Environmental complexity is more important than mutation in driving the evolution of latent novel traits in E. coli.

Recent experiments show that adaptive Darwinian evolution in one environment can lead to the emergence of multiple new traits that provide no immediate benefit in this environment. Such latent non-adaptive traits, however, can become adaptive in future environments. We do not know whether mutation or environment-driven selection is more important for the emergence of such traits. To find out, we evolve multiple wild-type and mutator E. coli populations under two mutation rates in simple (single antibiotic) environments and in complex (multi-antibiotic) environments. We then assay the viability of evolved populations in dozens of new environments and show that all populations become viable in multiple new environments different from those they had evolved in. The number of these new environments increases with environmental complexity but not with the mutation rate. Genome sequencing demonstrates the reason: Different environments affect pleiotropic mutations differently. Our experiments show that the selection pressure provided by an environment can be more important for the evolution of novel traits than the mutational supply experienced by a wild-type and a mutator strain of E. coli

PRESCRIPTION PATTERN ANALYSIS OF ANTIDEPRESSANTS IN PSYCHIATRIC OUTPATIENT DEPARTMENT OF TERTIARY CARE HOSPITAL IN INDIA

ABSTRACTObjectives: (1) To study the prescription pattern of antidepressants in treatment of depression in psychiatry outpatient department of tertiary carehospital in India, (2) to find the change in drug therapy during last 1 year of the treatment (old patients), (3) to study reason for a change in drugtherapy, and (4) to calculate prescribed daily dose (PDD) of the individual drugs.Methods: It was cross-sectional single centered observational study with a sample size of 284 cases. Case record forms were filled from case paper.Results were analyzed.Results: Monotherapy was practiced in 259 patients, i.e., 91.19% of the study population. A maximum number of patients (n=159, 55.98%) receivedescitalopram monotherapy. Polytherapy was practiced in 25 (8.8%) patients. Out of 160 old cases, 9 patients required a change in drug therapyeither in the form of drug or dose. PDD values were escitalopram: 12.30, fluoxetine: 18.43, paroxetine: 25, sertraline: 96.35, amitriptyline: 57.79,imipramine: 5.75, and mirtazapine: 17.67.Conclusion: From our study, it is concluded that the incidence of depression is more in females. Selective serotonin receptor inhibitors were themost common class of drugs used followed by tricyclic antidepressants. Escitalopram was most frequently prescribed antidepressant followed byamitriptyline. The prescription trend was toward monotherapy. Most patients continued treatment on the same medication. The poor therapeuticresponse was the most common reason for drug change.Keywords: Depression, Prescribed daily dose, Defined daily dose

Intestinal organoids model human responses to infection by commensal and Shiga toxin producing Escherichia coli

Infection with Shiga toxin (Stx) producing Escherichia coli O157:H7 can cause the potentially fatal complication hemolytic uremic syndrome, and currently only supportive therapy is available. Lack of suitable animal models has hindered study of this disease. Induced human intestinal organoids (iHIOs), generated by in vitro differentiation of pluripotent stem cells, represent differentiated human intestinal tissue. We show that iHIOs with addition of human neutrophils can model E. coli intestinal infection and innate cellular responses. Commensal and O157:H7 introduced into the iHIO lumen replicated rapidly achieving high numbers. Commensal E. coli did not cause damage, and were completely contained within the lumen, suggesting defenses, such as mucus production, can constrain non-pathogenic strains. Some O157:H7 initially co-localized with cellular actin. Loss of actin and epithelial integrity was observed after 4 hours. O157:H7 grew as filaments, consistent with activation of the bacterial SOS stress response. SOS is induced by reactive oxygen species (ROS), and O157:H7 infection increased ROS production. Transcriptional profiling (RNAseq) demonstrated that both commensal and O157:H7 upregulated genes associated with gastrointestinal maturation, while infection with O157:H7 upregulated inflammatory responses, including interleukin 8 (IL-8). IL-8 is associated with neutrophil recruitment, and infection with O157:H7 resulted in recruitment of human neutrophils into the iHIO tissue

Prospective Validation of Eight Different Adherence Measures for Use with Administrative Claims Data among Patients with Schizophrenia

ABSTRACTObjectiveThe aim of this study was to compare the predictive validity of eight different adherence measures by studying the variability explained between each measure and hospitalization episodes among Medicaid-eligible persons diagnosed with schizophrenia on antipsychotic monotherapy.MethodsThis study was a retrospective analysis of the Arkansas Medicaid administrative claims data. Continuously eligible adult schizophrenia (ICD-9-CM = 295.**) patients on antipsychotic monotherapy were identified in the recruitment period from July 2000 through April 2004. Adherence rates to antipsychotic therapy in year 1 were calculated using eight different measures identified from the literature. Univariate and multivariable logistic regression models were used to prospectively predict all-cause and mental health-related hospitalizations in the follow-up year.ResultsAdherence rates were computed for 3395 schizophrenic patients with a mean age of 42.9 years, of which 52.5% (n = 1782) were females, and 52.8% (n = 1793) were white. The proportion of days covered (PDC) and continuous measure of medication gaps measures of adherence had equal C-statistics of 0.571 in predicting both all-cause and mental health-related hospitalizations. The medication possession ratio (MPR) continuous multiple interval measure of oversupply were the second best measures with equal C-statistics of 0.568 and 0.567 for any-cause and mental health-related hospitalizations. The multivariate adjusted models had higher C-statistics but provided the same rank order results.ConclusionsMPR and PDC were among the best predictors of any-cause and mental health-related hospitalization, and are recommended as the preferred adherence measures when a single measure is sought for use with administrative claims data for patients not on polypharmacy

Detection Efficiencies and Generalized Breakdown Probabilities for Nanosecond-Gated Near Infrared Single-Photon Avalanche Photodiodes

A rigorous model is developed for determining single-photon quantum efficiency (SPQE) of single-photon avalanche photodiodes (SPADs) with simple or heterojunction multiplication regions. The analysis assumes nanosecond gated-mode operation of the SPADs and that band-to-band tunneling of carriers is the dominant source of dark current in the multiplication region. The model is then utilized to optimize the SPQE as a function of the applied voltage, for a given operating temperature and multiplication-region structure and material. The model can be applied to SPADs with In/sub 0.52/Al/sub 0.48/As or InP multiplication regions as well as In/sub 0.52/Al/sub 0.48/As--InP heterojunction multiplication regions for wavelengths of 1.3 and 1.55 /spl mu/m. The predictions show that the SPQE generally decreases with decreasing the multiplication-region thickness. Moreover, an InP multiplication region requires a lower breakdown electric field (and, hence, offers a higher SPQE) than that required by an In/sub 0.52/Al/sub 0.48/As layer of the same width. The model also shows that the fractional width of the In/sub 0.52/Al/sub 0.48/As layer in an In/sub 0.52/Al/sub 0.48/As--InP heterojunction multiplication region can be optimized to attain a maximum SPQE that is greater than that offered by an InP multiplication region. This effect becomes more pronounced in thin multiplication regions as a result of the increased significance of dead space

Relationship Between Operator Volume and Adverse Outcome in Contemporary Percutaneous Coronary Intervention Practice An Analysis of a Quality-Controlled Multicenter Percutaneous Coronary Intervention Clinical Database

ObjectivesThe aim of our study was to evaluate the volume-outcome relationship in a large, quality-controlled, contemporary percutaneous coronary interventions (PCI) database.BackgroundWhether the relationship between physician volume of PCI and outcomes still exists in the era of coronary stents is unclear.MethodsData on 18,504 consecutive PCIs performed by 165 operators in calendar year 2002 were prospectively collected in a regional consortium. Operators' volume was divided into quintiles (1 to 33, 34 to 89, 90 to 139, 140 to 206, and 207 to 582 procedures/year). The primary end point was a composite of major adverse cardiovascular events (MACE) including death, coronary artery bypass grafting, stroke or transient ischemic attack, myocardial infarction, and repeat PCI at the same site during the index hospital stay.ResultsThe unadjusted MACE rate was significantly higher in quintiles one and two of operator volume when compared with quintile five (7.38% and 6.13% vs. 4.15%, p = 0.002 and p = 0.0001, respectively). A similar trend was observed for in-hospital death. After adjustment for comorbidities, patients treated by low volume operators had a 63% increased odds of MACE (adjusted odds ratio [OR] 1.63, 95% confidence interval [CI] 1.29 to 2.06, p < 0.0001 for quintile [Q]1; adjusted OR 1.63, 95% CI 1.34 to 1.90, p < 0.0001 for Q2 vs. Q5), but not of in-hospital death. Overall, high volume operators had better outcomes than low volume operators in low-risk and high-risk patients.ConclusionsAlthough the relationship between operator volume and in-hospital mortality is no longer significant, the relationship between volume and any adverse outcome is still present. Technological advancements have not yet completely offset the influence of procedural volume on proficiency of PCIs

Anti-Lysophosphatidic Acid Antibodies Improve Traumatic Brain Injury Outcomes

BACKGROUND: Lysophosphatidic acid (LPA) is a bioactive phospholipid with a potentially causative role in neurotrauma. Blocking LPA signaling with the LPA-directed monoclonal antibody B3/Lpathomab is neuroprotective in the mouse spinal cord following injury. FINDINGS: Here we investigated the use of this agent in treatment of secondary brain damage consequent to traumatic brain injury (TBI). LPA was elevated in cerebrospinal fluid (CSF) of patients with TBI compared to controls. LPA levels were also elevated in a mouse controlled cortical impact (CCI) model of TBI and B3 significantly reduced lesion volume by both histological and MRI assessments. Diminished tissue damage coincided with lower brain IL-6 levels and improvement in functional outcomes. CONCLUSIONS: This study presents a novel therapeutic approach for the treatment of TBI by blocking extracellular LPA signaling to minimize secondary brain damage and neurological dysfunction