A case of severe adolescent obsessive-compulsive disorder treated with inpatient hospitalization, risperidone and sertraline

Background: The initial treatment of obsessive-compulsive disorder (OCD) has generally been limited to serotonergic agents, cognitive-behavioral therapy (CBT), or a combination of the two. These findings were supported by the POTS study for OCD in children and adolescents. However, treatment with serotonergic agents or CBT can take several weeks before benefit is seen; severe cases of OCD may require more immediate treatment. Case report: The authors present a case of severe OCD in an adolescent that required immediate treatment due to her critical medical condition. The patient's symptoms included not eating or taking medications or fluids by mouth due to fears of contamination. A medical hospitalization was previously required due to dehydration. As treatment with an SSRI would not have quick enough onset and the patient was initially resistant to participating in CBT, the patient was psychiatrically hospitalized and first started on liquid risperidone. After several doses of risperidone, the patient was able to participate in CBT and start sertraline. Discussion: The authors discuss the differential diagnosis of such a patient, including the continuum of OCD symptoms and psychotic symptoms. The authors discuss the different treatment options, including the utilization of inpatient psychiatric hospitalization. The authors discuss the potential risks and benefits of using atypical antipsychotics in lieu of benzodiazepines for the initial treatment of severe adolescent OCD. The authors also discuss other current treatment recommendations and rationale for the treatment that was pursued. Conclusions: This patient received benefit of her symptoms relatively quickly with psychiatric hospitalization and an atypical antipsychotic. The diagnosis of a psychotic disorder should be considered. These treatment options must be weighed against the risks of atypical antipsychotics, including extrapyramidal symptoms, weight gain, and metabolic syndrome; benzodiazepines also have their risks and benefits. Additionally, the cost of time and finances of inpatient hospitalization must be considered. More research is needed regarding the short- and long-term efficacy and safety of antipsychotics in the treatment of OCD in the child and adolescent population

Large-effect flowering time mutations reveal conditionally adaptive paths through fitness landscapes in Arabidopsis thaliana.

Contrary to previous assumptions that most mutations are deleterious, there is increasing evidence for persistence of large-effect mutations in natural populations. A possible explanation for these observations is that mutant phenotypes and fitness may depend upon the specific environmental conditions to which a mutant is exposed. Here, we tested this hypothesis by growing large-effect flowering time mutants of Arabidopsis thaliana in multiple field sites and seasons to quantify their fitness effects in realistic natural conditions. By constructing environment-specific fitness landscapes based on flowering time and branching architecture, we observed that a subset of mutations increased fitness, but only in specific environments. These mutations increased fitness via different paths: through shifting flowering time, branching, or both. Branching was under stronger selection, but flowering time was more genetically variable, pointing to the importance of indirect selection on mutations through their pleiotropic effects on multiple phenotypes. Finally, mutations in hub genes with greater connectedness in their regulatory networks had greater effects on both phenotypes and fitness. Together, these findings indicate that large-effect mutations may persist in populations because they influence traits that are adaptive only under specific environmental conditions. Understanding their evolutionary dynamics therefore requires measuring their effects in multiple natural environments

SCALING-UP” FIRE SPREAD ON WOOD CRIBS TO PREDICT A LARGESCALE TRAVELLING FIRE TEST USING CFD

Simulation-based approaches for characterising the fire behaviour of travelling fires in large compartments are a potentially valuable complement to experimental studies, providing useful insights on evolving boundary conditions for structural response. They are attractive in reduced costs and the possibility of carrying out systematic parametric studies free from some of the experimental uncertainties, but sufficiently general models have not been previously demonstrated. Here, we explore the potential for “scaling-up” a “stick-by-stick” CFD model which had been carefully calibrated against the results of experiments on an isolated crib, of 2.8 m diameter, to a uniformly distributed fuel bed of extent 4.2 × 14.0 m located within an open compartment 9 × 15 m in plan, with an internal height of 2.9 m. The results in terms of the fire spread and burn out predictions are very encouraging, and the heat release rate evolution is also consistent with the experimental value. There are some discrepancies in predicted gas phase temperatures, nevertheless, such discrepancies with this aspect of the model are unlikely to have any great significance in the prediction of fire spread on a horizontally orientated flat fuel bed, which is the prime interest of the current work. Thus, the established “numerical simulator” looks to have good potential as a tool to explore and characterise the behaviour of travelling fires subject to different compartment boundary conditions

DPYD and fluorouracil-based chemotherapy: Mini review and case report

5-Fluorouracil remains a foundational component of chemotherapy for solid tumour malignancies. While considered a generally safe and effective chemotherapeutic, 5-fluorouracil has demonstrated severe adverse event rates of up to 30%. Understanding the pharmacokinetics of 5-fluorouracil can improve the precision medicine approaches to this therapy. A single enzyme, dihydropyrimidine dehydrogenase (DPD), mediates 80% of 5-fluorouracil elimination, through hepatic metabolism. Importantly, it has been known for over 30-years that adverse events during 5-fluorouracil therapy are linked to high systemic exposure, and to those patients who exhibit DPD deficiency. To date, pre-treatment screening for DPD deficiency in patients with planned 5-fluorouracil-based therapy is not a standard of care. Here we provide a focused review of 5-fluorouracil metabolism, and the efforts to improve predictive dosing through screening for DPD deficiency. We also outline the history of key discoveries relating to DPD deficiency and include relevant information on the potential benefit of therapeutic drug monitoring of 5-fluorouracil. Finally, we present a brief case report that highlights a limitation of pharmacogenetics, where we carried out therapeutic drug monitoring of 5-fluorouracil in an orthotopic liver transplant recipient. This case supports the development of robust multimodality precision medicine services, capable of accommodating complex clinical dilemmas

Lessons Learned from Deploying an Analytical Task Management Database

Defining requirements, missions, technologies, and concepts for space exploration involves multiple levels of organizations, teams of people with complementary skills, and analytical models and simulations. Analytical activities range from filling a To-Be-Determined (TBD) in a requirement to creating animations and simulations of exploration missions. In a program as large as returning to the Moon, there are hundreds of simultaneous analysis activities. A way to manage and integrate efforts of this magnitude is to deploy a centralized database that provides the capability to define tasks, identify resources, describe products, schedule deliveries, and generate a variety of reports. This paper describes a web-accessible task management system and explains the lessons learned during the development and deployment of the database. Through the database, managers and team leaders can define tasks, establish review schedules, assign teams, link tasks to specific requirements, identify products, and link the task data records to external repositories that contain the products. Data filters and spreadsheet export utilities provide a powerful capability to create custom reports. Import utilities provide a means to populate the database from previously filled form files. Within a four month period, a small team analyzed requirements, developed a prototype, conducted multiple system demonstrations, and deployed a working system supporting hundreds of users across the aeros pace community. Open-source technologies and agile software development techniques, applied by a skilled team enabled this impressive achievement. Topics in the paper cover the web application technologies, agile software development, an overview of the system's functions and features, dealing with increasing scope, and deploying new versions of the system

Ocular iontophoresis of EGP-437 (dexamethasone phosphate) in dry eye patients: results of a randomized clinical trial

Michael A Patane¹, Amy Cohen¹, Stephen From¹, Gail Torkildsen², Donna Welch³, George W Ousler III³¹Eyegate Pharmaceuticals, Inc, Waltham, MA, USA; ²Andover Eye Associates, Andover, MA, USA; ³Ora, Inc, Andover, MA, USAPurpose: To assess safety and efficacy of EGP-437 (dexamethasone phosphate 40 mg/mL [DP]) in dry eye patients.Methods: The study employed a prospective, single-center, double-masked design utilizing a Controlled Adverse Environment (CAE). Patients (n = 103) with confirmed signs and symptoms of dry eye syndrome were randomized into 1 of 3 iontophoresis treatment groups: 7.5 mA-min at 2.5 mA (DP 7.5, n = 41); 10.5 mA-min at 3.5 mA (DP 10.5, n = 37); or 10.5 mA-min at 3.5 mA (placebo, n = 25). Three CAE visits and 4 follow-up visits occurred over 3 weeks. Patients meeting enrollment criteria received iontophoresis in both eyes after the second CAE exposure (visit 3) and before the third CAE exposure (visit 5). Primary efficacy endpoints were corneal staining and ocular discomfort. Secondary endpoints included tear film break-up time, ocular protection index (OPI), and symptomatology.Results: The DP 7.5 and DP 10.5 treatment groups showed statistically significant improvements in signs and symptoms of dry eye at various time points; however, the primary endpoints were not achieved. The DP 7.5 treatment group exhibited statistically significant improvements in corneal staining (when comparing the differences between study entry and exit, 3 weeks, P = 0.039), OPI (immediately following the second treatment, P = 0.048) and ocular discomfort at follow-up visits (a week after the first treatment, P = 0.032; 24 hours after the second treatment, P = 0.0032). Treatment-emergent adverse events (AEs) were experienced by 87% of patients and were consistent across all treatment groups. Most AEs were mild and no severe AEs were observed.Conclusion: Ocular iontophoresis of EGP-437 demonstrated statistically and clinically significant improvements in signs and symptoms of dry eye syndrome within a CAE model.Keywords: iontophoresis, dry eye, Controlled Adverse Environment (CAE), ocular protection index (OPI

LARGE SCALE FIRE TEST: TRAVELLING FIRE WITH FLASHOVER UNDER VENTILATION CONDITIONS AND ITS INFLUENCE ON THE SURROUNDING STEEL STRUCTURE

In the frame of the European RFCS-TRAFIR project, different natural fire tests in large compartment were conducted by Ulster University, involving steel structure and aiming at understanding the conditions in which a travelling fire develops, how it behaves and impacts the surrounding structure. During the experimental programme, the path and geometry of the travelling fire was studied and temperatures, heat fluxes and spread rates were measured. This paper presents the selected experimental data from the third fire test in terms of gas temperatures recorded in the test compartment at different positions and levels. The paper also presents the influence of the traveling fire with flashover on the surrounding structure via temperatures recorded in the selected steel columns and beams. The temperatures in the test compartment were found to be dependent on the positioning of the travelling fire as well as on the height from the floor level. It was found that the non-uniform temperatures in the compartment lead to transient heating of the nearby structural steel elements which is different from a standard furnace test. These non-uniform elevated temperatures result in a reduction of the fire resistance of the structural elements which may influence the global stability of the structure. The results obtained during the test and lessons learnt will help to understand the behaviour of the travelling fires and their influence on the structural members. This knowledge will help to reduce the travelling fire associated risks in future

Performance of concrete in fire: a review of the state of the art, with a case study of the windsor tower fire

This paper provides a “State of the Art” review on current research into the effects of fire exposures upon concrete. The principal influences of high temperature in concrete are loss of compressive strength and spalling, the forcible ejection of material from a member. Though a lot of information has been gathered on both phenomena, there remains a need for a broader understanding of the response of concrete structures to different heating regimes and the performance of complete concrete structures subjected to realistic fire exposures. There is a lack of information derived from large-scale tests on concrete buildings in natural fires. Besides undertaking further fire tests, lessons can also be learnt from real fires and the University of Edinburgh has embarked upon detailed studies of the serious fire in the Windsor Tower, Madrid. In order to properly characterise the fire and the performance of the structure a data-gathering exercise has been undertaken and computer modelling tools are being applied in order to obtain better insights into the structural response. There remains some uncertainty about the precise mechanism of fire spread, but an external route is likely, facilitated to some degree by the glazed curtain walling construction; lack of fire protection on the steelwork was the major reason for the subsequent partial collapse of the upper floors and the localised failure of a concrete portal frame can be attributed to the same reason

PU.1 opposes IL-7-dependent proliferation of developing b cells with involvement of the direct target gene bruton tyrosine kinase

Deletion of genes encoding the E26 transformation-specific transcription factors PU.1 and Spi-B in B cells (CD19-CreΔPB mice) leads to impaired B cell development, followed by B cell acute lymphoblastic leukemia at 100% incidence and with a median survival of 21 wk. However, little is known about the target genes that explain leukemogenesis in these mice. In this study we found that immature B cells were altered in frequency in the bone marrow of preleukemic CD19-CreΔPB mice. Enriched pro-B cells from CD19-CreDPB mice induced disease upon transplantation, suggesting that these were leukemia-initiating cells. Bone marrow cells from preleukemic CD19-CreΔPB mice had increased responsiveness to IL-7 and could proliferate indefinitely in response to this cytokine. Bruton tyrosine kinase (BTK), a negative regulator of IL-7 signaling, was reduced in preleukemic and leukemic CD19-CreΔPB cells compared with controls. Induction of PU.1 expression in cultured CD19-CreΔPB pro-B cell lines induced Btk expression, followed by reduced STAT5 phosphorylation and early apoptosis. PU.1 and Spi-B regulated Btk directly as shown by chromatin immunoprecipitation analysis. Ectopic expression of BTK was sufficient to induce apoptosis in cultured pro-B cells. In summary, these results suggest that PU.1 and Spi-B activate Btk to oppose IL-7 responsiveness in developing B cells