Physician attitudes about non-medical switching to biosimilars: results from an online physician survey in the United States.

OBJECTIVE: This study was designed to understand the level of familiarity of US rheumatologists, gastroenterologists and dermatologists with biosimilar therapies, their experience with non-medical switching (switching medications for reasons unrelated to patient health) of patients between biologics and their attitudes towards switching from a biologic to a biosimilar. METHODS: A total of 297 US physicians who currently prescribe biologics for their patients completed a 15-minute online survey. Rheumatologists, dermatologists and gastroenterologists were included. RESULTS: The majority of physicians (84%) did not want stable patients undergoing a non-medical switch to a biosimilar. While 60% of physicians believed non-medical switching to biosimilars may have a positive impact on healthcare system costs, multiple negative impacts were also expected. A majority of physicians anticipated a negative impact on patient mental health (59%), treatment efficacy (57%), patient safety (53%) and physician office management (60%). CONCLUSIONS: The majority of physicians had concerns regarding non-medical switching to biosimilars and the impact such switching would have on patient care and physician practice.

Patient attitudes about non-medical switching to biosimilars: results from an online patient survey in the United States.

OBJECTIVE: To evaluate patient attitudes regarding non-medical switching (NMS) to biosimilars among patients with autoimmune disease currently receiving a biologic. METHODS: An online survey was conducted among patients meeting the following criteria: ≥18 years of age; residing in the US; diagnosis of rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis or psoriatic arthritis; currently taking a biologic; and consenting to participate. Patients answered questions about their attitudes and experiences related to NMS. Descriptive statistics were used to summarize responses. RESULTS: A total of 1696 patients completed the 20-min survey. Eighty-five per cent of patients were concerned that biosimilars wouldn't treat their disease as well; 85% didn't want to switch to a biosimilar if their current biologic was helping their disease; and 83% were concerned that switching may cause more side-effects. Twenty per cent of patients had previously received notification about a potential NMS to another biologic (that was not a biosimilar) from their insurance company. Of these, 79% took at least one action to avoid the NMS and 45% ultimately switched. Of these patients (n = 150), 67% indicated that their previous biologic worked well for them and 70% didn't want to switch to another biologic. Most patients who switched (67%) did so to avoid paying a higher cost. More than half (56%) went without therapy for administrative reasons during the period of transition from the old biologic to the other treatment. CONCLUSIONS: Patients reported multiple concerns about NMS that might impact treatment outcomes, and many of the patients who non-medically switched in this survey missed treatments. Future studies should be conducted on patient expectations and experiences with NMS to understand the impact on healthcare delivery, treatment persistency, and patient outcomes. The patient perspective and experience should be considered by decision-makers when developing coverage policies for biosimilar medications and associated communication strategies.

Incentives for recruiting trainee participants in medical education research.

INTRODUCTION: In the growing field of medical education research, participant recruitment can be challenging. Incentives, either tangible or intangible, may be offered to encourage participation. This study aimed to understand these incentives and explore the relationship between study quality and incentives in medical education research. METHODS: We reviewed research studies examining medical trainees published in five major journals in 2008. Tangible and intangible incentives used in recruitment were extracted by two researchers. For each quantitative article, medical education research quality instrument (MERSQI) score was calculated and citation counts for all articles were compiled. RESULTS: Of 215 included articles, 8% explicitly reported incentives. Tangible incentives (value range $15-$60 USD) were offered in 7.9% of studies. Intangible incentives were identified in 30% of studies but only one specifically discussed their use. Tangible incentives correlated with a higher MERSQI score (p < 0.001) and with citations (p < 0.001). CONCLUSION: Most studies in medical education did not describe incentives for participation. Information regarding incentives should be reported in all studies to help inform future recruitment efforts and also to understand the study context including factors that may influence participants motivation.

The utility of vignettes to stimulate reflection on professionalism: theory and practice.

Professionalism remains a substantive theme in medical literature. There is an emerging emphasis on sociological and complex adaptive systems perspectives that refocuses attention from just the individual role to working within one's system to enact professionalism in practice. Reflecting on responses to professional dilemmas may be one method to help practicing physicians identify both internal and external factors contributing to (un) professional behavior. We present a rationale and theoretical framework that supports and guides a reflective approach to the self assessment of professionalism. Guided by principles grounded in this theoretical framework, we developed and piloted a set of vignettes on professionally challenging situations, designed to stimulate reflection in practicing physicians. Findings show that participants found the vignettes to be authentic and typical, and reported the group experience as facilitative around discussions of professional ambiguity. Providing an opportunity for physicians to reflect on professional behavior in an open and safe forum may be a practical way to guide physicians to assess themselves on professional behavior and engage with the complexities of their work. The finding that the focus groups led to reflection at a group level suggests that effective reflection on professional behavior may require a socially interactive process. Emphasizing both the behaviors and the internal and external context in which they occur can thus be viewed as critically important for understanding professionalism in practicing physicians.

Ion channels in presynaptic nerve terminals and control of transmitter release.

The primary function of the presynaptic nerve terminal is to release transmitter quanta and thus activate the postsynaptic target cell. In almost every step leading to the release of transmitter quanta, there is a substantial involvement of ion channels. In this review, the multitude of ion channels in the presynaptic terminal are surveyed. There are at least 12 different major categories of ion channels representing several tens of different ion channel types; the number of different ion channel molecules at presynaptic nerve terminals is many hundreds. We describe the different ion channel molecules at the surface membrane and inside the nerve terminal in the context of their possible role in the process of transmitter release. Frequently, a number of different ion channel molecules, with the same basic function, are present at the same nerve terminal. This is especially evident in the cases of calcium channels and potassium channels. This abundance of ion channels allows for a physiological and pharmacological fine tuning of the process of transmitter release and thus of synaptic transmission.

Commotio cordis: cardiovascular manifestations of a rare survivor.

Death due to low-energy chest wall trauma, commotio cordis, may occur in young athletes. Death is sudden and usually refractory to even immediate resuscitation efforts. Herein are described the clinical, angiographic, and hemodynamic data of a rare survivor. These observations suggest that commotio cordis not only may be secondary to ventricular fibrillation, but also may be associated with coronary vasospasm or segmental changes in myocardial contractility.

Development of a quantitative vancomycin immunoassay for the Abbott AxSYM analyzer.

A novel fluorescence polarization immunoassay for vancomycin on Abbott AxSYM analyzer is described. The immunoassay allows for the accurate quantification of vancomycin in the presence of the crystalline degradation product (CDP). It displays dilution linearity from 1.0 microg/ml to 100.0 microg/ml, coefficients of variation ranging from 2.94% to 4.26%, recovery from 98% to 105%, and a sensitivity of <2.0 microg/ml. The assay demonstrates no cross-reactivity to crystalline degradation product, and to commonly-prescribed and over-the-counter drugs, as well as a minimum interference from endogenous substances.

Bronchodilator delivery in acute airflow obstruction. A meta-analysis.

OBJECTIVE: To compare the effect of bronchodilator delivery by use of a metered-dose inhaler (MDI) or wet nebulizer on objective measurements of acute airflow obstruction in adult patients. METHODS: Published and unpublished research was identified by MEDLINE searches for articles published from 1966 to 1994, review of scientific citations, review of article bibliographies, communication with experts in the area of asthma therapy and aerosol delivery, primary investigators, and a manufacturer of spacer devices. Eighteen studies were selected from 159 potentially relevant articles by independent review in triplicate. Selection criteria included randomized trials that compared bronchodilator delivery by use of an MDI and wet nebulizer in adults with acute exacerbations of asthma or chronic obstructive pulmonary disease who were treated in an emergency department or a hospital. Data for patient characteristics, study setting, bronchodilator doses, outcomes, and methodological quality were independently extracted. RESULTS: Twelve studies with a total of 507 patients had sufficient data to calculate an effect size (in SD units) for improvement in airflow obstruction after bronchodilator delivery. All but 2 studies used spacer devices with the MDI. The overall treatment effect size was -0.02 (95% confidence interval [CI], -0.20 to 0.16) that favored the MDI, but the magnitude of the effect size was not clinically or statistically significant. No significant effect was observed in the subgroup analyses that compared the diagnosis: asthma, -0.17 (CI, -0.41 to 0.07) compared with chronic obstructive pulmonary disease, 0.23 (CI, -0.35 to 0.81); bronchodilator dose; or methodological quality. The results of a sensitivity analysis that included 5 of 6 excluded studies supported the findings from the primary analysis: 0.05 (CI, -0.11 to 0.20). CONCLUSIONS: Bronchodilator delivery by means of an MDI or wet nebulizer is equivalent in the acute treatment of adults with airflow obstruction. Spacer devices were used for bronchodilator delivery with an MDI in most studies and are recommended for the treatment of acute airflow obstruction. The choice of the delivery method will depend on the need for expedient treatment, availability of staff, consideration of costs, and findings from studies designed to evaluate treatment effects from larger than standard doses of bronchodilators delivered by use of an MDI.

How plants dispose of chlorophyll catabolites. Directly energized uptake of tetrapyrrolic breakdown products into isolated vacuoles.

During the yellowing of leaves the porphyrin moiety of chlorophyll is cleaved into colorless linear tetrapyrrolic catabolites, which eventually are deposited in the central vacuoles of mesophyll cells. In senescent cotyledons of rape, Brassica napus, three nonfluorescent chlorophyll catabolites (NCCs), accounting for practically all the chlorophyll broken down, were found to be located in the vacuoles (vacuoplasts) prepared from protoplasts. Transport of catabolites across the tonoplast was studied with vacuoles isolated from barley mesophyll protoplasts in conjunction with a radiolabeled NCC, Bn-NCC-1, prepared from senescent rape cotyledons. The uptake of Bn-NCC-1 into vacuoles was against a concentration gradient and strictly dependent on MgATP and it followed saturation kinetics with a Km of approximately 100 microM. Although the hydrolysis of ATP was required, transport was apparently independent of the vacuolar proton pumps: accumulation of the NCC occurred both in the presence of the H+-ATPase inhibitor bafilomycin and after destroying the DeltapH between the vacuolar sap and the medium. ATP could be replaced by GTP or UTP, and the transport was inhibited in the presence of vanadate. Chlorophyll catabolites isolated from senescent barley leaves competed with the rape-specific substrate for uptake into the vacuoles. Compounds such as the glutathione conjugate of N-ethylmaleimide and taurocholate, which are known to be transported across the tonoplast in a primary active mode, did not significantly inhibit uptake of Bn-NCC-1. Although the heme catabolites biliverdin and bilirubin inhibited the uptake of the NCC, this effect is caused by unspecific binding to the vacuolar membrane rather than to the specific inhibition of carrier-mediated transport. Taken together, the results demonstrate that barley mesophyll vacuoles are constitutively equipped with a directly energized carrier that transports tetrapyrrolic catabolites of chlorophyll into the vacuole.

Evaluation in the Health Resources and Services Administration. Improving program performance.

The mission of the Health Resources and Services Administration (HRSA) in the U.S. Department of Health and Human Services is to improve the health of the nation by assuring quality health care to underserved and vulnerable populations and by promoting a primary care and public health workforce. This article provides an overview of HRSA's prior work in performance measurement and highlights a current initiative designed to help the agency improve its performance measurement efforts in the context of the Government Performance and Results Act. This initiative began with an agencywide assessment of capacity to measure performance at program, bureau, and agency levels. Based on the findings, HRSA is moving forward both with technical assistance to individual bureaus in developing performance indicators and data sources and with activities to coordinate performance measurement for the agency as a whole.

Oscillations in the activity of a potassium channel at the presynaptic nerve terminal.

1. Periodic oscillations were detected in the activity of single macromolecules: potassium channels. 2. When potassium channels are repeatedly activated in isolated patches from fused synaptosomes of Torpedo electric organ, their behavior exhibits a departure from random activation. 3. The departure from random behavior is demonstrated by the runs test and by the lack of fit to Poisson distribution. 4. Under appropriate experimental conditions, the channels display periodic oscillations with a periodicity of approximately 20 s when activated at a rate of 1.25 Hz. 5. The oscillations do not arise from sampling, recording, or computational artifacts. 6. It is conceivable that single-channel oscillations play a role in the generation of membrane oscillations and thus may contribute to the oscillatory behavior of the nervous system.

The difference in shape of spontaneous and uniquantal evoked synaptic potentials in frog muscle.

1. Spontaneous and stimulation-induced uniquantal synaptic activity at the frog cutaneous pectoris muscle, treated with neostigmine, was recorded by focal extracellular microelectrodes. A monoexponential curve was fitted to the decay of each synaptic response. 2. A highly significant positive relationship was found between the amplitude and the decay time constant of spontaneous extracellular miniature endplate potentials (MEPPs(o)), whereas the relationship displayed by evoked uniquantal extracellular endplate potentials (EPPs(o)) was only slightly greater than zero. 3. The difference did not stem from changes in the muscle membrane conductance or from inclusion of outstanding MEPPs(o) formed as a result of the block of acetylcholinesterase. 4. The dependence of the rise time on the amplitude was also stronger in MEPPs(o) than in EPPs(o). 5. In the absence of neostigmine, MEPPs(o) exhibited a positive correlation between decay time constant and amplitude, while EPPs(o) did not show such a correlation. 6. In view of previously published models of transmitter release, it is suggested that spontaneous secretion of quanta occurs both within and outside the active zones facing postsynaptic areas of variable receptor density.

Cleavage of Chlorophyll-Porphyrin (Requirement for Reduced Ferredoxin and Oxygen).

The chemical structures of some colorless catabolites that accumulate in senescent leaves have been established recently (B. Krautler, B. Jaun, W. Amrein, K. Bortlik, M. Schellenberg, P. Matile [1992] Plant Physiol Biochem 30: 333-346; W. Muhlecker, B. Krautler, S. Ginsburg, P. Matile [1993] Helv Chim Acta 76: 2976-2980). Such studies suggest that oxygenolytic cleavage of chlorophyll-porphyrin may occur by the action of a dioxygenase. We have attempted to demonstrate such an enzyme activity and to explore the requirements of the cleavage reaction in a reconstituted system of chloroplast (Chlpl) components prepared from senescent rape (Brassica napus L.) cotyledons. Intact senescent Chpls (also referred to as gerontoplasts) contain small amounts of two fluorescent chlorophyll catabolites, Bn-FCC-1 and Bn-FCC-2, probably representing primary cleavage products. Upon the incubation of Gpls in the presence of glucose-6-phosphate (Glc6P) or ATP, these catabolites (predominantly FCC-1) were produced in organello. In a reconstituted system of thylakoids and stroma fraction the FCCs (predominantly FCC-2) were produced in the presence of ferredoxin (Fd) and cofactors (NADPH, Glc6P) helping to keep Fd in the reduced state. Reduced Fd could not be replaced by other electron donors, suggesting that the putative dioxygenase requires Fd for the operation of its redox cycle. Production of FCC-2 did not occur in the absence of oxygen and it was inhibited by chelators of Fe2+. The contributions to the production of FCCs from both parts of the reconstituted system, thylakoids and stroma, are heat labile. The enzymic process in the thylakoids yields pheophorbide a, the presumptive precursor of FCCs. However, native senescent thylakoids could not be replaced as a "substrate" by free pheophorbide a. The stromal enzyme appears to have an affinity for senescent thylakoids; thus, "loaded" thylakoids capable of FCC production in the presence of Fd and cofactors were obtained upon homogenization of senescent cotyledons in a medium containing sorbitol and ascorbate. Such thylakoids were inactive if prepared from mature green cotyledons. As senescence was induced, the capacity to generate FCCs appeared and peaked when about half of the chlorophyll had disappeared from the cotyledons. The effectiveness of a relevant inhibitor showed that cytoplasmic protein synthesis was required for inducing the catabolic machinery in the loaded thylakoids. Thylakoids from mature Chlpls were ineffective as substrate of the stromal enzyme prepared from Gpls. However, senescent thylakoids yielded FCCs if challenged with stroma from either Chlpls or Gpls. Therefore, the stromal part of the system is likely to be a constitutive enzyme, and the pace-setting step of the pathway of chlorophyll breakdown seems to be located in the thylakoids.

Identification of Catabolites of Chlorophyll-Porphyrin in Senescent Rape Cotyledons.

Developing shoots of rape seedlings (Brassica napus L.) were excised and fed with 4-[14C]5-aminolevulinic acid to label the pyrroles in chlorophyll (Chl) synthesized during the final phase of expansion and greening of the cotyledons. About 80% of 14C taken up into the cotyledons was incorporated into Chl. The subsequent incubation of labeled shoots in permanent darkness caused the rapid loss of labeled Chl while increasing proportions of 14C appeared in the fraction of water-soluble compounds. Reversed-phase high performance liquid chromatography resolved three nonfluorescent polar catabolites of Chl-porphyrin that were progressively accumulated as senescence advanced. At intermediate stages of senescence, the cotyledons contained a fluorescent radio-active derivative of Chl that was also detectable, together with traces of other putative fluorescent catabolites, in isolated senescent chloroplasts. The nonfluorescent catabolites, identified by means of radiolabeling, were also found to accumulate in attached cotyledons senescing under photoperiod; under these conditions, one of the compounds, NCC-1, was particularly abundant. The catabolites of rape exhibited the same ultraviolet spectra, characterized by a maximum at 320 nm, as a previously reported secoporphinoid catabolite from barley (B. Krautler, B. Jaun, W. Amrein, K. Bortlik, M. Schellenberg, P. Matile [1992] Plant Physiol Biochem 30: 333-346). Different polarities suggest, however, that the structures may be different. A terminology for Chl catabolites is proposed because present knowledge suggests that a large number of different structures results from species-specific processing of breakdown products and may require a suitable nomenclature.

A long closed state of the synaptosomal bursting potassium channel confers a statistical memory.

1. The statistical properties of the bursting potassium channel from fused Torpedo synaptosomes were studied by using patch-clamp recording and time series analysis. 2. Voltage steps produce channel openings; the number of channels opening fluctuates from trial to trial. The maximal current observed in each trial is strongly dependent on the previous history of the membrane patch. Trials with no activity are frequently clumped together and so are trials with intense activity. 3. Autocorrelation analysis reveals a strong interdependence of successive responses, which is voltage dependent. 4. We propose that the strong statistical interdependence of responses to successive depolarizing pulses (the statistical "memory") is a manifestation of a long lived closed state. We speculate that this statistical memory may be of significance in frequency modulation of transmitter release.

A bursting potassium channel in isolated cholinergic synaptosomes of Torpedo electric organ.

1. Pinched-off cholinergic nerve terminals (synaptosomes) prepared from the electric organ of Torpedo ocelata were fused into large structures (greater than 20 microns) using dimethyl sulphoxide and polyethylene glycol 1500, as previously described for synaptic vesicles from the same organ. 2. The giant fused synaptosomes were easily amenable to the patch clamp technique and 293 seals with a resistance greater than 4 G omega were obtained in the 'cell-attached' configuration. In a large fraction of the experiments, an 'inside-out' patch configuration was achieved. 3. Several types of unitary ionic currents were observed. This study describes the most frequently observed single-channel activity which was found in 247 out of the 293 membrane patches (84.3%). 4. The single-channel current-voltage relation was linear between -60 and 20 mV and showed a slope conductance of 23.8 +/- 1.3 pS when the pipette contained 350-390 mM-Na+ and the bath facing the inside of the synaptosomal membrane contained 390 mM-K+. 5. From extrapolated reversal potential measurements, it was concluded that this channel has a large selectivity for K+ over Na+ (70.4 +/- 11.5, mean +/- S.E.M.). Chloride ions are not transported significantly through this potassium channel. 6. This potassium channel has a low probability of opening. The probability of being in the open state increases upon depolarization and reaches about 1% when the inside of the patch is 20 mV positive compared to the pipette side. 7. The mean channel open time increases with depolarization; thus the product current x time (= charge) also increases upon depolarization, showing properties of an outward rectifier. 8. The potassium channel in the giant synaptosome membrane has a bursting behaviour. Open-time distribution, closed-time distribution and a Poisson analysis indicate that the minimal kinetic scheme requires one open state and three closed states.

Studies on new, centrally active and reversible acetylcholinesterase inhibitors.

We have synthesized the tertiary amines of pyridostigmine and neostigmine, 3-pyridinol dimethylcarbamate (norpyridostigmine) and 3-dimethylaminophenol dimethylcarbamate (norneostigmine) respectively, and we have tested their abilities to cross the blood-brain barrier and inhibit mouse brain AChE activity. The in vivo inhibition of AChE activity by norpyridostigmine reaches 72% at 10 minutes which is comparable to that seen with physostigmine (73% at 10 minutes). Inhibition by norneostigmine is less effective (50% at 10 minutes) and approaches that obtained with tetrahydroaminoacridine (57% at 10 minutes). These data show that both norpyridostigmine and norneostigmine cross the blood-brain barrier and that they are effective inhibitors of mouse brain AChE activity. These drugs could be useful in the treatment of memory impairment associated with Alzheimer's disease, and other memory disorders.