Depression,Coronary Artery Disease,and Physical Activity: How Much Exercise Is Enough?

PurposeThe mechanisms by which depressive symptoms negatively affect clinical outcomes in patients with coronary artery disease (CAD) remain poorly understood. Previous interventions that have attempted to treat depressive symptoms in patients with CAD to improve their clinical outcomes have been disappointing. Our objectives were, among a cohort of CAD patients, to evaluate the impact of depressive symptoms over time, controlling for comorbidity, in determining both successful long-term lifestyle change (ie, increased physical activity), and cardiovascular morbidity and mortality outcomes. In addition, we examined the impact of physical activity changes over time on 2 known mediators of cardiovascular morbidity: parasympathetic tone and inflammation.MethodsClinical data were previously collected (2004–2006) from 242 elective/urgent coronary angioplasty patients who participated in a prospective randomized controlled trial evaluating the efficacy of a behavioral intervention versus an educational control to motivate physical activity over 12 months. Exclusion criteria included: (1) inability to walk; (2) enrollment in other risk-reduction trials; (3) non-English speaking; and (4) lack of cardiologist’s permission to increase physical activity. Participants were assessed every 2 months for interval clinical events and physical activity. In addition, biomarkers were collected at baseline and at 12 months in a subset of 54 participants; these biomarkers included low-frequency heart rate variability (lfHRV), high-frequency heart rate variability (hfHRV), serum C-reactive protein, interleukin-6, and salivary cortisol.FindingsThe mean age of participants was 63 years and 30% were female. Overall, 37% had high depressive symptoms at baseline. Patients with high depressive symptoms who achieved an increase in physical activity of ≥336 kilocalories(kcal)/week by 12 months had significantly lower rates of cardiovascular morbidity/mortality (5.1% vs. 21.3%; odds ratio [OR], 0.20, [95% CI, 0.04–0.98]; P = 0.03). In a multivariate model examining cardiovascular morbidity/mortality in patients with high depressive symptoms, an increase in physical activity of ≥336 kcal/week reduced the risk of new cardiovascular morbidity/mortality (OR, 0.11 [95% CI, 0.02–0.81]; P < 0.03), and comorbidity increased the risk (OR, 1.58 [95% CI, 1.18–2.13]; P = 0.002). In a generalized structural equation model, increasing physical activity by ≥336 kcal/week decreased the risk of complications, and comorbidity increased the risk. Furthermore, increasing physical activity (≥336 kcal/week) predicted an increase in hfHRV, a marker of parasympathetic tone, and the increase in hfHRV predicted a reduction in the proinflammatory mediators interleukin-6 and C-reactive protein.ImplicationsThis study found a threshold in physical activity in CAD patients with depressive symptoms that is associated with a decrease in cardiovascular morbidity and mortality. Exercise maintenance at this level may improve clinical outcomes via enhanced parasympathetic tone and decreased inflammation. ClinicalTrials.gov identifier: NCT00248846.     

Assessing Risk and Predicting Outcomes in Coronary Artery Disease: Physiology, Anatomy, or Biology?

Cardiovascular imaging has been able to demonstrate its importance identifying subjects at risk for future cardiac events. There is extensive evidence demonstrating that anatomic, physiologic, and biologic data can successfully risk stratify patients. A plethora of biomarkers predictive of patients’ risk have been identified. Although cardiovascular imaging modalities are capable of patient risk stratification, whether they are cost effective over clinical, historical, and biochemical data is uncertain. The incremental value provided by stress positron emission tomography and single photon emission CT has been extensively demonstrated. In addition, an increasing body of evidence supports the concept that coronary CT angiography is also able to stratify patients in regard to their risk of future cardiovascular events. The availability of hybrid myocardial perfusion imaging/CT technology permits simultaneous acquisition of anatomic, functional, structural information, and the potential for use of molecular techniques. The future application of these modalities will require extending the risk stratification paradigm to the identification of optimal patient management.     

Knee Extensor Strength, Dynamic Stability, and Functional Ambulation: Are They Related in Parkinson's Disease?

Nocera JR, Buckley T, Waddell D, Okun MS, Hass CJ. Knee extensor strength, dynamic stability, and functional ambulation: are they related in Parkinson's disease?

Objective

To evaluate the relationship between knee extensor strength, postural stability, functional ambulation, and disease severity in Parkinson's disease (PD).

Design

A cohort study.

Setting

University research laboratory.

Participants

Patients (N=44) with idiopathic PD.

Intervention

Not applicable.

Main Outcome Measures

Participants were evaluated on their isokinetic knee extensor strength. Additionally, participants completed an assessment of their postural stability (Functional Reach Test for static stability and a dynamic postural stability assessment as measured by the center of pressure-center of mass moment arm during gait initiation). Participants also underwent an evaluation of their functional ambulation as measured by a 6-minute walk test. Lastly, participants were evaluated by a neurologist specially trained in movement disorders to assess neurologic status and disease severity using the Unified Parkinson's Disease Rating Scale and the Hoehn and Yahr disability score.

Results

Knee extensor strength positively correlated with dynamic postural stability and negatively correlated with disease severity. Further, dynamic postural stability was negatively correlated to disease severity and positively correlated with functional ambulation in this cohort of patients with PD (P<.05). The results also suggest that the Functional Reach Test may be a valuable assessment tool to examine postural stability in PD.

Conclusions

These findings suggest a malleable relationship between knee extensor strength, dynamic stability, and disease severity in PD. Although strength is only one piece of the puzzle in the functional outcome of PD, these findings may assist clinicians in designing appropriate interventions aimed at increasing function and decreasing fall risk in PD.     

Cost Per Responder Associated with Biologic Therapies for Crohn’s Disease, Psoriasis, and Rheumatoid Arthritis

Introduction

Biologic therapies have demonstrated efficacy and safety in several chronic systemic disorders. The authors indirectly compared response rates and costs per responder associated with biologic treatments for moderate-to-severe Crohn??s disease (CD), psoriasis (Ps), and/or rheumatoid arthritis (RA).

Methods

A systematic literature search was performed to identify phase 3 randomized controlled trials of biologics for CD (adalimumab, infliximab), Ps (adalimumab, etanercept, infliximab, ustekinumab 45 mg, ustekinumab 90 mg), or methotrexate-refractory RA (abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, tocilizumab). Food and Drug Administration-approved dosing schedules were evaluated. Published response rates were extracted, with response defined in CD, Ps, and RA as: ??70-point reduction in CD Activity Index at 12 months; ??75% improvement in Psoriasis Area and Severity Index at 3 months; and ??50% improvement in American College of Rheumatology component scores at 6 months. Within each indication, mixed-treatment comparison meta-analyses were conducted to derive pooled estimates and 95% CIs of response rate difference versus placebo for each biologic, adjusting for cross-trial variation in control-arm response rates. Cost per responder was estimated for each biologic as projected per patient drug costs (2011 US$) divided by response rate difference.

Results

Altogether, 23 publications were selected. In CD, 12-month cost per responder was estimated at $116,291 (95% CI $71,637?C208,348) for adalimumab and $125,169 (95% CI $60,532?C267,101) for infliximab. Among biologics approved in Ps, 3-month cost per responder was lowest for adalimumab ($9,756; 95% CI $8,668?C11,131), infliximab ($12,828; 95% CI $11,772?C13,922), and ustekinumab 45 mg ($13,821; 95% CI $12,599?C15,167). In RA, biologics with the lowest 6-month cost per responder were adalimumab ($27,853; 95% CI $19,284?C40,270), etanercept ($29,140; 95% CI $14,170?C61,030), and tocilizumab ($31,363; 95% CI $14,713?C64,232).

Conclusion

Meta-analyses of clinical trials found considerable variation in cost-effectiveness of biologic therapies for CD, Ps, and RA. These results may help determine biologic utilization in these chronic diseases.     

Genetics and Disease Prevention: Complementary or Contradictory?

Clinicians may feel that nothing can be done to change genes, so prevention in a genetic context seems ridiculous. The reality is that genetic preventive healthcare has been a part of clinical practice for years and that future applications are almost limitless. It will soon be possible to sequence an individual's genome, scan it for important gene variations, and create an individualized health plan to modify the effects of these variations, optimizing that individual's health over a lifetime. This article presents an overview of selected clinical disorders, describes ways in which genetics is already being used to improve clinical outcomes, and offers a glimpse into the future of personalized medicine.     

Cystatin C– and Creatinine-Based Estimated Glomerular Filtration Rate,Vascular Disease,and Mortality in Persons With Diabetes in the U.S.

OBJECTIVE

Serum cystatin C is an alternative to serum creatinine for estimating glomerular filtration rate (GFR), since cystatin C is less influenced by age and muscle mass. Among persons with diabetes, we compared the performance of GFR estimated using cystatin C (eGFR_cys) with that using creatinine (eGFR_cr) for the identification of reduced kidney function and its association with diabetes complications.

RESEARCH DESIGN AND METHODS

We analyzed data from adult participants from the 1999–2002 National Health and Nutrition Examination Survey with available cystatin C (N = 4,457). Kidney function was dichotomized as preserved (eGFR ≥60 mL/min/1.73 m²) or reduced (eGFR <60 mL/min/1.73 m²) using the 2012 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) cystatin C and the 2009 CKD-EPI creatinine equations.

RESULTS

Among 778 persons with diabetes, the prevalence of reduced kidney function was 16.5% using eGFR_cr and 22.0% using eGFR_cys. More persons with diabetes were reclassified from preserved kidney function by eGFR_cr to reduced kidney function by eGFR_cys than persons without diabetes (odds ratio 3.1 [95% CI 1.9–4.9], P < 0.001). The associations between lower eGFR and higher prevalence of albuminuria, retinopathy, peripheral arterial disease, and coronary artery disease were robust regardless of filtration marker. Similarly, the risk of all-cause mortality increased with lower eGFR_cr and eGFR_cys. Only lower eGFR_cys was significantly associated with cardiovascular mortality.

CONCLUSIONS

More persons with diabetes had reduced kidney function by eGFR_cys than by eGFR_cr, and lower eGFR_cys was strongly associated with diabetes complications. Whether eGFR_cys is superior to eGFR_cr in approximating true kidney function in a diabetic population requires additional study.     

Disease staging and PMCs. Can they improve DRGs?

Since the adoption of Medicare's Prospective Payment System (PPS), critics have raised concerns about the degree of variation in cost per case due to variability in severity of illness within DRGs. Using hospital (Part A) costs for all Medicare beneficiaries hospitalized in Michigan during 1982, this paper applies multivariate techniques to test the ability of two state-of-the-art case-mix measures to either replace or act as a severity modifier to DRGs. When compared with DRGs, neither Patient Management Categories (PMCs) nor Disease Staging explains any more of the variation in costs. Results show that DRGs explain 33%, while PMCs and Disease Staging explain 26% and 17%, respectively. The use of either alternative in tandem with DRGs explains only 1-2% more of the observed variation; however, both PMCs and Disease Staging identify subgroups of patients with significantly different costs. These findings suggest that the alternatives may prove modestly useful as DRG modifiers by identifying classes of patients that do not belong. More importantly, they offer a measure of "unrelated comorbidity" that may improve the performance of DRGs.     

Efficacy,Safety, and Tolerability of a Novel Cyclosporine,a Formulation for Dry Eye Disease: A Multicenter Phase II Clinical Study

PurposeThe purpose of this study was to explore the efficacy, safety, and tolerability of a novel cyclosporine formulation for dry eye disease (DED).MethodsThis is an exploratory, multicenter, single-blind, randomized, positive-controlled Phase II clinical trial between cyclosporine ophthalmic gel (CyclAGel) and an open-label comparator (Restasis, positive control). A total of 240 eligible patients with moderate to severe DED were randomized to 4 study groups: CyclAGel 0.05%/once daily (QD) (n = 59), CyclAGel 0.05%/BID (n = 60), CyclAGel 0.1%/QD (n = 60), and Restasis 0.05%/BID (n = 61). After receiving BID dosing of hypromellose eye drops during a 2-week run-in period, patients were randomized to the respective treatment group and dosed QD or BID for 12 weeks. Efficacy was assessed based on a number of sign and symptom end points, including eye dryness score (visual analog scale), 6 other parameters of symptoms for dryness (burning/stinging, itching, foreign body sensation, discomfort, sensitivity to light, and pain), and corneal fluorescein staining. The Schirmer test was used to assess dry eye symptoms (visual analog scale severity) at visit 3 (week 2), visit 4 (week 6), and visit 5 (week 12).FindingsCyclAGel showed a consistent improvement in eye dryness score and the 6 other parameters of symptoms for dryness, corneal fluorescein staining, breakup time, and Schirmer test scores compared with Restasis over the 12-week treatment period. However, there were no statistically significant differences between CyclAGel and Restasis after baseline corrections were made, and the results of the full analysis set remained consistent with those of the per-protocol set (P > 0.05). Moreover, each CyclAGel-treated group (0.05%/QD, 0.05%/BID, and 0.1%/QD) exerted better effects than the Restasis group, and CyclAGel 0.05%/QD showed the most significant improvement. The number of ocular-related treatment-emergent adverse events was low in all treatment groups, with no serious drug-related treatment-emergent adverse events.ImplicationsCyclAGel showed excellent safety, tolerability, and comfort profiles at 2 concentrations and frequency in moderate to severe DED.     

Microalbuminuria: A Genetic Link Between Diabetes and Cardiovascular Disease?

Non-insulin-dependent diabetes is associated with a 2–3 fold increased risk of cardiovascular disease. The poor relationship between this risk and either glycaemic control or diabetes duration suggests that some other aspect of the diabetic state, and not hyperglycaemia per se, mediates this risk. This other aspect of diabetes does not comprise alterations in recognized cardiovascular risk factors such as blood pressure or lipids, as the major component of the excess risk is in those diabetics with low levels of the other risk factors. It thus appears that there may be some factors that predispose both to diabetes and to cardiovascular disease. In insulin-dependent diabetics most of the excess risk of cardiovascular disease occurs in subjects with proteinuria, and microalbuminuria or proteinuria in non-insulin-dependent diabetics also substantially increases cardiovascular risk. Although changes in recognized risk factors in diabetics with nephropathy may partly explain these observations, we and others have shown that microalbuminuric non-diabetics also have a markedly increased prevalence of cardiovascular disease and substantially increased cardiovascular mortality. The observations that in insulin-dependent diabetics nephropathy shows family clustering and that these patients have elevated sodium lithium counter-transport rate, a possible genetic marker for the vascular complications of hypertension, have led to the suggestion that microalbuminuria may be a marker of a genetic predisposition to vascular disease. However, in a recent population study, we have found that microalbuminuric men are substantially shorter than normoalbuminuric men, raising instead the possibility that early environmental influences, in utero or in early neonatal life, may predispose to microalbuminuria in similar fashion to recent work which has associated low fetal and neonatal growth rate with both diabetes and other cardiovascular risk factors. Future work may determine the respective genetic and environmental contributions to microalbuminuria and to cardiovascular risk.     

Navigating Interprofessional Spaces: Experiences of Clients Living with Parkinson’s Disease,Students and Clinical Educators

When students in interprofessional education and practice programmes partner with clients living with a long-term condition, the potential for a better client and educational experience is enhanced when the focus is on client self-management and empowerment. This paper reports the findings from a phenomenological study into the experiences of five clients, six speech language therapy students, eight physiotherapy students, and two clinical educators participating in a university clinic-based interprofessional programme for clients living in the community with Parkinson’s Disease. Collaborative hermeneutic analysis was conducted to interpret the texts from client interviews and student and clinical educator focus groups held immediately after the programme. The overarching narratives emerging from the texts were: “client-centredness”; “who am I/why am I here?”; “understanding interprofessional collaboration and development”; “personal and professional development, awareness of self and others”; “the environment - safety and support”. These narratives and the meanings within them were drawn together to develop a tentative metaphor-based framework of “navigating interprofessional spaces” showing how the narratives and meanings are connected. The framework identifies a temporal journey toward interprofessional collaboration impacted by diverse identities and understandings of self and others, varying expectations and interpretations of the programme, intra- and interpersonal, cultural and contextual spaces, and uncertainty. Shifts in being and doing and uncertainty appear to characterise client-driven, self-management focused interprofessional teamwork for all participants. These findings indicate that students need ongoing opportunities to share explicit understandings of interprofessional teamwork and dispel assumptions, since isolated interprofessional experiences may only begin to address these temporal processes.     

Age at Development of Type 1 Diabetes�C and Celiac Disease�CAssociated Antibodies and Clinical Disease in Genetically Susceptible Children Observed From Birth

OBJECTIVE

To compare the ages and sequence in which antibodies associated with type 1 diabetes and celiac disease appear and overt diseases develop in children with an HLA-conferred susceptibility to both diseases.

RESEARCH DESIGN AND METHODS

We observed 2,052 children carrying genetic risks for both type 1 diabetes and celiac disease from birth until the median age of 5.7 years and analyzed diabetes- and celiac disease–associated antibodies in serum samples collected at 3- to 12-month intervals. Diabetes was confirmed by World Health Organization criteria and celiac disease by duodenal biopsies.

RESULTS

Altogether 342 children seroconverted to positivity for at least one diabetes-associated autoantibody and 88 to positivity for at least one celiac disease–associated antibody at the median ages of 3.0 and 1.5 years, respectively (P < 0.001). If only children with biochemically defined diabetes-associated autoantibodies against insulin, GAD, or IA-2A protein (n = 146) and children with tissue transglutaminase autoantibodies were compared (n = 86), the median seroconversion ages were 2.5 and 3.0 years (P = 0.011). Fifty-one children progressed to overt diabetes at 4.5 years and 44 children to celiac disease at 4.3 years (P = 0.257). Of the 19 children who developed both diabetes- and celiac disease–associated antibodies, 3 progressed to both diabetes and celiac disease.

CONCLUSIONS

Children with HLA-conferred susceptibility to type 1 diabetes and celiac disease develop celiac disease–associated antibodies mostly at a younger age or the same age at which they develop diabetes-associated autoantibodies. Clinical diabetes and celiac disease are commonly diagnosed at the same median age.The incidences of type 1 diabetes and celiac disease are increasing rapidly (1). These autoimmune diseases often occur together, as ∼4.5% of subjects with recent-onset type 1 diabetes also have celiac disease, and the coexistence is even more common in subjects with long-standing type 1 diabetes (2,3). Shared susceptibility alleles in the HLA region probably contribute to this coexistence (4). Although appearance of diabetes- and celiac disease–specific antibodies strongly indicates commencement of autoimmunity (5), antibodies also predict progression to the respective clinical diseases. However, in the case of diabetes, in particular, the time from autoimmunity to overt disease may vary from months to years. Interestingly, clinical type 1 diabetes is usually diagnosed first and celiac disease within the following few years (6,7). The order is rarely reversed (8).Although coexistence of type 1 diabetes and celiac disease has been studied mainly in clinical patients, Williams et al. (9) showed in a cross-sectional study that 5.4% of nondiabetic first-degree relatives of type 1 diabetic patients who were positive for diabetes-associated autoantibodies were positive also for tissue transglutaminase autoantibody (TGA). However, the findings of the Diabetes Autoimmunity Study in the Young (DAISY) indicated that the two types of antibodies rarely appeared simultaneously (10), whereas the German BabyDiab study suggested that celiac disease–associated antibodies invariably develop later than diabetes-associated autoantibodies (11,12).Here we report the age and order in which the diabetes- and celiac disease–associated antibodies and the two clinical diseases developed in children who carried genetic type 1 diabetes and celiac disease susceptibility and participated in the type 1 Diabetes Prediction and Prevention (DIPP) study.     

Merging Yoga and Occupational Therapy for Parkinson’s Disease: Program Adaptation and Development

Abstract

Purpose: To adapt the Merging Yoga and Occupational Therapy program and develop the Merging Yoga and Occupational Therapy for Parkinson’s disease (MY-OT for PD) program, designed to target fall risk management. Creating a new program involved the targeted development of Stage 1 manuals.

Methods: Researchers employed a pragmatic qualitative design to focus on meeting the purpose of the study. Stage 1 manuals were created following a literature review, a focus group of participants with PD, and individual interviews with experts in practice or research. Visual familiarization with data, generation of conclusions, and results verification were used to translate participant feedback into manual revisions.

Results: Themes included revisions to model, content, and delivery. Revisions were incorporated into Stage 1 manuals to create a PD-specific program to improve fall risk management.

Conclusion: A structured process is necessary to create Stage 1 manuals in a novel population prior to feasibility and pilot testing.     

Sexuality and Alzheimer's Disease: Can the Two Go Together?

The issue of sexual relations in nursing homes between patients with Alzheimer-related dementia is in ward practice largely characterized by confusion and ignorance. Staff are seriously conflicted on how to respond and almost totally untrained on the subject. Patients are being mistreated and humiliated. Central to this state of affairs is insufficient awareness of the ethical and human rights elements in nursing care. Two case studies illustrate the practical dilemmas nurses must solve. A decision-making process is set out to reach an ethical and practical conclusion. Recommendations for action by nurses, the nursing profession, nursing home owners, and policy-makers are given.     

HLA-A,B (Class I) and HLA-DR,DQ (Class II) Antigens in Turkish Patients with Recurrent Aphthous Ulceration and Beh?et's Disease

Objective

The aims of the present study were to typify the human leukocyte antigen system (HLA)-A, B (class I) and HLA-DR, DQ (class II) antigens and to assess the frequency of the presence of these antigens in the Turkish population with recurrent aphthous ulceration (RAU) and Behçet''s disease (BD) compared to healthy subjects.

Subjects and Methods

Thirty patients with RAU, 30 with BD, and 15 healthy subjects were included in the study. HLA typing was performed by serology with commercial kits for HLA class I and II (One Lambda, Canoga Park, Calif., USA).

Results

The HLA-A23 frequency was 26.7% in the RAU patients, which was significantly higher than the 3.3% frequency in the patients with BD (p < 0.05). The HLA-A24 frequency was 33.3% in the RAU patient group, which was significantly higher (p < 0.05) than the frequency in the healthy subjects (6.7%). Significantly higher frequencies (46.7%) of HLA-A30 were found in the healthy subjects compared to the BD (13.3%) and RAU (3.3%) patients (p < 0.05 and p < 0.01, respectively). A higher frequency of HLA-B13 was observed in the RAU (23.3%) patients compared to the BD (0%) patients (p < 0.01). A decrease was observed in HLA-DR10 and HLA-DR17 in the RAU patients (p < 0.05), while a higher frequency of HLA-DR10 was observed in the BD patients compared to the RAU patients (p < 0.01).

Conclusions

These results showed that RAU and BD were not in the same spectrum and the involvement of other genetic and/or environmental factors might be responsible for the development of these diseases and/or disease progression.Key Words: Recurrent aphthous ulceration, Behçet''s disease, HLA class I, HLA class II, Antigen     

Subacute Cutaneous Lupus Erythematosus: Clinical Characteristics,Disease Associations,Treatments, and Outcomes in a Series of 90 Patients at Mayo Clinic, 1996-2011

Objective

To characterize the clinical presentation, laboratory studies, disease associations, and treatments of subacute cutaneous lupus erythematosus (SCLE).