For many individuals, substance abuse possesses characteristics of chronic disorders in that individuals experience repeated cycles of cessation and relapse; hence viewing drug dependence as a chronic, relapsing disorder is increasingly accepted. The development of a treatment for a chronic disorder requires consideration of the ordering of treatments, the timing of changes in treatment, and the use of measures of response, burden and adherence collected during treatment to make further treatment decisions. Adaptive treatment strategies provide a vehicle through which these issues can be addressed and thus provide a means toward improving and informing the clinical management of chronic substance abuse disorders. The sequential multiple assignment randomized trial (SMART) is particularly useful in developing adaptive treatment strategies. Simple analyses that can be used with the SMART design are described. Furthermore the SMART design is compared with standard experimental designs.

Background Evidence regarding all-cause and cause-specific mortality in inflammatory bowel disease (IBD) is conflicting, and debate exists over appropriate study design to examine these important outcomes. We conducted a comprehensive meta-analysis of all-cause and cause-specific mortality in both Crohn’s disease (CD) and ulcerative colitis (UC), and additionally examined various effects of study design on this outcome. Methods A systematic search of PubMed and EMBASE was conducted to identify studies examining mortality rates relative to the general population. Pooled summary standardized mortality ratios (SMR) were calculated using random effect models. Results Overall, 35 original articles fulfilled the inclusion and exclusion criteria, reporting all-cause mortality SMRs varying from 0.44 to 7.14 for UC and 0.71 to 3.20 for CD. The all-cause mortality summary SMR for inception cohort and population cohort UC studies was 1.19 (95% confidence interval, 1.06–1.35). The all-cause mortality summary SMR for inception cohort and population cohort CD studies was 1.38 (95% confidence interval, 1.23–1.55). Mortality from colorectal cancer, pulmonary disease, and nonalcoholic liver disease was increased, whereas mortality from cardiovascular disease was decreased. Conclusions Patients with UC and CD have higher rates of death from all causes, colorectal-cancer, pulmonary disease, and nonalcoholic liver disease.

Background Timely recruiting and retaining participants into AD clinical trials is a challenge. We used conjoint analysis to identify how alterations in attributes of clinical trial design improve willingness to participate: risk, home visits, car service, or increased chance of receiving intervention. Method 108 study partners of very mild to severe stage AD patients rated willingness to allow their relative to participate in 8 clinical trials that varied combinations of the four attributes. Results The highest utility was for home visits (0.89) which essentially compensated for the disutility of high risk (−0.85). The combination of home visits and car service was redundant, with almost no increase in utility over home visits alone. Seventeen percent were willing to participate in a trial with no amenities; the addition of home visits increased predicted willingness to participate to 27%; low risk, home visits, and higher chance of active treatment increased predicted willingness to 60%. The value of reducing the hassles of travel correlated well with measures of AD severity (ADL r=0.41, p<0.001; BADL r=0.38, p<0.001; NPIQ severity p=0.24, p=0.01; NPIQ distress r=0.23, p<0.02). No association was found between degree of study partner burden and willingness to tolerate risk of an intervention. Conclusion Clinical trials that reduce travel inconvenience may offset the disincentive of study features such as the risk of intervention and may also increase willingness to participate. Redesigning trials may also help recruit patients with more severe AD. Shorter recruitment periods and increased retention rates may offset costs of these changes.

Changes in intracellular calcium concentration ([Ca2+]i) in paced fura 2-loaded myocytes isolated from Sham, renovascular hypertensive (Hyp), and myocardial-infarcted (MI) rats were examined. Compared with controls, Hyp myocytes paced at physiological rates had similar systolic but elevated diastolic [Ca2+]i. By contrast, systolic [Ca2+]i was significantly lower and diastolic [Ca2+]i higher in MI myocytes. The different patterns of alterations in [Ca2+]i dynamics in Hyp and MI myocytes may partly explain predominantly diastolic dysfunction in hypertensive hearts and systolic dysfunction in hearts surviving MI. In the presence of 1 microM isoproterenol, both Hyp and MI myocytes had much lower systolic [Ca2+]i when compared with their respective controls. Isoproterenol restored the elevated diastolic [Ca2+]i in Hyp myocytes toward normal but had no effect on the intrinsic differences in diastolic [Ca2+]i between Sham and MI myocytes. The observation that isoproterenol lowers diastolic [Ca2+]i in Hyp myocytes toward normal may provide a cellular mechanism for the lack of efficacy of beta-adrenergic blockers to improve diastolic compliance in patients with hypertensive hypertrophic cardiomyopathy.