Implementation Evaluation of a Complex Intervention to Improve Timeliness of Care for Veterans with Transient Ischemic Attack.

BACKGROUND: The Protocol-guided Rapid Evaluation of Veterans Experiencing New Transient Neurologic Symptoms (PREVENT) program was designed to address systemic barriers to providing timely guideline-concordant care for patients with transient ischemic attack (TIA). OBJECTIVE: We evaluated an implementation bundle used to promote local adaptation and adoption of a multi-component, complex quality improvement (QI) intervention to improve the quality of TIA care Bravata et al. (BMC Neurology 19:294, 2019). DESIGN: A stepped-wedge implementation trial with six geographically diverse sites. PARTICIPANTS: The six facility QI teams were multi-disciplinary, clinical staff. INTERVENTIONS: PREVENT employed a bundle of key implementation strategies: team activation; external facilitation; and a community of practice. This strategy bundle had direct ties to four constructs from the Consolidated Framework for Implementation Research (CFIR): Champions, Reflecting & Evaluating, Planning, and Goals & Feedback. MAIN MEASURES: Using a mixed-methods approach guided by the CFIR and data matrix analyses, we evaluated the degree to which implementation success and clinical improvement were associated with implementation strategies. The primary outcomes were the number of completed implementation activities, the level of team organization and > 15 points improvement in the Without Fail Rate (WFR) over 1 year. KEY RESULTS: Facility QI teams actively engaged in the implementation strategies with high utilization. Facilities with the greatest implementation success were those with central champions whose teams engaged in planning and goal setting, and regularly reflected upon their quality data and evaluated their progress against their QI plan. The strong presence of effective champions acted as a pre-condition for the strong presence of Reflecting & Evaluating, Goals & Feedback, and Planning (rather than the other way around), helping to explain how champions at the +2 level influenced ongoing implementation. CONCLUSIONS: The CFIR-guided bundle of implementation strategies facilitated the local implementation of the PREVENT QI program and was associated with clinical improvement in the national VA healthcare system. TRIAL REGISTRATION: clinicaltrials.gov: NCT02769338.

The protocol-guided rapid evaluation of veterans experiencing new transient neurological symptoms (PREVENT) quality improvement program: rationale and methods.

BACKGROUND: Transient ischemic attack (TIA) patients are at high risk of recurrent vascular events; timely management can reduce that risk by 70%. The Protocol-guided Rapid Evaluation of Veterans Experiencing New Transient Neurological Symptoms (PREVENT) developed, implemented, and evaluated a TIA quality improvement (QI) intervention aligned with Learning Healthcare System principles. METHODS: This stepped-wedge trial developed, implemented and evaluated a provider-facing, multi-component intervention to improve TIA care at six facilities. The unit of analysis was the medical center. The intervention was developed based on benchmarking data, staff interviews, literature, and electronic quality measures and included: performance data, clinical protocols, professional education, electronic health record tools, and QI support. The effectiveness outcome was the without-fail rate: the proportion of patients who receive all processes of care for which they are eligible among seven processes. The implementation outcomes were the number of implementation activities completed and final team organization level. The intervention effects on the without-fail rate were analyzed using generalized mixed-effects models with multilevel hierarchical random effects. Mixed methods were used to assess implementation, user satisfaction, and sustainability. DISCUSSION: PREVENT advanced three aspects of a Learning Healthcare System. Learning from Data: teams examined and interacted with their performance data to explore hypotheses, plan QI activities, and evaluate change over time. Learning from Each Other: Teams participated in monthly virtual collaborative calls. Sharing Best Practices: Teams shared tools and best practices. The approach used to design and implement PREVENT may be generalizable to other clinical conditions where time-sensitive care spans clinical settings and medical disciplines. TRIAL REGISTRATION: clinicaltrials.gov: NCT02769338 [May 11, 2016].

GAL-021, a new intravenous BKCa-channel blocker, is well tolerated and stimulates ventilation in healthy volunteers.

BACKGROUND: Potassium-channels in the carotid body and the brainstem are important regulators of ventilation. The BKCa-channel contains response elements for CO, O2, and CO2. Its block increases carotid body signalling, phrenic nerve activity, and respiratory drive. GAL-021, a new BKCa-channel blocker, increases minute ventilation in rats and non-human primates. This study assessed the single-dose safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of GAL-021 in healthy volunteers. METHODS: Thirty subjects participated in a nine-period, randomized, double-blinded, placebo-controlled, crossover, ascending dose, first-in-human study with i.v. infusions of 0.1-0.96 mg kg(-1) h(-1) for 1 h and intermediate doses up to 4 h. RESULTS: Adverse event rates were generally similar among dose levels and between placebo- and GAL-021-treated subjects. At higher GAL-021 doses, a mild/moderate burning sensation at the infusion site occurred during the infusion. No clinically significant changes in vital signs or clinical chemistries were noted. Minute ventilation increased (AUE0-1 h ≈ 16%, P<0.05) and end-tidal carbon dioxide ([Formula: see text]) decreased (AUE0-1 h ≈ 6%, P<0.05) during the first hour at 0.96 mg kg(-1) h(-1) with 1/2-maximal [Formula: see text] and [Formula: see text]-change occurring by 7.5 min. Drug concentration rose rapidly during the infusion and decreased rapidly initially (distribution t1/2 of 30 min) and then more slowly (terminal t1/2 of 5.6 h). CONCLUSIONS: GAL-021 was safe and generally well tolerated with adverse events comparable with placebo except for an infusion site burning sensation. GAL-021 stimulated ventilation at the highest doses suggesting that greater infusion rates may be required for maximum PD effects. GAL-021 had PK characteristics consistent with an acute care medication.

Presence of the metabolic syndrome is associated with shorter time to castration-resistant prostate cancer.

BACKGROUND: Metabolic syndrome (MS) is a set of risk factors that includes obesity and insulin resistance and has been implicated in the development of prostate cancer. Its impact on androgen deprivation therapy (ADT) efficacy has not been studied. PATIENTS AND METHODS: Retrospective study of prostate cancer patients seen from 1998 to 2005 in a medical oncology clinic. MS, as defined by modified Adult Treatment Panel III criteria, was assessed at the time of initiation of ADT. The study end points were time to prostate-specific antigen (PSA) progression and overall survival (OS) from time of starting ADT. RESULTS: Eighty-two patients treated with ADT and data to assess for presence of MS were identified. Median age in men with and without MS was 70 years and 49% of the patients evaluated met criteria for MS. Median time to PSA progression for patients with MS was 16 versus 36 months without MS (P=0.003). The median OS for patients with MS was 36.5 months after commencing ADT compared with 46.7 months for those patients without MS (P=0.061). CONCLUSIONS: This preliminary data suggest that MS is a risk factor for earlier development of castration-resistant prostate cancer and support the need for a prospective evaluation of this finding.

Metabolic setpoint control mechanisms in different physiological systems at rest and during exercise.

Using a number of different homeostatic control mechanisms in the brain and peripheral physiological systems, metabolic activity is continuously regulated at rest and during exercise to prevent catastrophic system failure. Essential for the function of these regulatory processes are baseline "setpoint" levels of metabolic function, which can be used to calculate the level of response required for the maintenance of system homeostasis after system perturbation, and to which the perturbed metabolic activity levels are returned to at the end of the regulatory process. How these setpoint levels of all the different metabolic variables in the different peripheral physiological systems are created and maintained, and why they are similar in different individuals, has not been well explained. In this article, putative system regulators of metabolic setpoint levels are described. These include that: (i) innate setpoint values are stored in a certain region of the central nervous system, such as the hypothalamus; (ii) setpoint values are created and maintained as a response to continuous external perturbations, such as gravity or "zeitgebers", (iii) setpoint values are created and maintained by complex system dynamical activity in the different peripheral systems, where setpoint levels are regulated by the ongoing feedback control activity between different peripheral variables; (iv) human anatomical and biomechanical constraints contribute to the creation and maintenance of metabolic setpoints values; or (v) a combination of all these four different mechanisms occurs. Exercise training and disease processes can affect these metabolic setpoint values, but the setpoint values are returned to pre-training or pre-disease levels if the training stimulus is removed or if the disease process is cured. Further work is required to determine what the ultimate system regulator of metabolic setpoint values is, why some setpoint values are more stringently protected by homeostatic regulatory mechanisms than others, and the role of conscious decision making processes in determining the regulation of metabolic setpoint values.

Exponential taper in arteries: an exact solution of its effect on blood flow velocity waveforms and impedance.

The dimensions and wall elasticity commonly taper along the length of mammalian arteries. The effects of taper on flow velocity waveforms can be included by either of two methods; to theoretically divide the artery into short sections wherein the properties are assumed constant (the approximate solution); or to find an exact solution incorporating the effects of taper. In this paper, an exact solution to the resulting, and previously unsolved nonlinear Ricatti equation for the impedance, is obtained by a process of substitutions. This solution is utilised to develop an exact expression for the flow velocity in the artery. The transmission line equations are then combined into a single integral expression for the entire artery and an exact solution to this is evaluated. This is the first solution to simultaneously account for both geometric and elastic taper, and it has been validated by comparing simulations of flow in the aorta of a dog to those using an infinitesimal approximate solution. The Pulsatility Index of the approximate solution requires at least 10 segments to converge to within 5% of that using the exact solution. The exact solution thus accurately accounts for the effects of exponential taper, and may be used to improve existing arterial models, which use the less accurate and more computationally cumbersome approximate solution.

The time course of functional coupling between human cortical motor areas during internally driven vs. externally cued movements.

The functional coupling between the primary motor cortex (M1) and the supplementary motor area (SMA) in the generation of internally paced versus externally cued rhythmic movements was explored using electroencephalography (EEG). This has important implications for the study of Parkinsonian patients who demonstrate decreased ability to perform internally paced rhythmic movement tasks. In particular, the temporal evolution of the coherence between M1 and SMA was studied using a recently developed time-frequency wavelet coherence algorithm. As this approach is not reliant upon pooling data from multiple trials to form a single estimate of the coherence for each subject, a subject by subject comparison is possible to determine subject specific frequencies of interest. It was found that at certain frequencies, the coupling between M1 and SMA was increased in the internally paced versus the externally triggered movement task. At only these specific frequencies did the peak of the coherence in the internal task precede that of the peak in the external task, which was time locked with the movement onset. This suggests a dual role of the M1-SMA coupling for both movement preparation and movement execution.

Rectification and non-linear pre-processing of EMG signals for cortico-muscular analysis.

Rectification of the electromyographic (EMG) signal is a commonly used pre-processing procedure that allows detection of significant coherence between EMG and measured cortical signals. However, despite its accepted and wide-spread use, no detailed analysis has been presented to offer insight into the precise function of rectification. We begin this paper with arguments based on single motor unit action potential (AP) trains to demonstrate that rectification effectively enhances the firing rate information of the signal. Enhancement is achieved by shifting the peak of the AP spectrum toward the lower firing rate frequencies, whilst maintaining the firing rate spectra. A similar result is obtained using the analytic envelope of the signal extracted using the Hilbert transform. This argument is extended to simulated EMG signals generated using a published EMG model. Detection of firing rate frequencies is obtained using phase randomised surrogate data, where the original EMG power spectrum exceeds the averaged rectified surrogate spectra at integer multiples of firing rate frequencies. Model simulations demonstrate that this technique accurately determines grouped firing rate frequencies. Extraction of grouped firing rate frequencies prior to coherency analyses may further aid interpretation of significant cortico-muscular coherence findings.

A transfer function-based mathematical model of the fetal-placental circulation.

The circulation of a human fetus has been modeled using a transfer function that is based on the arterial dimensions at 28 weeks gestational age (GA). These dimensions have then been adapted for growth between 28 and 40 weeks GA. The input to the model is a series of current pulses at the fetal heart rate, where current in the model is analogous to volume blood flow in the fetus. The arterial system is divided into short segments that are cascaded together. The respective transfer functions are based on the dimensions, wall properties and fluid characteristics at each frequency and GA. Bleed off conductances distribute current to circuits representing the various anatomical regions. In particular, the placenta is simplified to a symmetrically distributed network of branching vessels, each represented by a transfer function. All calculations are performed in the frequency domain, after which the inverse Fourier transform is used to calculate the currents that represent the time-domain blood flow waveforms. Simulated flow waveform resistance index and pulsatility index values are within 8% of those reported for human clinical studies, at all gestational ages.

A transmission line model of the human foetal circulatory system.

A transmission line model of the human foetal circulatory system is presented. The model has been developed in the frequency domain with the cardiac input modeled as a flow rather than as a pressure pulse and is structured upon electrical transmission line analogies. The model is formed by cascading solutions to the two-dimensional Navier-Stokes equations for both oscillatory and steady, laminar viscous fluid flow in isotropic visco-elastic tubes with thick walls, which are constrained by surrounding tissues. Simulations allow for representation of both forward and retrograde travelling flow and pressure waves in all of the main foetal arterial vessels. The solution is verified by a comparison of model generated Doppler indices in the thoracic aorta, abdominal aorta, iliac artery and both ends of the umbilical arteries with previously published indices obtained by clinical measurements in these arteries. For simulations of blood flow in a healthy foetus, the model generated Pulsatility and Resistance indices were on average within 8% of the corresponding clinical measurements. The model results also demonstrates that placental resistance must increase by a factor of three, corresponding to a 60% decrease in flow to the placenta, before umbilical arterial absent end diastolic flow is observed. Differences between indices obtained from simulations at opposite ends of the umbilical arteries increase with increasing placental resistance.

Analytical solution for pulsatile axial flow velocity waveforms in curved elastic tubes.

An analytical solution for pulsatile axial flow velocity waveforms in curved elastic tubes is presented. The result is obtained by exact solution of linearized Navier-Stokes and tube motion equations in a torroidal coordinate system. Fourier analysis is used to divide the flow into constant and oscillatory components which are separately considered. The solution is used to investigate the effects of curvature on volumetric axial velocity flow waveforms, as would be measured by Doppler ultrasound techniques. In typical human arteries, the greatest effects of curvature on the volumetric axial flow are exerted on the constant component and at low values of the frequency parameter for the oscillatory components. Here, the magnitude and phase angle of oscillatory flow in the curved tube, relative to that in the straight tube, differ by maximum values of 1.2% and 0.15 rad, respectively. However, constant flow may vary by as much as 60% at high Dean numbers. The solution is presented in a form similar to Womersley's solution for the straight elastic tube and may, thus, be incorporated into a transmission-line analog model. These models are frequently used to investigate axial flow velocity variations in mamillian circulatory systems and this work offers a tool which may extend these models to incorporate the effects of curvature.

The scientific foundation and efficacy of the use of canines as chemical detectors for explosives.

This article reviews the use of dogs as chemical detectors, and the scientific foundation and available information on the reliability of explosive detector dogs, including a comparison with analytical instrumental techniques. Compositions of common military and industrial explosives are described, including relative vapor pressures of common explosives and constituent odor signature chemicals. Examples of active volatile odor signature chemicals from parent explosive chemicals are discussed as well as the need for additional studies. The specific example of odor chemicals from the high explosive composition C-4 studied by solid phase microextraction indicates that the volatile odor chemicals 2-ethyl-1-hexanol and cyclohexanone are available in the headspace; whereas, the active chemical cyclo-1,3,5-trimethylene-2,4,6-trinitramine (RDX) is not. A detailed comparison between instrumental detection methods and detector dogs shows aspects for which instrumental methods have advantages, a comparable number of aspects for which detector dogs have advantages, as well as additional aspects where there are no clear advantages. Overall, detector dogs still represent the fastest, most versatile, reliable real-time explosive detection device available. Instrumental methods, while they continue to improve, generally suffer from a lack of efficient sampling systems, selectivity problems in the presence of interfering odor chemicals and limited mobility/tracking ability.

An outbreak of foodborne illness caused by Escherichia coli O39:NM, an agent not fitting into the existing scheme for classifying diarrheogenic E. coli.

An outbreak of gastrointestinal illness with clinical and epidemiologic features of enterotoxigenic Escherichia coli (ETEC) occurred among patrons of a restaurant during April 1991. Illnesses among several groups of patrons were characterized by diarrhea (100%) and cramps (79%-88%) lasting a median of 3-5 days. Median incubation periods ranged from 50 to 56 h. A nonmotile strain of E. coli (E. coli O39), which was negative for heat-labile (LT) and heat-stable (STa, STb) ETEC toxins, was isolated only from ill patrons. This organism produced enteroaggregative E. coli heat-stable enterotoxin 1 and contained the enteropathogenic E. coli gene locus for enterocyte effacement; it did not display mannose-resistant adherence, but produced attaching and effacing lesions in the absence of mannose on cultured HEp-2 cells. E. coli that are not part of highly characterized but narrowly defined groups may be important causes of foodborne illness.

Black Americans' and White Americans' views of the etiology and treatment of mental health problems.

Black Americans, in contrast to White Americans, use the mental health system in different ways. For example, Blacks tend to terminate treatment earlier than Whites. One explanation for the racial differences is that members of the two groups hold different views about mental health problems and their treatment. To test this explanation, subjects read and responded to questions about vignettes describing individuals encountering personal difficulties that ranged from adjustment challenges to severe psychiatric illness. Black American respondents rated spiritual factors as more important in the etiology and treatment of the difficulties than did Whites. The implications of these findings for theory and practice are discussed.

Effects of steroids on the olfactory function of the dog.

Twenty-four (24) mature, mixed breed, healthy dogs weighing from 14.6 kg to 27.6 kg were used to study the effects of various steroids on the olfactory function of the dog using olfactory detection threshold as an index. Two odorants were used, viz; benzaldehyde and eugenol. Of the various steroids used, only dexamethasone produced classical signs of Cushing's syndrome in the dogs. However, all dogs that received either dexamethasone alone or hydrocortisone plus DOCA exhibited a significant elevation in the olfactory detection threshold for both odorants without any observable structural alteration of the olfactory tissue using light microscopy. On the other hand, neither DOCA, hydrocortisone alone, nor any of the vehicles used in the study significantly altered the olfactory function of the dogs. The results show that Cushing's syndrome can be experimentally produced in dogs using exogenous steroids and that this condition diminishes the olfactory capability of the dog without producing classical signs of the disease.

Use of innate behaviors to evaluate sensory function in the dog.

The need to evaluate sensory function in the dog is discussed. A group of techniques that use innate behaviors (species-typical behaviors) and are effective in the evaluation of sensory function of domestic animals are described. Techniques to measure olfactory, gustatory, auditory, and visual function are included.

Preclinical trials using an immunoconjugate of T101 and methotrexate in an athymic mouse/human T-cell tumor model.

We made an immunoconjugate (IC) using the anti-CD5 monoclonal antibody T101 and the chemotherapeutic drug methotrexate. Methotrexate was conjugated to T101 using an active ester intermediate, yielding a drug: antibody molar ratio of 12.4. Although T101 immunoreactivity was not significantly altered by conjugation, the IC did not demonstrate antigen-specific cytotoxicity in vitro. Methotrexate activity, assayed in vitro, decreased approximately 100-fold following conjugation. The IC was tested for in vivo efficacy in athymic mice bearing human T-cell (MOLT 4) xenografts. Experimental arms used in the study included i.p. injections of saline, T101, methotrexate, the IC, and a mixture of T101 and methotrexate. Doses ranged from 500 micrograms T101 (17.5 micrograms methotrexate) to 2 mg T101 (70 micrograms methotrexate). Injections were administered only after palpable tumors were established. In experiments at all doses, totaling 66 animals per arm, injection of the IC significantly inhibited tumor growth, and resulted in more tumor regressions and fewer animal deaths than the other four experimental arms. These data demonstrate that the IC promotes a potential advantage over the use of methotrexate through an increase in the therapeutic index.

Cloning and high level expression of a chimeric antibody with specificity for human carcinoembryonic antigen.

A mouse/human chimeric antibody has been constructed by using variable light and variable heavy regions from a murine hybridoma specific for human carcinoembryonic antigen (CEA) (CEM231.6.7). These V regions were combined with kappa and gamma-1 constant region genes cloned from human lymphocytes. The chimeric constructs were sequentially electroporated into murine non-Ig-producing myeloma (P3.653) and hybridoma (SP2/0) cell. Significant differences were seen in expression levels between the two cell types. High levels of expression (24 to 32 micrograms/ml/10(6) cells) were seen with several of the anti-CEA SP2/0 transfectomas but not with the P3.653 cells. The SP2/0 transfectoma lines were adapted to serum-free, chemically defined media and grown in large scale fermentation cultures where they continued to secrete high levels of antibody. The chimeric antibodies remain reactive against human CEA with affinity constants comparable to that of the parental hybridoma antibody. High level expression will make practical the production of chimeric antibodies for in vivo therapeutic and diagnostic purposes.

Newly described muscle attachments to the anterior band of the articular disk of the temporomandibular joint.

The presence of these two muscle attachments will be helpful in treating TM disorders. Why they have not been previously described is a mystery, but it is more understandable when the difficulty of dissection is noted. Freeing the disk while investigating the retrodiskal area, and then performing fiber-by-fiber dissection of the deep masseter muscle are uncommon procedures. Muscle fibers often exist from the deep masseter muscle to the capsule of the TMJ, and these muscles could easily be mistaken for the fibers already known and, therefore, ignored when the masseter was removed in dissection. If the first specimen dissected had not been a well-developed male with strong tendon attachment, the attachments would have been missed in this case as well.

Anosmia associated with canine distemper.

The sense of smell in dogs infected with canine distemper virus (CDV) was examined by use of EEG olfactometry, behavioral olfactometry, and electro-olfactography. Infection with CDV was confirmed by a direct immunofluorescence technique in 8 active cases and was suggested by clinical history compatible with canine distemper 10 to 26 weeks earlier in 6 cases. Pathologic alterations of the olfactory mucosa in 3 clinically affected dogs was examined by light microscopy. Infection with CDV was found to be associated with anosmia and lack of recorded responses on electro-olfactogram in 8 of 8 dogs with clinical signs of acute distemper from naturally acquired infections. Anosmia was found in 5 of 6 dogs that had recovered from acute distemper 10 to 26 weeks earlier. The sixth dog had hyposmia, with abnormalities on the electro-olfactogram. Histologic examination was not performed on the 6 dogs that had recovered. Histologic lesions observed at necropsy in 3 dogs that had had clinical signs of acute distemper were those of subacute purulent rhinitis and atrophy of the olfactory epithelium. Altered olfactory function could be explained by mucopurulent exudate blocking odors from olfactory receptors in the acutely affected dogs, but alteration of olfactory function in the dogs that had recovered without clinical evidence of rhinitis could not be explained.