CXCL8/CXCR2 signaling mediates bone marrow fibrosis and is a therapeutic target in myelofibrosis.

Proinflammatory signaling is a hallmark feature of human cancer, including in myeloproliferative neoplasms (MPNs), most notably myelofibrosis (MF). Dysregulated inflammatory signaling contributes to fibrotic progression in MF; however, the individual cytokine mediators elicited by malignant MPN cells to promote collagen-producing fibrosis and disease evolution are yet to be fully elucidated. Previously, we identified a critical role for combined constitutive JAK/STAT and aberrant NF-κB proinflammatory signaling in MF development. Using single-cell transcriptional and cytokine-secretion studies of primary cells from patients with MF and the human MPLW515L (hMPLW515L) murine model of MF, we extend our previous work and delineate the role of CXCL8/CXCR2 signaling in MF pathogenesis and bone marrow fibrosis progression. Hematopoietic stem/progenitor cells from patients with MF are enriched for a CXCL8/CXCR2 gene signature and display enhanced proliferation and fitness in response to an exogenous CXCL8 ligand in vitro. Genetic deletion of Cxcr2 in the hMPLW515L-adoptive transfer model abrogates fibrosis and extends overall survival, and pharmacologic inhibition of the CXCR1/2 pathway improves hematologic parameters, attenuates bone marrow fibrosis, and synergizes with JAK inhibitor therapy. Our mechanistic insights provide a rationale for therapeutic targeting of the CXCL8/CXCR2 pathway among patients with MF.

Single-cell multiplexed cytokine profiling of CD19 CAR-T cells reveals a diverse landscape of polyfunctional antigen-specific response.

BACKGROUND: It remains challenging to characterize the functional attributes of chimeric antigen receptor (CAR)-engineered T cell product targeting CD19 related to potency and immunotoxicity ex vivo, despite promising in vivo efficacy in patients with B cell malignancies. METHODS: We employed a single-cell, 16-plex cytokine microfluidics device and new analysis techniques to evaluate the functional profile of CD19 CAR-T cells upon antigen-specific stimulation. CAR-T cells were manufactured from human PBMCs transfected with the lentivirus encoding the CD19-BB-z transgene and expanded with anti-CD3/anti-CD28 coated beads. The enriched CAR-T cells were stimulated with anti-CAR or control IgG beads, stained with anti-CD4 RPE and anti-CD8 Alexa Fluor 647 antibodies, and incubated for 16 h in a single-cell barcode chip (SCBC). Each SCBC contains ~12,000 microchambers, covered with a glass slide that was pre-patterned with a complete copy of a 16-plex antibody array. Protein secretions from single CAR-T cells were captured and subsequently analyzed using proprietary software and new visualization methods. RESULTS: We demonstrate a new method for single-cell profiling of CD19 CAR-T pre-infusion products prepared from 4 healthy donors. CAR-T single cells exhibited a marked heterogeneity of cytokine secretions and polyfunctional (2+ cytokine) subsets specific to anti-CAR bead stimulation. The breadth of responses includes anti-tumor effector (Granzyme B, IFN-γ, MIP-1α, TNF-α), stimulatory (GM-CSF, IL-2, IL-8), regulatory (IL-4, IL-13, IL-22), and inflammatory (IL-6, IL-17A) functions. Furthermore, we developed two new bioinformatics tools for more effective polyfunctional subset visualization and comparison between donors. CONCLUSIONS: Single-cell, multiplexed, proteomic profiling of CD19 CAR-T product reveals a diverse landscape of immune effector response of CD19 CAR-T cells to antigen-specific challenge, providing a new platform for capturing CAR-T product data for correlative analysis. Additionally, such high dimensional data requires new visualization methods to further define precise polyfunctional response differences in these products. The presented biomarker capture and analysis system provides a more sensitive and comprehensive functional assessment of CAR-T pre-infusion products and may provide insights into the safety and efficacy of CAR-T cell therapy.

Variables Measured During Cardiopulmonary Exercise Testing as Predictors of Mortality in Chronic Systolic Heart Failure.

BACKGROUND: Data from a cardiopulmonary exercise (CPX) test are used to determine prognosis in patients with chronic heart failure (HF). However, few published studies have simultaneously compared the relative prognostic strength of multiple CPX variables. OBJECTIVES: The study sought to describe the strength of the association among variables measured during a CPX test and all-cause mortality in patients with HF with reduced ejection fraction (HFrEF), including the influence of sex and patient effort, as measured by respiratory exchange ratio (RER). METHODS: Among patients (n = 2,100, 29% women) enrolled in the HF-ACTION (HF-A Controlled Trial Investigating Outcomes of exercise traiNing) trial, 10 CPX test variables measured at baseline (e.g., peak oxygen uptake [Vo2], exercise duration, percent predicted peak Vo2 [%ppVo2], ventilatory efficiency) were examined. RESULTS: Over a median follow-up of 32 months, there were 357 deaths. All CPX variables, except RER, were related to all-cause mortality (all p < 0.0001). Both %ppVo2 and exercise duration were equally able to predict (Wald chi-square: ∼141) and discriminate (c-index: 0.69) mortality. Peak Vo2 (ml·kg(-1)·min(-1)) was the strongest predictor of mortality among men (Wald chi-square: 129) and exercise duration among women (Wald chi-square: 41). Multivariable analyses showed that %ppVo2, exercise duration, and peak Vo2 (ml·kg(-1)·min(-1)) were similarly able to predict and discriminate mortality. In men, a 10% 1-year mortality rate corresponded to a peak Vo2 of 10.9 ml·kg(-1)·min(-1) versus 5.3 ml·kg(-1)·min(-1) in women. CONCLUSIONS: Peak Vo2, exercise duration, and % ppVo2 carried the strongest ability to predict and discriminate the likelihood of death in patients with HFrEF. The prognosis associated with a given peak Vo2 differed by sex. (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure; NCT00047437).

Religiosity and Spirituality During Cardiac Rehabilitation: A LONGITUDINAL EVALUATION OF PATIENT-REPORTED OUTCOMES AND EXERCISE CAPACITY.

PURPOSE: This study is a longitudinal evaluation of religiosity/spirituality (R/S) and religious coping in post-myocardial infarction and post-coronary artery bypass surgery patients during a 12-week cardiac rehabilitation program. This study examines change in R/S and the relationship between R/S and psychosocial outcomes and exercise capacity over time. METHODS: Cardiac rehabilitation patients (N = 105) completed measures of R/S, religious coping, quality of life (QOL), self-efficacy (SE), and energy expenditure (EE) at the beginning (baseline) and end of a 12-week program. Relationships between R/S and religious coping and QOL, SE, and EE were evaluated. RESULTS: A negative relationship emerged between baseline measures of R/S and religious coping and QOL, SE, and EE. There were significant increases in Good Deeds Coping, QOL, SE, and EE from baseline to end of program (Ps < .05). Baseline measures of Interpersonal Religious Support Coping were positively correlated with the change in EE from baseline to end (r = 0.21; P = .059), and there were positive correlations between the change in Experiential Religiosity (r = 0.32; P = .004) and Overall Religiosity (r = 0.25; P = .024) with the change in EE. DISCUSSION: The demonstrated relationships between R/S and Religious Coping and outcomes in cardiac patients provide compelling support for the development of spiritual care interventions for cardiac patients and evaluation of the impact of these interventions on physiological, medical, and psychological outcomes in these patients.

Activity of delafloxacin against methicillin-resistant Staphylococcus aureus: resistance selection and characterization.

OBJECTIVES: To determine the potential for delafloxacin to select for resistant mutants in methicillin-resistant Staphylococcus aureus (MRSA), including isolates with existing mutations in the quinolone resistance determining region (QRDR). METHODS: Susceptibility testing by broth microdilution was performed on 30 MRSA clinical isolates. For four of these isolates, the presence or absence of mutations in the QRDR was characterized. Resistance selection was performed on these four isolates by spreading cells on drug-containing agar plates followed by incubation for 48 h. Resistance frequencies and mutant prevention concentrations (MPCs) were calculated for each; PCR amplification and sequencing were performed using standard methods to characterize mutations in the QRDR. Growth rate analysis was performed and relative fitness was determined. RESULTS: Delafloxacin demonstrated potent in vitro activity against this set of MRSA isolates, with MICs of 0.008-1 mg/L and an MIC(50) and MIC(90) of 0.03 and 0.5 mg/L, respectively. Spontaneous delafloxacin resistance frequencies for the MRSA strains were 2 × 10(-9) to <9.5 × 10(-11). Delafloxacin MPCs were one to four times the MIC for any isolate, lower than those of comparator quinolones. Some delafloxacin-selected mutants showed a fitness cost when co-cultured with the parent strain. CONCLUSIONS: Delafloxacin demonstrates excellent antibacterial potency and exhibits a low probability for the selection of resistant mutants in MRSA. Although mutants can be selected at low frequencies in vitro from quinolone-resistant isolates, delafloxacin MICs and MPCs remain low and a fitness cost can be observed. Consequently delafloxacin warrants further investigation for the potential treatment of drug-resistant MRSA infections.

Relationships between changes in patient-reported health status and functional capacity in outpatients with heart failure.

BACKGROUND: Heart failure trials use a variety of measures of functional capacity and quality of life. Lack of formal assessments of the relationships between changes in multiple aspects of patient-reported health status and measures of functional capacity over time limits the ability to compare results across studies. METHODS: Using data from HF-ACTION (N = 2331), we used the Pearson correlation coefficients and predicted change scores from linear mixed-effects modeling to demonstrate the associations between changes in patient-reported health status measured with the EQ-5D visual analog scale and the Kansas City Cardiomyopathy Questionnaire (KCCQ) and changes in peak VO(2) and 6-minute walk distance at 3 and 12 months. We examined a 5-point change in KCCQ within individuals to provide a framework for interpreting changes in these measures. RESULTS: After adjustment for baseline characteristics, correlations between changes in the visual analog scale and changes in peak VO(2) and 6-minute walk distance ranged from 0.13 to 0.28, and correlations between changes in the KCCQ overall and subscale scores and changes in peak VO(2) and 6-minute walk distance ranged from 0.18 to 0.34. A 5-point change in KCCQ was associated with a 2.50-mL kg(-1) min(-1) change in peak VO(2) (95% CI 2.21-2.86) and a 112-m change in 6-minute walk distance (95% CI 96-134). CONCLUSIONS: Changes in patient-reported health status are not highly correlated with changes in functional capacity. Our findings generally support the current practice of considering a 5-point change in the KCCQ within individuals to be clinically meaningful.

Treatment of patients with intermediate cardiovascular risk: Are clinical measures enough?

AIM: Clinical measures of cardiovascular disease risk (CVD) are important tools for establishing therapy to lower CVD risk. Risk assessment has come under criticism because clinical measures can underestimate or overestimate CVD risk. We assessed CVD risk in 252 subjects without evidence of CVD to establish therapy of one or more risk factors from clinical indications. The subjects all had intermediate CVD risk using the Framingham score. RESULTS: Average age was 59.1 years. 23.8% were smokers, 59.1% were hypertensive, 65.1% had hyperlipidemia. BMI was greater than 30 kg/M(2) in 56% and diabetes was present in 43.7%. In this cohort, 86.9% required therapy for hypertension or hyperlipidemia, and this proportion increased to 95.6% when subjects with diabetes were included. Of the remaining 4.4% (11 subjects), 7 reached intermediate risk based on cigarette smoking and 4 based on age >65 years old. Among diabetics, 94/110 had another risk factor and would require statin and ACE or ARB therapy. CONCLUSIONS: Of subjects at intermediate risk for CVD, 98.4% would not require further testing to decide on therapy to lower CVD risk. Although 16 diabetic subjects had no other risk factors, current guidelines suggest that these subjects should be treated to reduce CVD risk.

Demographic differences in religious coping after a first-time cardiac event.

PURPOSE: The purpose of this project was to describe demographic characteristics of patients who may use religion as a coping response to a first-time cardiac event. METHODS: Patients (N = 105), who were enrolled in cardiac rehabilitation after a first-time myocardial infarction or coronary artery revascularization bypass surgery, completed the Religious Coping Activities Scale. Independent variables included age, gender, religious affiliation, diagnosis, marital status, and education level. The 6 types of religious coping activities were compared for each level of the independent variables. RESULTS: Significant differences emerged for gender, religious affiliation, marital status, and level of education. Women scored higher than men on spiritually based activities (T = 1550, P = .03), good deeds (T = 1504, P = .08), and religious avoidance coping (T = 1505, P = .08). Participants who claimed no religious affiliation scored lowest on good deeds (H[2] = 9.7, P = .008) and interpersonal religious support coping (H[2] = 13.4, P = .001) and higher on discontent coping (H[2] = 5.4, P = .07). Single participants scored higher on spiritually based coping than did married participants (T = 1251, P = .04) and lower on discontent coping (H[1] = 4.3, P = .04). Plead coping was an inverse function of education (H[3] = 6.8, P = .08). CONCLUSIONS: Patients beginning cardiac rehabilitation, particularly those with the demographic characteristics discussed in this study, may benefit from assessment of their desire for pastoral intervention.

Reducing cardiovascular disease risk in medically underserved urban and rural communities.

OBJECTIVES: The aim of this study is to evaluate methods for lowering cardiovascular disease (CVD) risk in asymptomatic urban and rural underserved subjects. BACKGROUND: Medically underserved populations are at increased CVD risk, and systems to lower CVD risk are needed. Nurse management (NM) and telemedicine (T) systems may provide low-cost solutions for this care. METHODS: We randomized 465 subjects without overt CVD, with Framingham CVD risk >10% to NM with 4 visits over 1 year, or NM plus T to facilitate weight, blood pressure (BP), and physical activity reporting. The study goal was to reduce CVD risk by 5%. RESULTS: Three hundred eighty-eight subjects completed the study. Cardiovascular disease risk fell by ≥ 5% in 32% of the NM group and 26% of the T group (P, nonsignificant). In hyperlipidemic subjects, total cholesterol decreased (NM -21.9 ± 39.4, T -22.7 ± 41.3 mg/dL) significantly. In subjects with grade II hypertension (systolic BP ≥ 160 mm Hg, 24% of subjects), both NM and T groups had a similar BP response (average study BP: NM 147.4 ± 17.5, T 145.3. ± 18.4, P is nonsignificant), and for those with grade I hypertension (37% of subjects), T had a lower average study BP compared to NM (NM 140.4 ± 16.9, T 134.6 ± 15.0, P = .058). In subjects at high risk (Framingham score ≥ 20%), risk fell 6.0% ± 9.9%; in subjects at intermediate risk (Framingham score ≥ 10, < 20), risk fell 1.3% ± 4.5% (P < .001 compared to high-risk subjects). Medication adherence was similar in both high- and intermediate-risk subjects. CONCLUSIONS: In 2 underserved populations, CVD risk was reduced by a nurse intervention; T did not add to the risk improvement. Reductions in BP and blood lipids occurred in both high- and intermediate-risk subjects with greatest reductions noted in the high-risk subjects. Frequent communication using a nurse intervention contributes to improved CVD risk in asymptomatic, underserved subjects with increased CVD risk. Telemedicine did not change the effectiveness of the nurse intervention.

Clinical and functional predictors of health-related quality of life during cardiac rehabilitation.

PURPOSE: This is a retrospective and descriptive analysis of demographic and clinical factors common among cardiac rehabilitation patients with high versus low perceptions of health-related quality of life(HRQOL). In addition, we describe the characteristics that are predictive of greater improvements in HRQOL during cardiac rehabilitation. METHODS: We included 970 patients (63.6 10.6 years; 71% male patients) referred to a 12-week program between 1996 and 2006 who all completed a HRQOL questionnaire at baseline and program completion.Patients were divided into 4 quartiles based on HRQOL scores at program entry. The Kruskall-Wallis test and χ² analyses determined differences between quartiles for continuous and categorical variables,respectively. In addition, regression models predicted changes in HRQOL during the course of the cardiac rehabilitation program. RESULTS: At program entry, quartile differences were found for diagnosis (P = .04), number of risk factors (P < .01), self-efficacy (P < .001), and caloric expenditure (P = .05). Significant predictors of change included baseline HRQOL sores, flexibility, and left ventricular ejection fraction (R² = 0.50; P = .001). CONCLUSIONS: The factors found that related to baseline HRQOL and were predictive of the change in HRQOL were primarily clinical and functional in nature. This suggests that those who have greater physical functionality, the confidence to perform physical tasks, and are not limited clinically, may more readily adapt to cardiac rehabilitation and progress more rapidly. Those patients with the poorest exercise capacities at entrance to the program tended to make the greatest gains in HRQOL.

Rural and urban characteristics impact cardiovascular risk reduction.

PURPOSE: Our aim was to provide a descriptive analysis of specific differences between rural and urban residents and the interaction between these differences and those who reduced cardiovascular disease (CVD) risk in response to intervention versus those who did not. METHODS: This study is a descriptive analysis comparing rural groups with urban groups and those who decreased CVD risk with those who did not. Two hundred five rural (median age = 64.0 years [interquartile = 57.0, 71.0], 56% men) and 183 urban (median age = 58.0 years [interquartile = 50.0, 65.0], 53% men) residents were included. RESULTS: Rural and urban groups differed (P < .05) for demographic, anthropometric, physiological, and health-related variables. Those who decreased CVD risk, regardless of rural or urban, had greater blood pressure, greater low-density lipoprotein cholesterol, lower walking distance, greater CVD risk score, greater metabolic syndrome score, and greater internal health locus of control (all P < .05). Interestingly, there were differences between those who decreased risk and those who did not within the rural and urban groups. Triglycerides, C-reactive protein, diabetes knowledge, risk perception, and outcome expectations were greater for the rural group who decreased their CVD risk versus those who did not (all P < .05). For the urban group, there was a greater powerful others locus of control for those who decreased CVD risk (P < .05). CONCLUSIONS: To maximize the likelihood of success, risk reduction intervention and educational strategies for urban and rural groups must be tailored to address unique demographic, physiological, and health-related characteristics.

Gender differences in cardiovascular risk factors and risk perception among individuals with diabetes.

PURPOSE: The purpose of this study was to examine gender-based differences in cardiovascular risk factors and risk perception among individuals with diabetes. METHODS: The sample consisted of patients with an established history of diabetes who were enrolled in a telemedicine trial to reduce cardiovascular disease (CVD) risk. All subjects had a 10% or greater risk on the Framingham risk index. Assessments included blood pressure, A1C, lipid profile, medication history, and knowledge and risk perception surveys. RESULTS: Data were available for 211 individuals with type 2 diabetes (88 men and 123 women). The women and men did not differ in age, body mass index, or Framingham risk. Only 37.4% of women and 40.9% of men were at an A1C target of <7%. Total cholesterol levels were significantly higher among women, and fewer women were at low-density lipoprotein or blood pressure targets. Knowledge of CVD was similar between the 2 sexes. However, women perceived their risk for CVD to be significantly higher than did men. CONCLUSION: Less favorable cardiovascular risk profiles are observed among women with diabetes as compared with their male counterparts. Multifaceted approaches to both diabetes management and education are needed to target CVD risk reduction among individuals with diabetes.

R chi-01, a new family of oxazolidinones that overcome ribosome-based linezolid resistance.

New and improved antibiotics are urgently needed to combat the ever-increasing number of multidrug-resistant bacteria. In this study, we characterized several members of a new oxazolidinone family, R chi-01. This antibiotic family is distinguished by having in vitro and in vivo activity against hospital-acquired, as well as community-acquired, pathogens. We compared the 50S ribosome binding affinity of this family to that of the only marketed oxazolidinone antibiotic, linezolid, using chloramphenicol and puromycin competition binding assays. The competition assays demonstrated that several members of the R chi-01 family displace, more effectively than linezolid, compounds known to bind to the ribosomal A site. We also monitored binding by assessing whether R chi-01 compounds protect U2585 (Escherichia coli numbering), a nucleotide that influences peptide bond formation and peptide release, from chemical modification by carbodiimide. The R chi-01 oxazolidinones were able to inhibit translation of ribosomes isolated from linezolid-resistant Staphylococcus aureus at submicromolar concentrations. This improved binding corresponds to greater antibacterial activity against linezolid-resistant enterococci. Consistent with their ribosomal A-site targeting and greater potency, the R chi-01 compounds promote nonsense suppression and frameshifting to a greater extent than linezolid. Importantly, the gain in potency does not impact prokaryotic specificity as, like linezolid, the members of the R chi-01 family show translation 50% inhibitory concentrations that are at least 100-fold higher for eukaryotic than for prokaryotic ribosomes. This new family of oxazolidinones distinguishes itself from linezolid by having greater intrinsic activity against linezolid-resistant isolates and may therefore offer clinicians an alternative to overcome linezolid resistance. A member of the R chi-01 family of compounds is currently undergoing clinical trials.

Accuracy of blood pressure measurements transmitted through a telemedicine system in underserved populations.

In underserved populations, inadequate surveillance and treatment allows hypertension to persist until actual cardiovascular events occur. Thus, we developed an Internet-based telemedicine system to address the suboptimal control of hypertension and other modifiable risk factors. To minimize cost, the subjects used home monitors for blood pressure (BP) measurements and entered these values into the telemedicine system. We hypothesized that patients could accurately measure their BP and transmit these values via a telemedicine system. Inner city and rural subjects (N = 464; 42% African-American or Hispanic) with 10% or greater 10-year risk of cardiovascular disease and with treatable risk factors were randomized into two groups, control group (CG) and telemedicine group (TG). Each subject received a home sphygmomanometer with memory. The TG recorded and entered BP at least weekly. During office visits, the BP meters were downloaded and recorded BP compared to BP values transmitted via telemedicine. The telemedicine (T) BP values were similar to the meter recorded (R) values (T: systolic/diastolic BP 133.4 +/- 11.1/77.5 +/- 6.8 mm Hg, and R: systolic/diastolic BP 136.4 +/- 11.9.4/79.7 +/- 7.5 mm Hg). The percent error was <1% for both systolic (-0.02 +/- 0.04%) and diastolic (-0.03 +/- 0.04%) BP. Lastly, the telemedicine BP values were similar to the office (O) BP values for systolic and diastolic BP (T: systolic/diastolic BP 133.4 +/- 11.1/77.5 +/- 6.8 mm Hg, and O: systolic/diastolic BP 136.3 +/- 20.5/78.1 +/- 10.5 mm Hg). In underserved populations, this inexpensive approach of patients using a home monitor and entering these values into a telemedicine system provided accurate BP data.

Using a telemedicine system to decrease cardiovascular disease risk in an underserved population: design, use, and interim results.

Cardiovascular disease is the leading cause of morbidity and mortality in the USA. Disease management programs, while successful, are intensive and expensive. Follow-up is often inadequate, incomplete, and inconsistent. To address these problems, we developed an Internet-Telemedicine system. Patients send/receive data to/from their care provider via the Internet. The system optimizes function and minimizes cost (all hardware is off the shelf and FDA approved). We are currently using this Telemedicine system in a prospective, randomized clinical trial, to reduce CVD risk in medically underserved populations. Over an 8-month time interval, we found very high rates of usage of the Telemedicine system (92%). This rate of self-monitoring greatly exceeded the self-monitoring rate in controls (48%). The patient-entered Telemedicine blood pressure values were similar to the meter recorded values and to the office values.

Cardiac rehabilitation outcomes no different after on-pump versus off-pump coronary artery bypass surgery.

PURPOSE: Clinical evidence supports lower morbidity with off-pump coronary revascularization surgery as well as superior short- and mid-term outcomes, equivalent graft patency, and reduced cost. The purpose of this study was to compare cardiac rehabilitation (CR) outcomes between patients undergoing on-pump versus off-pump coronary artery bypass surgery. METHODS: Data were retrospectively examined for patients who participated in CR between 1996 and 2004. Two hundred ninety-five patients who underwent bypass surgery and completed at least 80% of their 36 required sessions were divided into on-pump and off-pump groups. Pre- and post-CR measures included grip strength, flexibility, energy expended during class, quality of life, and self-efficacy. RESULTS: Both groups were similar with respect to age, sex, ejection fraction, and mean number of grafts. There were no statistical differences between the on-pump and off-pump groups (P > .05) for weight, abdominal and hip circumferences, grip strength, flexibility, and total energy expenditure. In addition, there were no between-group differences regarding quality of life and self-efficacy. Grip strength, flexibility, and energy expenditure during class improved with CR regardless of the surgical procedure (P = .001). Quality of life (P = .001) and self-efficacy (P = .001) also improved. CONCLUSIONS: The present data support the concept that although there are clinical advantages to off-pump surgery, there is no benefit over on-pump surgery regarding CR. Subsequently, patients undergoing off-pump surgery should be managed similarly as their on-pump counterparts.

Cardiovascular disease prevention for underserved patients using the Internet: bridging the digital divide.

For underserved populations, telemedicine can address the high prevalence and suboptimal control of cardiovascular disease (CVD) risk factors. However, Internet access issues may limit the successful application of telemedicine. We tested the hypothesis that computer skills, and not access per se, was the main obstacle to using the Internet for health care. After informed consent, 44 participants with little or no computer experience received 2 hours of training covering 14 basic computer use skills, Internet access, and our telemedicine system. The telemedicine system enables reporting blood pressure, weight, physical activity, cigarette use, provider feedback, personal medication information, and educational information about CVD risk factors. The patient population included 12 males and 32 females. Of this total were 23 African Americans. The average patient age was 60.4 +/- 3 years, and 64% had annual family incomes under 25,000 dollars. Eighty-two percent of the participants averaged 4 or higher (on a scale of 1 to 5) on basic computer skills. Only 11% had an average score below 3. Thirty-seven of 44 participants reported on their health status from a local Internet access site within 10 days. Participants' successful use of the telemedicine system was not correlated with age, gender, education level, or ownership of a computer. Computer skill score had a positive effect on system use. Underserved populations without computer experience or skills and at increased risk for CVD can be educated to use an Internet telemedicine system to communicate health status to their health care providers. Ownership of a computer was not a factor that predicted system use.

Ventilatory markers during exercise for congestive heart failure.

The exaggerated ventilatory response in patients with heart failure is clearly multifactorial and complex beyond a mere reduction in pulmonary blood flow. Pulmonary dysfunction, including ventilation-perfusion mismatching, decreased lung compliance, restriction, airway obstruction, decreased diffusion capacity, and decreases in respiratory muscle strength and endurance, contributes to an inefficient breathing pattern and increased work of breathing. This is further compounded by the limited ability of the failing heart to meet the metabolic demands of the respiratory muscles, leading to underperfusion and ischemia.Although VO2max has important implications with regard to functional capacity, exercise test personnel must be knowledgeable concerning the clinical physiology of ventilation during exercise in the patient with heart failure. Ventilatory markers, as Arena and coworkers have demonstrated, are most indicative of disease severity and enhance the prognostic value of the test results.

Stress examination of supination external rotation-type fibular fractures.

BACKGROUND: Deltoid incompetence in association with an isolated fibular fracture is assumed to be present if there is medial tenderness, ecchymosis, or substantial swelling. We sought to determine whether these soft-tissue indicators predict deltoid incompetence by comparing such findings with the findings on stress radiographs. METHODS: Over a thirty-two-month period, 138 patients who presented acutely with a Weber type-B supination-external rotation (SE) fibular fracture were evaluated for tenderness (in nine locations), ecchymosis, and swelling. Patients who presented with an apparently isolated fibular fracture and an intact ankle mortise (with a medial clear space of < or =4 mm and no talar subluxation) were evaluated with a stress radiograph to determine deltoid competence. Four groups of patients were identified: those who had an SE2 fracture (defined as those who had a stable ankle on the stress radiograph), those who had a stress (+) SE4 fracture (defined as those who had an unstable ankle on the stress radiograph), those who had an SE4 fracture (defined as those who presented with a wide medial clear space), and those who had a bimalleolar fracture. These four groups were compared with regard to tenderness, swelling, and ecchymosis at the time of initial presentation. Patients with SE2 injuries were allowed immediate weight-bearing. RESULTS: Of the ninety-seven patients who presented with an isolated fibular fracture and an intact mortise, sixty-one had a stable SE2 injury and thirty-six had an unstable stress (+) SE4 injury. All stable SE2 injuries healed with an intact mortise. Medial tenderness, ecchymosis, and swelling were not predictive of deltoid incompetence (instability). CONCLUSIONS: Stress radiographs allow for the accurate diagnosis of deltoid incompetence in patients with Weber type-B SE fibular fractures and no other osseous injury. Soft-tissue indicators are not accurate predictors of instability. If medial tenderness, ecchymosis, and swelling are used as operative indications, in some cases surgery may be performed on stable ankles.

Percutaneous pin placement in the medial calcaneus: is anywhere safe?

OBJECTIVE: To redefine the medical calcaneal anatomic safe zone for pin placement with respect to reproducible palpable landmarks. DESIGN: Anatomic study. SETTING: Medical school anatomy laboratory. INTERVENTIONS: Thirty-three fresh-frozen adult cadaveric feet were used. Three palpable anatomic landmarks were identified on each ankle and labeled as Point A (posteroinferior medial calcaneus), Point B (inferior medial malleolus), and Point C (navicular tuberosity). The medial neurovascular bundle was carefully dissected, and the medial calcaneal nerve, the most posterior branch of the lateral plantar nerve, the lateral plantar nerve, the medial plantar nerve, and the posterior tibial artery were identified. These structures were recorded at the point at which they transected a line from Point A to B and from Point A to C. Based on the findings of the first thirty-three feet, two pins were placed percutaneously into the medial calcaneus of ten additional feet. Pin 1 was placed one half the distance from Point A to B. Pin 2 was placed one third the distance from Point A to C. The neurovascular structures were then dissected and identified in relation to the pin position. RESULTS: The medial calcaneal, most posterior branch of the lateral plantar, and lateral plantar nerves are at significant risk for abutting the pins or being directly injured at the margins of these relative safe zones. CONCLUSION: The medial calcaneus provides a small window for safe percutaneous pin placement. Posterior to the halfway point from Point A to B and posterior to the one-third mark from Point A to C remain the relatively safest regions; a more posterior placement in the safe zone is safest. Careful blunt dissection and the use of cannulas may help to avoid neurovascular injury.