Advances in Epidemiological Methods and Utilisation of Large Databases: A Methodological Review of Observational Studies on Central Nervous System Drug Use in Pregnancy and Central Nervous System Outcomes in Children.

INTRODUCTION: Studies have used various epidemiological approaches to study associations between central nervous system (CNS) drug use in pregnancy and CNS outcomes in children. Studies have generally focused on clinical adverse effects, whereas variations in methodologies have not received sufficient attention. OBJECTIVE: Our objective was to review the methodological characteristics of existing studies to identify any limitations and recommend further research. METHODS: A systematic literature search was conducted on observational studies listed in PubMed from 1 January 1946 to 21 September 2017. Following independent screening and data extraction, we conducted a review addressing the trends of relevant studies, differences between various data sources, and methods used to address bias and confounders; we also conducted statistical analyses. RESULTS: In total, 111 observational studies, 25 case-control studies, and 86 cohort studies were included in the review. Publications dating from 1978 to 2006 mainly focused on antiepileptic drugs, but research on antidepressants increased from 2007 onwards. Only one study focused on antipsychotic use during pregnancy. A total of 46 studies obtained data from an administrative database/registry, 20 from ad hoc disease registries, and 41 from ad hoc clinical samples. Most studies (58%) adjusted the confounding factors using general adjustment, whereas only a few studies used advanced methods such as sibling-matched models and propensity score methods; 42 articles used univariate analyses and 69 conducted multivariable regression analyses. CONCLUSION: Multiple factors, including different study designs and data sources, have led to inconsistent findings in associations between CNS drug use in pregnancy and CNS outcomes in children. Researchers should allow for study designs with clearly defined exposure periods, at the very least in trimesters, and use advanced confounding adjustment methodology to increase the accuracy of the findings.

Do large mergers increase or decrease the productivity of pharmaceutical R&D?

There is current uncertainty regarding the effects of mergers on pharmaceutical R&D productivity, with various mechanisms reported by which mergers could either help or harm R&D, and mixed empirical findings in prior analyses. Here, we present an analysis that is novel in several ways: we use downstream measures of R&D productivity, account for both inputs and outputs in our calculations, and use a self-controlled design. We find that recent large pharmaceutical mergers are associated with statistically significant increases in R&D productivity. These results are perhaps not surprising in light of the broader literature on R&D productivity that points to two factors as instrumental in driving higher R&D productivity (depth of scientific information, and objectivity of decision-making based on that information), both of which could be expected to increase because of a merger.

Monitoring of typodont root movement via crown superimposition of single cone-beam computed tomography and consecutive intraoral scans.

INTRODUCTION: The purpose of this study was to develop a new methodology to visualize in 3 dimensions whole teeth, including the roots, at any moment during orthodontic treatment without the need for multiple cone-beam computed tomography (CBCT) scans. METHODS: An extraoral typodont model was created using extracted teeth placed in a wax base. These teeth were arranged to represent a typical malocclusion. Initial records of the malocclusion, including CBCT and intraoral surface scans, were taken. Threshold segmentation of the CBCT was performed to generate a 3-dimensional virtual model. This model and the intraoral surface scan model were superimposed to generate a complete set of digital composite teeth composed of high-resolution surface scan crowns sutured to the CBCT roots. These composite teeth were individually isolated from their respective arches for single-tooth manipulations. Orthodontic treatment for the malocclusion typodont model was performed, and posttreatment intraoral surface scans before and after bracket removal were taken. A CBCT scan after bracket removal was also obtained. The isolated composite teeth were individually superimposed onto the posttreatment surface scan, creating the expected root position setup. To validate this setup, it was compared with the posttreatment CBCT scan, which showed the true positions of the roots. Color displacement maps were generated to confirm accurate crown superimpositions and to measure the discrepancies between the expected and the true root positions. RESULTS: Color displacement maps through crown superimpositions showed differences between the expected and true root positions of 0.1678 ± 0.3178 mm for the maxillary teeth and 0.1140 ± 0.1587 mm for the mandibular teeth with brackets. Once the brackets were removed, differences of 0.1634 ± 0.3204 mm for the maxillary teeth and 0.0902 ± 0.2505 mm for the mandibular teeth were found. CONCLUSIONS: A new reliable approach was demonstrated in an ex-vivo typdont model to have the potential to track the 3-dimensional positions of whole teeth including the roots, with only the initial CBCT scan and consecutive intraoral scans. Since the presence of brackets in the intraoral scan had a minimal influence in the analysis, this method can be applied at any stage of orthodontic treatment.

Response to nocturnal alarms using a real-time glucose sensor.

BACKGROUND: The objective of this study was to determine how subjects responded to alarms for hypo- and hyperglycemia while they were sleeping. RESEARCH DESIGN AND METHODS: Twenty subjects with type 1 diabetes (4-17 years old) were admitted to a clinical research center for approximately 24 h. Each subject wore two GlucoWatch G2 Biographers (GW2B) (Cygnus, Inc., Redwood City, CA) and was videotaped using an infrared camera from 9 p.m. to 7 a.m. The videotapes were reviewed to determine if the GW2B alarms were audible on the tape and to document the subject's response to the alarms. Because many alarms can occur surrounding a change in blood glucose, GW2B alarm "events" are defined as a one or more alarms separated from previous alarms by more than 30 min. RESULTS: Downloaded data from the biographers identified 240 individual alarms, 75% of which occurred while the subject was sleeping. Of the 240 alarms 68% were audible on the videotape. Subjects awoke to 29% of individual alarms and to 66% of alarm events. Subjects 4-6 years old responded to 17% of alarms, 7-11 year olds responded to 20% of alarms, adolescents responded to 53% of alarms, and parents responded to 37% of alarms. Subjects awoke to 40% of the first alarm during the night, but to only 28% of subsequent alarms. There were 11 events when the glucose was confirmed to be < or = 70 mg/dL, and in each case the subject was awoken. Fifty-five percent of alarm events occurred when there was no hypo- or hyperglycemia confirmed by a reference glucose value. CONCLUSIONS: Subjects awoke to 29% of individual alarms and to 66% of alarm events. Subjects awoke during all alarm events when hypoglycemia was confirmed, but there was a high incidence of false alarms.

BioSTORM: a system for automated surveillance of diverse data sources.

Heightened concerns about bioterrorism are forcing changes to the traditional biosurveillance-model. Public health departments are under pressure to follow multiple, non-specific, pre-diagnostic indicators, often drawn from many data sources. As a result, there is a need for biosurveillance systems that can use a variety of analysis techniques to rapidly integrate and process multiple diverse data feeds using a variety of problem solving techniques to give timely analysis. To meet these requirements, we are developing a new system called BioSTORM (Biological Spatio-Temporal Outbreak Reasoning Module).

Knowledge-based bioterrorism surveillance.

An epidemic resulting from an act of bioterrorism could be catastrophic. However, if an epidemic can be detected and characterized early on, prompt public health intervention may mitigate its impact. Current surveillance approaches do not perform well in terms of rapid epidemic detection or epidemic monitoring. One reason for this shortcoming is their failure to bring existing knowledge and data to bear on the problem in a coherent manner. Knowledge-based methods can integrate surveillance data and knowledge, and allow for careful evaluation of problem-solving methods. This paper presents an argument for knowledge-based surveillance, describes a prototype of BioSTORM, a system for real-time epidemic surveillance, and shows an initial evaluation of this system applied to a simulated epidemic from a bioterrorism attack.

Levels of polybrominated diphenyl ether (PBDE) flame retardants in animals representing different trophic levels of the North Sea food Web.

The levels of individual PBDE congeners were investigated in the invertebrate species whelk (Buccinum undatum), seastar (Asterias rubens), and hermit crab (Pagurus bernhardus), the gadoid fish species whiting (Merlangius merlangus) and cod (Gadus morhua), and the marine mammal species harbor seal (Phoca vitulina) and harbor porpoise (Phocoena phocoena). These species are all important representatives of different trophic levels of the North Sea food web. All six major PBDE congeners detected (BDEs 28, 47, 99, 100, 153, and 154) are most prevalent in the commercial Penta-BDE formulation. There is no evidence for the occurrence of the Octa-BDE formulation in the North Sea food web, since its dominant congener, BDE183, was never detected. BDE209, the main congener (> 97%) in the Deca-BDE formulation, was detected only in a minority of the samples and always in concentrations around the limit of detection. Since BDE209 is often the major BDE congener in sediments from the area, the main reason for its low concentrations in biota from the North Sea seems to be a relatively low bioaccumulation potential. This can either be due to a low uptake rate of the very large molecule or a relatively rapid excretion after biotransformation. Since all invertebrates investigated are sentinel species, they are highly representative for the area of capture. The highest lipid-normalized concentrations of PBDEs in the invertebrates occurred near the mouth of the river Tees at the East coast of the UK. The geographical distribution of the PBDEs can be explained by the residual currents in the area. The direction of these currents differs between the summer and the winter season as a result of the presence or absence of vertical summer stratification of the deeper waters north of the Dogger Bank. Summer stratification results in the development of a density-driven bottom water current formed after the onset of vertical stratification of the water column in May leaving the UK coast near Flamborough Head toward the Dogger Bank. In winter, the residual currents run in a more southerly direction and follow the UK coastline. The distribution pattern of the PCBs and p,p'-DDE in the invertebrates was entirely different from that of the PBDEs, which could be expected, since the use of these organochlorines in western Europe peaked in the 1960s and 1970s but has been forbidden more than two decades ago, whereas the production and use of the penta-BDE formulation is of a more recent origin. The higher trophic levels of the North Sea food web were represented by the predatory gadoid fish species whiting and cod and the marine mammal species harbor seal and harbor porpoise. The lipid-normalized levels of the six major PBDE congeners in fish were similar to the levels in the invertebrates, but a biomagnification step in concentrations of generally more than an order of magnitude occurred from gadoid fish to marine mammals. Based on the limited number of samples, no differences could be observed between harbor seal and harbor porpoise. In summary, the results in three species of sentinel invertebrates from a network of stations covering a major part of the North Sea basin showed that the estuary of the river Tees at the UK East coast is a major source for tri- to hexa-PBDEs. Throughout the food-chain, the most marked increase in (lipid-normalized) levels of all six PBDE congeners occurred from predatory (gadoid) fish to marine mammals, agreeing with the transition from gill-breathing to lung-breathing animals. This has serious consequences for the route of elimination of POPs, since their elimination from the blood into the ambient seawater via the gill-membrane is no longer possible.

A student-initiated interactive course as a model for teaching reproductive health.

OBJECTIVE: Medical students at Stanford University established an elective lecture series in reproductive health to teach 10 women's health competencies to preclinical medical students. In the second year, student organizers implemented interactive components to improve the number of competencies students learned. STUDY DESIGN: We surveyed students from the first two years this series was offered to assess their preferred modes of learning and the number of competencies students perceived they had gained. Students were asked to self-assess their learning of key reproductive health competencies taught in the course. RESULTS: We identified 4 factors associated with statistically significant improvements in the number of competencies students learned, according to self-assessment. CONCLUSION: Students who felt they learned more competencies agreed that they were active participants in the course, that their preferred style of learning was matched by the course, and that they had received academic credit for the course. Furthermore, students who attended an innovative reproductive health fair organized by students participating in the course perceived that they had learned significantly more competencies. We expect these self-assessed improvements to correlate with increased demonstration of the competencies as students progress to the clinical level.