Journal Club

1. Journal Club TishaR. Joy, MD; AlaaMonjed, MD; Guang Yong Zou, PhD; Robert A. Hegele, MD; Charlotte G. McDonald, MD, MSc; and Jeffrey L. Mahon, MD, MSc N-of-1 (Single-Patient) Trials for Statin-Related Myalgia Intern Med. 2014;160(5):301-310-310 Beuschlein F1, Fassnacht M, Assié G, Calebiro D, Stratakis CA, Osswald A, Ronchi CL, Wieland T, Sbiera S, Faucz FR, Schaak K, Schmittfull A, Schwarzmayr T, Barreau O, Vezzosi D, Rizk-Rabin M, Zabel U, Szarek E, Salpea P, Forlino A, Vetro A, Zuffardi O, Kisker C, Diener S, Meitinger T, Lohse MJ, Reincke M, Bertherat J, Strom TM, Allolio B. Constitutive Activation of PKA Catalytic Subunit in Adrenal Cushing's Syndrome. N Engl J Med. 2014 Feb 26. [Epub ahead of print] 埼玉医科大学　総合医療センター　内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田　昌文　 Matsuda, Masafumi 2014年3月13日8:30-8:55 ８階　医局

2. Single-patient trials, also known as n-of-1 trials and individual-patient trials, have the potential to address these critiques. Single-patient trials are multiple-period crossover experiments comparing two or more treatments within individual patients. Unlike parallel-group RCTs, single-patient trials can be used to estimate individual treatment effects directly. This allows single-patient trials to identify the best treatment for each individual patient and, thereby serving as a promising clinical decision tool for individual patients in the spirit of patient-centered outcomes research (PCOR). J ClinEpidemiol. 2013 Aug;66(8 Suppl):S21-8. N-of-1 trials (single-patient, randomized, multiple crossover, blinded comparisons of an active treatment vs. placebo) are the most effective way to limit these biases in individual patients because each patient serves as his or her own control

3. Drs. Joy, McDonald, and Mahon: Western University, Schulich School of Medicine and Dentistry, 268 Grosvenor Street, London, Ontario N6A 4V2, Canada. Dr. Monjed: Al-hejra Street, PO Box 463, Makkah, Saudi Arabia. Dr. Zou: Robarts Clinical Trials, PO Box 5015, 100 Perth Drive, London, Ontario N6A 5K8, Canada. Dr. Hegele: Vascular Biology, Robarts Research Institute, 1511 Richmond Street North, London, Ontario N6A 5B7, Canada. Ann Intern Med. 2014;160(5):301-310-310. doi:10.7326/M13-1921

4. Background: Statin-related myalgia is difficult to distinguish from other conditions causing myalgia and may often lead to statin discontinuation. Objective: To compare the effect of statin rechallenge with placebo in patients with prior statin-related myalgia and to determine whether patients resumed statin therapy after evaluating the results.

5. Setting: Tertiary care lipid clinic. Patients: Patients with prior statin-related myalgia with or without mild elevation of creatine kinase levels. Intervention: Rechallenge with the statin that was previously associated with myalgia within 3 weeks of open-label use versus matching placebo. Measurements: Weekly visual analogue scale (VAS) scores for myalgia and specific symptoms (VAS myalgia score and symptom-specific VAS score, respectively), pain interference scores, and pain severity scores were recorded during the 3-week periods when patients were receiving placebo or statin. The primary outcome was the VAS myalgia score (range, 0 to 100 mm).

11. The VAS myalgia scores for patients 1 to 8 are presented according to each treatment period (active [solid circle, solid line] and placebo [solid square, dotted line]). A full n-of-1 trial consisted of 6 treatment periods (3 active and 3 placebo). Treatment periods were 3 wk in duration. The VAS myalgia scores were completed at the end of each week in the treatment periods. Higher VAS myalgia scores signify greater muscle pain. Patient 6 crossed over early during treatment period 1, resulting in only 2 VAS myalgia scores for that period. Patient 7 forgot to complete 1 of 3 VASs for myalgia in treatment period 6, and patient 8 discontinued the n-of-1 trial after completing 5 treatment periods. VAS visual analogue scale.

12. For the PSS, the patients showed statistically greater discomfort during statin treatment versus placebo, but the mean difference did not meet the prespecified clinically significant difference of 1 point.

13. Results: Eight patients (mean age, 66 years [SD, 8 years]; 88% women, all with high 10-year Framingham cardiovascular risk) participated in n-of-1 trials. Seven patients completed 3 treatment pairs, and 1 completed 2 treatment pairs. For each n-of-1 trial, no statistically significant differences were seen between statin and placebo in the VAS myalgia score, symptom-specific VAS score, pain interference score, and pain severity score. Five patients resumed open-label statin treatment, with a median posttrial follow-up of 10 months.

14. Limitation: Results are limited by the small sample size and cannot be extended to patients with longer onset of myalgia after statin initiation. Conclusion: In selected patients with a history of statin-related myalgia whose symptoms are difficult to evaluate, n-of-1 trials may be a useful method for determining statin tolerability. Primary Funding Source: Western University, London, Ontario, Canada.

15. Message 　スタチン関連筋痛症既往患者8人を対象に、スタチン治療再開の判断に対するN-of-1二重盲検試験の有用性を検証。視覚的アナログスケールの筋痛症スコアにおける、スタチンとプラセボの統計学的有意差はなかった。中央値10カ月の追跡期間中に5人がスタチンを再開した。N-of-1試験でスタチンへの忍容性を評価できる可能性が示唆された。

17. Department of International Health (Human Nutrition), Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (Jones-Smith); School of Public Health, University of California, Berkeley (Dow); Independent consultant, Sacramento, California (Chichlowska). JAMA. 2014;311(9):929-936. doi:10.1001/jama.2014.604

18. Importance Economic resources have been inversely associated with risk of childhood overweight/obesity. Few studies have evaluated whether this association is a direct effect of economic resources or is attributable to unmeasured confounding or reverse causation. American Indian–owned casinos have resulted in increased economic resources for some tribes and provide an opportunity to test whether these resources are associated with overweight/obesity. Objective To assess whether openings or expansions of American Indian–owned casinos were associated with childhood overweight/obesity risk.

19. Design, Setting, and Participants  We used repeated cross-sectional anthropometric measurements from fitness testing of American Indian children (aged 7-18 years) from 117 school districts that encompassed tribal lands in California between 2001 and 2012. Children in school districts encompassing American Indian tribal lands that either gained or expanded a casino were compared with children in districts with tribal lands that did not gain or expand a casino. Main Outcomes and Measures  Per capita annual income, median annual household income, percentage of population in poverty, total population, child overweight/obesity (body mass index [BMI] ≥85th age- and sex-specific percentile) and BMI z score.

22. a Data are expressed as mean (SD) unless otherwise indicated. b Slot machines per capita were calculated for each school district in every year and represent the number of slot machines per single-race American Indian living on tribal lands within the school district; places with zero slot machines are included in the estimate. c Overweight/obesity was defined as85th percentile for age- and sex-specific body mass index based on the 2000 Centers for Disease Control and Prevention/National Center for Health Statistics (CDC) growth charts. d Based on 22 863 observations between years 2001 and 2012. e Body mass index z score was based on the age- and sex-specific 2000 CDC growth charts.

25. a The statistical models for body mass index z score are district fixed-effects linear regression models; the statistical models for overweight/obesity are district fixed-effects linear probability models. In addition to including district fixed effects (ie, an indicator variable for each district), all models also include indicator variables for each year, an ordered categorical variable for year to provide a linear time trend, and interactions terms between district indicator variables and the linear time trend to allow the trend in BMI z score/obesity to vary by district (coefficients are not shown). All models used robust standard errors that also correct for correlated outcomes within individuals and school districts. Casino slot machines per capita were calculated for each school district in every year and represent the number of slot machines per single-race American Indian living on tribal lands within the school district. This number could change over time for each school district, depending on casino opening and expansion dates. b Body mass index z scores were age- and sex-specific using the 2000 Centers for Disease Control and Prevention/National Center for Health Statistics (CDC) growth charts. c Overweight/obesity was defined as a having a body mass index z score85th percentile of the age- and sex-specific 2000 CDC growth charts. d P<.05.

26. Results  Of the 117 school districts, 57 gained or expanded a casino, 24 had a preexisting casino but did not expand, and 36 never had a casino. The mean slots per capita was 7 (SD, 12) and the median was 3 (interquartile range [IQR], 0.3-8). Among districts where a casino opened or expanded, the mean change in slots per capita was 13 (SD, 19) and the median was 3 (IQR, 1-11). Forty-eight percent of the anthropometric measurements were classified as overweight/obese (11 048/22 863). Every casino slot machine per capita gained was associated with an increase in per capita annual income (β = $541; 95% CI, $245-$836) and a decrease in percentage in poverty (β = −0.6%; 95% CI, −1.1% to −0.20%) among American Indians living on tribal lands. Among American Indian children, every slot machine per capita gained was associated with a decreased probability of overweight/obesity by 0.19 percentage points (95% CI, −0.26 to −0.11 percentage points) and a decrease in BMI z score (β = −0.003; 95% CI, −0.005 to −0.0002).

27. Conclusions and Relevance  In this study, opening or expanding a casino was associated with increased economic resources and decreased risk of childhood overweight/obesity. Given the limitations of an ecological study, further research is needed to better understand the mechanisms behind this association.

28. Message 米国で先住民所有のカジノの新設または拡大と、先住民居留区の小児の過体重・肥満リスクの関連を検証。先住民1人当たりのスロットマシン台数の増加は、1人当たり年間所得の増加および貧困率の低下と関連した。スロットの1台増加は、小児の過体重・肥満率の0.19パーセントポイント低下および体格指数Zスコアの低下と関連した。