Decision Making Within and Outside Standard Operating Procedures: Paradoxical Use of Operational Discretion in Firefighters.

OBJECTIVE: To understand how firefighters' use of rules (i.e., standard operating procedures [SOPs]) and deliberative decision making (i.e., operational discretion [OD]) interacts with acute stress. BACKGROUND: Current operational guidance for UK firefighters combines the provision of SOPs, for routine incidents, with the use of OD, under prescribed conditions (e.g., when there is a risk to human life). However, our understanding of the use of SOPs and OD is limited. METHODS: Incident commanders (ICs; n = 43) responded to simulated emergency incidents, which either licensed the use of OD or required use of a SOP. Video footage of IC behavior was used to code their response as involving a SOP or OD, while levels of acute stress were assessed using a blood-based measure and self-report. RESULTS: ICs were less likely to use OD selectively in the simulated emergency incident that licensed its use than in the one for which use of an SOP was appropriate; IC command level did not affect this pattern of results; and the incident that licensed OD resulted in more acute stress than the incident that required use of a SOP. CONCLUSION: SOPs and OD were not used in the manner prescribed by current operational guidance in simulated emergency incidents. APPLICATION: These results suggest that firefighter training in SOPs and OD should be augmented alongside personal resilience training, given the impact of stress on health and wellbeing, but also to improve the deployment of SOPs and OD under stress.

Studying the right transporter at the right time: an in vitro strategy for assessing drug-drug interaction risk during drug discovery and development.

INTRODUCTION: Transporters are significant in dictating drug pharmacokinetics, thus inhibition of transporter function can alter drug concentrations resulting in drug-drug interactions (DDIs). Because they can impact drug toxicity, transporter DDIs are a regulatory concern for which prediction of clinical effect from in vitro data is critical to understanding risk. AREA COVERED: The authors propose in vitro strategies to assist mitigating/removing transporter DDI risk during development by frontloading specific studies, or managing patient risk in the clinic. An overview of clinically relevant drug transporters and observed DDIs is provided, alongside presentation of key considerations/recommendations for in vitro study design evaluating drugs as inhibitors or substrates. Guidance on identifying critical co-medications, clinically relevant disposition pathways, and using mechanistic static equations for quantitative prediction of DDI is compiled. EXPERT OPINION: The strategies provided will facilitate project teams to study the right transporter at the right time to minimize development risks associated with DDIs. To truly alleviate or manage clinical risk, the industry will benefit from moving away from current qualitative basic static equation approaches to transporter DDI hazard assessment towards adopting the use of mechanistic models to enable quantitative DDI prediction, thereby contextualizing risk to ascertain whether a transporter DDI is simply pharmacokinetic or clinically significant requiring intervention.

Progesterone Metabolism by Human and Rat Hepatic and Intestinal Tissue.

Following oral administration, the bioavailability of progesterone is low and highly variable. As a result, no clinically relevant, natural progesterone oral formulation is available. After oral delivery, first-pass metabolism initially occurs in the intestines; however, very little information on progesterone metabolism in this organ currently exists. The aim of this study is to investigate the contributions of liver and intestine to progesterone clearance. In the presence of NADPH, a rapid clearance of progesterone was observed in human and rat liver samples (t1/2 2.7 and 2.72 min, respectively). The rate of progesterone depletion in intestine was statistically similar between rat and human (t1/2 197.6 min in rat and 157.2 min in human). However, in the absence of NADPH, progesterone was depleted at a significantly lower rate in rat intestine compared to human. The roles of aldo keto reductases (AKR), xanthine oxidase (XAO) and aldehyde oxidase (AOX) in progesterone metabolism were also investigated. The rate of progesterone depletion was found to be significantly reduced by AKR1C, 1D1 and 1B1 in human liver and by AKR1B1 in human intestine. The inhibition of AOX also caused a significant reduction in progesterone degradation in human liver, whereas no change was observed in the presence of an XAO inhibitor. Understanding the kinetics of intestinal as well as liver metabolism is important for the future development of progesterone oral formulations. This novel information can inform decisions on the development of targeted formulations and help predict dosage regimens.

Multi-energy spectral photon-counting computed tomography (MARS) for detection of arthroplasty implant failure.

To determine whether state-of-the-art multi-energy spectral photon-counting computed tomography (MARS) can detect knee arthroplasty implant failure not detected by standard pre-operative imaging techniques. A total knee arthroplasty (TKA) removed from a patient was reviewed. The extracted prosthesis [NexGen Legacy Posterior Stabilized (LPS) TKA] was analyzed as were pre-operative imaging examination and compared with a MARS-CT examination obtained of the extracted TKA prosthesis. Radiographs, fluoroscopy, ultrasound and MRI preoperatively did not reveal the cause of the implant failure. MARS CT images of the extracted prosthesis clearly showed the presence of posteromedial polyethylene and tibial tray wear which is compatible with the clinical appearance of the extracted TKA. MARS can identify polyethylene insert and metallic tibial tray wear as a cause of TKA failure, that could not be identified with on standard pre-operative imaging. Although clinical MARS CT system is still under development, this case does illustrate its potential clinical usefulness. This is the first study to document how MARS CT imaging can detect orthopedic implant failure not detected by standard current imaging techniques. This system has a potential clinical application in orthopedic patients.

Mechanistic In Vitro Studies Indicate that the Clinical Drug-Drug Interaction between Telithromycin and Simvastatin Acid Is Driven by Time-Dependent Inhibition of CYP3A4 with Minimal Effect on OATP1B1.

A previous attempt to accurately quantify the increased simvastatin acid exposure due to drug-drug interaction (DDI) with coadministered telithromycin, using a mechanistic static model, substantially underpredicted the magnitude of the area under the plasma concentration-time curve ratio (AUCR) based on reversible inhibition of CYP3A4 and organic anion transporting polypeptide 1B1 (OATP1B1). To reconcile this disconnect between predicted and clinically observed AUCR, telithromycin was evaluated as a time-dependent inhibitor of CYP3A4 in vitro, as well as an inhibitor of OATP1B1. Telithromycin inhibited OATP1B1-mediated [3H]-estradiol 17ß-d-glucuronide (0.02 µM) transport with a mean IC50 of 12.0 ± 1.45 µM and was determined by IC50 shift and kinetic analyses to be a competitive reversible inhibitor of CYP3A4-mediated midazolam1- hydroxylation with a mean absolute inhibition constant (Ki) value of 3.65 ± 0.531 µM. The 2.83-fold shift in IC50 (10.4-3.68 µM) after a 30-minute metabolic preincubation confirmed telithromycin as a time-dependent inhibitor of CYP3A4; the mean inhibitor concentration that causes half-maximal inactivation of enzyme (KI) and maximal rate of inactivation of enzyme (kinact) values determined for inactivation were 1.05 ± 0.226 µM and 0.02772 ± 0.00272 min-1, respectively. After the integration of an enzyme time-dependent inhibition component into the previous mechanistic static model using the in vitro inhibitory kinetic parameters determined above, the newly predicted simvastatin acid AUCR (10.8 or 5.4) resulting from perturbation of its critical disposition pathways matched the clinically observed AUCR (10.8 or 4.3) after coadministration, or staggered administration, with telithromycin, respectively. These results indicate the time-dependent inhibition of CYP3A4 by telithromycin as the primary driver underlying its clinical DDI with simvastatin acid.

How older adults and their informal carers prevent falls: An integrative review of the literature.

Falls in older persons are prevalent and costly for the individual and the health system. Falls prevention guidelines have been developed from best evidence to minimise falls in older persons. AIM: To synthesise the literature on falls prevention strategies used by community dwelling older persons and/or their informal carers and to compare the commonly adopted strategies with those recommended by falls prevention guidelines. DATA SOURCES: Health sciences databases for full text articles published in English plus reference list searching of included articles. REVIEW METHOD: An integrative review approach. Studies were included if they identified fall prevention management strategies used by community dwelling older adults and/or their informal carers. Quality appraisal was undertaken using appropriate Joanna Briggs Institute critical appraisal tools. Information relevant to the aim of the review were extracted and coded into categories then inductively sorted into sub-themes and themes. RESULTS: Of the seventeen studies included in the review, eleven identified older adults' falls prevention strategies, two investigated fall prevention strategies used by carers, and four explored perspectives of older persons together with their carers, representing the perspectives of an estimated 501 older persons and 102 carers. Strategies used by older adults arose because of self-awareness about their changing physical ability, and advice and support mainly from family or friends. Carer fall prevention strategy was predominantly around protection of the older adult from falling by discouraging independence. CONCLUSIONS: The fall self-management strategies adopted by older adults and their carers to prevent falls, in the main, do not align with international best practice fall prevention guidelines.

Metabolic Hydrolysis of Aromatic Amides in Selected Rat, Minipig, and Human In Vitro Systems.

The release of aromatic amines from drugs and other xenobiotics resulting from the hydrolysis of metabolically labile amide bonds presents a safety risk through several mechanisms, including geno-, hepato- and nephrotoxicity. Whilst multiple in vitro systems used for studying metabolic stability display serine hydrolase activity, responsible for the hydrolysis of amide bonds, they vary in their efficiency and selectivity. Using a range of amide-containing probe compounds (0.5-10 µM), we have investigated the hydrolytic activity of several rat, minipig and human-derived in vitro systems - including Supersomes, microsomes, S9 fractions and hepatocytes - with respect to their previously observed human in vivo metabolism. In our hands, human carboxylesterase Supersomes and rat S9 fractions systems showed relatively poor prediction of human in vivo metabolism. Rat S9 fractions, which are commonly utilised in the Ames test to assess mutagenicity, may be limited in the detection of genotoxic metabolites from aromatic amides due to their poor concordance with human in vivo amide hydrolysis. In this study, human liver microsomes and minipig subcellular fractions provided more representative models of human in vivo hydrolytic metabolism of the aromatic amide compounds tested.

Beam profile assessment in spectral CT scanners.

In this paper, we present a method that uses a combination of experimental and modeled data to assess properties of x-ray beam measured using a small-animal spectral scanner. The spatial properties of the beam profile are characterized by beam profile shape, the angular offset along the rotational axis, and the photon count difference between experimental and modeled data at the central beam axis. Temporal stability of the beam profile is assessed by measuring intra- and interscan count variations. The beam profile assessment method was evaluated on several spectral CT scanners equipped with Medipix3RX-based detectors. On a well-calibrated spectral CT scanner, we measured an integral count error of 0.5%, intrascan count variation of 0.1%, and an interscan count variation of less than 1%. The angular offset of the beam center ranged from 0.8° to 1.6° for the studied spectral CT scanners. We also demonstrate the capability of this method to identify poor performance of the system through analyzing the deviation of the experimental beam profile from the model. This technique can, therefore, aid in monitoring the system performance to obtain a robust spectral CT; providing the reliable quantitative images. Furthermore, the accurate offset parameters of a spectral scanner provided by this method allow us to incorporate a more realistic form of the photon distribution in the polychromatic-based image reconstruction models. Both improvements of the reliability of the system and accuracy of the volume reconstruction result in a better discrimination and quantification of the imaged materials.

Evaluation of a photon counting Medipix3RX cadmium zinc telluride spectral x-ray detector.

We assess the performance of a cadmium zinc telluride (CZT)-based Medipix3RX energy-resolving and photon-counting x-ray detector as a candidate for spectral microcomputed tomography (micro-CT) imaging. It features an array of 128 × 128 , 110 - µ m 2 pixels, each with four simultaneous threshold counters that utilize real-time charge summing. Each pixel's response is assessed by imaging with a range of incident x-ray intensities and detector integration times. Energy-related assessments are made by exposing the detector to the emission from an I-125 radioisotope brachytherapy seed. Long-term stability is assessed by repeating identical exposures over the course of 1 h. The high yield of properly functioning pixels (98.8%), long-term stability (linear regression of whole-chip response over 1 h of acquisitions: y = - 0.0038 x + 2284 ; standard deviation: 3.7 counts), and energy resolution [2.5 keV full-width half-maximum (FWHM) (single pixel), 3.7 keV FWHM (across the full image)] make this device suitable for spectral micro-CT.

A Hybrid 2D/3D User Interface for Radiological Diagnosis.

This paper presents a novel 2D/3D desktop virtual reality hybrid user interface for radiology that focuses on improving 3D manipulation required in some diagnostic tasks. An evaluation of our system revealed that our hybrid interface is more efficient for novice users and more accurate for both novice and experienced users when compared to traditional 2D only interfaces. This is a significant finding because it indicates, as the techniques mature, that hybrid interfaces can provide significant benefit to image evaluation. Our hybrid system combines a zSpace stereoscopic display with 2D displays, and mouse and keyboard input. It allows the use of 2D and 3D components interchangeably, or simultaneously. The system was evaluated against a 2D only interface with a user study that involved performing a scoliosis diagnosis task. There were two user groups: medical students and radiology residents. We found improvements in completion time for medical students, and in accuracy for both groups. In particular, the accuracy of medical students improved to match that of the residents.

Mechanistic in vitro studies confirm that inhibition of the renal apical efflux transporter multidrug and toxin extrusion (MATE) 1, and not altered absorption, underlies the increased metformin exposure observed in clinical interactions with cimetidine, trimethoprim or pyrimethamine.

Metformin is a common co-medication for many diseases and the victim of clinical drug-drug interactions (DDIs) perpetrated by cimetidine, trimethoprim and pyrimethamine, resulting in decreased active renal clearance due to inhibition of organic cation transport proteins and increased plasma exposure of metformin. To understand whether area under the plasma concentration-time curve (AUC) increases relate to absorption, in vitro inhibitory potencies of these drugs against metformin transport by human organic cation transporter (OCT) 1, and the apical to basolateral absorptive permeability of metformin across Caco-2 cells in the presence of therapeutic intestinal concentrations of cimetidine, trimethoprim or pyrimethamine, were determined. Whilst all inhibited OCT1, none enhanced metformin's absorptive permeability (~0.5 × 10-6  cm/sec) suggesting that DDI AUC changes are not related to absorption. Subsequently, to understand whether inhibition of renal transporters are responsible for AUC increases, in vitro inhibitory potencies against metformin transport by human OCT2, multidrug and toxin extrusion (MATE) 1 and MATE2-K were determined. Ensuing IC50 values were incorporated into mechanistic static equations, alongside unbound maximal plasma concentration and transporter fraction excreted values, in order to calculate theoretical increases in metformin AUC due to inhibition by cimetidine, trimethoprim or pyrimethamine. Calculated theoretical fold-increases in metformin exposure confirmed solitary inhibition of renal MATE1 to be the likely mechanism underlying the observed exposure changes in clinical DDIs. Interestingly, clinically observed increases in metformin AUC were predicted more closely when the renal transporter fraction excreted value derived from oral metformin administration, rather than intravenous, was utilized in theoretical calculations, likely reflecting the "flip-flop" pharmacokinetic profile of the drug.

Evaluation of a photon counting Medipix3RX CZT spectral x-ray detector.

We assessed the performance of a cadmium zinc telluride (CZT)-based Medipix3RX x-ray detector as a candidate for micro-computed tomography (micro-CT) imaging. This technology was developed at CERN for the Large Hadron Collider. It features an array of 128 by 128, 110 micrometer square pixels, each with eight simultaneous threshold counters, five of which utilize real-time charge summing, significantly reducing the charge sharing between contiguous pixels. Pixel response curves were created by imaging a range of x-ray intensities by varying x-ray tube current and by varying the exposure time with fixed x-ray current. Photon energy-related assessments were made by flooding the detector with the tin foil filtered emission of an I-125 radioisotope brachytherapy seed and sweeping the energy threshold of each of the four charge-summed counters of each pixel in 1 keV steps. Long term stability assessments were made by repeating exposures over the course of one hour. The high properly-functioning pixel yield (99%), long term stability (linear regression of whole-chip response over one hour of acquisitions: y = -0.0038x + 2284; standard deviation: 3.7 counts) and energy resolution (2.5 keV FWHM (single pixel), 3.7 keV FWHM across the full image) make this device suitable for spectral micro-CT. The charge summing performance effectively reduced the measurement corruption caused by charge sharing which, when unaccounted for, shifts the photon energy assignment to lower energies, degrading both count and energy accuracy. Effective charge summing greatly improves the potential for calibrated, energy-specific material decomposition and K edge difference imaging approaches.

An Investigation of Operational Decision Making in Situ: Incident Command in the U.K. Fire and Rescue Service.

OBJECTIVE: The aim of this study was to better understand the nature of decision making at operational incidents in order to inform operational guidance and training. BACKGROUND: Normative models of decision making have been adopted in the guidance and training for emergency services. In these models, it is assumed that decision makers assess the current situation, formulate plans, and then execute the plans. However, our understanding of how decision making unfolds at operational incidents remains limited. METHOD: Incident commanders, attending 33 incidents across six U.K. Fire and Rescue Services, were fitted with helmet-mounted cameras, and the resulting video footage was later independently coded and used to prompt participants to provide a running commentary concerning their decisions. RESULTS: The analysis revealed that assessment of the operational situation was most often followed by plan execution rather than plan formulation, and there was little evidence of prospection about the potential consequences of actions. This pattern of results was consistent across different types of incident, characterized by level of risk and time pressure, but was affected by the operational experience of the participants. CONCLUSION: Decision making did not follow the sequence of phases assumed by normative models and conveyed in current operational guidance but instead was influenced by both reflective and reflexive processes. APPLICATION: These results have clear implications for understanding operational decision making as it occurs in situ and suggest a need for future guidance and training to acknowledge the role of reflexive processes.

Energy calibration of the pixels of spectral X-ray detectors.

The energy information acquired using spectral X-ray detectors allows noninvasive identification and characterization of chemical components of a material. To achieve this, it is important that the energy response of the detector is calibrated. The established techniques for energy calibration are not practical for routine use in pre-clinical or clinical research environment. This is due to the requirements of using monochromatic radiation sources such as synchrotron, radio-isotopes, and prohibitively long time needed to set up the equipment and make measurements. To address these limitations, we have developed an automated technique for calibrating the energy response of the pixels in a spectral X-ray detector that runs with minimal user intervention. This technique uses the X-ray tube voltage (kVp) as a reference energy, which is stepped through an energy range of interest. This technique locates the energy threshold where a pixel transitions from not-counting (off) to counting (on). Similarly, we have developed a technique for calibrating the energy response of individual pixels using X-ray fluorescence generated by metallic targets directly irradiated with polychromatic X-rays, and additionally γ-rays from (241)Am. This technique was used to measure the energy response of individual pixels in CdTe-Medipix3RX by characterizing noise performance, threshold dispersion, gain variation and spectral resolution. The comparison of these two techniques shows the energy difference of 1 keV at 59.5 keV which is less than the spectral resolution of the detector (full-width at half-maximum of 8 keV at 59.5 keV). Both techniques can be used as quality control tools in a pre-clinical multi-energy CT scanner using spectral X-ray detectors.

Study of scan protocol for exposure reduction in hybrid spectral micro-CT.

The hybrid spectral micro-computed tomography (CT) architecture integrates a conventional imaging chain and an interior spectral imaging chain, and has been proven to be an important development in spectral CT. The motivation for this study is to minimize X-ray exposure for hybrid spectral micro-CT using both simulated and experimental scan data while maintaining the spectral fidelity of the reconstruction. Three elements of the hybrid scan protocol are investigated: truncation of the interior spectral chain and the numbers of projections for each of the global and interior imaging chains. The effect of these elements is quantified by analyzing how each affects the reconstructed spectral accuracy. The results demonstrate that there is significant scope for reduction of radiation exposure in the hybrid scan protocol. It appears decreasing the number of conventional projections offers the most potential for exposure reduction, while further reduction is possible by decreasing the interior FOV and number of spectral projections.

Toward quantifying the composition of soft tissues by spectral CT with Medipix3.

PURPOSE: To determine the potential of spectral computed tomography (CT) with Medipix3 for quantifying fat, calcium, and iron in soft tissues within small animal models and surgical specimens of diseases such as fatty liver (metabolic syndrome) and unstable atherosclerosis. METHODS: The spectroscopic method was applied to tomographic data acquired using a micro-CT system incorporating a Medipix3 detector array with silicon sensor layer and microfocus x-ray tube operating at 50 kVp. A 10 mm diameter perspex phantom containing a fat surrogate (sunflower oil) and aqueous solutions of ferric nitrate, calcium chloride, and iodine was imaged with multiple energy bins. The authors used the spectroscopic characteristics of the CT number to establish a basis for the decomposition of soft tissue components. The potential of the method of constrained least squares for quantifying different sets of materials was evaluated in terms of information entropy and degrees of freedom, with and without the use of a volume conservation constraint. The measurement performance was evaluated quantitatively using atheroma and mouse equivalent phantoms. Finally the decomposition method was assessed qualitatively using a euthanized mouse and an excised human atherosclerotic plaque. RESULTS: Spectral CT measurements of a phantom containing tissue surrogates confirmed the ability to distinguish these materials by the spectroscopic characteristics of their CT number. The assessment of performance potential in terms of information entropy and degrees of freedom indicated that certain sets of up to three materials could be decomposed by the method of constrained least squares. However, there was insufficient information within the data set to distinguish calcium from iron within soft tissues. The quantification of calcium concentration and fat mass fraction within atheroma and mouse equivalent phantoms by spectral CT correlated well with the nominal values (R(2) = 0.990 and R(2) = 0.985, respectively). In the euthanized mouse and excised human atherosclerotic plaque, regions of calcium and fat were appropriately decomposed according to their spectroscopic characteristics. CONCLUSIONS: Spectral CT, using the Medipix3 detector and silicon sensor layer, can quantify certain sets of up to three materials using the proposed method of constrained least squares. The system has some ability to independently distinguish calcium, fat, and water, and these have been quantified within phantom equivalents of fatty liver and atheroma. In this configuration, spectral CT cannot distinguish iron from calcium within soft tissues.

Spectral Hounsfield units: a new radiological concept.

OBJECTIVE: Computed tomography (CT) uses radiographical density to depict different materials; although different elements have different absorption fingerprints across the range of diagnostic X-ray energies, this spectral absorption information is lost in conventional CT. The recent development of dual energy CT (DECT) allows extraction of this information to a useful but limited extent. However, the advent of new photon counting chips that have energy resolution capabilities has put multi-energy or spectral CT (SCT) on the clinical horizon. METHODS: This paper uses a prototype SCT system to demonstrate how CT density measurements vary with kilovoltage. RESULTS: While radiologists learn about linear attenuation curves during radiology training, they do not usually need a detailed understanding of this phenomenon in their clinical practice. However SCT requires a paradigm shift in how radiologists think about CT density. CONCLUSION: Because radiologists are already familiar with the Hounsfield Unit (HU), it is proposed that a modified HU be used that includes the mean energy used to obtain the image, as a conceptual bridge between conventional CT and SCT. A suggested format would be: HU(keV). KEY POINTS: • Spectral computed tomography uses K-edge and slope effects to identify element signatures. • New visualisation tools will be required to efficiently display spectral CT information. • This paper demonstrates HU variation with keV using the Medipix3 chip. • HU ( keV ) is a suggested format when stating spectral HU measurements.

Previous PICC placement may be associated with catheter-related infections in hemodialysis patients.

BACKGROUND: Catheter-related infections (CRIs) are a significant source of morbidity and mortality in hemodialysis patients. The identification of novel, modifiable risk factors for CRIs may lead to improved outcomes in this population. Peripherally inserted central catheters (PICCs) have been hypothesized to compromise vascular access due to vascular damage and venous thrombosis, whereas venous thrombosis has been linked to the development of CRIs. Here we examine the association between PICC placement and CRIs. METHODS: A retrospective review was performed of all chronic hemodialysis catheter placements and exchanges performed at a large university hospital from September 2003 to September 2008. History of PICC line use was determined by examining hospital radiologic records from December 1993 to September 2008. Catheter-related complications were assessed and correlated with PICC line history. RESULTS: One hundred eighty-five patients with 713 chronic tunneled hemodialysis catheter placements were identified. Thirty-eight of those patients (20.5%) had a history of PICC placement; these patients were more likely to have CRIs (odds ratio = 2.46, 95% confidence interval = 1.71-3.53, p < .001) compared with patients without a history of PICC placement. There was no difference between the two groups in age or number of catheters placed. CONCLUSION: Previous PICC placement may be associated with catheter-related infections in hemodialysis patients.

Gadolinium concentration analysis in brain phantom by X-ray fluorescence.

We have measured the X-ray fluorescence from gadolinium as a function of concentration and position in tumors of different sizes and shapes in a head phantom. The gadolinium fluorescence was excited with a 36 GBq Am-241 source. The fluorescence signal was detected with a CdTe detector and a multi-channel analyzer. The fluorescence peak was clearly separated from the scattered X-rays. Concentrations of 5.62-78.63 mg/ml of Gd ion were used in 1, 2, and 3 cm diameter spherical tumors and a 2x4 cm oblate spheroid tumor. The data show trends approaching saturation for the highest concentrations, probably due to reabsorption in the tumor. A comparison of X-ray photographic imaging and densitometer measurements to determine concentration is also presented.

Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia.

Schizophrenia is a devastating neurodevelopmental disorder whose genetic influences remain elusive. We hypothesize that individually rare structural variants contribute to the illness. Microdeletions and microduplications >100 kilobases were identified by microarray comparative genomic hybridization of genomic DNA from 150 individuals with schizophrenia and 268 ancestry-matched controls. All variants were validated by high-resolution platforms. Novel deletions and duplications of genes were present in 5% of controls versus 15% of cases and 20% of young-onset cases, both highly significant differences. The association was independently replicated in patients with childhood-onset schizophrenia as compared with their parents. Mutations in cases disrupted genes disproportionately from signaling networks controlling neurodevelopment, including neuregulin and glutamate pathways. These results suggest that multiple, individually rare mutations altering genes in neurodevelopmental pathways contribute to schizophrenia.