Creation of a novel algorithm to identify patients with Becker and Duchenne muscular dystrophy within an administrative database and application of the algorithm to assess cardiovascular morbidity

BACKGROUND: Outcome analyses in large administrative databases are ideal for rare diseases such as Becker and Duchenne muscular dystrophy. Unfortunately, Becker and Duchenne do not yet have specific International Classification of Disease-9/-10 codes. We hypothesised that an algorithm could accurately identify these patients within administrative data and improve assessment of cardiovascular morbidity. METHODS: Hospital discharges (n=13,189) for patients with muscular dystrophy classified by International Classification of Disease-9 code: 359.1 were identified from the Pediatric Health Information System database. An identification algorithm was created and then validated at three institutions. Multi-variable generalised linear mixed-effects models were used to estimate the associations of length of stay, hospitalisation cost, and 14-day readmission with age, encounter severity, and respiratory disease accounting for clustering within the hospital. RESULTS: The identification algorithm improved identification of patients with Becker and Duchenne from 55% (code 359.1 alone) to 77%. On bi-variate analysis, left ventricular dysfunction and arrhythmia were associated with increased cost of hospitalisation, length of stay, and mortality (p<0.001). After adjustment, Becker and Duchenne patients with left ventricular dysfunction and arrhythmia had increased length of stay with rate ratio 1.4 and 1.2 (p<0.001 and p=0.004) and increased cost of hospitalization with rate ratio 1.4 and 1.4 (both p<0.001). CONCLUSIONS: Our algorithm accurately identifies patients with Becker and Duchenne and can be used for future analysis of administrative data. Our analysis demonstrates the significant effects of cardiovascular disease on length of stay and hospitalisation cost in patients with Becker and Duchenne. Better recognition of the contribution of cardiovascular disease during hospitalisation with earlier more intensive evaluation and therapy may help improve outcomes in this patient population

The Correlation of Skeletal and Cardiac Muscle Dysfunction in Duchenne Muscular Dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is characterized by progressive skeletal muscle and cardiac dysfunction. While skeletal muscle dysfunction precedes cardiomyopathy, the relationship between the progressive decline in skeletal and cardiac muscle function is unclear. This relationship is especially important given that the myocardial effects of many developing DMD therapies are largely unknown. OBJECTIVE: Our objective was to assess the relationship between progression of skeletal muscle weakness and onset of cardiac dysfunction in DMD. METHODS: A total of 77 DMD subjects treated at a single referral center were included. Demographic information, quantitative muscle testing (QMT), subjective muscle strength, cardiac function, and current and retrospective medications were collected. A Spearman rank correlation was used to evaluate for an association between subjective strength and fractional shortening. The effects of total QMT and arm QMT on fractional shortening were examined in generalized least square with and without adjustments for age, ambulatory status, and duration of corticosteroids and cardiac specific medications. RESULTS: We found a significant correlation between maintained subjective skeletal muscle arm and leg strength and maintained cardiac function as defined by fractional shortening (rho=0.47, p=0.004 and rho=0.48, p=0.003, respectively). We also found a significant association between QMT and fractional shortening among non-ambulatory DMD subjects (p=0.03), while this association was not significant in ambulatory subjects. CONCLUSIONS: Our findings allow us to conclude that in this population, there exists a significant relationship between skeletal muscle and cardiac function in non-ambulatory DMD patients. While this does not imply a causal relationship, a possible association between skeletal and cardiac muscle function suggests that researchers should carefully monitor cardiac function, even when the primary outcome measures are not cardiac in nature

Measuring vincristine-induced peripheral neuropathy in children with acute lymphoblastic leukemia

BACKGROUND: Vincristine-induced peripheral neuropathy (VIPN) is difficult to quantify in children. OBJECTIVE: The study objective was to examine the reliability, validity, and clinical feasibility of several VIPN measures for use in children with acute lymphoblastic leukemia. INTERVENTIONS/METHODS: Children (N = 65) aged 1–18 years receiving vincristine at four academic centers participated in the study. Baseline and pre-vincristine VIPN assessments were obtained using the Total Neuropathy Score-Pediatric Vincristine (TNS-PV), the National Cancer Institute Common Terminology Criteria for Adverse Events, the Balis grading scale, and the FACES pain scale. TNS-PV scores (n = 806) were obtained over 15 weeks. Blood was obtained at several time-points to quantify pharmacokinetic parameters. RESULTS: Cronbach’s alpha for a reduced TNS-PV scale was 0.84. TNS-PV scores correlated with cumulative vincristine dosage (r = 0.53, p = 0.01), pharmacokinetic parameters (r = 0.41, p = 0.05), and grading scale scores (r = 0.46 – 0.52; p = 0.01). FACES scores correlated with the TNS-PV neuropathic pain item (r = 0.48; p = 0.01), and were attainable in all ages. A 2-item V-Rex score (vibration and reflex items) was the most responsive to change (es 0.65, p < 0.001). TNS-PV scores were attainable in 95% of children ≥ 6 years. CONCLUSIONS: The TNS-PV is reliable and valid for measuring VIPN. It is sensitive to change over time (15 weeks) and feasible for use in children ≥ 6 years of age. IMPLICATIONS FOR PRACTICE: The TNS-PV may be a useful tool for assessing vincristine toxicity in children with acute lymphoblastic leukemia

Increased number of circulating CD8/CD26 T cells in the blood of Duchenne muscular dystrophy patients is associated with augmented binding of adenosine deaminase and higher muscular strength scores.

Duchenne muscular dystrophy (DMD) is an X-linked disorder that leads to cardiac and skeletal myopathy. The complex immune activation in boys with DMD is incompletely understood. To better understand the contribution of the immune system into the progression of DMD, we performed a systematic characterization of immune cell subpopulations obtained from peripheral blood of DMD subjects and control donors. We found that the number of CD8 cells expressing CD26 (also known as adenosine deaminase complexing protein 2) was increased in DMD subjects compared to control. No differences, however, were found in the levels of circulating factors associated with pro-inflammatory activation of CD8/CD26 cells, such as tumor necrosis factor-α (TNFα), granzyme B, and interferon-γ (IFNγ). The number of CD8/CD26 cells correlated directly with quantitative muscle testing (QMT) in DMD subjects. Since CD26 mediates binding of adenosine deaminase (ADA) to the T cell surface, we tested ADA-binding capacity of CD8/CD26 cells and the activity of bound ADA. We found that mononuclear cells (MNC) obtained from DMD subjects with an increased number of CD8/CD26 T cells had a greater capacity to bind ADA. In addition, these MNC demonstrated increased hydrolytic deamination of adenosine to inosine. Altogether, our data demonstrated that (1) an increased number of circulating CD8/CD26 T cells is associated with preservation of muscle strength in DMD subjects, and (2) CD8/CD26 T cells from DMD subjects mediated degradation of adenosine by adenosine deaminase. These results support a role for T cells in slowing the decline in skeletal muscle function, and a need for further investigation into contribution of CD8/CD26 T cells in the regulation of chronic inflammation associated with DMD