Determination of potential toxicodynamic differences of pyrethroid insecticides on native voltage-sensitive sodium channels in juvenile versus adult rat brain.

Microtransplantation of neurolemma tissue fragments from mammalian brain into the plasma membrane of Xenopus laevis oocytes is a tool to examine the endogenous structure and function of various ion channels and receptors associated with the central nervous system. Microtransplanted neurolemma can originate from a variety of sources, contain ion channels and receptors in their native configuration, and are applicable to examine diseases associated with different channelopathies. Here, we examined potential age-related differences in voltage-sensitive sodium channel (VSSC) expression and concentration-dependent responses to pyrethroids following the microtransplantation of juvenile or adult rat brain tissue (neurolemma) into X. laevis oocytes. Using automated western blotting, adult neurolemma exhibited a 2.5-fold higher level of expression of VSSCs compared with juvenile neurolemma. The predominant isoform expressed in both tissues was Nav1.2. However, adult neurolemma expressed 2.8-fold more Nav1.2 than juvenile and expressed Nav1.6 at a significantly higher level (2.2-fold). Microtransplanted neurolemma elicited ion currents across the plasma membrane of oocytes following membrane depolarization using two electrode voltage clamp electrophysiology. A portion of this current was sensitive to tetrodotoxin (TTX) and this TTX-sensitive current was abolished when external sodium ion was replaced by choline ion, functionally demonstrating the presence of native VSSC. Increasing concentrations of permethrin or deltamethrin exhibited concentration-dependent increases in inward TTX-sensitive current in the presence of niflumic acid from both adult and juvenile tissues following a pulsed depolarization of the oocyte plasma membrane. Concentration-dependent response curves illustrate that VSSCs associated with juvenile neurolemma were up to 2.5-fold more sensitive to deltamethrin than VSSCs in adult neurolemma. In contrast, VSSCs from juvenile neurolemma were less sensitive to permethrin than adult VSSCs at lower concentrations (0.6-0.8-fold) but were more sensitive at higher concentrations (up to 2.4-fold). Nonetheless, because the expected concentrations in human brains following realistic exposure levels are approximately 21- (deltamethrin) to 333- (permethrin) times below the threshold concentration for response in rat neurolemma-injected oocytes, age-related differences, if any, are not likely to be toxicologically relevant.

Using financial incentives to improve value in orthopaedics.

BACKGROUND: A variety of reforms to traditional approaches to provider payment and benefit design are being implemented in the United States. There is increasing interest in applying these financial incentives to orthopaedics, although it is unclear whether and to what extent they have been implemented and whether they increase quality or reduce costs. QUESTIONS/PURPOSES: We reviewed and discussed physician- and patient-oriented financial incentives being implemented in orthopaedics, key challenges, and prerequisites to payment reform and value-driven payment policy in orthopaedics. METHODS: We searched the MEDLINE database using as search terms various provider payment and consumer incentive models. We retrieved a total of 169 articles; none of these studies met the inclusion criteria. For incentive models known to the authors to be in use in orthopaedics but for which no peer-reviewed literature was found, we searched Google for further information. RESULTS: Provider financial incentives reviewed include payments for reporting, performance, and patient safety and episode payment. Patient incentives include tiered networks, value-based benefit design, reference pricing, and value-based purchasing. Reform of financial incentives for orthopaedic surgery is challenged by (1) lack of a payment/incentive model that has demonstrated reductions in cost trends and (2) the complex interrelation of current pay schemes in today's fragmented environment. Prerequisites to reform include (1) a reliable and complete data infrastructure; (2) new business structures to support cost sharing; and (3) a retooling of patient expectations. CONCLUSIONS: There is insufficient literature reporting the effects of various financial incentive models under implementation in orthopaedics to know whether they increase quality or reduce costs. National concerns about cost will continue to drive experimentation, and all anticipated innovations will require improved collaboration and data collection and reporting.

Split-plot designs for robotic serial dilution assays.

This article explores effective implementation of split-plot designs in serial dilution bioassay using robots. We show that the shortest path for a robot to fill plate wells for a split-plot design is equivalent to the shortest common supersequence problem in combinatorics. We develop an algorithm for finding the shortest common supersequence, provide an R implementation, and explore the distribution of the number of steps required to implement split-plot designs for bioassay through simulation. We also show how to construct collections of split plots that can be filled in a minimal number of steps, thereby demonstrating that split-plot designs can be implemented with nearly the same effort as strip-plot designs. Finally, we provide guidelines for modeling data that result from these designs.

Quality measurement in orthopaedics: the purchasers' view.

While all of medicine is under pressure to increase transparency and accountability, joint replacement subspecialists will face special scrutiny. Disclosures of questionable consulting fees, a demographic shift to younger patients, and uncertainty about the marginal benefits of product innovation in a time of great cost pressure invite a serious and progressive response from the profession. Current efforts to standardize measures by the National Quality Forum and PQRI will not address the concerns of purchasers, payors, or policy makers. Instead, they will ask the profession to document its commitment to appropriateness, stewardship of resources, coordination of care, and patient-centeredness. One mechanism for addressing these expectations is voluntary development of a uniform national registry for joint replacements that includes capture of preoperative appropriateness indicators, device monitoring information, revision rates, and structured postoperative patient followup. A national registry should support performance feedback and quality improvement activity, but it must also be designed to satisfy payor, purchaser, policymaker, and patient needs for information. Professional societies in orthopaedics should lead a collaborative process to develop metrics, infrastructure, and reporting formats that support continuous improvement and public accountability.

The missing link: bridging the patient-provider health information gap.

Widespread adoption of information technology is now regarded as a pathway to improving health care and achieving the Institute of Medicine's highly regarded six aims for redesigning care. Achieving these aims requires fresh approaches to health system design, including continuous healing relationships between physicians and patients and provision of tools to help patients be more active participants in their own care. Personal health records (PHRs) might allow patients and providers to develop new ways of collaborating and provide the basis for broader transformation of the health care system. Federal policies can be key catalysts in accelerating PHR development and adoption.

Assessing parallelism prior to determining relative potency.

In the course of preparing a revision to Chapter (111) of the U.S. Pharmacopeia, the revision committee came to a unanimous agreement that the method for assessing parallelism that is currently presented in (111) and in the European Pharmacopeia's Chapter 5.3 is flawed and should be replaced. The symptoms are that perfectly acceptable assay results may fail due to good precision and that obviously faulty assay results may pass due to poor precision. The flaw is that the wrong statistical technique has been used. We propose an alternative approach based on the equivalence testing paradigm that does not have these shortcomings. Equivalence testing requires the establishment of equivalence limits. Specific approaches for establishing equivalence limits are discussed.

Pain measurement and pain behavior.

This study examined relationships between chronic pain patients' ratings of pain severity, and other patient ratings about severity of associated impairment, and a series of behavioral measures of health care utilization and activity patterns. Prior to being evaluated, a sample of 150 chronic pain patients completed diary forms on which they recorded severity of pain on a 0-10 scale. Subjects were divided into high-medium-low on mean pain ratings, and were compared on the other measures obtained either from diary forms or at time of evaluation. Patient generated statements about severity of pain and extent of functional impairment from pain interrelated positively. However, these measures showed few relationships to medication consumption, health care utilization, diary recorded activity level, or to patient reported frequency counts of engaging in a set of commonplace activities. The results were interpreted to suggest that, in chronic pain, there may be a questionable relationship between what people say about their pain and what they do. Accordingly, the evaluation of chronic pain should include analyses of patient behavior.

Quality Care for People with HIV/AIDS: patients' perspectives.

PURPOSE: To explore patient preferences to aid in the development of quality measures to assess quality of health care for people living with human immunodeficiency virus/acquired immunodeficiency disease (HIV/AIDS). METHOD: This study involved three 2-hour focus groups with 29 people living with HIV/AIDS in Portland, Oregon, and San Francisco, California. Eighteen quality of care indicators for HIV/AIDS health care were presented to each group and quantitative rankings were obtained. Aggregated weightings were used to rank and prioritize the quality measures for further exploration. RESULTS: Participants identified 38 themes relevant to high-quality care for HIV/AIDS. Patients ranked the following candidate measures most important: effective relationship with provider, prevention of opportunistic infections, involvement in care and treatment decisions, being offered antiretroviral treatment, and access to health care services. We observed attitudinal differences among focus group participants that corresponded to gender and race/ethnicity. CONCLUSION: Participants favored quality information that rated the experience of care and outcome measures including indicators of access to services, standard treatments, and competence of the providers. Patient perspectives can inform the development of quality measures that are meaningful to consumers and can assist in the design of services that meet patients' demographic and socioeconomic needs.

Improving quality through public disclosure of performance information.

Despite a growing consensus that serious quality problems afflict U.S. health care, state and federal governments have done little to improve the quality of care. Proposed health insurance reforms, including a Medicare prescription drug benefit and the use of tax credits for insurance expansion, could create a mechanism for stimulating and then monitoring improvements in quality. We propose legislative requirements that any new expenditure of federal funds for health benefits be accompanied by public disclosure of performance information regarding quality, effectiveness, and safety. Such disclosure could yield diverse public and institutional benefits.

Consumers and quality-driven health care: a call to action.

A key strategy for driving improvements in health care quality is providing comparative quality information to consumers. This strategy will not work, and could even be counterproductive, unless (1) consumers are convinced that quality problems are real and consequential and that quality can be improved; (2) purchasers and policymakers make sure that quality reporting is standardized and universal; (3) consumers are given quality information that is relevant and easy to understand and use; (4) the dissemination of quality information is improved; and (5) purchasers reward quality improvements and providers create the information and organizational infrastructure to achieve them.

Understanding the continuum of palliative care for patients and their caregivers.

We describe a process for assisting seriously ill patients and their caregivers in prioritizing their preferences for care during advanced illness. Thirty-two seriously ill patients and their caregivers participated in seven 90-minute focus groups conducted cross-sectionally in Denver, Colorado; San Francisco, California; and Washington State. Fourteen expert-defined end-of-life quality indicators were presented to each group, and quantitative unweighted rankings were obtained through patient and caregiver preferences. Aggregated weightings were used to rank the top five quality measures for exploration of open-ended questions. Pain management was the most important quality indicator among all three groups. Overlap in preferences were found for at least two of the groups for symptom management, monitoring medical issues, advance care preferences and assessment of family and caregiver involvement. Caregivers were more focused on bereavement support. Variation in preferences for end-of-life care by patients and their caregivers reflects the need to understand the individual decision-making regarding end-of-life care. Quality improvement activities are beginning to address these needs.

Online consumer surveys as a methodology for assessing the quality of the United States health care system.

BACKGROUND: Interest in monitoring the quality of health care in the United States has increased in recent years. However, the policy objectives associated with collecting this information are constrained by the limited availability of timely and relevant data at a reasonable cost. Online data-collection technologies hold the promise of gathering data directly and inexpensively from large, representative samples of patients and consumers. These new information technologies also permit efficient, real-time assessment in such areas as health status, access to care, and other aspects of the care experience that impact health outcomes. OBJECTIVE: This study investigates the feasibility, validity, and generalizability of consumer online surveys to measure key aspects of health care quality in the United States. METHODS: Surveys about the health and health care experiences of a general adult population and of adults with diabetes were administered online and by telephone. The online survey drew from a sample frame of nearly 1 million consumers and used a single e-mail notification. The random-digit-dial methodology included 6 follow-up calls. Results from the online sample were compared to the telephone sample and to national benchmark data. RESULTS: Survey responses about quality of care collected using online and telephone methods were commensurate once they were weighted to represent the demographic distribution of the 2000 United States Census. Expected variations in health and health care quality across demographic and socioeconomic groups were largely observed, as were hypothesized associations among quality indicators and other variables. Fewer individuals were required to be contacted to achieve target sample sizes using online versus telephone methods. Neither method yielded representative cohorts of nonwhite individuals. CONCLUSIONS: Conclusions about the level and variations in health care quality in the United States are similar using data collected in this study compared to data collected using other telephone-based survey methods. As is typical for national telephone surveys conducted by the National Center for Health Statistics, stratified sampling and weighting of survey responses is necessary for results to be generalizable. Online methods are more appropriate for understanding health care quality than for conducting epidemiologic assessments of health in the United States.

Making space for disruption: putting patients at the center of health care.

"Disruptive innovation" will only stimulate the transformation of health care when the regulatory and payment environment allows consumers to set our society's priorities for value. Legislators need to put patients' interests before those of the powerful lobbies that are in front of them every day. Purchasers must hold their health plans to higher, more patient-centered standards. Both government and private payers need to reset the rules to allow into their networks "disrupters" that will deliver more cost-effective care for patients.

Interlaboratory comparison of results of an anthrax lethal toxin neutralization assay for assessment of functional antibodies in multiple species.

The anthrax lethal toxin neutralization assay (TNA) will likely be used to correlate the protection offered by new anthrax vaccines in animal models to the immunogenicity that will be provided in humans. TNA data are being generated in several different laboratories to measure the immune responses in rabbits, nonhuman primates, and humans. In order to compare data among species and laboratories, a collaborative study was conducted in which 108 samples from the three species were analyzed in seven independent laboratories. Six of the seven laboratories had participated in an interlaboratory technology transfer of the TNA. Analysis of the titration curves generated by samples from each species indicated that the behaviors of the samples from all species were similar; the upper and lower asymptotes and the slopes of the curves were less than 30% divergent from those for human reference material. Dilutional linearity was consistent among samples from each species, with spike to effective dilution at 50% inhibition (ED(50)) slopes of less than 1.2 for all species. Agreement among the laboratories with consensus values was within 10% of the ED(50)s for all samples and within 7.5% of the quotients of the test sample ED(50) and the reference standard ED(50) (NF(50)s) for all samples. The relative standard deviations obtained when data from all laboratories and for all species were combined were 45% for the ED(50)s and 35% for the NF(50)s. These precision data suggest that the NF(50) readout may normalize the values generated by different laboratories. This study demonstrates that the TNA is a panspecies assay that can be performed in several different laboratories with a high degree of quantitative agreement and precision.

Hydrogen atom abstraction by a high-valent manganese(V)-oxo corrolazine.

High-valent metal-oxo complexes are postulated as key intermediates for a wide range of enzymatic and synthetic processes. To gain an understanding of these processes, the reactivity of an isolated, well-characterized Mn(V)-oxo complex, (TBP8Cz)MnVO (1), (TBP8Cz = octakis(para-tert-butylphenyl)corrolazinato(3-)) has been examined. This complex has been shown to oxidize a series of substituted phenols (4-X-2,6-t-Bu2C6H2OH, X = C(CH3)3 (3), H, Me, OMe, CN), resulting in the production of phenoxyl radicals and the MnIII complex [(TBP8Cz)MnIII] (2). Kinetic studies have led to the determination of second-order rate constants for the phenol substrates, which give a Hammett correlation ((log k''x/k''H) vs sigmap+) with rho = -1.26. A plot of log k versus BDE(O-H) also reveals a linear correlation. These data, combined with a KIE of 5.9 for 3-OD, provide strong evidence for a concerted hydrogen-atom-abstraction mechanism. Substrates with C-H bonds (1,4-cyclohexadiene and 9,10-dihydroanthracene) are also oxidized via H-atom abstraction by 1, although at a much slower rate. Given the stability of 1, and in particular its low redox potential, (-0.05 V vs SCE), the observed H atom abstraction ability is surprising. These findings support a hypothesis regarding how certain heme enzymes can perform difficult H-atom abstractions while avoiding the generation of high-valent metal-oxo intermediates with oxidation potentials that would lead to the destruction of the surrounding protein environment.

An isolable, nonreducible high-valent manganese(V) imido corrolazine complex.

The manganese(V) imido complex [(TBP8Cz)Mn(V)(NMes)] (2) was synthesized from the Mn(III) complex [(TBP8Cz)Mn(III)] (1) and thermolysis of mesityl azide. An X-ray structure of 2 reveals a short Mn-N distance [1.595(4) A], consistent with the Mn-N triple bond expected for a manganese(V) imido species. This high-valent species is remarkably inert to one- and two-electron reductive processes such as NR group transfer to alkenes or H-atom abstraction from O-H bonds. Electrochemical studies support this lack of reactivity. In contrast, oxidation of 2 is easily accomplished by treatment with [(4-BrC6H4)3N]*+SbCl6, giving a pi-radical-cation complex.