Jonathan D. Mahnken

Restoration of function after brain damage using a neural prosthesis

Significance Closed-loop systems, or brain–machine–brain interfaces (BMBIs), have not been widely developed for brain repair. In this study, we targeted spared motor and somatosensory regions of the rat brain after traumatic brain injury for establishment of a functional bridge using a battery-powered microdevice. The results show that by using discriminated action potentials as a trigger for stimulating a distant cortical location, rapid recovery of fine motor skills is facilitated. This study provides strong evidence that BMBIs can be used to bridge damaged neural pathways functionally and promote recovery after brain injury. Although this study is restricted to a rodent model of TBI, it is likely that the approach will also be applicable to other types of acquired brain injuries. Neural interface systems are becoming increasingly more feasible for brain repair strategies. This paper tests the hypothesis that recovery after brain injury can be facilitated by a neural prosthesis serving as a communication link between distant locations in the cerebral cortex. The primary motor area in the cerebral cortex was injured in a rat model of focal brain injury, disrupting communication between motor and somatosensory areas and resulting in impaired reaching and grasping abilities. After implantation of microelectrodes in cerebral cortex, a neural prosthesis discriminated action potentials (spikes) in premotor cortex that triggered electrical stimulation in somatosensory cortex continuously over subsequent weeks. Within 1 wk, while receiving spike-triggered stimulation, rats showed substantially improved reaching and grasping functions that were indistinguishable from prelesion levels by 2 wk. Post hoc analysis of the spikes evoked by the stimulation provides compelling evidence that the neural prosthesis enhanced functional connectivity between the two target areas. This proof-of-concept study demonstrates that neural interface systems can be used effectively to bridge damaged neural pathways functionally and promote recovery after brain injury.

The prevalence of and factors associated with chronic atrial fibrillation in Medicare/Medicaid-eligible dialysis patients

Atrial fibrillation is an important comorbidity with substantial therapeutic implications in dialysis patients but its prevalence varies in different studies. We used a database that includes patients in the United States on hemodialysis who were eligible for government assistance with prescription drugs. We then used ICD-9 codes from billing claims in this database to identify patients with chronic atrial fibrillation. Multivariable logistic regression was used to determine adjusted prevalence odds ratios for associated factors. Of 63,884 individuals, the prevalence of chronic atrial fibrillation was 7%. The factors of age over 60 years, male, Caucasian, body mass index over 25 kg/m(2), coronary artery disease, and heart failure were all significantly associated with chronic atrial fibrillation. Prevalence rates, particularly in younger patients, were far higher than those reported in an age group-matched nondialysis population. Thus, given its clinical impact, future efforts are needed to examine risk factors for adverse outcomes in chronic atrial fibrillation, and to identify appropriate management strategies for this disorder, as well as opportunities for quality improvement in this vulnerable population.

Effect of varying levels of disease management on smoking cessation: a randomized trial.

Context Smoking cessation is difficult and may require repeated or intensive interventions. Contribution In this multicenter trial, 750 primary care patients who smoked at least 10 cigarettes per day were randomly assigned to pharmacotherapy (nicotine patch or bupropion), pharmacotherapy supplemented with up to 2 calls from trained counselors, or pharmacotherapy supplemented with up to 6 counseling calls. Utilization of the interventions, which were offered every 6 months for 2 years, declined over time. Smoking abstinence rates at 2 years were 23%, 24%, and 28% in the 3 groups. Caution Pharmacotherapy was free. Smoking abstinence was self-reported. The Editors Cigarette smoking is a chronic illness characterized by repeated cycles of quit attempts and relapse. Most models for addressing smoking cessation are based on single, short-term interventions lasting only a few weeks or months (1). Although most smokers will not quit after a single intervention, few studies have addressed the chronic nature of nicotine dependence by providing systematic, repetitive treatment opportunities (1). Providing treatment only to smokers who are already prepared to quit further limits the reach of current smoking cessation interventions (2). New models of chronic disease care might provide an alternative approach for expanding the reach and effectiveness of smoking cessation efforts (3). Physicians are in direct contact with approximately 70% of smokers each year (4, 5). Their potential role in promoting smoking cessation has been well delineated and incorporated into current clinical practice guidelines (1). With the development of new, more effective prescription pharmacotherapy for smoking cessation, the role of primary care practices in promoting smoking cessation is now more important than ever. Unfortunately, only half of the smokers who see their physicians are asked about their smoking (6), and even fewer receive advice from their health care provider to quit or receive pharmacotherapy or follow-up (4, 7). Smoking cessation counseling competes with other pressing clinical tasks, and beyond brief advice, many physicians feel they are too busy to routinely and repeatedly counsel participants who smoke (810). To assist primary care physicians in the treatment of rural smokers, we developed KanQuit, a smoking cessation program based on the chronic care model (4), which integrates principles of disease management into the treatment of smokers seen in rural primary care. Our objective was to enroll smokers, regardless of their willingness to quit, into a disease registry and compare cessation rates among smokers who received pharmacotherapy alone or combined with either moderate-intensity or high-intensity disease management that includes counseling and provider feedback. Methods Design Overview We did a randomized, single-blind trial of varying levels of disease management for smoking cessation. We recruited participants who smoked more than 10 cigarettes per day from rural primary care clinics across Kansas and randomly assigned them to receive pharmacotherapy alone, pharmacotherapy supplemented by 1 to 2 counseling calls every 6 months (moderate-intensity disease management), or pharmacotherapy supplemented by up to 6 counseling calls every 6 months (high-intensity disease management). For recipients of moderate-intensity and high-intensity disease management, we faxed periodic progress reports to their physician. We offered all participants free pharmacotherapy (either bupropion or transdermal nicotine patch) every 6 months. We enrolled participants from June 2004 to October 2005 and followed them for 24 months, completing follow-up in December 2007. All participants provided written informed consent. The University of Kansas Medical Centers Human Subjects Committee approved the study. Setting and Participants We conducted our study in 50 rural primary care practices in the Kansas Physicians Engaged in Prevention Research network (11). As part of a rural primary care research experience, trained medical students systematically screened participants, identified smokers, and recruited them for this study, regardless of their interest in quitting (12). We considered smokers eligible if they had a primary care physician who participated in this study; were older than 18 years; smoked more than 10 cigarettes per day for at least 1 year and for at least 25 of the past 30 days; spoke English; and had a telephone. We excluded smokers if they were pregnant or planned to become pregnant, planned to move out of the study area, had signs of dementia or mental illness that would preclude participation, or lived with a smoker already enrolled in the study. Of the 1827 smokers we screened, 61% met criteria for study entry (Figure 1). Of these, we enrolled 67%. Figure 1. Study flow diagram. HDM = high-intensity disease management; MDM = moderate-intensity disease management; PM = pharmacotherapy management. Randomization and Interventions Participant Randomization Randomization occurred at the participant level. A computer-generated random-number table was used to generate allocation cards in blocks of 24, with allocation equally distributed across treatment groups. To conceal allocation, we placed these cards in sequentially numbered, opaque, sealed envelopes. After research assistants verified participant eligibility and completed the baseline assessment, the project director opened the next sequential sealed envelope and determined the participants treatment allocation. One of 9 counselors trained in smoking cessation and motivational interviewing (12) conducted all interventions from a single central site. We assigned participants to counselors without regard to practice site. Pharmacotherapy At baseline, all smokers received a health education mailing that consisted of a welcome letter, information about the use of bupropion and the nicotine patch for smoking cessation, and copies of You Can Quit Smoking: Consumer Guide (13) and When Smokers QuitThe Health Benefits Over Time (14). At baseline and at 6, 12, and 18 months, participants received a mailed offer for free pharmacotherapy that consisted of either a 6-week course of a nicotine patch (21 mg/d) or a 7-week course of sustained-release bupropion (150 mg twice daily). Participants interested in using either medication could return a postage-paid postcard or call a toll-free number. We screened all participants who requested pharmacotherapy for potential contraindications (15). Participants with absolute contraindications for a given drug were ineligible to receive that drug but were offered the option of receiving the other drug. Participants with contraindications to both drugs were not eligible to receive medication from the study but could participate in all other aspects of the intervention. For participants who requested bupropion and those with relative contraindications to the nicotine patch, research staff faxed a prescription request to their primary care physicians. This prescription request delineated any relative contraindications or potential drug interactions. For these participants, their physicians made the final assessment of the appropriateness of the bupropion or the patch. For participants without contraindications to the nicotine patch or on receipt of a faxed, signed prescription, the bupropion or patches were mailed to the participant along with instructions for use. Disease Management In addition to pharmacotherapy, the moderate-intensity and high-intensity disease management groups received educational support, telephone counseling, and periodic progress reports with counseling suggestions faxed to their physician. Every 6 months, they received a KanQuit newsletter that addressed tips on quitting smoking, talking with their physician about smoking, and using pharmacotherapy for cessation. The newsletters were personalized to include study updates, counselor photographs, physician feature stories, and testimonials of participants who had quit smoking. We offered participants assigned to moderate-intensity disease management up to 2 telephone-based counseling sessions every 6 months (1 session to promote a quit attempt and 1 additional follow-up session for those who made a quit attempt). We offered participants assigned to high-intensity disease management up to 6 counseling calls every 6 months to either promote quitting or prevent relapse. We scheduled calls at the participants convenience, and they varied according to the participants quit plan but followed a rough schedule of calls at 1, 3, 6, 9, and 16 weeks after the onset of each 6-month treatment cycle. Counselors used motivational interviewing techniques and followed a semistructured protocol to promote a cessation attempt or, for abstinent smokers, to encourage relapse prevention. During counseling calls, case managers reminded participants about the availability of pharmacotherapy and, for interested participants, provided immediate support for acquiring either the nicotine patch or bupropion, as described previously. We faxed personalized progress reports with suggestions for interventions to the participants physician after the first counseling call (both moderate-intensity and high-intensity disease management participants) and after the last counseling call (high-intensity disease management participants only) during each 6-month cycle. We faxed additional progress reports to the participants physician whenever the moderate-intensity or high-intensity disease management participant set a quit date. Outcomes, Measurements, and Follow-up Research assistants who were blinded to treatment group assignment conducted assessments by telephone at baseline and at 6, 12, 18, and 24 months. Primary Outcome The primary outcome measure was self-reported 7-day abstinence at 24 months, defined as not having smoked a cigarette during the previous 7 days. Although self-reported abstinence has been co

Identifying incident oral and pharyngeal cancer cases using Medicare claims.

BackgroundBaseline and trend data for oral and pharyngeal cancer incidence is limited. A new algorithm was derived using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database to create an algorithm to identify incident cases of oral and pharyngeal cancer using Medicare claims.MethodsUsing a split-sample approach, Medicare claims’ procedure and diagnosis codes were used to generate a new algorithm to identify oral and pharyngeal cancer cases and validate its operating characteristics.ResultsThe algorithm had high sensitivity (95%) and specificity (97%), which varied little by age group, sex, and race and ethnicity.ConclusionExamples of the utility of this algorithm and its operating characteristics include using it to derive baseline and trend estimates of oral and pharyngeal cancer incidence. Such measures could be used to provide incidence estimates where they are lacking or to serve as comparator estimates for tumor registries.

Interhemispheric connections of the ventral premotor cortex in a new world primate

This study describes the pattern of interhemispheric connections of the ventral premotor cortex (PMv) distal forelimb representation (DFL) in squirrel monkeys. Our objectives were to describe qualitatively and quantitatively the connections of PMv with contralateral cortical areas. Intracortical microstimulation techniques (ICMS) guided the injection of the neuronal tract tracers biotinylated dextran amine or Fast blue into PMv DFL. We classified the interhemispheric connections of PMv into three groups. Major connections were found in the contralateral PMv and supplementary motor area (SMA). Intermediate interhemispheric connections were found in the rostral portion of the primary motor cortex, the frontal area immediately rostral and ventral to PMv (FR), cingulate motor areas (CMAs), and dorsal premotor cortex (PMd). Minor connections were found inconsistently across cases in the anterior operculum (AO), posterior operculum/inferior parietal cortex (PO/IP), and posterior parietal cortex (PP), areas that consistently show connections with PMv in the ipsilateral hemisphere. Within‐case comparisons revealed that the percentage of PMv connections with contralateral SMA and PMd are higher than the percentage of PMv connections with these areas in the ipsilateral hemisphere; percentages of PMv connections with contralateral M1 rostral, FR, AO, and the primary somatosensory cortex are lower than percentages of PMv connections with these areas in the ipsilateral hemisphere. These studies increase our knowledge of the pattern of interhemispheric connection of PMv. They help to provide an anatomical foundation for understanding PMvs role in motor control of the hand and interhemispheric interactions that may underlie the coordination of bimanual movements. J. Comp. Neurol. 505:701–715, 2007.

Early biomechanical markers of postural instability in Parkinson's disease

Current clinical assessments do not adequately detect the onset of postural instability in the early stages of Parkinsons disease (PD). The aim of this study was to identify biomechanical variables that are sensitive to the effects of early Parkinsons disease on the ability to recovery from a balance disturbance. Ten adults diagnosed with idiopathic PD and no clinically detectable postural instability, and ten healthy age-range matched controls (HC) completed the study. The first step in the response to a backwards waist pull was quantified in terms of strategy, temporal, kinematic, kinetic, and center of pressure (COP) variables. People with PD, compared to HC, tended to be less consistent in the choice of stepping limb, utilized more time for weight shift, used a modified ankle joint motion prior to liftoff, and the COP was further posterior at landing. The study results demonstrate that PD changes the response to a balance disturbance which can be quantified using biomechanical variables even before the presence of clinically detectable postural instability. Further studies are required to determine if these variables are sensitive and specific to postural instability.

Geographic Variation in Cardioprotective Antihypertensive Medication Usage in Dialysis Patients

BACKGROUND Despite their high risk of adverse cardiac outcomes, persons on long-term dialysis therapy have had lower use of antihypertensive medications with cardioprotective properties, such as angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs), β-blockers, and calcium channel blockers, than might be expected. We constructed a novel database that permits detailed exploration into the demographic, clinical, and geographic factors associated with the use of these agents in hypertensive long-term dialysis patients. STUDY DESIGN National cross-sectional retrospective analysis linking Medicaid prescription drug claims with US Renal Data System core data. SETTING & PARTICIPANTS 48,882 hypertensive long-term dialysis patients who were dually eligible for Medicaid and Medicare services in 2005. FACTORS Demographics, comorbid conditions, functional status, and state of residence. OUTCOMES Prevalence of cardioprotective antihypertensive agents in Medicaid pharmacy claims and state-specific observed to expected ORs of medication exposure. MEASUREMENTS Factors associated with medication use were modeled using multilevel logistic regression models. RESULTS In multivariable analyses, cardioprotective antihypertensive medication exposure was associated significantly with younger age, female sex, nonwhite race, intact functional status, and use of in-center hemodialysis. Diabetes was associated with a statistically significant 28% higher odds of ACE-inhibitor/ARB use, but congestive heart failure was associated with only a 9% increase in the odds of β-blocker use and no increase in ACE-inhibitor/ARB use. There was substantial state-by-state variation in the use of all classes of agents, with a greater than 2.9-fold difference in adjusted-rate ORs between the highest and lowest prescribing states for ACE inhibitors/ARBs and a 3.6-fold difference for β-blockers. LIMITATIONS Limited generalizability beyond study population. CONCLUSIONS In publicly insured long-term dialysis patients with hypertension, there were marked differences in use rates by state, potentially due in part to differences in Medicaid benefits. However, geographic characteristics also were associated with exposure, suggesting clinical uncertainty about the utility of these medications.

Fracture Risk in Nursing Home Residents Initiating Antipsychotic Medications

To determine whether antipsychotic medication initiation is associated with subsequent fracture in nursing home residents, whether fracture rates differ between users of first‐ and second‐generation antipsychotics, and whether fracture rates differ between users of haloperidol, risperidone, olanzapine, and quetiapine.

Associations of interleukin-6, C-reactive protein and serum amyloid A with mortality in haemodialysis patients.

Background:  Individuals with end‐stage renal disease (ESRD) manifest a chronic inflammatory state. Serum albumin, C‐reactive protein (CRP), interleukin‐6 (IL‐6) and serum amyloid A (SAA) have been associated with mortality in ESRD, although reports vary as to whether they are true independent markers of mortality. We undertook a prospective study to determine whether these markers could predict mortality in ESRD.

Design and baseline characteristics from the KAN-QUIT disease management intervention for rural smokers in primary care

OBJECTIVE To describe the design, implementation, baseline data, and feasibility of establishing a disease management program for smoking cessation in rural primary care. METHOD The study is a randomized clinical trial evaluating a disease management program for smoking cessation. The intervention combined pharmacotherapy, telephone counseling, and physician feedback, and repeated intervention over two years. The program began in 2004 and was implemented in 50 primary care clinics across the State of Kansas. RESULTS Of eligible patients, 73% were interested in study participation. 750 enrolled participants were predominantly Caucasian, female, employed, and averaged 47.2 years of age (SD=13.1). In addition to smoking, 427 (57%) had at least one additional major risk factor for cardiovascular disease (diabetes, hypertension, high cholesterol, heart disease or stroke). Participants smoked on average 23.7 (SD=10.4) cigarettes per day, were contemplating (61%) or preparing to quit (30%), were highly motivated and confident of their ability to quit smoking, and reported seeing their physicians multiple times in the past twelve months (Median=3.50; Mean=5.48; SD=6.58). CONCLUSION Initial findings demonstrate the willingness of patients to enroll in a two-year disease management program to address nicotine dependence, even among patients not ready to make a quit attempt. These findings support the feasibility of identifying and enrolling rural smokers within the primary care setting.