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.

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.

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.

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.

Prospective evaluation of total hip arthroplasty with a cementless, anatomically designed, porous-coated femoral implant: mean 11-year follow-up.

The performance of an anatomically designed femoral implant with porous titanium mesh coating was assessed in patients undergoing total hip arthroplasty. The stem, with built-in 12 degrees anteversion, was implanted in neutral position relative to the long axis of the femur through a cementless press-fit application. The only requirement was the presence of sufficient thickness within the cortical bone of the femoral metaphysis to support the stem. Ninety-one evaluable patients were followed up for a minimum of 10 years. Patients tolerated weight-bearing activity within 24 hours after surgery. Only 1 femoral component required revision because of loosening. Most patients showed uniform bony ingrowth. Quality of life was markedly improved. The anatomically designed, porous-coated implant provides robust performance which has general utility in a wide range of patients.

Bioanalytical method validation for macromolecules in support of pharmacokinetic studies.

The development and validation of ligand binding assays used in the support of pharmacokinetic studies has been the focus of various workshops and publications in recent years, all in an effort to establish a guidance document for standardization of these bioanalytical methods. This summary report of the workshop from 2003 focuses on the issues discussed in presentations and notes points of discussion and areas of consensus among the participants.

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.

Synthesis, characterization, and physicochemical properties of manganese(III) and manganese(V)-oxo corrolazines.

The structural and physicochemical properties of the manganese-corrolazine (Cz) complexes (TBP8Cz)Mn(V)O (1) and (TBP8Cz)Mn(III) (2) (TBP = p-tert-butylphenyl) have been determined. Recrystallization of 2 from toluene/MeOH resulted in the crystal structure of (TBP8Cz)Mn(III)(CH3OH) (2 x MeOH). The packing diagram of 2 x MeOH reveals hydrogen bonds between MeOH axial ligands and meso N atoms of adjacent molecules. Solution binding studies of 2 with different axial ligands (Cl-, Et3PO, and Ph3PO) reveal strong binding, corroborating the preference of the Mn(III) ion for a five-coordinate environment. High-frequency and field electron paramagnetic resonance (HFEPR) spectroscopy of solid 2 x MeOH shows that 2 x MeOH is best described as a high-spin (S = 2) Mn(III) complex with zero-field splitting parameters typical of corroles. Structural information on 1 was obtained through an X-ray absorption near-edge structure (XANES)/extended X-ray absorption fine structure (EXAFS) study and compared to XANES/EXAFS data for 2 x MeOH. The XANES data for 1 shows an intense pre-edge transition characteristic of a high-valent metal-oxo species, and a best fit of the EXAFS data gives a short Mn-O bond distance of 1.56 A, confirming the structure of the metal-oxo unit in 1. Detailed spectroelectrochemical studies of 1 and 2 were performed revealing multiple reversible redox processes for both complexes, including a relatively low potential for the Mn(V) --> Mn(IV) process in 1 (near 0.0 V vs saturated calomel reference electrode). Chemical reduction of 1 results in the formation of a Mn(III)Mn(IV)(mu-O) dimer as characterized by electron paramagnetic resonance spectroscopy.

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.

How accurate is information that patients contribute to their Electronic Health Record?

Increased patient interaction with medical records and the advent of personal health records (PHRs) may increase patients' ability to contribute valid information to their Electronic Medical Record (EHR) medical record. Patient input through a secure connection, whether it be a patient portal or PHR, will integrate many aspects of a patient's health and may help lessen the information gap between patients and providers. Patient reported data should be considered a viable method of enhancing documentation but will not likely be as complete and accurate as more comprehensive data-exchange between providers.

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.

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.