Patient-specific Instrumentation Versus Standard Surgical Instruments in Primary Reverse Total Shoulder Arthroplasty: A Retrospective Comparative Clinical Study.

Aims: Patient-specific instrumentation (PSI) in primary shoulder arthroplasty has been studied; results supported the positive impact of the PSI on the glenoid positioning. Nevertheless, no clinical outcomes have been reported. We compare the clinical outcomes of primary reverse total shoulder arthroplasty using PSI versus the standard methods. Methods: Fifty-three patients with full records and a minimum of 24-months follow-up were reviewed, 35 patients received primary standard RSTA, and 18 patients received primary PSI RSTA. All patients were operated on in a single center. The median follow-up was 46 months (53 months in the standard group vs 39 months in the PSI group). Results: There was an overall significant post-operative improvement in the whole cohort (P< 0.05). The standard group had more deformed glenoids (B2, B3, C&D) and significantly low preoperative constant score and forward flexion (P=0.02 & 0.034). Compared to the PSI group (all were A1, A2, B1 &one type D), there were no statistically significant differences in any clinical outcome postoperatively. PSI neither prolonged the waiting time to surgery (P=0.693) nor the intraoperative time (P=0.962). Radiologically, PSI secured a higher percentage of optimum baseplate position and screw anchorage; however, no statistical correlation was found. Conclusion: In this series, both groups achieved comparable good outcomes. PSI did not achieve significantly better clinical outcomes than Standard after primary RSTA. Yet comparison has some limitations. PSI did not negatively impact the waiting time or the surgical time.

Histopathological dataset and demographic details of synovial tissues from patients with end-stage osteoarthritis, soft tissue and traumatic injuries of the knee.

Degradation of articular cartilage is the defining feature of end-stage osteoarthritis (OA) with osteophytes, subchondral sclerosis, malalignment and joint space narrowing being additional indicators of advanced disease. Obesity, older age and female gender are OA risk factors. Differing degrees of synovitis are observed in OA, soft tissue and traumatic injuries of the knee. The synovium is also subject to systemic, enhanced lipids and inflammatory mediators characteristic of obesity. Synovial cellular composition changes specific to OA and associated with its handling of cartilage debris are unclear. Triangulation of data from three knee pathologies was used to highlight findings pertaining to OA compared to non-OA. OA patient data was compared to non-OA from knee ligament and tibial frature patients at surgery. Knee pathology, gender and BMI informed patient identification. Once consented, patient inclusion and characterisation utilised data from clinical assessments, blood tests, function scores, and radiological imaging, scores and intraoperative assessment. Intra-operative synovial tissues from the same site and processed identically underpins in-depth analyses and comparisons of histopathological images from these different knee pathologies. This supports the identification of distinct changes in the cellular composition of the knee synovium characteristic of OA. This data underpins a better understanding of OA pathogenesis and disease progression vital for the design of targeted therapeutics. The tissue and cell data include detailed results from the semi-quantitative synovitis score established by Krenn and observational data for morphological features such as cartilage debris inclusion, inflammatory cells aggregate and infiltration. This histopathological data is presented in the context of detailed clinical and functional information. This data and the holistic study design can be used as a foundation for the multifactorial collection and analysis of clinical data from OA patients, OA severity measures, tissue immuno-histology and synovial inflammation analysis to underpin the details and comparisons needed in further studies into OA and its treatment globally.

Open sternoclavicular osteophyte debridement in the surgical management of sternoclavicular osteoarthritis: clinical outcome of a new procedure.

Introduction: Symptomatic sternoclavicular osteoarthritis is uncommon but remains the most frequent non-traumatic condition affecting the sternoclavicular joint and tends to have a predilection for middle-aged women. It responds well to conservative management. Surgery is indicated when conservative management fails. We present the clinical outcome of open symptomatic sternoclavicular osteophyte debridement, a new operation for treating recalcitrant symptomatic sternoclavicular osteoarthritis. Methods: Five patients (five symptomatic sternoclavicular joints) with symptomatic sternoclavicular osteoarthritis underwent open sternoclavicular debridement following failure of conservative treatment. There were three females and two males. Mean age was 46.6 years (range 37.17-66). Four cases were primary osteoarthritis and one case was secondary to trauma. They were reviewed at mean follow-up at 35.4 months with minimum follow-up of 29 months. Assessment included Quick Disabilities of Arm Shoulder and Hand (DASH) and subjective patient satisfaction score. Results: There was no post-operative complication. Mean Quick DASH score 10.9 (range 0-29.5) at mean 35.4-month follow-up (range 29-43 months). Three patients reported excellent and two reported good outcome as per subjective satisfaction score. Conclusions: Open sternoclavicular debridement has proved to be a simple, safe and highly effective new surgical treatment for patients with symptomatic sternoclavicular osteoarthritis unresponsive to non-operative management.

Medication Optimization Using Pharmacogenomic Testing in a Complex Mental Health Population Prescribed Psychiatric Polypharmacy.

The use of polypharmacy has become significantly more common over the past two decades, increasing the risk of drug-drug interactions and adverse drug reactions. Pharmacogenomic (PGx) assays have the purported benefit of being able to predict an individual's response to a specific medication based on genetic markers, which may facilitate the development of optimized medication regimens for patients prescribed polypharmacy. This 12-week pilot study examined the impact of the PGx results on the clinical management of Veterans who were prescribed psychiatric polypharmacy. Psychiatric medication providers were given access to the PGx assay results, including notification of drug-drug-gene interactions computed from an algorithm decision tool, to assist with medication management decisions. Veteran outpatients (N = 53) prescribed polypharmacy (mean = 13.15 medications) were enrolled into the study. In 92.4% of cases, providers changed medications at baseline, with 83% of providers indicating that they changed their original medication plan based on the PGx results. Clinical improvement over the 12-week treatment phase was seen in depression (F(1.63, 45) = 5.45, P = .01, η2  = .11) and mental health quality of life (F(2.00, 45) = 4.16, P < .05, η2  = .16). Adverse drug effects were unchanged or improved over time. Rates of polypharmacy remained unchanged. The results suggest that medication changes based on the PGx assay may be beneficial in a complex patient population prescribed polypharmacy.

Detection of Isopeptide Bonds in Monoclonal Antibody Aggregates.

PURPOSE: A major difficulty in monoclonal antibody (mAb) therapeutic development is product aggregation. In this study, intermolecular isopeptide bonds in mAb aggregates were characterized for the first time. We aim to propose a mechanism of covalent aggregation in a model antibody using stressed studies at raised temperatures to aid in the understanding of mAb aggregation pathways. METHODS: Aggregate fractions were generated using raised temperature and were purified using size-exclusion chromatography (SEC). The fractions were tryptically digested and characterized using liquid chromatography hyphenated to tandem mass-spectrometry (LC-MS/MS). RESULTS: An increased amount of clipping between aspartic acid and proline in a solvent accessible loop in the constant heavy 2 (CH2) domain of the mAb was observed under these conditions. Detailed peptide mapping revealed 14 isopeptide bonds between aspartic acid at that cleavage site and lysine residues on adjacent antibodies. Two additional isopeptide bonds were identified between the mAb HC N-terminal glutamic acid or a separate aspartic acid to lysine residues on adjacent antibodies. CONCLUSIONS: Inter-protein isopeptide bonds between the side chains of acidic amino acids (aspartate and glutamate) and lysine were characterized for the first time in mAb aggregates. A chemical mechanism was presented whereby spontaneous isopeptide bond formation could be facilitated via either the aspartic acid side chain or C-terminus.

Mapping language networks and their association with verbal abilities in paediatric epilepsy using MEG and graph analysis.

Recent theoretical models of language have emphasised the importance of integration within distributed networks during language processing. This is particularly relevant to young patients with epilepsy, as the topology of the functional network and its dynamics may be altered by the disease, resulting in reorganisation of functional language networks. Thus, understanding connectivity within the language network in patients with epilepsy could provide valuable insights into healthy and pathological brain function, particularly when combined with clinical correlates. The objective of this study was to investigate interactions within the language network in a paediatric population of epilepsy patients using measures of MEG phase synchronisation and graph-theoretical analysis, and to examine their association with language abilities. Task dependent increases in connectivity were observed in fronto-temporal networks during verb generation across a group of 22 paediatric patients (9 males and 13 females; mean age 14 years). Differences in network connectivity were observed between patients with typical and atypical language representation and between patients with good and poor language abilities. In addition, node centrality in left frontal and temporal regions was significantly associated with language abilities, where patients with good language abilities had significantly higher node centrality within inferior frontal and superior temporal regions of the left hemisphere, compared to patients with poor language abilities. Our study is one of the first to apply task-based measures of MEG network synchronisation in paediatric epilepsy, and we propose that these measures of functional connectivity and node centrality could be used as tools to identify critical regions of the language network prior to epilepsy surgery.

Establishing a Developmentally Appropriate fMRI Paradigm Relevant to Presurgical Mapping of Memory in Children.

Functional magnetic resonance imaging (fMRI) is an established eloquent cortex mapping technique that is now an integral part of the pre-operative work-up in candidates for epilepsy surgery. Emerging evidence in adults with epilepsy suggests that material-specific fMRI paradigms can predict postoperative memory outcomes, however these paradigms are not suitable for children. In pediatric age, the use of memory fMRI paradigms designed for adults is complicated by the effect of developmental stages in cognitive maturation, the impairment experienced by some people with temporal lobe epilepsy (TLE) and the normal representation of memory function during development, which may differ from adults. We present a memory fMRI paradigm designed to activate mesial temporal lobe structures that is brief, independent of reading ability, and therefore a novel candidate for use in children. Data from 33 adults and 19 children (all healthy controls) show that the paradigm captures the expected leftward asymmetry of mesial temporal activation in adults. A more symmetrical pattern was observed in children, consistent with the progressive emergence of hemispheric specialisation across childhood. These data have important implications for the interpretation of presurgical memory fMRI in the pediatric setting. They also highlight the need to carefully consider the impact of cognitive development on fMRI tools used in clinical practice.

MEG Assessment of Expressive Language in Children Evaluated for Epilepsy Surgery.

Establishing language dominance is an important step in the presurgical evaluation of patients with refractory epilepsy. In the absence of a universally accepted gold-standard non-invasive method to determine language dominance in the preoperative assessment, a range of tools and methodologies have recently received attention. When applied to pediatric age, many of the proposed methods, such as functional magnetic resonance imaging (fMRI), may present some challenges due to the time-varying effects of epileptogenic lesions and of on-going seizures on maturational phenomena. Magnetoencephalography (MEG) has the advantage of being insensitive to the distortive effects of anatomical lesions on brain microvasculature and to differences in the metabolism or vascularization of the developing brain and also provides a less intimidating recording environment for younger children. In this study we investigated the reliability of lateralized synchronous cortical activation during a verb generation task in a group of 28 children (10 males and 18 females, mean age 12 years) with refractory epilepsy who were evaluated for epilepsy surgery. The verb generation task was associated with significant decreases in beta oscillatory power (13-30 Hz) in frontal and temporal lobes. The MEG data were compared with other available presurgical non-invasive data including cortical stimulation, neuropsychological and fMRI data on language lateralization where available. We found that the lateralization of MEG beta power reduction was concordant with language dominance determined by one or more different assessment methods (i.e. cortical stimulation mapping, neuropsychological, fMRI or post-operative data) in 89% of patients. Our data suggest that qualitative hemispheric differences in task-related changes of spectral power could offer a promising insight into the contribution of dominant and non-dominant hemispheres in language processing and may help to characterize the specialization and lateralization of language processes in children.

Results of cementless total elbow arthroplasty using the Discovery elbow system at a mean follow-up of 61.8 months.

BACKGROUND: The available literature on the use of a cementless total elbow arthroplasty (TEA) design and its results are limited. This clinical study reports the outcome of the cementless Discovery elbow system. METHODS: Patients were operated on by a single surgeon between 2007 and 2014. Nineteen patients (20 elbows) were available for review, 2 women (1 bilateral TEA) and 17 men. The age of the patients ranged from 27 to 75 years (mean, 48 years). The mean follow-up was 61.8 months (range, 12-156 months). Patients were assessed for range of motion, pain, and satisfaction level. Outcome scores included the Mayo Elbow Performance Score, the Liverpool Elbow Score, and the 12-Item Short Form Health Survey (version 1). Radiographs were reviewed to evaluate for loosening. RESULTS: The mean Mayo Elbow Performance Score was 77.25, and the mean Liverpool Elbow Score was 6.76. The mean flexion range was 123°, and the mean extension lag was 35°. The mean pronation was 59°, and the mean supination was 58°. On radiologic evaluation, there were no signs of loosening; however, in 2 cases, nonprogressive radiolucent lines were observed. No signs of infection were detected at final follow-up, and no elbows were revised. More than 90% of patients were satisfied with the overall outcome. CONCLUSION: The cementless TEA seems to be a reliable option for treatment of varying elbow diseases. Long-term results are needed to assess the survivorship of this design.

Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance.

Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual.

Prospective assessment of autism traits in children exposed to antiepileptic drugs during pregnancy.

PURPOSE: The association between autism spectrum disorders (ASDs) and prenatal anticonvulsant exposure is increasingly investigated, but comprehensive, blinded assessment using a validated instrument for autism within a well-characterized prospective cohort has not been conducted. Thus, existing studies may represent an underestimate of the true risk. Herein we present a prospective cohort study in children exposed to anticonvulsants during pregnancy, with all assessments conducted by examiners who were blinded to drug-exposure status. METHODS: Participants were 105 Australian children aged 6-8 years who were recruited via the Australian Pregnancy Register for Women on Antiepileptic Medication. Maternal epilepsy, pregnancy, and medical history data were obtained prospectively. Autism traits were assessed using the Childhood Autism Rating Scale (CARS). RESULTS: Eleven children (10.5%) had elevated CARS scores. Two were exposed to valproate monotherapy (2/26; 7.7%), two to carbamazepine monotherapy (2/34; 5.9%), and seven to valproate in polytherapy (7/15; 46.7%). Linear regression analysis showed that the mean valproate dose during pregnancy was a significant predictor of CARS scores after controlling for polytherapy, mean carbamazepine dose, folic acid use, seizures during pregnancy, tobacco and marijuana use, maternal intelligence quotient (IQ), and socioeconomic status. First trimester folic acid supplementation and marijuana use were also significant predictors of CARS scores. SIGNIFICANCE: Using direct assessment of children in our prospective study, we found an elevated rate of autism traits across the sample. The most important determinant of association with autistic traits was higher doses of sodium valproate exposure. The use of valproate in women who may become pregnant is now generally avoided; however, there are insufficient data regarding the risk of ASD with low-dose valproate. If this risk is no greater than with other antiepileptic drugs (AED)s, it may enable women with genetic generalized epilepsy to retain optimal seizure control as well as minimize harm to their unborn child.

Total elbow arthroplasty: a prospective clinical outcome study of Discovery Elbow System with a 4-year mean follow-up.

BACKGROUND: Total elbow arthroplasty (TEA) is increasingly used for the treatment of advanced elbow conditions to reduce pain and improve function. However, TEA is still associated with a higher complication rate than total hip and knee arthroplasty despite advances in the design and surgical techniques. This prospective clinical study reports the outcome of the Discovery Elbow System (Biomet, Warsaw IN, USA), which has been in clinical use in the United Kingdom since 2003. METHODS: The study included a total of 100 Discovery Elbows (April 2003 to January 2010) with a minimum 2-year follow-up, including 75 primary and 25 revisions (60% women and 40% men; mean age, 62 years). Outcome was assessed by means of the Liverpool Elbow Score, pain experience, patient satisfaction, range of motion, and radiographic imaging. RESULTS: The mean follow-up period was 48.5 months (range, 24-108 months). The Liverpool Elbow Score improved from 3.79 to 6.36 (P < .001). The percentage of pain-free patients was substantially increased from 7% preoperatively to 64% at the final follow-up. The patient satisfaction rate was over 90%. The flexion-extension arc and pronation-supination arc increased from 72° to 93° and from 86° to 111°, respectively (P < .001). Major postoperative complications included deep infection (2%), progressive aseptic loosening requiring revision (primary, 5%; revision 12%), persistent ulnar neuropathy (3%), and periprosthetic fracture (primary, 6.8%; revision, 8%). CONCLUSION: The Discovery Elbow System resulted in improved function, reduced pain, and high patient satisfaction. Long-term results are required to assess the survivorship of this system.

An integrated approach for prospectively investigating a mode-of-action for rodent liver effects.

Registration of new plant protection products (e.g., herbicide, insecticide, or fungicide) requires comprehensive mammalian toxicity evaluation including carcinogenicity studies in two species. The outcome of the carcinogenicity testing has a significant bearing on the overall human health risk assessment of the substance and, consequently, approved uses for different crops across geographies. In order to understand the relevance of a specific tumor finding to human health, a systematic, transparent, and hypothesis-driven mode of action (MoA) investigation is, appropriately, an expectation by the regulatory agencies. Here, we describe a novel approach of prospectively generating the MoA data by implementing additional end points to the standard guideline toxicity studies with sulfoxaflor, a molecule in development. This proactive MoA approach results in a more robust integration of molecular with apical end points while minimizing animal use. Sulfoxaflor, a molecule targeting sap-feeding insects, induced liver effects (increased liver weight due to hepatocellular hypertrophy) in an initial palatability probe study for selecting doses for subsequent repeat-dose dietary studies. This finding triggered the inclusion of dose-response investigations of the potential key events for rodent liver carcinogenesis, concurrent with the hazard assessment studies. As predicted, sulfoxaflor induced liver tumors in rats and mice in the bioassays. The MoA data available by the time of the carcinogenicity finding supported the conclusion that the carcinogenic potential of sulfoxaflor was due to CAR/PXR nuclear receptor activation with subsequent hepatocellular proliferation. This MoA was not considered to be relevant to humans as sulfoxaflor is unlikely to induce hepatocellular proliferation in humans and therefore would not be a human liver carcinogen.

Measurement of deoxyinosine adduct: Can it be a reliable tool to assess oxidative or nitrosative DNA damage?

Adenosine deaminases (ADA) are key enzymes that deaminate adenosine (A) or deoxyadenosine (dA) and produce inosine or deoxyinosine (dI), respectively. While ADA only deaminates free dA, reactive nitrogen species (RNS) or reactive oxygen species (ROS) deaminate adenine base on the DNA and leave dI, which is a pre-mutagenic lesion. Therefore, dI adduct in the genomic DNA has been considered a biomarker of DNA damage caused by RNS or by ROS. In the presented study, genomic DNA was isolated from frozen calf thymus in low or room temperature, with or without an addition of antioxidant. The number of dI in the DNA was measured using liquid chromatography-tandem mass spectrometry. While low temperature (LT) work-up with an addition of antioxidant in reagents helped to prevent artifactual formation of oxidative DNA lesions in the calf thymus DNA (CTD), it also significantly inhibited activities of proteinase, which in turn resulted in significant ADA contamination in the final DNA samples. ADA remained in LT-CTD completely deaminated most dA when the DNA was subjected to enzymatic hydrolysis to single nucleosides. The ADA contamination in the DNA was significantly reduced when DNA was isolated from pre-isolated nuclear fraction rather than from entire tissue homogenates. However, enzymes used for DNA hydrolysis were confirmed to contain significant amounts of ADA. Therefore, these enzymes would increase deamination of dA during DNA hydrolysis. Artifactual dI production by contaminated ADA was dramatically reduced by an addition of EHNA (erythro-9-(2-hydroxy-3-nonyl)adenine), which is a potent inhibitor of ADA. However, time- and temperature-dependent dI production from dA in phosphate buffer solution was observed. More importantly, TEMPO, an antioxidant commonly used to prevent DNA oxidation, was found to deaminate dA independent to ADA. Overall, these findings indicate that assay methods measuring dI or other dA DNA adducts in genomic DNA should be carefully validated to minimize artificial errors caused by dA deamination. Recommendations to overcome those technical challenges were discussed in this presentation.

Genetic damage, but limited evidence of oxidative stress markers in diethyl maleate-induced glutathione depleted mouse lymphoma L5178Y (TK(+/-)) cell cultures.

Depletion of glutathione (GSH) in cells exposed to certain xenobiotics has been proposed to result in oxidative stress, which could lead to damage of cellular macromolecules such as proteins, lipids, and DNA. Diethyl maleate (DEM) is known to conjugate with GSH and rapidly lower cellular GSH levels. The objective of this study was to investigate the influence of DEM-induced GSH depletion on various genotoxicity and gene expression end points in mouse lymphoma L5178Y (TK(+/-)) cell cultures. Cells were exposed to DEM for 4 h at concentrations of 0, 6.7, 13.5, 26.9, 53.8, 107.6, 215.3, and 430.6 µg/mL (0.039-2.5 mM). Genotoxicity was evaluated by examining the induction of in vitro micronuclei (20 h post-treatment) and DNA strand breaks as measured by comet (immediately following treatment), and correlating these observations to cellular GSH levels. In the current study, GSH was decreased more than 50% at the lowest test concentration (6.7 µg/mL) and more than 95% at ≥ 107.6 µg/mL. A significant increase in micronuclei and DNA strand breaks was observed at concentrations of ≥ 26.9 µg/mL. Gene expression of seven apoptosis and oxidative-stress related genes showed significant alterations in only three genes only at the highest test concentration. Quantifiable levels of 8-OH-dG (≥ 2 adducts per 1 × 10(8) NT) were not detected at any treatment concentration. These results demonstrate an association between DEM-induced genotoxicity and GSH depletion in mouse lymphoma L5178Y (TK(+/-)) cells, but not with other oxidative markers.

Quantitation of glutathione by liquid chromatography/positive electrospray ionization tandem mass spectrometry.

Glutathione (GSH) is a tripeptide composed of glutamate, cysteine, and glycine. It is present in practically all cells and has several important roles, such as preventing the oxidation of the sulfhydryl groups of proteins within a cell. Evidence for GSH deficiency or depletion has been found in a variety of diseases and toxicity-related studies, including diabetes and induction of oxidative stress to form reactive oxygen species which cause DNA, lipid, and protein oxidations. A simple, selective, and sensitive analytical method for measuring low levels of GSH in biological fluids would therefore be desirable to conduct GSH deficiency or depletion-related mechanistic toxicity studies. Here a method for both low- and high-level quantitation of GSH from cultured cells and rat liver tissues via liquid chromatography/positive electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) has been developed. The lower limit of quantitation (LOQ) of the method was 5 ng/mL. The method is linear over a wide dynamic concentration range of 5.0 to 5000.0 ng/mL, with a correlation coefficient R2 > 0.99. The intra-day assay precision relative standard deviation (RSD) values for all quality control (QC) samples were < or =16.31%, with accuracy values ranging from 94.13 to 97.80%. The inter-day assay precision RSD values for all QC samples were < or =15.94%, with accuracy values ranging from 94.51 to 100.29%. With this method, low levels of GSH from diethyl maleate (DEM)-treated mouse lymphoma cells, and GSH in rat liver tissues, were quantified.

Abstinence, anticipation, reduction, and treatment (AART): a stepwise approach to the management of atypical antipsychotic side effects.

Antipsychotic medications, specifically the atypical agents, serve as first-line treatment options for patients with psychotic disorders, including individuals with schizophrenia or schizoaffective disorder. Atypical antipsychotics are also often prescribed off-label as either the primary treatment or as an adjunctive treatment for individuals with other disorders, including mood disorders without psychosis, behavioral disorders, and insomnia. Despite the generally superior side-effect profiles of atypical antipsychotics compared with typical antipsychotic agents, the atypicals have been associated with a number of serious side effects, including metabolic disorders, cardiovascular disorders, seizures, hyperprolactinemia, and movement disorders. This article offers a stepwise approach to the management of antipsychotic side effects: Abstinence, Anticipation, Reduction, and Treatment (AART). The steps in AART are hierarchical, but often overlap in the areas of risk prevention and minimization. The authors discuss issues relevant to each level of intervention and provide suggestions for integrating the AART approach into a comprehensive treatment plan. By incorporating this stepwise approach into their clinical decision-making process, prescribers may be able to optimize the risk:benefit ratio associated with the prescription of atypical antipsychotics.

Combination antipsychotic therapy in clinical practice.

OBJECTIVE: Surveys have shown that antipsychotic drug combinations are frequently prescribed, yet few clinical studies have examined this practice. Experts have generally recommended antipsychotic combinations, especially those combining an atypical and a conventional antipsychotic, as a measure of last resort. A survey of prescribers was conducted to examine why combination antipsychotic therapy is being used in outpatient clinical practice. METHODS: Antipsychotic prescribing practices in the Department of Veterans Affairs Puget Sound Health System were reviewed for a six-month period during 1998-1999. Data on the use of atypical and conventional antipsychotics in combination were collected. RESULTS: A total of 1,794 patients received prescriptions for at least one antipsychotic medication during the study period, of which 715 (40 percent) received an atypical agent. Ninety-three patients (13 percent) who were treated with an atypical antipsychotic received a prescription for combination antipsychotic therapy for at least 30 days. In cases in which both a conventional and an atypical agent were prescribed, the primary reason given for adding a conventional antipsychotic medication was to treat persistent positive symptoms. The primary reason an atypical agent was added to a conventional agent was to switch medications to the atypical agent; however, a significant number of patients became "stuck" on the combination. CONCLUSIONS: The results of this study support previous reports of the frequent use of combination antipsychotic therapy in clinical practice. Prospective controlled trials are needed to substantiate perceptions that combination antipsychotic therapy is clinically beneficial and to provide guidelines on when and for whom antipsychotic polypharmacy should be considered.