Cytochrome P450 interactions are common and consequential in Massachusetts hospital discharges.

Despite the recognition that drug-drug interactions contribute substantially to preventable health-care costs, the prevalence of such interactions related to the cytochrome P450 system in clinical practice remains poorly characterized. This study drew retrospective hospital discharge cohorts from a large health claims data set and a large health system data set. For every hospital discharge, frequency of co-occurrence of substrates and inducers or inhibitors at cytochrome P450 2D6, 2C19, 3A4 and 1A2 were determined. A total of 124 520 individuals in the state of Massachusetts (health claims cohort) and 77 026 individuals in two large academic medical centers (electronic health record (EHR) cohort) were examined. In the claims cohort, 35 157 (28.2%) exhibited at least one CYP450 drug-drug interaction at hospital discharge, whereas in the EHR cohort, 36 750 (47.7%) had at least one interaction. The most commonly affected CYP450 systems were 2C19 and 2D6, with putative interactions observed in at least 10% of individuals at discharge in each cohort. Odds of hospital readmission within 90 days among those discharged with at least one interaction were 10-16% greater, with mean health-care cost $574/month greater over the subsequent year, after adjusting for age, sex, insurance type, total number of medications prescribed, Charlson comorbidity score and presence or absence of a psychiatric diagnosis. These two distinct clinical data types show that CYP450 drug-drug interactions are prevalent and associated with greater probability of early hospital readmission and greater health-care cost, despite the widespread availability and application of drug-drug interaction checking software.

Polygenic loading for major depression is associated with specific medical comorbidity.

Major depressive disorder frequently co-occurs with medical disorders, raising the possibility of shared genetic liability. Recent identification of 15 novel genetic loci associated with depression allows direct investigation of this question. In cohorts of individuals participating in biobanks at two academic medical centers, we calculated polygenic loading for risk loci reported to be associated with depression. We then examined the association between such loading and 50 groups of clinical diagnoses, or topics, drawn from these patients' electronic health records, determined using a novel application of latent Dirichilet allocation. Three topics showed experiment-wide association with the depression liability score; these included diagnostic groups representing greater prevalence of mood and anxiety disorders, greater prevalence of cardiac ischemia, and a decreased prevalence of heart failure. The latter two associations persisted even among individuals with no mood disorder diagnosis. This application of a novel method for grouping related diagnoses in biobanks indicate shared genetic risk for depression and cardiac disease, with a pattern suggesting greater ischemic risk and diminished heart failure risk.

Prevalence and implications of cytochrome P450 substrates in Massachusetts hospital discharges.

The cytochrome P450 (CYP450) system of drug-metabolizing enzymes may contribute to individual variation in drug response. We examined prevalence of CYP450 substrates at hospital discharge for patients in two cohorts: insurance claims of Massachusetts residents and the medical records of two academic medical centers. The claims cohort included 47 473 individuals (38.2%) treated with at least one CYP450 2D6, 2C19, 3A4 or 1A2 substrate. The electronic medical records cohort included 45 905 individuals (57.4%) treated with at least one substrate. In adjusted models, substrates of CYP450 2D6 and 2C19 were associated with greater risk for 90-day readmission in both cohorts (odds ratios of 1.104 and 1.128 (P<0.001), respectively). Presence of any CYP450 substrate was associated with increased monthly medical costs (+$397, P<0.003). These analyses of more than 300 000 admissions using two different cohorts and data types indicate that CYP450 substrates are associated with greater readmission rates and greater health-care cost.

Predicting early psychiatric readmission with natural language processing of narrative discharge summaries.

The ability to predict psychiatric readmission would facilitate the development of interventions to reduce this risk, a major driver of psychiatric health-care costs. The symptoms or characteristics of illness course necessary to develop reliable predictors are not available in coded billing data, but may be present in narrative electronic health record (EHR) discharge summaries. We identified a cohort of individuals admitted to a psychiatric inpatient unit between 1994 and 2012 with a principal diagnosis of major depressive disorder, and extracted inpatient psychiatric discharge narrative notes. Using these data, we trained a 75-topic Latent Dirichlet Allocation (LDA) model, a form of natural language processing, which identifies groups of words associated with topics discussed in a document collection. The cohort was randomly split to derive a training (70%) and testing (30%) data set, and we trained separate support vector machine models for baseline clinical features alone, baseline features plus common individual words and the above plus topics identified from the 75-topic LDA model. Of 4687 patients with inpatient discharge summaries, 470 were readmitted within 30 days. The 75-topic LDA model included topics linked to psychiatric symptoms (suicide, severe depression, anxiety, trauma, eating/weight and panic) and major depressive disorder comorbidities (infection, postpartum, brain tumor, diarrhea and pulmonary disease). By including LDA topics, prediction of readmission, as measured by area under receiver-operating characteristic curves in the testing data set, was improved from baseline (area under the curve 0.618) to baseline+1000 words (0.682) to baseline+75 topics (0.784). Inclusion of topics derived from narrative notes allows more accurate discrimination of individuals at high risk for psychiatric readmission in this cohort. Topic modeling and related approaches offer the potential to improve prediction using EHRs, if generalizability can be established in other clinical cohorts.

Limb lengthening in children with Russell-Silver syndrome: a comparison to other etiologies.

INTRODUCTION/BACKGROUND: Russell-Silver syndrome (RSS) is the combination of intrauterine growth retardation, difficulty feeding, and postnatal growth retardation. Leg length discrepancy (LLD) is one of four major diagnostic criteria of RSS and is present in most cases. We aimed to ascertain whether pediatric RSS patients will adequately consolidate bony regenerate following leg lengthening. MATERIALS AND METHODS: We retrospectively reviewed pediatric RSS patients who underwent limb lengthening and compared them to a similar group of patients with LLD resulting from tumor, trauma, or congenital etiology. The primary outcome measurement was the bone healing index (BHI). RESULTS: The RSS group included seven lengthened segments in five patients; the comparison group included 21 segments in 19 patients. The groups had similar lengthening amounts (3.3 vs. 3.9 cm, p = 0.507). The RSS group healed significantly faster (lower BHI) than the control group (BHI 29 vs. 43 days/cm, p = 0.028). Secondary analysis showed no difference between RSS and trauma patients in terms of the BHI (29 vs. 31); however, the BHI of the RSS group was significantly lower than both of the other congenital etiologies (29 vs. 41, p = 0.032) and tumor patients (29 vs. 66, p = 0.019). The RSS patients had fewer and less significant complications than the controls. DISCUSSION: The limb lengthening regenerate healing of RSS patients is faster than the healing of patients with other congenital etiologies and tumor patients, and is as fast as the regenerate healing of patients with posttraumatic LLD. Although all RSS patients were treated with human growth hormone (hGH), we are unable to isolate the hGH contribution to the regenerate bone healing. We conclude that RSS patients can have safe limb lengthening.

A long term study of Charnley total hip replacements.

This study concerns our first 100 Charnley low friction arthroplasties. The follow-up of the surviving forty hips ranged from 14.4 to 16.2 years (average 15.3 years). Thirty-nine of the original 100 hips were lost to follow-up due to death. Twenty-one could not be traced. There had been six known failures (defined as removal or revision of the prosthesis), two of which occurred in the surviving forty hips. Femoral component failure had occurred twice as often as acetabular failure. Survival analysis was performed using the last follow-up from all 100 hips. This depicted 91% survival of the arthroplasty (both components), 91% survival of the femoral component, and 96% survival of the acetabular component at fifteen years. Clinical evaluation of the surviving forty hips revealed 87.5% good and excellent results. This represented a small decline from 95% good and excellent results in the same hips at the ten year follow-up. Radiographic evaluation of thirty-two of forty hips demonstrated 6% migration of acetabular components, and 7% loose femoral components, while 31% of the acetabular components and 50% of the femoral components showed no sign of loosening. Femoral loosening was positively correlated with femoral shaft diameter. Measurable polyethylene wear was present in twenty-seven of thirty-two hips. The wear ranged from 0.2 to 8.5 millimeters (average 1.85 millimeters). Wear was associated with male sex and with calcar resorption.

A fifteen-year follow-up study of one hundred Charnley low-friction arthroplasties.

This two-part study concerns the fate of 100 Charnley low-friction arthroplasties performed in 92 patients at The Hospital for Special Surgery. The first part of the study is a clinical and radiographic evaluation of the 40 hips that were available for follow-up at an average of 15.3 years after surgery. The second part is a survival analysis of the arthroplasty, the individual components, and the patients, using data from all 100 arthroplasties. The authors conclude that the vast majority of older patients who undergo cemented total hip arthroplasty will not require a subsequent arthroplasty, and will have satisfactory pain relief for the remainder of their lives.

Use of 300-msec microwave irradiation for enzyme inactivation: a study of effects of sodium pentobarbital on acetylcholine concentration in mouse brain regions.

Microwave irradiation of 6 kw at 2450 MHz for 300 msec was sufficient to completely inactivate mouse brain cholinesterase and choline acetyltransferase. After this method of sacrifice, the acetylcholine contents of mouse brain regions, given in nanomoles per gram, were found to be: striatum, 81; medulla-pons, 44; diencephalon-midbrain, 34; hippocampus, 31; cerebral cortex, 26; and cerebellum, 17. Sodium pentobarbital caused a dose-dependent increase in whole brain acetylcholine. A maximal increase of 81% in whole brain was seen at 15 minutes with 80 mg/kg of sodium pentobarbital. The increase in acetylcholine after sodium pentobarbital treatment was not caused by anoxia from respiratory depression or by hypothermia. All brain regions except the cerebellum exhibited an increase in acetylcholine after pentobarbital treatment. Fifteen minutes after treatment, cerebellar acetylcholine was significantly decreased. However, at the time when half of the animals had regained the righting reflex, the unconscious mice showed an increase in cerebellar acetylcholine which was statistically significant as compared to control. The relative accumulation rate of acetylcholine calculated for cerebral cortex and hippocampus was higher than that for striatum although the absolute rate of accumulation of ACh was higher in the striatum. Thus, after sodium pentobarbital treatment, the cerebral cortex and hippocampus exhibit a greater cholinergic response than the striatum.