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We consider the analysis of clinical trials that involve randomization to an active treatment (T = 1) or a control treatment (T = 0), when the active treatment is subject to all-or-nothing compliance. We compare three approaches to estimating treatment efficacy in this situation: as-treated analysis, per-protocol analysis, and instrumental variable (IV) estimation, where the treatment effect is estimated using the randomization indicator as an IV. Both model- and method-of-moment based IV estimators are considered. The assumptions underlying these estimators are assessed, standard errors and mean squared errors of the estimates are compared, and design implications of the three methods are examined. Extensions of the methods to include observed covariates are then discussed, emphasizing the role of compliance propensity methods and the contrasting role of covariates in these extensions. Methods are illustrated on data from the Women Take Pride study, an assessment of behavioral treatments for women with heart disease.

This article reviews methods for comparative effectiveness research using observational data. The basic idea is using an observational study to emulate a hypothetical randomised trial by comparing initiators versus non-initiators of treatment. After adjustment for measured baseline confounders, one can then conduct the observational analogue of an intention-to-treat analysis. We also explain two approaches to conduct the analogues of per-protocol and as-treated analyses after further adjusting for measured time-varying confounding and selection bias using inverse-probability weighting. As an example, we implemented these methods to estimate the effect of statins for primary prevention of coronary heart disease (CHD) using data from electronic medical records in the UK. Despite strong confounding by indication, our approach detected a potential benefit of statin therapy. The analogue of the intention-to-treat hazard ratio (HR) of CHD was 0.89 (0.73, 1.09) for statin initiators versus non-initiators. The HR of CHD was 0.84 (0.54, 1.30) in the per-protocol analysis and 0.79 (0.41, 1.41) in the as-treated analysis for 2 years of use versus no use. In contrast, a conventional comparison of current users versus never users of statin therapy resulted in a HR of 1.31 (1.04, 1.66). We provide a flexible and annotated SAS program to implement the proposed analyses.

To estimate the effect of a 3-year commitment to remain tobacco free on tobacco uptake among high school students in Sweden. The commitment is developed in the form of a contract between a child and a significant adult, constituting the core component of Tobacco-free Duo (T-Duo), a Swedish school-based tobacco prevention program. Secondary analysis of data from a cluster randomized controlled trial. Participants were 586 students in high schools assigned to the intervention arm of T-Duo. At inception, participants attended grade 7 (i.e., age 12–13). Only students who were tobacco naïve at baseline for the respective outcome and participated in all follow-ups were included. The exposure was defined as signing a 3-year contract with a significant adult, categorized as “stable contract” (3 years contract with the same contract partner), “unstable” (signed a contract sometime during follow-up but this was not sustained over time and/or with the same partner), and “no contract” at all during the intervention period. The primary outcome was having never tried cigarette smoking at the end of grade 9. Exposure and outcomes were self-reported in yearly questionnaires. Of 586 students, 321 (55%) held a stable contract, 204 (35%) an unstable contract, and 61 (10%) did not sign a contract at all. At the end of grade 9 (age 15–16), the relative risk (RR) to remain cigarette free was 1.11 (95% CI 1.00–1.22) (Number Needed to Treat = 10) among students in any type of contract compared to students that did not write a contract at all. The RRs for remaining tobacco free (secondary outcomes) ranged from 1.07 (0.98–1.16) for regular snus use to 1.16 (1.00–1.35) for any type of tobacco use. A commitment to remain tobacco free through a child–adult contract seems to exert a preventive effect on the uptake of tobacco use among Swedish adolescents over 3 school years. The current findings apply to a selected sample of both schools and students. Registration: Current Controlled Trials ISRCTN52858080 Date: January 4, 2019, retrospectively registered.

The association between compliance which induces treatment exposure levels, and treatment‐free hazards is often called a selection effect in line with missing data terminology. An “as‐treated” analysis, such as a PH analysis, with the currently received treatment as a time‐dependent covariate, compares hazards between differently treated groups at a given time and thus estimates a mix of selection and causal effects. An “on‐treatment” analysis censors patients as soon as they go off the assigned treatment and thus generates informative censoring for the same reason. Structural accelerated failure time (SAFT) models and structural PH models have been designed to avoid these biases. This chapter explains their key features and potential through a simple example. One can propose many different maps of the observed into the treatment‐specific survival distributions. This may happen on a PH scale or involve time‐dependent measures of effect in the SAFT setting.

This chapter contains sections titled: Aims Background Reading and questions Worked example Exercise Quick quiz Critical appraisal References

Rising land surface temperature (LST), urban heat island (UHI) effects, and stress on surface-, processed-, potable-, and ground-water resources are some undesirable ecological changes due to rapid urbanization. Treating and reusing city-generated wastewater for maintaining urban green spaces (UGS) helps in reducing/preventing groundwater extraction, ensuring sufficient supply of potable water, and bringing down LST. However, the benefits of reusing treated wastewater in UGS for enhancing regulatory ecosystem services (RES) and ushering in a circular economy are yet to be realized. In view of these, the transportation costs of treated wastewater for irrigating the UGS of Panaji city—proposed to be developed as a smart city—were assessed. Field surveys were conducted at seven gardens/parks to collect the primary data on vegetation type (ground cover, hedge plants, and trees) and their daily water requirement. As the main focus of this study, a cost–benefit analysis of (a) drawing the groundwater using borewells versus use of treated wastewater from the city’s STP, and (b) two modes of treated wastewater transport: water tankers vs. pipeline was performed. Our analyses suggest that the copiously available 14 MLD treated wastewater from the STP, which meets all the safety standards, is far in excess of the current requirement of 6.24 MLD for watering the vegetation in all 17 parks/gardens in the city. Pipeline is an efficient (less energy, labor, and time) and economical (~47% more than water that is tanker-based) transportation mode. By utilizing the otherwise unused treated wastewater, which is processed at a cost of over USD half a million annually, the RES offered by the use of treated wastewater are (a) partially curtailing a combined loss of ~16 MLD due to the extraction of groundwater plus evapotranspiration (@8.86 mm d−1) from Panaji city’s 1.86 km2 UGS, and (b) reduction in LST ~3–4 °C in all of Panaji city. In addition, with the proficient and sustainable management of UGS and the meeting of many UNSDGs, the enhanced vegetation growth plus elevated carbon sequestration rates in the UGS are possible through the reuse of treated wastewater.

Objective To summarise the adverse events (AE) reported in patients with rheumatoid arthritis (RA) treated with protein kinase inhibitors (PKi), and identify family and molecule-related AEs. Methods Systematic review of the PKi used in clinical trials (CTs) in RA. Medline, Embase, Cochrane Library, Web of Knowledge, and international abstracts of congress were reviewed, (up to 31 October 2012). Search was limited to interventional studies of PKi used in CTs in RA, written in English, and reporting frequencies of AE. Diseases with similar comorbidity burden also were included. Frequency of AE, serious AE (SAE), death and discontinuation due to  AEs (DCAE) were recorded. Risk of bias was assessed. Meta-analysis was carried using pooled relative risk (RR) with 95% CI as effect measure. Results The search produced 4410 hits. Forty-one articles reporting data on 21 PKi of the Janus kinase (JAK), SYK, p38 and cKit families were selected for detailed analysis. In patients treated with p38 inhibitors, RR for dizziness was 2.36 (1.20 to 4.63), and in patients treated with c-Kit inhibitors, RR for oedema was 3.43 (1.58 to 7.42). In patients treated with the JAK inhibitor tofacitinib, RR for hypercholesterolaemia was 1.70 (1.10 to 2.63) that was dose related. In patients treated with the Syk inhibitor fostamatinib, pooled RR for hypertransaminasaemia, hypertension, diarrhoea and neutropenia were 2.93 (1.02 to 8.43), 2.80 (1.58 to 5.99), 5.20 (3.19 to 8.49) and 9.24 (2.22 to 38.42), respectively. Serious infections and malignancies were not significantly more frequent in PKi-treated patients than in comparator groups. Conclusions Event rates of serious infections and malignancies with PKi are not different from biologics. In addition, PKi have a unique safety profile related to target and off-target inhibition of kinases, at times dose related.

This study was aimed to evaluate the involvement of CB2 cannabinoid receptors (CB2r) in the rewarding, reinforcing and motivational effects of nicotine. Conditioned place preference (CPP) and intravenous self-administration experiments were carried out in knockout mice lacking CB2r (CB2KO) and wild-type (WT) littermates treated with the CB2r antagonist AM630 (1 and 3 mg/kg). Gene expression analyses of tyrosine hydroxylase (TH) and α3- and α4-nicotinic acetylcholine receptor subunits (nAChRs) in the ventral tegmental area (VTA) and immunohistochemical studies to elucidate whether CB2r colocalized with α3- and α4-nAChRs in the nucleus accumbens and VTA were performed. Mecamylamine-precipitated withdrawal syndrome after chronic nicotine exposure was evaluated in CB2KO mice and WT mice treated with AM630 (1 and 3 mg/kg). CB2KO mice did not show nicotine-induced place conditioning and self-administered significantly less nicotine. In addition, AM630 was able to block (3 mg/kg) nicotine-induced CPP and reduce (1 and 3 mg/kg) nicotine self-administration. Under baseline conditions, TH, α3-nAChR, and α4-nAChR mRNA levels in the VTA of CB2KO mice were significantly lower compared with WT mice. Confocal microscopy images revealed that CB2r colocalized with α3- and α4-nAChRs. Somatic signs of nicotine withdrawal (rearings, groomings, scratches, teeth chattering, and body tremors) increased significantly in WT but were absent in CB2KO mice. Interestingly, the administration of AM630 blocked the nicotine withdrawal syndrome and failed to alter basal behavior in saline-treated WT mice. These results suggest that CB2r play a relevant role in the rewarding, reinforcing, and motivational effects of nicotine. Pharmacological manipulation of this receptor deserves further consideration as a potential new valuable target for the treatment of nicotine dependence.

Multidisciplinary care has become the preferred model of care for patients with amyotrophic lateral sclerosis (ALS). It is assumed that the sum of interventions associated with this approach has a positive effect on survival. The objective of the study was to evaluate the impact of a multidisciplinary care approach on the survival of patients with ALS. We performed a retrospective review of prospectively collected data in a tertiary referral center in Spain. Participants were patients with definite or probable ALS managed in a multidisciplinary care program. We compared demographic and survival data of patients with definite or probable ALS treated in a referral center without and with implementation of a multidisciplinary care program. We performed time-dependent multivariate survival analysis of the use of noninvasive mechanical ventilation (NIMV) and gastrostomy. We evaluated 398 consecutive patients, of whom 54 were treated by a general neurologist and 344 were treated in the multidisciplinary care clinic. Patients receiving multidisciplinary care were older (62 vs 58 years), tended to have bulbar onset disease (30% vs 17.7%), and were more likely to receive riluzole (88.7% vs 29.6%, <0.01), NIMV (48.8% vs 29.6%, >0.001), and nutrition via gastrostomy (32.3% vs 3.7%, <0.01). Kaplan-Meier analysis showed a 6-month increase in survival (log-rank, 16.03, <0.001). Application of the Andersen-Gill model showed that the variables associated with reduced mortality were reduced time to NIMV and gastrostomy and the duration of both, thus reflecting compliance. Multidisciplinary care increased the survival of ALS patients in our study population. Timely use of respiratory support and gastrostomy are fundamental aspects of this benefit.

This chapter contains sections titled: Introduction Data description and mass categorization Nonparametric analysis of satellite reliability by mass category Parametric analysis of satellite reliability by mass category Orbit characterization Nonparametric analysis of spacecraft reliability by mass and orbit category Parametric analysis of satellite reliability by mass and orbit category Hypotheses for causal explanations Appendix: Tabular data and confidence interval analysis