The care of adults with congenital heart disease across the globe: Current assessment and future perspective

The number of adults with congenital heart disease (CHD) has increased markedly over the past few decades as a result of astounding successes in pediatric cardiac care. Nevertheless, it is now well understood that CHD is not cured but palliated, such that life-long expert care is required to optimize outcomes. All countries in the world that experience improved survival in CHD must face new challenges inherent to the emergence of a growing and aging CHD population with changing needs and medical and psychosocial issues. Founded in 1992, the International Society for Adult Congenital Heart Disease (ISACHD) is the leading global organization of professionals dedicated to pursuing excellence in the care of adults with CHD worldwide. Recognizing the unique and varied issues involved in caring for adults with CHD, ISACHD established a task force to assess the current status of care for adults with CHD across the globe, highlight major challenges and priorities, and provide future direction. The writing committee consisted of experts from North America, South America, Europe, South Asia, East Asia, and Oceania. The committee was divided into subgroups to review key aspects of adult CHD (ACHD) care. Regional representatives were tasked with investigating and reporting on relevant local issues as accurately as possible, within the constraints of available data. The resulting ISACHD position statement addresses changing patterns of worldwide epidemiology, models of care and organization of care, education and training, and the global research landscape in ACHD.

Treatment planning aspects and Monte Carlo methods in proton therapy

Over the last years, the interest in proton radiotherapy is rapidly increasing. Protons provide superior physical properties compared with conventional radiotherapy using photons. These properties result in depth dose curves with a large dose peak at the end of the proton track and the finite proton range allows sparing the distally located healthy tissue. These properties offer an increased flexibility in proton radiotherapy, but also increase the demand in accurate dose estimations. To carry out accurate dose calculations, first an accurate and detailed characterization of the physical proton beam exiting the treatment head is necessary for both currently available delivery techniques: scattered and scanned proton beams. Since Monte Carlo (MC) methods follow the particle track simulating the interactions from first principles, this technique is perfectly suited to accurately model the treatment head. Nevertheless, careful validation of these MC models is necessary. While for the dose estimation pencil beam algorithms provide the advantage of fast computations, they are limited in accuracy. In contrast, MC dose calculation algorithms overcome these limitations and due to recent improvements in efficiency, these algorithms are expected to improve the accuracy of the calculated dose distributions and to be introduced in clinical routine in the near future.

Management of fever and neutropenia in paediatric cancer patients: room for improvement?

PURPOSE OF REVIEW Fever and neutropenia is the most common complication in the treatment of childhood cancer. This review will summarize recent publications that focus on improving the management of this condition as well as those that seek to optimize translational research efforts. RECENT FINDINGS A number of clinical decision rules are available to assist in the identification of low-risk fever and neutropenia however few have undergone external validation and formal impact analysis. Emerging evidence suggests acute fever and neutropenia management strategies should include time to antibiotic recommendations, and quality improvement initiatives have focused on eliminating barriers to early antibiotic administration. Despite reported increases in antimicrobial resistance, few studies have focused on the prediction, prevention, and optimal treatment of these infections and the effect on risk stratification remains unknown. A consensus guideline for paediatric fever and neutropenia research is now available and may help reduce some of the heterogeneity between studies that have previously limited the translation of evidence into clinical practice. SUMMARY Risk stratification is recommended for children with cancer and fever and neutropenia. Further research is required to quantify the overall impact of this approach and to refine exactly which children will benefit from early antibiotic administration as well as modifications to empiric regimens to cover antibiotic-resistant organisms.

Clinical effectiveness of cognitive behavioral therapy for depression in routine care: A propensity score based comparison between randomized controlled trials and clinical practice

Background: The efficacy of cognitive behavioral therapy (CBT) for the treatment of depressive disorders has been demonstrated in many randomized controlled trials (RCTs). This study investigated whether for CBT similar effects can be expected under routine care conditions when the patients are comparable to those examined in RCTs. Method: N=574 CBT patients from an outpatient clinic were stepwise matched to the patients undergoing CBT in the National Institute of Mental Health Treatment of Depression Collaborative Research Program (TDCRP). First, the exclusion criteria of the RCT were applied to the naturalistic sample of the outpatient clinic. Second, propensity score matching (PSM) was used to adjust the remaining naturalistic sample on the basis of baseline covariate distributions. Matched samples were then compared regarding treatment effects using effect sizes, average treatment effect on the treated (ATT) and recovery rates. Results: CBT in the adjusted naturalistic subsample was as effective as in the RCT. However, treatments lasted significantly longer under routine care conditions. Limitations: The samples included only a limited amount of common predictor variables and stemmed from different countries. There might be additional covariates, which could potentially further improve the matching between the samples. Conclusions: CBT for depression in clinical practice might be equally effective as manual-based treatments in RCTs when they are applied to comparable patients. The fact that similar effects under routine conditions were reached with more sessions, however, points to the potential to optimize treatments in clinical practice with respect to their efficiency.

Enhanced Recovery after Urological Surgery: A Contemporary Systematic Review of Outcomes, Key Elements, and Research Needs

CONTEXT Enhanced Recovery after Surgery (ERAS) programs are multimodal care pathways that aim to decrease intra-operative blood loss, decrease postoperative complications, and reduce recovery times. OBJECTIVE To overview the use and key elements of ERAS pathways, and define needs for future clinical trials. EVIDENCE ACQUISITION A comprehensive systematic MEDLINE search was performed for English language reports published before May 2015 using the terms "postoperative period," "postoperative care," "enhanced recovery after surgery," "enhanced recovery," "accelerated recovery," "fast track recovery," "recovery program," "recovery pathway", "ERAS," and "urology" or "cystectomy" or "urologic surgery." EVIDENCE SYNTHESIS We identified 18 eligible articles. Patient counseling, physical conditioning, avoiding excessive alcohol and smoking, and good nutrition appeared to protect against postoperative complications. Fasting from solid food for only 6h and perioperative liquid-carbohydrate loading up to 2h prior to surgery appeared to be safe and reduced recovery times. Restricted, balanced, and goal-directed fluid replacement is effective when individualized, depending on patient morbidity and surgical procedure. Decreased intraoperative blood loss may be achieved by several measures. Deep vein thrombosis prophylaxis, antibiotic prophylaxis, and thermoregulation were found to help reduce postsurgical complications, as was a multimodal approach to postoperative nausea, vomiting, and analgesia. Chewing gum, prokinetic agents, oral laxatives, and an early resumption to normal diet appear to aid faster return to normal bowel function. Further studies should compare anesthetic protocols, refine analgesia, and evaluate the importance of robot-assisted surgery and the need/timing for drains and catheters. CONCLUSIONS ERAS regimens are multidisciplinary, multimodal pathways that optimize postoperative recovery. PATIENT SUMMARY This review provides an overview of the use and key elements of Enhanced Recovery after Surgery programs, which are multimodal, multidisciplinary care pathways that aim to optimize postoperative recovery. Additional conclusions include identifying effective procedures within Enhanced Recovery after Surgery programs and defining needs for future clinical trials.

Contrasting growth and water use efficiency after thinning in mixed Abies pinsapo–Pinus pinaster–Pinus sylvestris forests

Foresters frequently lack sufficient information about thinning intensity effects to optimize semi-natural forest management and their effects and interaction with climate are still poorly understood. In an Abies pinsapo–Pinus pinaster–Pinus sylvestris forest with three thinning intensities, a dendrochronologial approach was used to evaluate the short-term responses of basal area increment (BAI), carbon isotope (δ13C) and water use efficiency (iWUE) to thinning intensity and climate. Thinning generally increased BAI in all species, except for the heavy thinning in P. sylvestris. Across all the plots, thinning increased 13C-derived water-use efficiency on average by 14.49% for A. pinsapo, 9.78% for P. sylvestris and 6.68% for P. pinaster, but through different ecophysiological mechanisms. Our findings provide a robust mean of predicting water use efficiency responses from three coniferous species exposed to different thinning strategies which have been modulated by climatic conditions over time.

Production Streamlining through Design, Implementation, and Analysis of Lean Manufacturing Methods

Through the correct implementation of lean manufacturing methods, a company can greatly improve their business. Over a period of three months at TTM Technologies, I utilized my knowledge to fix existing problems ans streamline production. In addition, other trouble areas in their production process were discovered and proper lean methods were used to address them. TTM Technologies saw many changed in the right direction over this time period.

Pharmacogenetics of the human glutathione S-transferase P1 gene in the metabolism and therapeutic efficacy of cis-diamminedichloroplatinum

The human GSTP1 gene has been shown, conclusively, to be polymorphic. The three main GSTP1 alleles, GSTP1*A, GSTP1*B, and GSTP1*C, encode proteins which differ in the 3-dimensional structure of their active sites and in their function in phase II metabolism of carcinogens, mutagens, and anticancer agents. Although, it is well established that GSTP1 is over expressed in many human tumors and that the levels of GSTP1 expression correlate directly with tumor resistance to chemotherapy and inversely with patient survival, the significance of the polymorphic GSTP1 gene locus on tumor response to chemotherapy remains unclear. The goal of this project was to define the role and significance of the polymorphic GSTP1 gene locus in GSTP1-based tumor drug resistance and as a determinant of patient response to chemotherapy. The hypothesis to be tested was that the polymorphic GSTP1 gene locus will confer to tumors a differential ability to metabolize cisplatin resulting in a GSTP1 genotype-based sensitivity to cisplatin. The study examined: (a) whether the different GSTP 1 alleles confer different levels of cellular protection against cisplatin-induced cytotoxicity, (b) whether the allelic GSTP1 proteins metabolize cisplatin with different efficiencies, and (c) whether the GSTP1 genotype is a determinant of tumor response to cisplatin therapy. The results demonstrate that the GSTP1 alleles differentially protect tumors against cisplatin-induced apoptosis and clonogenic cell kill in the rank order: GSTP1*C > GSTP1*B > GSTP1*A. The same rank order was observed for the kinetics of GSTP1-catalyzed cisplatin metabolism, both in cell-free and cellular systems, to the rate-limiting monoglutathionyl-platinum metabolite, which was characterized, for the first time, by mass spectral analysis. Finally, this study demonstrates that both GSTP1 genotype and the level of GSTP1 expression significantly contribute to tumor sensitivity to cisplatin treatment. Overall, the results of this project show that the polymorphic GSTP1 gene locus plays a significant role in tumor sensitivity to cisplatin treatment. Furthermore, these studies have contributed to the overall understanding of the significance of the polymorphic GSTP1 gene locus in tumor resistance to cancer chemotherapy and have provided the basis for further investigations into how this can be utilized to optimize and individualize cancer chemotherapy for cancer patients. ^

Prime and boost vaccination against HER2/neu in breast cancer

Breast cancer is the most common cancer among women with approximately 180,000 new cases being diagnosed yearly in the United States (1). HER2/neu gene amplification and subsequent protein overexpression is found in 20–30% of breast cancer patients and can lead to the promotion of various metastasis-related properties (2–4) and/or resistance to cancer therapies such as chemotherapy and radiation (5). ^ The protein product of the HER2/neu gene, p185, is a proven target for immunological therapy. Recently, passive immunotherapy with the monoclonal antibody Trastuzumab® has validated an immunological approach to HER2/neu+ breast cancer. Immunity to HER2/ neu, when found in breast cancer patients, is of low magnitude. Vaccination-induced HER2/neu-specific antibodies and HER2/neu-specific cytotoxic T cells could result in long-lived immunity with therapeutic benefit. Many features of DNA vaccines and attenuated viral vectors may contribute to the efficacy of prime-boost vaccination. In particular, vaccines capable of eliciting strong cell-mediated immunity are thought to hold the greatest promise for control of cancer (6–9). ^ To optimize cellular immunization to HER2/neu in my study, the HER2/neu gene was presented to the immune system using a priming vector followed by a second vector used as the boost. In both animals and humans, priming with DNA and boosting with a poxviruses, vaccinia or canarypox appears to be particularly promising for induction of a broad immune responses (10). ^ I tested three gene vaccines encoding the HER2/neu gene: (1) a plasmid, SINCP, that contains part of the genome of Sindbis virus; (2) Viral Replicon Particles (VRP) of Venezuela Equine Encephalitis virus (VEE) and (3) E1/E2a-deleted human Type 5 Adenovirus. In SINCP and the VRP, the caspid and envelope genes of the virus were deleted and replaced with the gene for HER2/neu. SINCP-neu, VRP- neu and Adeno-neu when used alone were effective vaccines protecting healthy mice from challenge with a breast cancer cell line injected in the mammary fat pad or injected i.v. to induce experimental lung metastasis. However, SINCP-neu, VRP-neu or Adeno-neu when used alone were not able to prolong survival of mice in therapeutic models in which vaccination occurred after injection of a breast cancer cell line. ^ When the vaccines were combined in a mixed regimen of a SINCP- neu prime VRP-neu or Adeno-neu boost, there was a significant difference in tumor growth and survival in the therapeutic vaccine models. In vitro assays demonstrated that vaccination with each of the three vaccines induced IgG specific for p185, the gene product of HER2/neu, induced p185-specific T lymphocytes, as measured by tetramer analysis. Vaccination also induced intracellular INF-γ and a positive ELISPOT assay. These findings indicate that SINCP-neu, VRP-neu and Adeno-neu, used alone or in combination, may have clinical potential as adjuvant immunotherapy for the treatment of HER2/neu-expressing tumors. ^

The design and evaluation of a 2D dose verification system for intensity modulated radiotherapy

The usage of intensity modulated radiotherapy (IMRT) treatments necessitates a significant amount of patient-specific quality assurance (QA). This research has investigated the precision and accuracy of Kodak EDR2 film measurements for IMRT verifications, the use of comparisons between 2D dose calculations and measurements to improve treatment plan beam models, and the dosimetric impact of delivery errors. New measurement techniques and software were developed and used clinically at M. D. Anderson Cancer Center. The software implemented two new dose comparison parameters, the 2D normalized agreement test (NAT) and the scalar NAT index. A single-film calibration technique using multileaf collimator (MLC) delivery was developed. EDR2 film's optical density response was found to be sensitive to several factors: radiation time, length of time between exposure and processing, and phantom material. Precision of EDR2 film measurements was found to be better than 1%. For IMRT verification, EDR2 film measurements agreed with ion chamber results to 2%/2mm accuracy for single-beam fluence map verifications and to 5%/2mm for transverse plane measurements of complete plan dose distributions. The same system was used to quantitatively optimize the radiation field offset and MLC transmission beam modeling parameters for Varian MLCs. While scalar dose comparison metrics can work well for optimization purposes, the influence of external parameters on the dose discrepancies must be minimized. The ability of 2D verifications to detect delivery errors was tested with simulated data. The dosimetric characteristics of delivery errors were compared to patient-specific clinical IMRT verifications. For the clinical verifications, the NAT index and percent of pixels failing the gamma index were exponentially distributed and dependent upon the measurement phantom but not the treatment site. Delivery errors affecting all beams in the treatment plan were flagged by the NAT index, although delivery errors impacting only one beam could not be differentiated from routine clinical verification discrepancies. Clinical use of this system will flag outliers, allow physicists to examine their causes, and perhaps improve the level of agreement between radiation dose distribution measurements and calculations. The principles used to design and evaluate this system are extensible to future multidimensional dose measurements and comparisons. ^

Foodborne illness, food inspection policy and restaurants in the U.S.

Objectives. The purpose of this paper is to conduct a literature review of research relating to foodborne illness, food inspection policy, and restaurants in the United States. Aim 1: To convey the public health importance of studying restaurant food inspection policies and suggest that more research is needed in this field, Aim 2: To conduct a systematic literature review of recent literature pertaining to this subject such that future researchers can understand the: (1) Public perception and expectations of restaurant food inspection policies; (2) Arguments in favor of a grade card policy; and, conversely; (3) Reasons why inspection policies may not work. ^ Data/methods. This paper utilizes a systematic review format to review articles relating to food inspections and restaurants in the U.S. Eight articles were reviewed. ^ Results. The resulting data from the literature provides no conclusive answer as to how, when, and in what method inspection policies should be carried out. The authors do, however, put forward varying solutions as to how to fix the problem of foodborne illness outbreaks in restaurants. These solutions include the implementation of grade cards in restaurants and, conversely, a complete overhaul of the inspection policy system.^ Discussion. The literature on foodborne disease, food inspection policy, and restaurants in the U.S. is limited and varied. But, from the research that is available, we can see that two schools of thought exist. The first of these calls for the implementation of a grade card system, while the second proposes a reassessment and possible overhaul of the food inspection policy system. It is still unclear which of these methods would best slow the increase in foodborne disease transmission in the U.S.^ Conclusion. In order to arrive at solutions to the problem of foodborne disease transmission as it relates to restaurants in this country, we may need to look at literature from other countries and, subsequently, begin incremental changes in the way inspection policies are developed and enforced.^

Advanced Protein Modeling Method: Benchmarking and Applications in Computer-Aided Drug Discovery

Development of homology modeling methods will remain an area of active research. These methods aim to develop and model increasingly accurate three-dimensional structures of yet uncrystallized therapeutically relevant proteins e.g. Class A G-Protein Coupled Receptors. Incorporating protein flexibility is one way to achieve this goal. Here, I will discuss the enhancement and validation of the ligand-steered modeling, originally developed by Dr. Claudio Cavasotto, via cross modeling of the newly crystallized GPCR structures. This method uses known ligands and known experimental information to optimize relevant protein binding sites by incorporating protein flexibility. The ligand-steered models were able to model, reasonably reproduce binding sites and the co-crystallized native ligand poses of the β2 adrenergic and Adenosine 2A receptors using a single template structure. They also performed better than the choice of template, and crude models in a small scale high-throughput docking experiments and compound selectivity studies. Next, the application of this method to develop high-quality homology models of Cannabinoid Receptor 2, an emerging non-psychotic pain management target, is discussed. These models were validated by their ability to rationalize structure activity relationship data of two, inverse agonist and agonist, series of compounds. The method was also applied to improve the virtual screening performance of the β2 adrenergic crystal structure by optimizing the binding site using β2 specific compounds. These results show the feasibility of optimizing only the pharmacologically relevant protein binding sites and applicability to structure-based drug design projects.

Structural determinants of subunit -subunit interactions and subcellular localization of the calcium /calmodulin -dependent protein kinase II

The multifunctional Ca$\sp{2+}$/calmodulin-dependent protein kinase II (CaM kinase) is a Ser/Thr directed protein kinase that participates in diverse Ca$\sp{2+}$ signaling pathways in neurons. The function of CaM kinase depends upon the ability of subunits to form oligomers and to interact with other proteins. Oligomerization is required for autophosphorylation which produces significant functional changes that include Ca$\sp{2+}$/calmodulin-independent activity and calmodulin trapping. Associations with other proteins localize CaM kinase to specific substrates and effectors which serves to optimize the efficiency and speed of signal transduction. In this thesis, we investigate the interactions that underlie the appropriate positioning of CaM kinase activity in cells. We demonstrate that the subcellular distribution of CaM kinase is dynamic in hippocampal slices exposed to anoxic/aglycemic insults and to high K$\sp{+}$-induced depolarization. We determine the localization of CaM kinase domains expressed in neurons and PC-12 cells and find that the C-terminal domain of the $\alpha$ subunit is necessary for localization to dendrites. Moreover, monomeric forms of the enzyme gain access to the nucleus. Attempts made to identify novel CaM kinase binding proteins using the yeast two-hybrid system resulted in the isolation of hundreds of positive clones. Those that have been sequenced are identical to CaM kinase isoforms. Finally, we report the discovery of specific regions within the C-terminal domain that are necessary and sufficient for subunit-subunit interactions. Differences between the $\alpha$ and $\beta$ isoforms were discovered that indicate unique structural requirements for oligomerization. A model for how CaM kinase subunits interact to form holoenzymes and how structural heterogeneity might influence CaM kinase function is presented. ^

Specific conductivity and hydrogen ions measured on two ice core (NEEM and NGRIP)

A stratigraphy-based chronology for the North Greenland Eemian Ice Drilling (NEEM) ice core has been derived by transferring the annual layer counted Greenland Ice Core Chronology 2005 (GICC05) and its model extension (GICC05modelext) from the NGRIP core to the NEEM core using 787 match points of mainly volcanic origin identified in the electrical conductivity measurement (ECM) and dielectrical profiling (DEP) records. Tephra horizons found in both the NEEM and NGRIP ice cores are used to test the matching based on ECM and DEP and provide five additional horizons used for the timescale transfer. A thinning function reflecting the accumulated strain along the core has been determined using a Dansgaard-Johnsen flow model and an isotope-dependent accumulation rate parameterization. Flow parameters are determined from Monte Carlo analysis constrained by the observed depth-age horizons. In order to construct a chronology for the gas phase, the ice age-gas age difference (Delta age) has been reconstructed using a coupled firn densification-heat diffusion model. Temperature and accumulation inputs to the Delta age model, initially derived from the water isotope proxies, have been adjusted to optimize the fit to timing constraints from d15N of nitrogen and high-resolution methane data during the abrupt onset of Greenland interstadials. The ice and gas chronologies and the corresponding thinning function represent the first chronology for the NEEM core, named GICC05modelext-NEEM-1. Based on both the flow and firn modelling results, the accumulation history for the NEEM site has been reconstructed. Together, the timescale and accumulation reconstruction provide the necessary basis for further analysis of the records from NEEM.

Physicochemical and photosynthetic characteristics of water samples obtained during a CCGS Amundsen cruise in 2008

During summer 2008, as part of the Circumpolar Flaw Lead system study, we measured phytoplankton photosynthetic parameters to understand regional patterns in primary productivity, including the degree and timescale of photoacclimation and how variability in environmental conditions influences this response. Photosynthesis-irradiance measurements were taken at 15 sites primarily from the depth of the subsurface chlorophyll a (Chl a) maximum (SCM) within the Beaufort Sea flaw lead polynya. The physiological response of phytoplankton to a range of light levels was used to assess maximum rates of carbon (C) fixation (P*m), photosynthetic efficiency (alpha*), photoacclimation (Ek), and photoinhibition (beta*). SCM samples taken along a transect from under ice into open water exhibited a >3-fold increase in alpha* and P*m, showing these parameters can vary substantially over relatively small spatial scales, primarily in response to changes in the ambient light field. Algae were able to maintain relatively high rates of C fixation despite low light at the SCM, particularly in the large (>5 µm) size fraction at open water sites. This may substantially impact biogenic C drawdown if species composition shifts in response to future climate change. Our results suggest that phytoplankton in this region are well acclimated to existing environmental conditions, including sea ice cover, low light, and nutrient pulses. Furthermore, this photoacclimatory response can be rapid and keep pace with a developing SCM, as phytoplankton maintain photosynthetic rates and efficiencies in a narrow ''shade-acclimated'' range.