSE: To present an association between acquired pits of the optic nerve (APON) and prior laser-assisted in situ keratomileusis (LASIK). MATERIALS AND METHODS: A retrospective case series of patients with an optic disc pit on clinical exam and a history of LASIK. Spectralis Optical Coherence Tomography images and Humphrey Visual Fields were reviewed from prior visits. Extended-depth optical coherence tomography was performed of the optic nerve head at subsequent visits after patients were identified. RESULTS: Seven patients, aged 45-73 years, were identified each with unilateral optic disc pits. Optic disc pits were located inferior in six patients and centrally in one patient. All demonstrated thinning on optical coherence tomography and six patients had corresponding visual field defects. Four patients identified these defects after their LASIK procedure while two patients were unaware of their reproducible visual field defects. All patients were treated with drops initially. One patient underwent laser trabeculoplasty, and three underwent a trabeculectomy after demonstrating progression on maximum tolerated medical therapy. CONCLUSION: This series describes a possible association between LASIK and APON. Given the similarity and severity of vision loss associated with the optic nerve pits in these patients after LASIK, increased awareness and caution is suggested while considering LASIK in susceptible individuals. HOW TO CITE THIS ARTICLE: Smith AK, Bussel I, Ling J, et al. Acquired Optic Pits Associated with Laser-assisted In Situ Keratomileusis: A Case Series. J Curr Glaucoma Pract 2020;14(3):106-108.

The Effect of a Screen Protector on Blue Light Intensity Emitted from Different Hand-held Devices.

PURPOSE: In response to growing concern about the effect of blue light on ocular tissue, companies have created mobile device screen protectors to block blue light. This project evaluates one of these screen protectors' ability to reduce blue light intensity. METHODS: The intensity of light at 450 nm from an iPhone 8, iPhone X, and iPad was measured in a dark room. The averages of three measurements were taken with and without the screen protector at different distances, settings of brightness, and Apple's night shift (NS) mode. Results were analyzed using paired t-tests. RESULTS: At 33 cm, 100% brightness, and 0% NS, the screen protector decreased intensity by 43.9%, 32.3%, and 34.9% for the iPhone 8, iPhone X, and iPad, respectively. At 33 cm and 100% brightness, increasing NS mode from 0% to 100% decreased intensity by 81.2%, 84.2%, and 86.5%. At 33 cm without NS, decreasing the brightness from 100% to 0% decreased intensity by 99.5%, 99.8%, and 97.8%. CONCLUSIONS: The screen protector decreased the intensity at 450 nm for every setting other than those at 0% brightness. Decreasing brightness and applying NS mode were more effective in reducing blue light. More research is needed to determine the benefits of decreasing blue light exposure from electronic devices.

Integrated hearing and chewing modules decoupled in a Cretaceous stem therian mammal.

On the basis of multiple skeletal specimens from Liaoning, China, we report a new genus and species of Cretaceous stem therian mammal that displays decoupling of hearing and chewing apparatuses and functions. The auditory bones, including the surangular, have no bone contact with the ossified Meckel's cartilage; the latter is loosely lodged on the medial rear of the dentary. This configuration probably represents the initial morphological stage of the definitive mammalian middle ear. Evidence shows that hearing and chewing apparatuses have evolved in a modular fashion. Starting as an integrated complex in non-mammaliaform cynodonts, the two modules, regulated by similar developmental and genetic mechanisms, eventually decoupled during the evolution of mammals, allowing further improvement for more efficient hearing and mastication.

Determination of tie-line fields for coexisting lipid phases: an ESR study.

A novel method we refer to as the tie-line field (TLF) method has been developed to globally determine the tie lines of any three-component two-phase coexistence region by fitting electron-spin resonance (ESR) spectra obtained from compositions on the coexistence curve and within the coexistence region. The TLF method is illustrated by applying it to the liquid-ordered (Lo) and liquid-disordered (Ld) phase coexistence region of the lipid system brain-sphingomyelin/dioleoylphosphatidylcholine/cholesterol (SPM/DOPC/chol), for which an estimate of a tie-line was previously obtained by an earlier method also using ESR spectra. The essential aspect of the TLF method is the unique parametrization of the coexistence region called a "ruled surface". The use of the ruled surface enables one to guarantee that tie lines do not cross, as required by the phase rule, whereas previous methods lack this important constraint. It also makes simultaneous use of the full data set in determining the TLF and leads to a more efficient experimental design than previously used. The method is first tested out on synthetic data sets, then least-squares fitting of the ESR spectra with the parametrized model results in a tie-line field consistent with other known information on this lipid system. The best-fit tie-line field consists of the set of tie lines which are not exactly parallel; they exhibit a gradual change in slope with the largest slope within the coexistence region connecting the coexistence curve compositions with the highest and lowest cholesterol concentrations. The results are compared with those from more constrained methods of representing the tie-line fields as well as with the previous tie-line determination for the SPM/DOPC/chol system. An accurate determination of the tie-line field of phase coexistence regions in lipid systems is a necessary step in determining coexisting lipid compositions to serve as models of cell plasma membranes.

Propagation of Pericentral Necrosis During Acetaminophen-Induced Liver Injury: Evidence for Early Interhepatocyte Communication and Information Exchange.

Acetaminophen (APAP)-induced liver injury is clinically significant, and APAP overdose in mice often serves as a model for drug-induced liver injury in humans. By specifying that APAP metabolism, reactive metabolite formation, glutathione depletion, and mitigation of mitochondrial damage within individual hepatocytes are functions of intralobular location, an earlier virtual model mechanism provided the first concrete multiattribute explanation for how and why early necrosis occurs close to the central vein (CV). However, two characteristic features could not be simulated consistently: necrosis occurring first adjacent to the CV, and subsequent necrosis occurring primarily adjacent to hepatocytes that have already initiated necrosis. We sought parsimonious model mechanism enhancements that would manage spatiotemporal heterogeneity sufficiently to enable meeting two new target attributes and conducted virtual experiments to explore different ideas for model mechanism improvement at intrahepatocyte and multihepatocyte levels. For the latter, evidence supports intercellular communication via exosomes, gap junctions, and connexin hemichannels playing essential roles in the toxic effects of chemicals, including facilitating or counteracting cell death processes. Logic requiring hepatocytes to obtain current information about whether downstream and lateral neighbors have triggered necrosis enabled virtual hepatocytes to achieve both new target attributes. A virtual hepatocyte that is glutathione-depleted uses that information to determine if it will initiate necrosis. When a less-stressed hepatocyte is flanked by at least two neighbors that have triggered necrosis, it too will initiate necrosis. We hypothesize that the resulting intercellular communication-enabled model mechanism is analogous to the actual explanation for APAP-induced hepatotoxicity at comparable levels of granularity.

LinkHub: a Semantic Web system that facilitates cross-database queries and information retrieval in proteomics.

BACKGROUND: A key abstraction in representing proteomics knowledge is the notion of unique identifiers for individual entities (e.g. proteins) and the massive graph of relationships among them. These relationships are sometimes simple (e.g. synonyms) but are often more complex (e.g. one-to-many relationships in protein family membership). RESULTS: We have built a software system called LinkHub using Semantic Web RDF that manages the graph of identifier relationships and allows exploration with a variety of interfaces. For efficiency, we also provide relational-database access and translation between the relational and RDF versions. LinkHub is practically useful in creating small, local hubs on common topics and then connecting these to major portals in a federated architecture; we have used LinkHub to establish such a relationship between UniProt and the North East Structural Genomics Consortium. LinkHub also facilitates queries and access to information and documents related to identifiers spread across multiple databases, acting as "connecting glue" between different identifier spaces. We demonstrate this with example queries discovering "interologs" of yeast protein interactions in the worm and exploring the relationship between gene essentiality and pseudogene content. We also show how "protein family based" retrieval of documents can be achieved. LinkHub is available at hub.gersteinlab.org and hub.nesg.org with supplement, database models and full-source code. CONCLUSION: LinkHub leverages Semantic Web standards-based integrated data to provide novel information retrieval to identifier-related documents through relational graph queries, simplifies and manages connections to major hubs such as UniProt, and provides useful interactive and query interfaces for exploring the integrated data.

Why Do Long-Distance Travelers Have Improved Pancreatectomy Outcomes?

BACKGROUND: Centralization of complex surgical care has led patients to travel longer distances. Emerging evidence suggested a negative association between increased travel distance and mortality after pancreatectomy. However, the reason for this association remains largely unknown. We sought to unravel the relationships among travel distance, receiving pancreatectomy at high-volume hospitals, delayed surgery, and operative outcomes. STUDY DESIGN: We identified 44,476 patients who underwent pancreatectomy for neoplasms between 2004 and 2013 at the reporting facility from the National Cancer Database. Multivariable analyses were performed to examine the independent relationships between increments in travel distance mortality (30-day and long-term survival) after adjusting for patient demographics, comorbidity, cancer stage, and time trend. We then examined how additional adjustment of procedure volume affected this relationship overall and among rural patients. RESULTS: Median travel distance to undergo pancreatectomy increased from 16.5 to 18.7 miles (p for trend < 0.001). Although longer travel distance was associated with delayed pancreatectomy, it was also related to higher odds of receiving pancreatectomy at a high-volume hospital and lower postoperative mortality. In multivariable analysis, difference in mortality among patients with varying travel distance was attenuated by adjustment for procedure volume. However, longest travel distance was still associated with a 77% lower 30-day mortality rate than shortest travel among rural patients, even when accounting for procedure volume. CONCLUSIONS: Our large national study found that the beneficial effect of longer travel distance on mortality after pancreatectomy is mainly attributable to increase in procedure volume. However, it can have additional benefits on rural patients that are not explained by volume. Distance can represent a surrogate for rural populations.