PDZ domain-binding motif regulates cardiomyocyte compartment-specific NaV1.5 channel expression and function

BACKGROUND Sodium channel NaV1.5 underlies cardiac excitability and conduction. The last 3 residues of NaV1.5 (Ser-Ile-Val) constitute a PDZ domain-binding motif that interacts with PDZ proteins such as syntrophins and SAP97 at different locations within the cardiomyocyte, thus defining distinct pools of NaV1.5 multiprotein complexes. Here, we explored the in vivo and clinical impact of this motif through characterization of mutant mice and genetic screening of patients. METHODS AND RESULTS To investigate in vivo the regulatory role of this motif, we generated knock-in mice lacking the SIV domain (ΔSIV). ΔSIV mice displayed reduced NaV1.5 expression and sodium current (INa), specifically at the lateral myocyte membrane, whereas NaV1.5 expression and INa at the intercalated disks were unaffected. Optical mapping of ΔSIV hearts revealed that ventricular conduction velocity was preferentially decreased in the transversal direction to myocardial fiber orientation, leading to increased anisotropy of ventricular conduction. Internalization of wild-type and ΔSIV channels was unchanged in HEK293 cells. However, the proteasome inhibitor MG132 rescued ΔSIV INa, suggesting that the SIV motif is important for regulation of NaV1.5 degradation. A missense mutation within the SIV motif (p.V2016M) was identified in a patient with Brugada syndrome. The mutation decreased NaV1.5 cell surface expression and INa when expressed in HEK293 cells. CONCLUSIONS Our results demonstrate the in vivo significance of the PDZ domain-binding motif in the correct expression of NaV1.5 at the lateral cardiomyocyte membrane and underline the functional role of lateral NaV1.5 in ventricular conduction. Furthermore, we reveal a clinical relevance of the SIV motif in cardiac disease.

Patient-rated Outcomes of Lumbar Fusion in Patients with Degenerative Disease of the Lumbar Spine: Does Age Matter?

Introduction: Current demographic changes are characterized by population aging, such that the surgical treatment of degenerative spine conditions in the elderly is gaining increasing relevance. However, there is a general reluctance to consider spinal fusion procedures in this patient age group due to the increased likelihood of complications. The aim of this study was to assess the patient-rated outcome and complication rates associated with lumbar fusion procedures in three different age groups. Methods: This was a retrospective analysis of prospectively collected data from consecutive patients who underwent first-time, one to three level posterior instrumented fusion between 2004 and 2011, due to degenerative disease of the lumbar spine. Data were obtained from our Spine Surgery Outcomes Database (linked to the International Spine Tango Register). Before surgery, patients completed the multidimensional Core Outcome Measures Index (COMI), and at 3 and 12 months after surgery they completed the COMI and rated the Global Treatment Outcome (GTO) and their satisfaction with care. Patients were divided into three groups according to their age: younger (≥50y <65y; n = 317), older (≥65y <80y; n = 350), and geriatric (≥ 80y; n = 40). Results: 707 consecutive patients were included. The preoperative comorbidity status differed significantly (p < 0.0001) between the age groups, with the highest scores in the geriatric group. General medical complications during surgery were lower in the younger age group (7%) than in the older (13.4%; p = 0.006) and geriatric groups (17.5%; p = 0.007). Duration of hospital stay was longer (p = 0.006) in the older group (10.8 ± 3.7 days) than the younger (10.0 ± 3.6 days) group. There were no significant group differences (p>0.05) for any of the COMI domains covering pain, function, symptom specific well-being, general quality of life, and social and work disability at either 3 months’ or 12 months’ follow-up. Similarly, there were no differences (p>0.05) between the age groups for GTO and patient-rated satisfaction at either follow-up. Conclusions: Preoperative comorbidity and general medical complications during lumbar fusion for degenerative disorders of the lumbar spine are both greater in geriatric patients than in younger patients. However, patient-rated outcome is as good in the elderly as it is in younger age groups. These data suggest that geriatric age per se is not a contraindication to instrumented fusion for lumbar degenerative disease.

Risk factors for patient-reported medical errors in eleven countries

OBJECTIVES The aim of this study was to identify common risk factors for patient-reported medical errors across countries. In country-level analyses, differences in risks associated with error between health care systems were investigated. The joint effects of risks on error-reporting probability were modelled for hypothetical patients with different health care utilization patterns. DESIGN Data from the Commonwealth Fund's 2010 lnternational Survey of the General Public's Views of their Health Care System's Performance in 11 Countries. SETTING Representative population samples of 11 countries were surveyed (total sample = 19,738 adults). Utilization of health care, coordination of care problems and reported errors were assessed. Regression analyses were conducted to identify risk factors for patients' reports of medical, medication and laboratory errors across countries and in country-specific models. RESULTS Error was reported by 11.2% of patients but with marked differences between countries (range: 5.4-17.0%). Poor coordination of care was reported by 27.3%. The risk of patient-reported error was determined mainly by health care utilization: Emergency care (OR = 1.7, P < 0.001), hospitalization (OR = 1.6, P < 0.001) and the number of providers involved (OR three doctors = 2.0, P < 0.001) are important predictors. Poor care coordination is the single most important risk factor for reporting error (OR = 3.9, P < 0.001). Country-specific models yielded common and country-specific predictors for self-reported error. For high utilizers of care, the probability that errors are reported rises up to P = 0.68. CONCLUSIONS Safety remains a global challenge affecting many patients throughout the world. Large variability exists in the frequency of patient-reported error across countries. To learn from others' errors is not only essential within countries but may also prove a promising strategy internationally.

Gender-Specific Associations between Circulating T-Cadherin and High Molecular Weight-Adiponectin in Patients with Stable Coronary Artery Disease.

Close relationships exist between presence of adiponectin (APN) within vascular tissue and expression of T-cadherin (T-cad) on vascular cells. APN and T-cad are also present in the circulation but here their relationships are unknown. This study investigates associations between circulating levels of high molecular weight APN (HMW-APN) and T-cad in a population comprising 66 women and 181 men with angiographically proven stable coronary artery disease (CAD). Plasma HMW-APN and T-cad were measured by ELISA and analysed for associations with baseline clinical characteristics and with each other. In multivariable analysis BMI and HDL were independently associated with HMW-APN in both genders, while diabetes and extent of coronary stenosis were independently associated with T-cad in males only. Regression analysis showed no significant association between HMW-APN and T-cad in the overall study population. However, there was a negative association between HMW-APN and T-cad (P=0.037) in a subgroup of young men (age <60 years, had no diabetes and no or 1-vessel CAD) which persisted after multivariable analysis with adjustment for all potentially influential variables (P=0.021). In the corresponding subgroup of women there was a positive association between HMW-APN and T-cad (P=0.013) which disappeared after adjustment for HDL. After exclusion of the young men, a positive association (P=0.008) between HMW-APN and T-cad was found for the remaining participants of the overall population which disappeared after adjustment for HDL and BMI. The existence of opposing correlations between circulating HMW-APN and T-cad in male and female patient populations underscores the necessity to consider gender as a confounding variable when evaluating biomarker potentials of APN and T-cad.

A Specific Mapping Study Using Fluorescence Sentinel Lymph Node Detection in Patients with Intermediate- and High-risk Prostate Cancer Undergoing Extended Pelvic Lymph Node Dissection.

Sentinel lymph node (SLN) detection techniques have the potential to change the standard of surgical care for patients with prostate cancer. We performed a lymphatic mapping study and determined the value of fluorescence SLN detection with indocyanine green (ICG) for the detection of lymph node metastases in intermediate- and high-risk patients undergoing radical prostatectomy and extended pelvic lymph node dissection. A total of 42 patients received systematic or specific ICG injections into the prostate base, the midportion, the apex, the left lobe, or the right lobe. We found (1) that external and internal iliac regions encompass the majority of SLNs, (2) that common iliac regions contain up to 22% of all SLNs, (3) that a prostatic lobe can drain into the contralateral group of pelvic lymph nodes, and (4) that the fossa of Marcille also receives significant drainage. Among the 12 patients who received systematic ICG injections, 5 (42%) had a total of 29 lymph node metastases. Of these, 16 nodes were ICG positive, yielding 55% sensitivity. The complex drainage pattern of the prostate and the low sensitivity of ICG for the detection of lymph node metastases reported in our study highlight the difficulties related to the implementation of SNL techniques in prostate cancer. PATIENT SUMMARY There is controversy about how extensive lymph node dissection (LND) should be during prostatectomy. We investigated the lymphatic drainage of the prostate and whether sentinel node fluorescence techniques would be useful to detect node metastases. We found that the drainage pattern is complex and that the sentinel node technique is not able to replace extended pelvic LND.

The influence of naturalistic, directionally non-specific motion on the spatial deployment of visual attention in right-hemispheric stroke

An impairment of the spatial deployment of visual attention during exploration of static (i.e., motionless) stimuli is a common finding after an acute, right-hemispheric stroke. However, less is known about how these deficits: a) are modulated through naturalistic motion (i.e., without directional, specific spatial features); and, b) evolve in the subacute/chronic post-stroke phase. In the present study, we investigated free visual exploration in three patient groups with subacute/chronic right-hemispheric stroke and in healthy subjects. The first group included patients with left visual neglect and a left visual field defect (VFD), the second patients with a left VFD but no neglect, and the third patients without neglect or VFD. Eye movements were measured in all participants while they freely explored a traffic scene without (static condition) and with (dynamic condition) naturalistic motion, i.e., cars moving from the right or left. In the static condition, all patient groups showed similar deployment of visual exploration (i.e., as measured by the cumulative fixation duration) as compared to healthy subjects, suggesting that recovery processes took place, with normal spatial allocation of attention. However, the more demanding dynamic condition with moving cars elicited different re-distribution patterns of visual attention, quite similar to those typically observed in acute stroke. Neglect patients with VFD showed a significant decrease of visual exploration in the contralesional space, whereas patients with VFD but no neglect showed a significant increase of visual exploration in the contralesional space. No differences, as compared to healthy subjects, were found in patients without neglect or VFD. These results suggest that naturalistic motion, without directional, specific spatial features, may critically influence the spatial distribution of visual attention in subacute/chronic stroke patients.

Measuring health state preferences for hemophilia: Development of a disease-specific utility instrument

Research has shown that disease-specific health related quality of life (HRQoL) instruments are more responsive than generic instruments to particular disease conditions. However, only a few studies have used disease-specific instruments to measure HRQoL in hemophilia. The goal of this project was to develop a disease-specific utility instrument that measures patient preferences for various hemophilia health states. The visual analog scale (VAS), a ranking method, and the standard gamble (SG), a choice-based method incorporating risk, were used to measure patient preferences. Study participants (n = 128) were recruited from the UT/Gulf States Hemophilia and Thrombophilia Center and stratified by age: 0–18 years and 19+. ^ Test retest reliability was demonstrated for both VAS and SG instruments: overall within-subject correlation coefficients were 0.91 and 0.79, respectively. Results showed statistically significant differences in responses between pediatric and adult participants when using the SG (p = .045). However, no significant differences were shown between these groups when using the VAS (p = .636). When responses to VAS and SG instruments were compared, statistically significant differences in both pediatric (p < .0001) and adult (p < .0001) groups were observed. Data from this study also demonstrated that persons with hemophilia with varying severity of disease, as well as those who were HIV infected, were able to evaluate a range of health states for hemophilia. This has important implications for the study of quality of life in hemophilia and the development of disease-specific HRQoL instruments. ^ The utility measures obtained from this study can be applied in economic evaluations that analyze the cost/utility of alternative hemophilia treatments. Results derived from the SG indicate that age can influence patients' preferences regarding their state of health. This may have implications for considering treatment options based on the mean age of the population under consideration. Although both instruments independently demonstrated reliability and validity, results indicate that the two measures may not be interchangeable. ^

Patient perceptions of balance in prostate cancer screening decision aids

Purpose. Recent reports reveals that studies of decision aids reported concern about the balance and accuracy of information included in decision aids. This study explores measures of balance in patient decision aids through a review of prostate cancer screening decision aid studies and analysis of patients’ rating of a patient decision aid for prostate cancer screening. ^ Methods. A data-abstraction form was used to collect the key characteristics, pertaining to balance, of studies included in the review. The key characteristics included (1) sample characteristics (age, race, family history of prostate cancer, and education), (2) description of the decision aid and how it was implemented, and (3) if a measure of balance was used for process evaluation and the rating. A summary table was used to report the findings. Deidentified data was received from a decision aid control trial and logistic regression analysis was used to test the association between the dependent variable (balance) and the independent variables (age, family history, race, screening preference at baseline, education, health insurance status). ^ Conclusion. Three sociodemographic variables remained significant in the final regression model: African American race, education and PSA history. Further research is needed to determine if these variables can predict a man’s perception of balance in prostate cancer screening decision aids. If a patient’s perceptions of balance can be predicted based on specific characteristics, patient report may not be the most objective method of evaluating the acceptability of a decision.^

Management and outcomes of anorectal infection in the cancer patient

Background. The objective of this retrospective cohort study is to examine the presentation and outcomes for a contemporary series of cancer patients with anorectal infection. In addition, we seek to identify factors which are associated with surgical intervention. ^ Methods. The study cohort was identified from ICD-9 codes for diagnosis of infection of the anal and rectal region and patients who underwent a surgical oncology consultation between 1/2000 and 12/2006. Clinical presentation, treatment rendered, and outcomes were retrospectively recorded. ^ Results. Of the 100 patients evaluated by the surgical oncology service for anorectal infection, 42 were treated non-operatively and 58 underwent surgical intervention. Factors associated with surgical intervention based on logistic multivariable analysis included the diagnosis of an abscess (odds ratio [OR] 10.5; 95% confidence interval [CI] 2.9-38.5) and the documentation of erythema on physical examination (OR 3.1; 95% CI 1.1-8.4). Thrombocytopenia (platelets < 50,000) was associated with non-operative management (OR 0.3; 95% CI 0.1-0.7). Incision and drainage was the most common surgical procedure (79%) while a wide debridement for a necrotizing soft tissue infection was required in 2 patients. Infection-specific 90-day mortality was only 1% (N=1). However, the median overall survival for the entire cohort was only 14.4 months (95% CI 7.9-19.5). ^ Conclusions. Non-operative management is a reasonable treatment option for anorectal infection in patients with cancer. Identification of an abscess, erythema on physical exam, and thrombocytopenia were associated with management strategy. Although rare, necrotizing soft tissue infections are associated with significant mortality. ^

Glioma-specific alternative RNA splicing: A role for polypyrimidine tract binding protein-1

Alternative RNA splicing plays an integral role in cell fate determination and function, especially in the cells of the brain. Errors in RNA processing contribute to diseases such as cancer, where it leads to the production of oncogenic proteins or the loss of tumor suppressors. In silica mining suggests that hundreds of splice isoforms are misexpressed in the glial cell-derived glioma. However, there is little experimental evidence of the prevalence and contribution of these changes and whether they contribute to the formation and progression of this devastating malignancy. To determine the frequency of these aberrant events, global profiling of alternative RNA splice patterns in glioma and nontumor brain was conducted using an exon array. Most splicing changes were less than 5-fold in magnitude and 14 cassette exon events were validated, including 7 previously published events. To determine the possible causes of missplicing, the differential expression levels of splicing factors in these two tissues were also analyzed. Six RNA splicing factors had greater than 2-fold changes in expression. The highest differentially expressed factor was polypyrimidine tract binding protein-1 (PTB). Evaluation by immunohistochemistry determined that this factor was elevated in both early and late stages of glioma. Glial cell-specific PTB expression in the adult brain led me to examine the role of PTB in gliomagenesis. Downregulation of PTB slowed glioma cell proliferation and migration and enhanced cell adhesion to fibronectin and vitronectin. To determine whether PTB was affecting these processes through splicing, genome-wide exon expression levels were correlated with PTB levels. Surprisingly, previously reported PTB target transcripts were insensitive to changes in PTB levels in both patient samples and PTB-depleted glioma cells. Only one validated glioma-specific splice target, RTN4/Nogo, had a significant PTB-mediated splicing change. Downregulation of PTB enhanced inclusion of its alternative exon 3, which encodes an auxiliary domain within a neurite inhibitor protein. Overexpression of this splice isoform in glioma cells slowed proliferation in a manner similar to that observed in PTB knockdown cells. In summary, aberrant expression of splicing factors such as PTB in glioma may elicit changes in splicing patterns that enhance tumorigenesis. ^

Revisiting health literacy and its impact on patient-physician communication

Objective. To review professional literature on health literacy and its impact on patient-physician communication, to describe significant literature on this issue, and to summarize implications of the findings from this literature. Design. Update of a review of literature. Data sources: MEDLINE. Review Methods. Articles dealing with the impact of health literacy on patient-physician communication were selected. The articles addressed at least one of four criteria on the subject: prevalence of the problem; effect of health literacy on patient-physician communication; association of health literacy to health outcomes; and interventions to enhance communication with patients exhibiting limited health literacy. Results. Approximately 623 articles were selected for review; 87 were fully reviewed and found to be relevant to the issue; and 25 articles were cited. Conclusion. Limited health literacy is extremely widespread throughout the U.S., particularly among specific populations. Providers must be aware that patients often process health care decision making differently from their own familiar procedures and that by taking the steps to make medical language and health information simpler and the time to confirm patient understanding, health outcomes of limited health literacy populations will improve. ^

Comparing experience of diabetes care with chronic illness care in the primary care clinic using the Patient Assessment of Chronic Illness Care (PACIC)

Purpose. The overall purpose of the study was to evaluate the patient experience relevant to the Chronic Care Model as measured by the PACIC. Chronic illness care of patients with diabetes was compared to those with other chronic illnesses. In addition, chronic illness care of Hispanics was compared to those of other race/ethnicity. ^ Methods. The setting of this study was 20 primary care practices located in San Antonio, TX. The subjects in this study were consecutive adult patients age >18 yrs. Data was collected via a survey (PACIC) administered to 40-60 consecutive adult patients in each primary care clinic who presented for a scheduled appointment. ^ Results. Patient experience of the Chronic Care Model is different among those with diabetes than those with other chronic diseases: those with diabetes report a higher PACIC score. (P = 0.012) Although Hispanic patients report a higher PACIC score, patient experience of the Chronic Care Model among Hispanic patients is not significantly different than that of patients of other race/ethnicity regardless of chronic disease. (P = 0.053) After controlling for the patient characteristics of age, education, health status, and race/ethnicity, the diabetes status of the patient remains significantly associated with the outcome, the PACIC score. (P = 0.033) ^ Conclusions. Diabetes is associated with a greater experience of the Chronic Care model. Contributing factors to diabetes patients’ greater experience of the Chronic Care Model include the greater heath care use and higher self-care needs unique to individuals with diabetes. Special consideration must be given to the specific needs diabetic patients to ensure effective interventions, higher patient education, greater patient compliance, and lower health care costs. ^

Family health history discussion in patient-provider encounters

Ascertaining the family health history (FHH) may provide insight into genetic and environmental susceptibilities specific to a variety of chronic diseases, including type II diabetes mellitus. However, discussion of FHH during patient-provider encounters has been limited and uncharacterized. A longitudinal, observational study was conducted in order to compare the content of FHH topics in a convenience sample of 37 patients, 13 new and 24 established. Each patient had an average of three follow-up encounters involving 6 staff physicians at the Audie L. Murphy Memorial Veterans Hospital (VHA) in San Antonio, TX from 2003 to 2005. A total of 131 encounters were analyzed in this study. The average age of the selected population was 68 years and included 35 males and two females. Transcriptions of encounters were obtained, coded and analyzed, in NVIVO 8. Of the 131 total encounters transcribed among the 37 patients, only 24 encounters (18.3%) included discussion of FHH. Additionally, the relationship between FHH discussion and discussion of self-care management (SCM) topics were assessed. In this study, providers were more likely to initiate discussion on family health history among new patients in the first encounter (ORnew = 8.55, 95% CI: 1.49–52.90). The discussion of FHH occurred sporadically in established patients throughout the longitudinal study with no apparent pattern. Provider-initiated FHH discussion most frequently had satisfactory level(s) of discussion while patient-initiated FHH discussion most frequently had minimal level(s) of discussion. FHH discussion most oftentimes involved topics of cancer and cardiovascular disease among primary-degree familial relationships. Overall, family health histories are largely, an underutilized tool in personalized preventive care.^

Doctor-patient communication in the medical interaction: Context, implications, and practice

Effective communication; whether from an interpersonal, mass media, or global perspective, is a critical component in public health. It is an essential conduit in increasing public awareness of available health resources, potential health hazards and related disease prevention strategies, and in delivering better health care. Within this context, available literature asserts doctor-patient communication as central to healthcare delivery. It has been shown to affect patient health outcomes, satisfaction with care, adherence to treatment recommendations, and even understanding of medical information. While research supports the essential imperative of interventions aimed at teaching doctors and patients the communication skills necessary for a successful and meaningful medical interaction, most interventions to date, focus on teaching these communication skills to doctors and seem to rely, largely, on mass media for providing patients with the information needed to increase communication efficacy. This study sought to fill a significant gap in the doctor-patient communication literature by reviewing the context of the doctor-patient exchange in the medical interaction, the implications of this exchange in resulting care of the patient, and the potential improvements to practice through interventions aimed at improving the communication exchange. Closing with an evaluation of a patient-centered communication intervention, the “How to Talk to Your Doctor” (HTTTYD) program that combines previously identified optimal strategies for improving communication between doctors and patients, this study examined the patients’ perspective of their potential as better communicators in the medical interaction. ^ Specific Aims, Hypotheses or Questions (Aim I) To examine the context of health communication within a public health framework and its relation to health care delivery. (Aim II) To review doctor-patient communication as a central focus within health care delivery and the resulting implications to patient care. (Aim III) To assess the utility of interventions to improve doctor-patient communication. Specifically, to evaluate the effectiveness of a patient-centered community education intervention, the “How to Talk to Your Doctor” (HTTTYD) program, aimed at improving patient communication efficacy.^

DISEASE-RELATED INFORMATION NEEDS OF CANCER PATIENTS AGES 11-20: A COMPARISON OF PATIENT-PARENT AND PATIENT-PHYSICIAN PERCEPTIONS

Innovative, aggressive treatments and prolonged survival rates for patients with childhood cancers have placed new demands on the patient, parent and physician. As a result, counterproductive coping behaviors are often noted in adolescent cancer patients.^ One of the main ways the environment is manipulated by the individual to achieve personal comfort is through selectivity of information. An individual will usually pull the support personally needed to cope from the environment if sufficient resources are available. However, information provided young cancer patients is often filtered through the physicians and parents perspectives of the patient's needs without systematic input from the patient. In order to ensure that adequate information resources are available to help teenage patients cope with their illness, health professionals must have insights into the information needs of those patients. No previous efforts to address this subject were found in the literature.^ This study was designed to identify adolescent perspectives of their disease-related information needs and to compare their viewpoints with those of their parents and physicians. Sixty-five outpatient cancer patients (ages 11-20) receiving treatment at the University of Texas M. D. Anderson Hospital and Tumor Institute in Houston, Texas, 60 of their parents, and 53 physicians, who were involved in the treatment of pediatric patients at M. D. Anderson, were asked to complete self-administered questionnaires. The questionnaires used were developed, administered and analyzed by the investigator. Specific areas addressed in the questionnaires included: Perceptions of cancer-related tests and treatments, the importance of 30 disease-related items of information, responses evoked by receipt of information, current and preferred sources of information, delivery of information at the time of diagnosis, and disease-related information requested for patients, family, friends and teachers.^ Adolescent perceptions of their information needs and their preferences for delivery of information were determined. The relationships between patient-parent and patient-physician perceptions were then analyzed to determine areas in which agreements and disparities in viewpoint existed. Programmatic and research recommendations were then provided.^ Hopefully, through these efforts, the adolescent patient will be helped to receive relevant information support from those deemed to be most important to his/her efforts to cope with cancer. ^