A multiscale functional map of somatic mutations in cancer integrating protein structure and network topology.

A major goal of cancer biology is to understand the mechanisms underlying tumorigenesis driven by somatically acquired mutations. Existing computational approaches focus on either scoring the pathogenicity of mutations or characterizing their effects at specific scales. Here, we established a unified computational framework, NetFlow3D, that systematically maps the multiscale mechanistic effects of somatic mutations in cancer. The establishment of NetFlow3D hinges upon the Human Protein Structurome, a complete repository we first compiled that incorporates the 3D structures of every single protein as well as the binding interfaces for all known PPIs in humans. The vast majority of 3D structural information was resolved by recent deep learning algorithms. By applying NetFlow3D to 415,017 somatic protein-altering mutations in 5,950 TCGA tumors across 19 cancer types, we identified 1,656 intra- and 3,343 inter-protein 3D clusters of mutations throughout the Human Protein Structurome, of which ~50% would not have been found if using only experimentally-determined protein structures. These 3D clusters have converging effects on 377 cellular subnetworks. Compared to canonical PPI network analyses, NetFlow3D achieved a 5.5-fold higher statistical power for identifying significantly dysregulated subnetworks. The majority of identified subnetworks were previously obscured by the overwhelming background noise of non-clustered passenger mutations, including portions of non-canonical PRC1, mediator complex, MCM2-7 complex, neddylation of cullins, complement system, TRiC, etc. NetFlow3D and our pan-cancer results can be accessed from http://netflow3d.yulab.org. This work shows that mapping how individual mutations act across scales requires the integration of their local spatial organization on protein structures and their global topological organization in the PPI network.

Genome maps across 26 human populations reveal population-specific patterns of structural variation.

Large structural variants (SVs) in the human genome are difficult to detect and study by conventional sequencing technologies. With long-range genome analysis platforms, such as optical mapping, one can identify large SVs (>2 kb) across the genome in one experiment. Analyzing optical genome maps of 154 individuals from the 26 populations sequenced in the 1000 Genomes Project, we find that phylogenetic population patterns of large SVs are similar to those of single nucleotide variations in 86% of the human genome, while ~2% of the genome has high structural complexity. We are able to characterize SVs in many intractable regions of the genome, including segmental duplications and subtelomeric, pericentromeric, and acrocentric areas. In addition, we discover ~60 Mb of non-redundant genome content missing in the reference genome sequence assembly. Our results highlight the need for a comprehensive set of alternate haplotypes from different populations to represent SV patterns in the genome.

Orbital Inflammatory Syndrome and Anterior Uveitis: A Case Series.

PURPOSE: To describe four cases of orbital inflammatory syndrome (OIS) with associated anterior uveitis that have presented within 2 years to our practice. METHODS: Charts of patients diagnosed with OIS from June 2013 to May 2015 were reviewed. RESULTS: Four patients, three children and one adult, presented with orbital swelling, pain, and varying degrees of vision loss. Treatment with intravenous methylprednisolone resulted in significant symptomatic improvement in all cases initially; when symptoms recurred, the patients had evidence of anterior uveitis. With continued systemic therapy and the addition of topical prednisolone, the patients all achieved control of their uveitis and OIS and are well controlled with regular outpatient follow-up. CONCLUSIONS: Reports of OIS-associated with uveitis are relatively rare. The presentation of three pediatric patients and one adult patient to the same practice with OIS and secondary uveitis within a 2-year period may indicate that the association is underreported.

Building confidence in quantitative systems pharmacology models: An engineer's guide to exploring the rationale in model design and development.

This tutorial promotes good practice for exploring the rationale of systems pharmacology models. A safety systems engineering inspired notation approach provides much needed rigor and transparency in development and application of models for therapeutic discovery and design of intervention strategies. Structured arguments over a model's development, underpinning biological knowledge, and analyses of model behaviors are constructed to determine the confidence that a model is fit for the purpose for which it will be applied.

Genome-Wide Structural Variation Detection by Genome Mapping on Nanochannel Arrays.

Comprehensive whole-genome structural variation detection is challenging with current approaches. With diploid cells as DNA source and the presence of numerous repetitive elements, short-read DNA sequencing cannot be used to detect structural variation efficiently. In this report, we show that genome mapping with long, fluorescently labeled DNA molecules imaged on nanochannel arrays can be used for whole-genome structural variation detection without sequencing. While whole-genome haplotyping is not achieved, local phasing (across >150-kb regions) is routine, as molecules from the parental chromosomes are examined separately. In one experiment, we generated genome maps from a trio from the 1000 Genomes Project, compared the maps against that derived from the reference human genome, and identified structural variations that are >5 kb in size. We find that these individuals have many more structural variants than those published, including some with the potential of disrupting gene function or regulation.

Agent-Based Modeling in Systems Pharmacology.

Modeling and simulation (M&S) techniques provide a platform for knowledge integration and hypothesis testing to gain insights into biological systems that would not be possible a priori. Agent-based modeling (ABM) is an M&S technique that focuses on describing individual components rather than homogenous populations. This tutorial introduces ABM to systems pharmacologists, using relevant case studies to highlight how ABM-specific strengths have yielded success in the area of preclinical mechanistic modeling.

First pandemic A (H1N1) pdm09 outbreak in a private school, Bangkok, Thailand, June 2009.

OBJECTIVE: On June 9, 2009, the Thailand Ministry of Public Health received their first report of an outbreak of the pandemic A (HIN1) pdm09 that occurred in a school. The authors conducted a study to describe the epidemiological characteristics of the outbreak and its resurgence, estimate the basic reproduction number (R) and review recommendations for prevention and control. MATERIAL AND METHOD: Active case finding in the school and reviewing reports to the national surveillance system identified 184 students infected by the new virus. A survey described the illness in the students and the prevention and control measures taken by the school. The basic reproduction number was estimated from data in the early epidemic phase. The other survey was done to assess factors contributing to the resurgence of the outbreak. RESULTS: Students with the pandemic A (HINI) pdm09 had a mild illness resembling seasonal influenza. Overcrowding in the classroom and activities that mixed students from different classes contributed to transmission in the school. The basic reproduction number for this school-based setting is 3.58. The second outbreak occurred because of poor monitoring of absenteeism and management of ill students. CONCLUSION: This was the first outbreak ofthepandemic A (HIN1) pdm09 in Thailand. The source could not be identified. Effective control measures monitoring, screening, strict personal hygiene and proper management of ill students.

Lessons from the 2006 Louisiana health and population survey.

The 2005 hurricane season caused extensive damage and induced a mass migration of approximately 1.1 million people from southern Louisiana in the United States. Current and accurate estimates of population size and demographics and an assessment of the critical needs for public services were required to guide recovery efforts. Since forecasts using pre-hurricane data may produce inaccurate estimates of the post-hurricane population, a household survey in 18 hurricane-affected parishes was conducted to provide timely and credible information on the size of these populations, their demographics and their condition. This paper describes the methods used, the challenges encountered, and the key factors for successful implementation. This post-disaster survey was unique because it identified the needs of the people in the affected parishes and quantified the number of people with these needs. Consequently, this survey established new population and health indicator baselines that otherwise would have not been available to guide the relief and recovery efforts in southern Louisiana.

Oral anticoagulation in the hospital: analysis of patients at risk.

Warfarin is one of the most commonly used medications associated with adverse events. Warfarin therapy is often initiated or continued in the hospital, yet hospitalization increases the risk of poor anticoagulation control with warfarin. To help understand this, we retrospectively reviewed the records of patients admitted to our hospital during a 6-month period who were given at least one dose of warfarin. To explore factors that may have contributed to poor anticoagulation control, we compared characteristics of patients with an international normalized ratio (INR) ≥ 5 at some point during hospitalization with those of a group of matched controls who also received warfarin and had INR <5. Among the 35 patients identified who had an INR ≥ 5, concomitant use of antibiotics was more common than among 105 matched controls; improper warfarin dosing also appeared to contribute to the high INRs. These findings indicate possible targets for intervention to improve patient safety.

Safety and efficacy of levetiracetam for critically ill patients with seizures.

INTRODUCTION: In intensive care unit (ICU) patients, seizure or status epilepticus treatment with intravenous benzodiazepines or conventional antiepileptic drugs (AEDs), such as phenytoin, may be accompanied by cardiovascular depression or hypotension. Levetiracetam (LVM) is a novel AED that does not undergo extensive liver metabolism, does not require drug level monitoring, and is not associated with hemodynamic instability. We retrospectively analyzed the use, safety, and efficacy of LVM in ICU patients. METHODS: Collected data included age, sex, therapy indication and duration, dosing regimen, documented seizure activity, ICU admission diagnoses, length of ICU stay, serum creatinine, liver function tests, adverse reactions, concomitant use of other AEDs, and drug interactions. RESULTS: Fifty-one patients were identified (26 males; mean (SD) age, 58.2 (19.8) years). Most patients (65%) did not receive a loading dose; the most common loading dose was 1,500 mg (50% of 18 patients). The most common maintenance dose was 500 mg twice daily (59% of 51 patients), and average duration of therapy was 13.6 (12.7) days. Approximately 47% of patients had preexisting liver disease, and 25% had elevated serum creatinine. Twenty-two patients received LVM therapy for seizure prophylaxis; 29 for acute seizure treatment. Ninety-three percent of patients treated with LVM for acute seizure had no subsequent seizures; the remaining patients (7%) required additional AEDs. One patient receiving LVM for seizure prophylaxis had documented seizures requiring additional AEDs. No adverse hemodynamic events or cardiac arrhythmias were reported. CONCLUSION: LVM appears to be safe for ICU patients when dosing is adjusted for renal function.

Repeated dosing of 23.4% hypertonic saline for refractory intracranial hypertension. A case report.

BACKGROUND: Hypertonic saline (HTS) at a concentration of 23.4% is an emerging therapy for intracranial hypertension. Compared to mannitol which can be given as a single bolus or as repeated bolus dosing, little data exists regarding safety or efficacy of repeated dosing of 23.4% HTS. We report the first case of 16 doses of 23.4% HTS over a 5 day period in a patient with refractory intracranial hypertension. CASE REPORT: A 43-year-old woman with Fisher 3 subarachnoid hemorrhage and hydrocephalus requiring an external ventricular drain developed global cerebral edema on computed tomography. Medically refractory intracranial hypertension ensued which required repeated dosing of 23.4% HTS. Reductions in intracranial pressure (ICP) occurred after each dose of 23.4% HTS. No central nervous system complications occurred. Anasarca was the only observed complication, which responded to furosemide diuresis. CONCLUSION: Repeated dosing of 23.4% HTS was effective in reducing ICP in a case of medically refractory intracranial hypertension without major systemic complications. Prospective studies should address the safety and efficacy of repeat dose 23.4% HTS on serum sodium, intracranial pressure, and complications.

Are nitrate levels in groundwater stable over time?

Epidemiologists often use a retrospective study design to examine for associations between an exposure and the occurrence of adverse health effects. Several of these studies used this approach to examine for an association between elevated levels of nitrate in drinking water and related health effects such as methemoglobinemia, cancer, neural tube effects, or spontaneous abortions. Often, data on exposures that occurred before these health outcomes were not available. Consequently, researchers use measurements of exposures at the time of the study to represent exposures that occurred before people developed these conditions. An opportunity to examine the stability of nitrate in water occurred during a survey of private water wells in nine Midwestern states. In this survey, water samples from 853 homes with drilled wells were collected in May 1994 and in September 1995 and nitrate-nitrogen (nitrate-N) was measured by the colorimetric cadmium reduction method. Nitrate-N levels from the same well over time were assessed by a mixed-effects analysis of variance. Analysis showed no significant difference in between the initial level and those measured 16 months later. Furthermore, analysis showed that most of the variance in the nitrate concentrations in well water was due to well-to-well variation (89%) rather than to residual error (12%). This observation showed that a single measurement of nitrate in water from drilled wells could represent longer periods of exposure.

Exotropia and face turn in children with homonymous hemianopia.

Four children developed homonymous hemianopia, exotropia with the deviating eye pointing in the direction of the field defect, and a face turn toward the side of the defect following complete third cranial nerve palsy after brain tumor resection, an in utero middle cerebral artery infarction, nonaccidental head trauma, and a hemispherectomy for an intractable seizure disorder. We present evidence that the exotropia and face turn are part of an adaptive mechanism to increase the useful visual field.

Maternal exposure to polybrominated and polychlorinated biphenyls: infant birth weight and gestational age.

Understanding the influence of maternal exposures on gestational age and birth weight is essential given that pre-term and/or low birth weight infants are at risk for increased mortality and morbidity. We performed a retrospective analysis of a cohort exposed to polybrominated biphenyls (PBB) through accidental contamination of cattle feed and polychlorinated biphenyls (PCB) through residual contamination in the geographic region. Our study population consisted of 444 mothers and their 899 infants born between 1975 and 1997. Using restricted maximum likelihood estimation, no significant association was found between estimated maternal serum PBB at conception or enrollment PCB levels and gestational age or infant birth weight in unadjusted models or in models that adjusted for maternal age, smoking, parity, infant gender, and decade of birth. For enrollment maternal serum PBB, no association was observed for gestational age. However, a negative association with high levels of enrollment maternal serum PBB and birth weight was suggested. We also examined the birth weight and gestational age among offspring of women with the highest (10%) PBB or PCB exposure, and observed no significant association. Because brominated compounds are currently used in consumer products and therefore, are increasingly prevalent in the environment, additional research is needed to better understand the potential relationship between in utero exposure to brominated compounds and adverse health outcomes.

Key factors for civilian injuries and deaths from exploding landmines and ordnance.

OBJECTIVE: To identify risk factors for death or injury from landmines and ordnance in Kabul City, Afghanistan, so programs can target preventive actions. METHODS: Active surveillance in hospitals and communities for injuries and deaths from landmine and ordnance explosions in Kabul City. RESULTS: Of the 571 people the authors identified during the 25-month period, 161 suffered a traumatic amputation and 94 were killed from a landmine or ordnance explosion. Of those asked, 19% of victims had received mine awareness education before the incident, and of those, the majority was injured while handling or playing with an explosive device. Most victims were young males with a few years of education. The occupation types most at risk were students and laborers, and unemployment was common among the victims. Collecting wood or paper and playing with or handling an explosive were the most frequent activities associated with injuries and deaths. CONCLUSIONS: From May 1996 to July 1998, explosions from landmines and ordnance claimed 571 victims and were an important preventable cause of injury and death among people in Kabul City. Prevention strategies should focus on high-risk groups and changing risky behaviors, such as tampering with explosive devices.

Inorganic arsenic in cooked rice and vegetables from Bangladeshi households.

Many Bangladeshi suffer from arsenic-related health concerns. Most mitigation activities focus on identifying contaminated wells and reducing the amount of arsenic ingested from well water. Food as a source of arsenic exposure has been recently documented. The objectives of this study were to measure the main types of arsenic in commonly consumed foods in Bangladesh and estimate the average daily intake (ADI) of arsenic from food and water. Total, organic and inorganic, arsenic were measured in drinking water and in cooked rice and vegetables from Bangladeshi households. The mean total arsenic level in 46 rice samples was 358 microg/kg (range: 46 to 1,110 microg/kg dry weight) and 333 microg/kg (range: 19 to 2,334 microg/kg dry weight) in 39 vegetable samples. Inorganic arsenic calculated as arsenite and arsenate made up 87% of the total arsenic measured in rice, and 96% of the total arsenic in vegetables. Total arsenic in water ranged from 200 to 500 microg/L. Using individual, self-reported data on daily consumption of rice and drinking water the total arsenic ADI was 1,176 microg (range: 419 to 2,053 microg), 14% attributable to inorganic arsenic in cooked rice. The ADI is a conservative estimate; vegetable arsenic was not included due to limitations in self-reported daily consumption amounts. Given the arsenic levels measured in food and water and consumption of these items, cooked rice and vegetables are a substantial exposure pathway for inorganic arsenic. Intervention strategies must consider all sources of dietary arsenic intake.