Therapeutic angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with critical limb ischemia

This study evaluated the efficacy and safety of intramuscular administration of NV1FGF, a plasmid-based angiogenic gene delivery system for local expression of fibroblast growth factor 1 (FGF-1), versus placebo, in patients with critical limb ischemia (CLI). In a double-blind, randomized, placebo-controlled, European, multinational study, 125 patients in whom revascularization was not considered to be a suitable option, presenting with nonhealing ulcer(s), were randomized to receive eight intramuscular injections of placebo or 2.5 ml of NV1FGF at 0.2 mg/ml on days 1, 15, 30, and 45 (total 16 mg: 4 x 4 mg). The primary end point was occurrence of complete healing of at least one ulcer in the treated limb at week 25. Secondary end points included ankle brachial index (ABI), amputation, and death. There were 107 patients eligible for evaluation. Improvements in ulcer healing were similar for use of NV1FGF (19.6%) and placebo (14.3%; P = 0.514). However, the use of NV1FGF significantly reduced (by twofold) the risk of all amputations [hazard ratio (HR) 0.498; P = 0.015] and major amputations (HR 0.371; P = 0.015). Furthermore, there was a trend for reduced risk of death with the use of NV1FGF (HR 0.460; P = 0.105). The adverse event incidence was high, and similar between the groups. In patients with CLI, plasmid-based NV1FGF gene transfer was well tolerated, and resulted in a significantly reduced risk of major amputation when compared with placebo.

On the modeling of drug induced respiratory depression in the non-steady-state

The ability of anesthetic agents to provide adequate analgesia and sedation is limited by the ventilatory depression associated with overdosing in spontaneously breathing patients. Therefore, quantitation of drug induced ventilatory depression is a pharmacokinetic-pharmacodynamic problem relevant to the practice of anesthesia. Although several studies describe the effect of respiratory depressant drugs on isolated endpoints, an integrated description of drug induced respiratory depression with parameters identifiable from clinically available data is not available. This study proposes a physiological model of CO2 disposition, ventilatory regulation, and the effects of anesthetic agents on the control of breathing. The predictive performance of the model is evaluated through simulations aimed at reproducing experimental observations of drug induced hypercarbia and hypoventilation associated with intravenous administration of a fast-onset, highly potent anesthetic mu agonist (including previously unpublished experimental data determined after administration of 1 mg alfentanil bolus). The proposed model structure has substantial descriptive capability and can provide clinically relevant predictions of respiratory inhibition in the non-steady-state to enhance safety of drug delivery in the anesthetic practice.

Study of water use and supply in the district of Independencia, Peru

Peru is a developing country with abundant fresh water resources, yet the lack of infrastructure leaves much of the population without access to safe water for domestic uses. The author of this report was a Peace Corps Volunteer in the sector of water & sanitation in the district of Independencia, Ica, Peru. Independencia is located in the arid coastal region of the country, receiving on average 15 mm of rain annually. The water source for this district comes from the Pisco River, originating in the Andean highlands and outflowing into the Pacific Ocean near the town of Pisco, Peru. The objectives of this report are to assess the water supply and sanitation practices, model the existing water distribution system, and make recommendations for future expansion of the distribution system in the district of Independencia, Peru. The assessment of water supply will be based on the results from community surveys done in the district of Independencia, water quality testing done by a detachment of the U.S. Navy, as well as on the results of a hydraulic model built in EPANET 2.0 to represent the distribution system. Sanitation practice assessments will be based on the surveys as well as observations from the author while living in Peru. Recommendations for system expansions will be made based on results from the EPANET model and the municipality’s technical report for the existing distribution system. Household water use and sanitation surveys were conducted with 84 families in the district revealing that upwards of 85% store their domestic water in regularly washed containers with lids. Over 80% of those surveyed are drinking water that is treated, mostly boiled. Of those surveyed, over 95% reported washing their hands and over 60% mentioned at least one critical time for hand washing when asked for specific instances. From the surveys, it was also discovered that over 80% of houses are properly disposing of excrement, in either latrines or septic tanks. There were 43 families interviewed with children five years of age or under, and just over 18% reported the child had a case of diarrhea within the last month at the time of the interview. Finally, from the surveys it was calculated that the average water use per person per day is about 22 liters. Water quality testing carried out by a detachment of the U.S. Navy revealed that the water intended for consumption in the houses surveyed was not suitable for consumption, with a median E. coli most probable number of 47/100 ml for the 61 houses sampled. The median total coliforms was 3,000 colony forming units per 100 ml. EPANET was used to simulate the water delivery system and evaluate its performance. EPANET is designed for continuous water delivery systems, assuming all pipes are always flowing full. To account for the intermittent nature of the system, multiple EPANET network models were created to simulate how water is routed to the different parts of the system throughout the day. The models were created from interviews with the water technicians and a map of the system created using handheld GPS units. The purpose is to analyze the performance of the water system that services approximately 13,276 people in the district of Independencia, Peru, as well as provide recommendations for future growth and improvement of the service level. Performance evaluation of the existing system is based on meeting 25 liters per person per day while maintaining positive pressure at all nodes in the network. The future performance is based on meeting a minimum pressure of 20 psi in the main line, as proposed by Chase (2000). The EPANET model results yield an average nodal pressure for all communities of 71 psi, with a range from 1.3 – 160 psi. Thus, if the current water delivery schedule obtained from the local municipality is followed, all communities should have sufficient pressure to deliver 25 l/p/d, with the exception of Los Rosales, which can only supply 3.25 l/p/d. However, if the line to Los Rosales were increased from one to four inches, the system could supply this community with 25 l/p/d. The district of Independencia could greatly benefit from increasing the service level to 24-hour water delivery and a minimum of 50 l/p/d, so that communities without reliable access due to insufficient pressure would become equal beneficiaries of this invaluable resource. To evaluate the feasibility of this, EPANET was used to model the system with a range of population growth rates, system lifetimes, and demands. In order to meet a minimum pressure of 20 psi in the main line, the 6-inch diameter main line must be increased and approximately two miles of trench must be excavated up to 30 feet deep. The sections of the main line that must be excavated are mile 0-1 and 1.5-2.5, and the first 3.4 miles of the main line must be increased from 6 to 16 inches, contracting to 10 inches for the remaining 5.8 miles. Doing this would allow 24-hour water delivery and provide 50 l/p/d for a range of population growth rates and system lifetimes. It is expected that improving the water delivery service would reduce the morbidity and mortality from diarrheal diseases by decreasing the recontamination of the water due to transport and household storage, as well as by maintaining continuous pressure in the system to prevent infiltration of contaminated groundwater. However, this expansion must be carefully planned so as not to affect aquatic ecosystems or other districts utilizing water from the Pisco River. It is recommended that stream gaging of the Pisco River and precipitation monitoring of the surrounding watershed is initiated in order to begin a hydrological study that would be integrated into the district’s water resource planning. It is also recommended that the district begin routine water quality testing, with the results available to the public.

Quantum modeling of bioconjugated nanomaterials

In recent years, the bio-conjugated nanostructured materials have emerged as a new class of materials for the bio-sensing and medical diagnostics applications. In spite of their multi-directional applications, interfacing nanomaterials with bio-molecules has been a challenge due to somewhat limited knowledge about the underlying physics and chemistry behind these interactions and also for the complexity of biomolecules. The main objective of this dissertation is to provide such a detailed knowledge on bioconjugated nanomaterials toward their applications in designing the next generation of sensing devices. Specifically, we investigate the changes in the electronic properties of a boron nitride nanotube (BNNT) due to the adsorption of different bio-molecules, ranging from neutral (DNA/RNA nucleobases) to polar (amino acid molecules). BNNT is a typical member of III-V compounds semiconductors with morphology similar to that of carbon nanotubes (CNTs) but with its own distinct properties. More specifically, the natural affinity of BNNTs toward living cells with no apparent toxicity instigates the applications of BNNTs in drug delivery and cell therapy. Our results predict that the adsorption of DNA/RNA nucleobases on BNNTs amounts to different degrees of modulation in the band gap of BNNTs, which can be exploited for distinguishing these nucleobases from each other. Interestingly, for the polar amino acid molecules, the nature of interaction appeared to vary ranging from Coulombic, van der Waals and covalent depending on the polarity of the individual molecules, each with a different binding strength and amount of charge transfer involved in the interaction. The strong binding of amino acid molecules on the BNNTs explains the observed protein wrapping onto BNNTs without any linkers, unlike carbon nanotubes (CNTs). Additionally, the widely varying binding energies corresponding to different amino acid molecules toward BNNTs indicate to the suitability of BNNTs for the biosensing applications, as compared to the metallic CNTs. The calculated I-V characteristics in these bioconjugated nanotubes predict notable changes in the conductivity of BNNTs due to the physisorption of DNA/RNA nucleobases. This is not the case with metallic CNTs whose transport properties remained unaltered in their conjugated systems with the nucleobases. Collectively, the bioconjugated BNNTs are found to be an excellent system for the next generation sensing devices.

Drug targeting using OX7-immunoliposomes: correlation between Thy1.1 antigen expression and tissue distribution in the rat

OX7 monoclonal antibody F((ab')2) fragments directed against Thy1.1 antigen can be used for drug targeting by coupling to the surface of drug-loaded liposomes. Such OX7-conjugated immunoliposomes (OX7-IL) were used recently for drug delivery to rat glomerular mesangial cells, which are characterized by a high level of Thy1.1 antigen expression. In the present study, the relationship between OX7-IL tissue distribution and target Thy1.1 antigen localization in different organs in rat was investigated. Western blot and immunohistofluorescence analysis revealed a very high Thy1.1 expression in brain cortex and striatum, thymus and renal glomeruli. Moderate Thy1.1 levels were observed in the collecting ducts of kidney, lung tissue and spleen. Thy1.1 was not detected in liver and heart. There was a poor correlation between Thy1.1 expression levels and organ distribution of fluorescence- or (14)C-labeled OX7-IL. The highest overall organ density of OX7-IL was observed in the spleen, followed by lung, liver and kidney. Heart and brain remained negative. With respect to intra-organ distribution, a localized and distinct signal was observed in renal glomerular mesangial cells only. As a consequence, acute pharmacological (i.e. toxic) effects of doxorubicin-loaded OX7-IL were limited to renal glomeruli. The competition with unbound OX7 monoclonal antibody F((ab')2) fragments demonstrated that the observed tissue distribution and acute pharmacological effects of OX7-IL were mediated specifically by the conjugated OX7 antibody. It is concluded that both the high target antigen density and the absence of endothelial barriers are needed to allow for tissue-specific accumulation and pharmacological effects of OX7-IL. The liposomal drug delivery strategy used is therefore specific toward renal glomeruli and can be expected to reduce the risk of unwanted side effects in other tissues.

Fetal gene therapy: opportunities and risks

Advances in human prenatal medicine and molecular genetics have allowed the diagnosis of many genetic diseases early in gestation. In-utero transplantation of allogeneic hematopoietic stem cells (HSC) has been successfully used as a therapy in different animal models and recently also in human fetuses. Unfortunately, clinical success of this novel treatment is limited by the lack of donor cell engraftment in non-immunocompromised hosts and is thus restricted to diseases where the fetus is affected by severe immunodeficiency. Gene therapy using genetically modified autologous HSC circumvents allogeneic HLA barriers and constitutes one of the most promising new approaches to correct genetic deficits in the fetus. Recent developments of strategies to overcome failure of efficient transduction of quiescent hematopoietic cells include the use of new vector constructs and transduction protocols. These improvements open new perspectives for gene therapy in general and for prenatal gene transfer in particular. The fetus may be especially susceptible for successful gene therapy due to the immunologic naiveté of the immature hematopoietic system during gestation, precluding an immune reaction towards the transgene. Ethical issues, in particular those regarding treatment safety, must be taken into account before clinical trials with fetal gene therapy in human pregnancies can be initiated.

Heart failure gene therapy: the path to clinical practice

Gene therapy, aimed at the correction of key pathologies being out of reach for conventional drugs, bears the potential to alter the treatment of cardiovascular diseases radically and thereby of heart failure. Heart failure gene therapy refers to a therapeutic system of targeted drug delivery to the heart that uses formulations of DNA and RNA, whose products determine the therapeutic classification through their biological actions. Among resident cardiac cells, cardiomyocytes have been the therapeutic target of numerous attempts to regenerate systolic and diastolic performance, to reverse remodeling and restore electric stability and metabolism. Although the concept to intervene directly within the genetic and molecular foundation of cardiac cells is simple and elegant, the path to clinical reality has been arduous because of the challenge on delivery technologies and vectors, expression regulation, and complex mechanisms of action of therapeutic gene products. Nonetheless, since the first demonstration of in vivo gene transfer into myocardium, there have been a series of advancements that have driven the evolution of heart failure gene therapy from an experimental tool to the threshold of becoming a viable clinical option. The objective of this review is to discuss the current state of the art in the field and point out inevitable innovations on which the future evolution of heart failure gene therapy into an effective and safe clinical treatment relies.

New approach to direct stenting using a novel "all-in-one" coronary stent system via 5 French diagnostic catheters: a pilot study

OBJECTIVES We sought to evaluate the strategy success and short term clinical outcomes of direct stenting via 5 French (F) diagnostic catheters using a novel bare metal stent with integrated delivery system (IDS) (Svelte Medical Systems, New Providence, NJ) and compare the results to a conventionally treated matched group. METHODS Fifteen consecutive patients with lesions deemed suitable for direct stenting using a bare metal stent were included. The primary endpoint was the strategy success defined as the ability to successfully treat a target lesion via a 5 F diagnostic catheter with a good angiographic result (TIMI III flow, residual stenosis ≤20%). Procedure and fluoroscopy times, contrast agent use, cost, and short-term clinical outcomes were compared to a matched group treated via conventional stenting. RESULTS The primary endpoint was reached in 14/15 patients (93%). There were no significant differences in procedural (58.6 min ± 12.7 vs. 57.4 min ± 14.2) or fluoroscopy times (10.0 min ± 4.3 vs.10.1 min ± 3.9) or contrast agent use (193.7 ml ± 54.8 vs. 181.4 ml ± 35.6). However, there were significant reductions in materials used in the study group compared to the control group equating to cost savings of almost US $600 per case (US $212.44 ± 258.09 vs. US $804.69 ± 468.11; P = 0.001). CONCLUSIONS Direct stenting using a novel bare metal stent with an IDS via 5 F diagnostic catheters is a viable alternative to conventional stenting in selected patients and is associated with significant cost savings.

A compact and portable deposition chamber to study nanoparticles in air-exposed tissue

BACKGROUND Epidemiological studies show that elevated levels of particulate matter in ambient air are highly correlated with respiratory and cardiovascular diseases. Atmospheric particles originate from a large number of sources and have a highly complex and variable composition. An assessment of their potential health risks and the identification of the most toxic particle sources would require a large number of investigations. Due to ethical and economic reasons, it is desirable to reduce the number of in vivo studies and to develop suitable in vitro systems for the investigation of cell-particle interactions. METHODS We present the design of a new particle deposition chamber in which aerosol particles are deposited onto cell cultures out of a continuous air flow. The chamber allows for a simultaneous exposure of 12 cell cultures. RESULTS Physiological conditions within the deposition chamber can be sustained constantly at 36-37°C and 90-95% relative humidity. Particle deposition within the chamber and especially on the cell cultures was determined in detail, showing that during a deposition time of 2 hr 8.4% (24% relative standard deviation) of particles with a mean diameter of 50 nm [mass median diameter of 100 nm (geometric standard deviation 1.7)] are deposited on the cell cultures, which is equal to 24-34% of all charged particles. The average well-to-well variability of particles deposited simultaneously in the 12 cell cultures during an experiment is 15.6% (24.7% relative standard deviation). CONCLUSIONS This particle deposition chamber is a new in vitro system to investigate realistic cell-particle interactions at physiological conditions, minimizing stress on the cell cultures other than from deposited particles. A detailed knowledge of particle deposition characteristics on the cell cultures allows evaluating reliable dose-response relationships. The compact and portable design of the deposition chamber allows for measurements at any particle sources of interest.

Targeted Multistage Delivery of Nanoparticles to the Bone Marrow

Bone marrow is a target organ site involved in multiple diseases including myeloproliferative disorders and hematologic malignancies and metastases from breast and prostate. Most of these diseases are characterized with poor quality of life, and the treatment options are only palliative due to lack of delivery mechanisms for systemically injected drugs which results in dose limitation to protect the healthy hematopoietic cells. Therefore, there is a critical need to develop effective therapeutic strategies that allow for selective delivery of therapeutic payload to the bone marrow. Nanotechnology-based drug delivery systems provide the opportunity to deliver drugs to the target tissue while decreasing exposure to normal tissues. E-selectin is constitutively expressed on the bone marrow vasculature, but almost absent in normal vessels, and therefore, E-selectin targeted drug delivery presents an ideal strategy for the delivery of therapeutic nanoparticles to the bone marrow. The objective of this study was to develop a novel bone marrow targeted multistage vector (MSV) via E-selectin for delivery of therapeutics and imaging agents. To achieve this goal, Firstly, an E-selectin thioaptamer (ESTA) ligand was identified through a two-step screening from a combinatorial thioaptamer library. Next, ESTA-conjugated MSV (ESTA-MSV) were developed and evaluated for their stability and binding to E-selectin expressing endothelial cells. Different types of nanoparticles including liposomes, quantum dots, and iron oxide nanoparticles were loaded into the porous structure of ESTA-MSV. In vivo targeting experiments demonstrated 8-fold higher accumulation of ESTA-MSV in the mouse bone marrow as compared to non-targeted MSV Furthermore, intravenous injection of liposomes loaded ESTA-MSV resulted in a significantly higher accumulation of liposome in the bone marrow space as compared to injection of non-targeted MSV or liposomes alone. Overall this study provides first evidence that E-selectin targeted multistage vector preferentially targets to bone marrow vasculature and delivers larger amounts of nanoparticles. This delivery strategy holds potential for the selective delivery of large amounts of therapeutic payload to the vascular niches in the bone marrow for the treatment of bone marrow associated diseases.

Cytochrome P450 in mammalian brain: Purification, anatomical distribution and regulation of the cytochrome P450 monooxygenase system in rat brain

The cytochrome P450 (P450) monooxygenase system plays a major role in metabolizing a wide variety of xenobiotic as well as endogenous compounds. In performing this function, it serves to protect the body from foreign substances. However, in a number of cases, P450 activates procarcinogens to cause harm. In most animals, the highest level of activity is found in the liver. Virtually all tissues demonstrate P450 activity, though, and the role of the P450 monooxygenase system in these other organs is not well understood. In this project I have studied the P450 system in rat brain; purifying NADPH-cytochrome P450 reductase (reductase) from that tissue. In addition, I have examined the distribution and regulation of expression of reductase and P450 in various anatomical regions of the rat brain.^ NADPH-cytochrome P450 reductase was purified to apparent homogeneity and cytochrome P450 partially purified from whole rat brain. Purified reductase from brain was identical to liver P450 reductase by SDS-PAGE and Western blot techniques. Kinetic studies utilizing cerebral P450 reductase reveal Km values in close agreement with those determined with enzyme purified from rat liver. Moreover, the brain P450 reductase was able to function successfully in a reconstituted microsomal system with partially purified brain cytochrome P450 and with purified hepatic P4501A1 as measured by 7-ethoxycoumarin and 7-ethoxyresorufin O-deethylation. These results indicate that the reductase and P450 components may interact to form a competent drug metabolism system in brain tissue.^ Since the brain is not a homogeneous organ, dependent upon the well orchestrated interaction of numerous parts, pathology in one nucleus may have a large impact upon its overall function. Hence, the anatomical distribution of the P450 monooxygenase system in brain is important in elucidating its function in that organ. Related to this is the regulation of P450 expression in brain. In order to study these issues female rats--both ovariectomized and not--were treated with a number of xenobiotic compounds and sex steroids. The brains from these animals were dissected into 8 discrete regions and the presence and relative level of message for P4502D and reductase determined using polymerase chain reaction. Results of this study indicate the presence of mRNA for reductase and P4502D isoforms throughout the rat brain. In addition, quantitative PCR has allowed the determination of factors affecting the expression of message for these enzymes. ^

The evolution and assessment of pharmaceutical care: Structure, processes, and outcomes

The evolution of pharmaceutical care is identified through a complete review of the literature published in the American Journal of Health-System Pharmacy, the sole comprehensive publication of institutional pharmacy practice. The evolution is categorized according to characteristics of structure (organizational structure, the role of the pharmacist), process (drug delivery systems, formulary management, acquiring drug products, methods to impact drug therapy decisions), and outcomes (cost of drug delivery, cost of drug acquisition and use, improved safety, improved health outcomes) recorded from the 1950s through the 1990s. While significant progress has been made in implementing basic drug distribution systems, levels of pharmacy involvement with direct patient care is still limited.^ A new practice framework suggests enhanced direct patient care involvement through increase in the efficiency and effectiveness of traditional pharmacy services. Recommendations advance internal and external organizational structure relationships that position pharmacists to fully use their unique skills and knowledge to impact drug therapy decisions and outcomes. Specific strategies facilitate expansion of the breadth and scope of each process component in order to expand the depth of integration of pharmacy and pharmaceutical care within the broad healthcare environment. Economic evaluation methods formally evaluate the impact of both operational and clinical interventions.^ Outcome measurements include specific recommendations and methods to increase efficiency of drug acquisition, emphasizing pharmacists' roles that impact physician prescribing decisions. Effectiveness measures include those that improve safety of drug distribution systems, decrease the potential of adverse drug therapy events, and demonstrate that pharmaceutical care can significantly contribute to improvement in overall health status.^ The implementation of the new framework is modeled on a case study at the M.D. Anderson Cancer Center. The implementation of several new drug distribution methods facilitated the redeployment of personnel from distributive functions to direct patient care activities with significant personnel and drug cost reduction. A cost-benefit analysis illustrates that framework process enhancements produced a benefit-to-cost ratio of 7.9. In addition, measures of effectiveness demonstrated significant levels of safety and enhanced drug therapy outcomes. ^

Interactions of Polyvinylpyrrolidone with Chlorin e6-Based Photosensitizers Studied by NMR and Electronic Absorption Spectroscopy

Polyvinylpyrrolidone (PVP) can act as potential drug delivery vehicle for porphyrin-based photosensitizers in photodynamic therapy (PDT) to enhance their stability and prevent porphyrin self-association. In the present study the interactions of PVP (MW 10 kDa) were probed with five different derivatives of chlorin e6 (CE6) bearing either one of the amino acids serine, lysine, tyrosine or arginine, or monoamino-hexanoic acid as substituent. All derivatives of CE6 (xCE) formed aggregates of a similar structure in aqueous buffer in the millimolar range. In the presence of PVP monomerization of all xCE aggregates could be proved by 1H NMR spectroscopy. xCE-PVP complex formation was confirmed by 1H NMR T2 relaxation and diffusion ordered spectroscopy (DOSY). 1H1H-NOESY data suggested that the xCE uptake into the PVP polymer matrix is governed by hydrophobic interactions. UV–vis absorption and fluorescence emission bands of xCE in the micromolar range revealed characteristic PVP-induced bathochromic shifts. The presented data point out the potential of PVP as carrier system for amphiphilic derivatives of chlorin e6. The capacity of PVP to monomerize xCE aggregates may enhance their efficiency as possible photosensitizers in PDT.

Evaluating the impact of vertical integration on health system peformance

Vertical integration is grounded in economic theory as a corporate strategy for reducing cost and enhancing efficiency. There were three purposes for this dissertation. The first was to describe and understand vertical integration theory. The review of the economic theory established vertical integration as a corporate cost reduction strategy in response to environmental, structural and performance dimensions of the market. The second purpose was to examine vertical integration in the context of the health care industry, which has greater complexity, higher instability, and more unstable demand than other industries, although many of the same dimensions of the market supported a vertical integration strategy. Evidence on the performance of health systems after integration revealed mixed results. Because the market continues to be turbulent, hybrid non-owned integration in the form of alliances have increased to over 40% of urban hospitals. The third purpose of the study was to examine the application of vertical integration in health care and evaluate the effects. The case studied was an alliance formed between a community hospital and a tertiary medical center to facilitate vertical integration of oncology services while maintaining effectiveness and preserving access. The economic benefits for 1934 patients were evaluated in the delivery system before and after integration with a more detailed economic analysis of breast, lung, colon/rectal, and non-malignant cases. A regression analysis confirmed the relationship between the independent variables of age, sex, location of services, race, stage of disease, and diagnosis, and the dependent variable, cost. The results of the basic regression model, as well as the regression with first-order interaction terms, were statistically significant. The study shows that vertical integration at an intermediate health care system level has economic benefits. If the pre-integration oncology group had been treated in the post-integration model, the expected cost savings from integration would be 31.5%. Quality indicators used were access to health care services and research treatment protocols, and access was preserved in the integrated model. Using survival as a direct quality outcome measure, the survival of lung cancer patients was statistically the same before and after integration. ^

Validation of an instrument for assessing the medicolegal death investigation system: A public health approach

Background. This study validated the content of an instrument designed to assess the performance of the medicolegal death investigation system. The instrument was modified from Version 2.0 of the Local Public Health System Performance Assessment Instrument (CDC) and is based on the 10 Essential Public Health Services. ^ Aims. The aims were to employ a cognitive testing process to interview a randomized sample of medicolegal death investigation office leaders, qualitatively describe the results, and revise the instrument accordingly. ^ Methods. A cognitive testing process was used to validate the survey instrument's content in terms of the how well participants could respond to and interpret the questions. Twelve randomly selected medicolegal death investigation chiefs (or equivalent) that represented the seven types of medicolegal death investigation systems and six different state mandates were interviewed by telephone. The respondents also were representative of the educational diversity within medicolegal death investigation leadership. Based on respondent comments, themes were identified that permitted improvement of the instrument toward collecting valid and reliable information when ultimately used in a field survey format. ^ Results. Responses were coded and classified, which permitted the identification of themes related to Comprehension/Interpretation, Retrieval, Estimate/Judgment, and Response. The majority of respondent comments related to Comprehension/Interpretation of the questions. Respondents identified 67 questions and 6 section explanations that merited rephrasing, adding, or deleting examples or words. In addition, five questions were added based on respondent comments. ^ Conclusion. The content of the instrument was validated by cognitive testing method design. The respondents agreed that the instrument would be a useful and relevant tool for assessing system performance. ^