Emulating a target trial in case-control designs: an application to statins and colorectal cancer

BACKGROUND: Previous case-control studies have reported a strong association between statin use and lower cancer risk. It is unclear whether this association reflects a benefit of statins or is the result of design decisions that cannot be mapped to a (hypothetical) target trial (that would answer the question of interest). METHODS: We outlined the protocol of a target trial to estimate the effect of statins on colorectal cancer incidence among adults with low-density lipoprotein (LDL) cholesterol below 5 mmol/L. We then emulated the target trial using linked electronic health records of 752 469 eligible UK adults (CALIBER 1999-2016) under both a cohort design and a case-control sampling of the cohort. We used pooled logistic regression to estimate intention-to-treat and per-protocol effects of statins on colorectal cancer, with adjustment for baseline and time-varying risk factors via inverse-probability weighting. Finally, we compared our case-control effect estimates with those obtained using previous case-control procedures. RESULTS: Over the 6-year follow-up, 3596 individuals developed colorectal cancer. Estimated intention-to-treat and per-protocol hazard ratios were 1.00 (95% confidence interval [CI]: 0.87, 1.16) and 0.90 (95% CI: 0.71, 1.12), respectively. As expected, adequate case-control sampling yielded the same estimates. By contrast, previous case-control analytical approaches yielded estimates that appeared strongly protective (odds ratio 0.57, 95% CI: 0.36, 0.91, for ≥5 vs. <5 years of statin use). CONCLUSIONS: Our study demonstrates how to explicitly emulate a target trial using case-control data to reduce discrepancies between observational and randomized trial evidence. This approach may inform future case-control analyses for comparative effectiveness research

Avoidable flaws in observational analyses: an application to statins and cancer

The increasing availability of large healthcare databases is fueling an intense debate on whether real-world data should play a role in the assessment of the benefit–risk of medical treatments. In many observational studies, for example, statin users were found to have a substantially lower risk of cancer than in meta-analyses of randomized trials. Although such discrepancies are often attributed to a lack of randomization in the observational studies, they might be explained by flaws that can be avoided by explicitly emulating a target trial (the randomized trial that would answer the question of interest). Using the electronic health records of 733,804 UK adults, we emulated a target trial of statins and cancer and compared our estimates with those obtained using previously applied analytic approaches. Over the 10-yr follow-up, 28,408 individuals developed cancer. Under the target trial approach, estimated observational analogs of intention-to-treat and per-protocol 10-yr cancer-free survival differences were −0.5% (95% confidence interval (CI) −1.0%, 0.0%) and −0.3% (95% CI −1.5%, 0.5%), respectively. By contrast, previous analytic approaches yielded estimates that appeared to be strongly protective. Our findings highlight the importance of explicitly emulating a target trial to reduce bias in the effect estimates derived from observational analyses

Use of a Hybrid Adeno-Associated Viral Vector Transposon System to Deliver the Insulin Gene to Diabetic NOD Mice.

Previously, we used a lentiviral vector to deliver furin-cleavable human insulin (INS-FUR) to the livers in several animal models of diabetes using intervallic infusion in full flow occlusion (FFO), with resultant reversal of diabetes, restoration of glucose tolerance and pancreatic transdifferentiation (PT), due to the expression of beta (β)-cell transcription factors (β-TFs). The present study aimed to determine whether we could similarly reverse diabetes in the non-obese diabetic (NOD) mouse using an adeno-associated viral vector (AAV) to deliver INS-FUR ± the β-TF Pdx1 to the livers of diabetic mice. The traditional AAV8, which provides episomal expression, and the hybrid AAV8/piggyBac that results in transgene integration were used. Diabetic mice that received AAV8-INS-FUR became hypoglycaemic with abnormal intraperitoneal glucose tolerance tests (IPGTTs). Expression of β-TFs was not detected in the livers. Reversal of diabetes was not achieved in mice that received AAV8-INS-FUR and AAV8-Pdx1 and IPGTTs were abnormal. Normoglycaemia and glucose tolerance were achieved in mice that received AAV8/piggyBac-INS-FUR/FFO. Definitive evidence of PT was not observed. This is the first in vivo study using the hybrid AAV8/piggyBac system to treat Type 1 diabetes (T1D). However, further development is required before the system can be used for gene therapy of T1D

The DRESS trial: a feasibility randomized controlled trial of a neuropsychological approach to dressing therapy for stroke inpatients

Objective: To investigate two approaches to treating patients with persistent dressing problems and cognitive difficulties following stroke. Design: Pilot randomized controlled trial. Setting: Inpatient stroke rehabilitation service. Subjects: Seventy consecutive stroke patients with persistent dressing problems and accompanying cognitive difficulties at two weeks after their stroke. Interventions: Patients were randomly allocated to six weeks of either a systematic neuropsychological approach, based on analysis of dressing problems and further cognitive testing, or to the control group who received conventional (functional) dressing practice. Both groups received treatment three times a week in accordance with two separately prepared manuals. Main measures: Nottingham Stroke Dressing Assessment (NSDA), Line Cancellation, 10-hole peg transfer test, Object Decision, Gesture Imitation. Patients were assessed at six weeks after randomization by an independent assessor masked to group allocation. Results: Both neuropsychological and functional groups improved performance on the NSDA over the treatment period (31% and 22%, respectively) but there was no significant difference between groups at six weeks. However, the neuropsychological group showed a significantly greater improvement on a line cancellation test of visual neglect (t(62) = 2.1, P < 0.05) and a planned subanalysis for those with right hemisphere damage showed a trend towards better dressing outcome (P = 0.07, one-tailed). Conclusions: Results demonstrate the potential benefits of a systematic neuropsychological approach to dressing therapy, particularly for patients with right hemisphere damage. This study suggests the need for a phase III study evaluating the efficacy of a systematic neuropsychological approach in treating dressing difficulties, targeting patients with right hemisphere stroke and visuospatial impairments

Charged-Higgs phenomenology in the Aligned two-Higgs-doublet model

The alignment in flavour space of the Yukawa matrices of a general two-Higgs-doublet model results in the absence of tree-level flavour-changing neutral currents. In addition to the usual fermion masses and mixings, the aligned Yukawa structure only contains three complex parameters, which are potential new sources of CP violation. For particular values of these three parameters all known specific implementations of the model based on discrete Z_2 symmetries are recovered. One of the most distinctive features of the two-Higgs-doublet model is the presence of a charged scalar. In this work, we discuss its main phenomenological consequences in flavour-changing processes at low energies and derive the corresponding constraints on the parameters of the aligned two-Higgs-doublet model.Comment: 46 pages, 19 figures. Version accepted for publication in JHEP. References added. Discussion slightly extended. Conclusions unchange

Rare Z-decay into light CP-odd Higgs bosons: a comparative study in different new physics models

Various new physics models predict a light CP-odd Higgs boson (labeled as $a$) and open up new decay modes for Z-boson, such as $Z \to \bar{f} f a$, $Z\to a\gamma$ and $Z\to aaa$, which could be explored at the GigaZ option of the ILC. In this work we investigate these rare decays in several new physics models, namely the type-II two Higgs doublet model (type-II 2HDM), the lepton-specific two Higgs doublet model (L2HDM), the nearly minimal supersymetric standard model (nMSSM) and the next-to-minimal supersymmetric standard model (NMSSM). We find that in the parameter space allowed by current experiments, the branching ratios can reach $10^{-4}$ for $Z \to \bar{f} f a$ ($f=b,\tau$), $10^{-9}$ for $Z\to a\gamma$ and $10^{-3}$ for $Z\to aaa$, which implies that the decays $Z \to \bar{f} f a$ and $Z \to a a a$ may be accessible at the GigaZ option. Moreover, since different models predict different patterns of the branching ratios, the measurement of these rare decays at the GigaZ may be utilized to distinguish the models.Comment: Version in JHEP (discussions added, errors corrected

The importance of the exposome and allostatic load in the planetary health paradigm

In 1980, Jonas Salk (1914-1995) encouraged professionals in anthropology and related disciplines to consider the interconnections between "planetary health," sociocultural changes associated with technological advances, and the biology of human health. The concept of planetary health emphasizes that human health is intricately connected to the health of natural systems within the Earth's biosphere; experts in physiological anthropology have illuminated some of the mechanisms by which experiences in natural environments (or the built environment) can promote or detract from health. For example, shinrin-yoku and related research (which first emerged from Japan in the 1990s) helped set in motion international studies that have since examined physiological responses to time spent in natural and/or urban environments. However, in order to advance such findings into planetary health discourse, it will be necessary to further understand how these biological responses (inflammation and the collective of allostatic load) are connected to psychological constructs such as nature relatedness, and pro-social/environmental attitudes and behaviors. The exposome refers to total environmental exposures-detrimental and beneficial-that can help predict biological responses of the organism to environment over time. Advances in "omics" techniques-metagenomics, proteomics, metabolomics-and systems biology are allowing researchers to gain unprecedented insight into the physiological ramifications of human behavior. Objective markers of stress physiology and microbiome research may help illuminate the personal, public, and planetary health consequences of "extinction of experience." At the same time, planetary health as an emerging multidisciplinary concept will be strengthened by input from the perspectives of physiological anthropology.Peer reviewe

Nanolitre real-time PCR detection of bacterial, parasitic, and viral agents from patients with diarrhoea in Nunavut, Canada

Background. Little is known about the microbiology of diarrhoeal disease in Canada&#x0027;s Arctic regions. There are a number of limitations of conventional microbiology testing techniques for diarrhoeal pathogens, and these may be further compromised in the Arctic, given the often long distances for specimen transport. Objective. To develop a novel multiple-target nanolitre real-time reverse transcriptase (RT)-PCR platform to simultaneously test diarrhoeal specimens collected from residents of the Qikiqtani (Baffin Island) Region of Nunavut, Canada, for a wide range of bacterial, parasitic and viral agents. Study design/methods. Diarrhoeal stool samples submitted for bacterial culture to Qikiqtani General Hospital in Nunavut over an 18-month period were tested with a multiple-target nanolitre real-time PCR panel for major diarrhoeal pathogens including 8 bacterial, 6 viral and 2 parasitic targets. Results. Among 86 stool specimens tested by PCR, a total of 50 pathogens were detected with 1 or more pathogens found in 40 (46.5%) stool specimens. The organisms detected comprised 17 Cryptosporidium spp., 5 Clostridium difficile with toxin B, 6 Campylobacter spp., 6 Salmonella spp., 4 astroviruses, 3 noroviruses, 1 rotavirus, 1 Shigella spp. and 1 Giardia spp. The frequency of detection by PCR and bacterial culture was similar for Salmonella spp., but discrepant for Campylobacter spp., as Campylobacter was detected by culture from only 1/86 specimens. Similarly, Cryptosporidium spp. was detected in multiple samples by PCR but was not detected by microscopy or enzyme immunoassay. Conclusions. Cryptosporidium spp., Campylobacter spp. and Clostridium difficile may be relatively common but possibly under-recognised pathogens in this region. Further study is needed to determine the regional epidemiology and clinical significance of these organisms. This method appears to be a useful tool for gastrointestinal pathogen research and may also be helpful for clinical diagnostics and outbreak investigation in remote regions where the yield of routine testing may be compromised

Central engine afterglow of Gamma-ray Bursts

Before 2004, nearly all GRB afterglow data could be understood in the context of the external shocks model. This situation has changed in the past two years, when it became clear that some afterglow components should be attributed to the activity of the central engine; i.e., the {\it central engine afterglow}. We review here the afterglow emission that is directly related to the GRB central engine. Such an interpretation proposed by Katz, Piran & Sari, peculiar in pre-{\it Swift} era, has become generally accepted now.Comment: 4 pages including 1 figure. Presented at the conference "Astrophysics of Compact Objects" (July 1-7, 2007; Huangshan, China