Exact Lagrangian submanifolds in simply-connected cotangent bundles

We consider exact Lagrangian submanifolds in cotangent bundles. Under certain additional restrictions (triviality of the fundamental group of the cotangent bundle, and of the Maslov class and second Stiefel-Whitney class of the Lagrangian submanifold) we prove such submanifolds are Floer-cohomologically indistinguishable from the zero-section. This implies strong restrictions on their topology. An essentially equivalent result was recently proved independently by Nadler, using a different approach.Comment: 28 pages, 3 figures. Version 2 -- derivation and discussion of the spectral sequence considerably expanded. Other minor change

Birational cobordism invariance of uniruled symplectic manifolds

A symplectic manifold $(M,\omega)$ is called {\em (symplectically) uniruled} if there is a nonzero genus zero GW invariant involving a point constraint. We prove that symplectic uniruledness is invariant under symplectic blow-up and blow-down. This theorem follows from a general Relative/Absolute correspondence for a symplectic manifold together with a symplectic submanifold. A direct consequence is that symplectic uniruledness is a symplectic birational invariant. Here we use Guillemin and Sternberg's notion of cobordism as the symplectic analogue of the birational equivalence.Comment: To appear in Invent. Mat

Viewpoint: Estimating the causal effects of policies and programs

Estimation, inference and interpretation of the causal effects of programs and policies have all advanced dramatically over the past 25 years. We highlight three particularly important intellectual trends: an improved appreciation of the substantive importance of heterogeneous responses and of their methodological implications, a stronger focus on internal validity brought about by the “credibility revolution,” and the scientific value that follows from grounding estimation and interpretation in economic theory. We discuss a menu of commonly employed partial equilibrium approaches to the identification of causal effects, emphasizing that the researcher’s central intellectual contribution always consists of making an explicit case for a specific causal interpretation given the relevant economic theory, the data, the institutional context and the economic question of interest. We also touch on the importance of general equilibrium effects and full cost–benefit analyses.RésuméPoint de vue: Sur l’estimation des effets causatifs des politiques et programmes. Dans le monde de l’estimation, l’inférence et l’interprétation des effets causatifs des programmes et des politiques, il y a eu des progrès dramatiques au cours des derniers 25 ans. Les auteurs soulignent trois tendances intellectuelles particulièrement importantes : une appréciation améliorée de l’importance substantielle des réponses hétérogènes et de leur importance méthodologique, une focalisation plus robuste sur la validité interne engendrée par la « révolution de la crédibilité », et la valeur scientifique qui découle d’un ancrage de l’estimation et de l’interprétation dans la théorie économique. On discute un éventail d’approches d’équilibre partiel à l’identification des effets causatifs, mettant au premier plan que la contribution intellectuelle centrale du chercheur consiste à bâtir un argumentaire explicite pour une interprétation causale spécifique compte tenu de la théorie économique pertinente, des données, du contexte institutionnel, et de la question économique d’intérêt. On mentionne aussi l’importance des effets d’équilibre général et des analyses de tous les coûts et avantages.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134884/1/caje12217.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134884/2/caje12217_am.pd

Within study comparisons and risk of bias in international development: Systematic review and critical appraisal

Background Many systematic reviews incorporate nonrandomised studies of effects, sometimes called quasi‐experiments or natural experiments. However, the extent to which nonrandomised studies produce unbiased effect estimates is unclear in expectation or in practice. The usual way that systematic reviews quantify bias is through “risk of bias assessment” and indirect comparison of findings across studies using meta‐analysis. A more direct, practical way to quantify the bias in nonrandomised studies is through “internal replication research”, which compares the findings from nonrandomised studies with estimates from a benchmark randomised controlled trial conducted in the same population. Despite the existence of many risks of bias tools, none are conceptualised to assess comprehensively nonrandomised approaches with selection on unobservables, such as regression discontinuity designs (RDDs). The few that are conceptualised with these studies in mind do not draw on the extensive literature on internal replications (within‐study comparisons) of randomised trials. Objectives Our research objectives were as follows: Objective 1: to undertake a systematic review of nonrandomised internal study replications of international development interventions. Objective 2: to develop a risk of bias tool for RDDs, an increasingly common method used in social and economic programme evaluation. Methods We used the following methods to achieve our objectives. Objective 1: we searched systematically for nonrandomised internal study replications of benchmark randomised experiments of social and economic interventions in low‐ and middle‐income countries (L&MICs). We assessed the risk of bias in benchmark randomised experiments and synthesised evidence on the relative bias effect sizes produced by benchmark and nonrandomised comparison arms. Objective 2: We used document review and expert consultation to develop further a risk of bias tool for quasi‐experimental studies of interventions (ROBINS‐I) for RDDs. Results Objective 1: we located 10 nonrandomised internal study replications of randomised trials in L&MICs, six of which are of RDDs and the remaining use a combination of statistical matching and regression techniques. We found that benchmark experiments used in internal replications in international development are in the main well‐conducted but have “some concerns” about threats to validity, usually arising due to the methods of outcomes data collection. Most internal replication studies report on a range of different specifications for both the benchmark estimate and the nonrandomised replication estimate. We extracted and standardised 604 bias coefficient effect sizes from these studies, and present average results narratively. Objective 2: RDDs are characterised by prospective assignment of participants based on a threshold variable. Our review of the literature indicated there are two main types of RDD. The most common type of RDD is designed retrospectively in which the researcher identifies post‐hoc the relationship between outcomes and a threshold variable which determines assignment to intervention at pretest. These designs usually draw on routine data collection such as administrative records or household surveys. The other, less common, type is a prospective design where the researcher is also involved in allocating participants to treatment groups from the outset. We developed a risk of bias tool for RDDs. Conclusions Internal study replications provide the grounds on which bias assessment tools can be evidenced. We conclude that existing risk of bias tools needs to be further developed for use by Campbell collaboration authors, and there is a wide range of risk of bias tools and internal study replications to draw on in better designing these tools. We have suggested the development of a promising approach for RDD. Further work is needed on common methodologies in programme evaluation, for example on statistical matching approaches. We also highlight that broader efforts to identify all existing internal replication studies should consider more specialised systematic search strategies within particular literatures; so as to overcome a lack of systematic indexing of this evidence

The future is now: Model-based clinical trial design for Alzheimer's disease

Failures in trials for Alzheimer's disease (AD) may be attributable to inadequate dosing, population selection, drug inefficacy, or insufficient design optimization. The Coalition Against Major Diseases (CAMD) was formed in 2008 to develop drug development tools (DDT) to expedite drug development for AD and Parkinson's disease.1 CAMD led a process that successfully advanced a clinical trial simulation (CTS) tool for AD through the formal regulatory review process at the US Food and Drug Administration (FDA) and European Medicines Agency (EMA)

Comparison of pharmacist managed anticoagulation with usual medical care in a family medicine clinic

Background The beneficial outcomes of oral anticoagulation therapy are dependent upon achieving and maintaining an optimal INR therapeutic range. There is growing evidence that better outcomes are achieved when anticoagulation is managed by a pharmacist with expertise in anticoagulation management rather than usual care by family physicians. This study compared a pharmacist managed anticoagulation program (PC) to usual physician care (UC) in a family medicine clinic. Methods A retrospective cohort study was carried out in a family medicine clinic which included a clinical pharmacist. In 2006, the pharmacist assumed anticoagulation management. For a 17-month period, the PC group (n = 112) of patients on warfarin were compared to the UC patients (n = 81) for a similar period prior to 2006. The primary outcome was the percentage of time patients' INR was in the therapeutic range (TTR). Secondary outcomes were the percentage of time in therapeutic range within ± 0.3 units of the recommended range (expanded TTR) and percentage of time the INR was >5.0 or <1.5. Results The baseline characteristics were similar between the groups. Fifty-five percent of the PC group was male with a mean age of 67 years; 51% of the UC group was male with a mean age of 71 years. The most common indications for warfarin in both groups were atrial fibrillation, mechanical heart valves and deep vein thrombosis. The TTR was 73% for PC and 65% for UC (p 5 were 0.3% for PC patients and 0.1% for UC (p < 0.0001). Conclusion The pharmacist-managed anticoagulation program within a family practice clinic compared to usual care by the physicians achieved significantly better INR control as measured by the percentage of time patients' INR values were kept in both the therapeutic and expanded range. Based on the results of this study, a collaborative family practice clinic using pharmacists and physicians may be an effective model for anticoagulation management with these results verified in future prospective randomized studies

Transhiatal vs extended transthoracic resection in oesophageal carcinoma: patients' utilities and treatment preferences

To assess patients' utilities for health state outcomes after transhiatal or transthoracic oesophagectomy for oesophageal cancer and to investigate the patients' treatment preferences for either procedure. The study group consisted of 48 patients who had undergone either transhiatal or transthoracic oesophagectomy. In an interview they were presented with eight possible health states following oesophagectomy. Visual Analogue Scale and standard gamble techniques were used to measure utilities. Treatment preference for either transhiatal or transthoracic oesophagectomy was assessed. Highest scores were found for the patients' own current health state (Visual Analogue Scale: 0.77; standard gamble: 0.97). Lowest scores were elicited for the health state ‘irresectable tumour’ (Visual Analogue Scale: 0.13; standard gamble: 0.34). The Visual Analogue Scale method produced lower estimates (P<0.001) than the standard gamble method for all health states. Most patient characteristics and clinical factors did not correlate with the utilities. Ninety-five per cent of patients who underwent a transthoracic procedure and 52% of patients who underwent a transhiatal resection would prefer the transthoracic treatment. No significant associations between any patient characteristics or clinical characteristics and treatment preference were found. Utilities after transhiatal or transthoracic oesophagectomy were robust because they generally did not vary by patient or clinical characteristics. Overall, most patients preferred the transthoracic procedure