Gene therapy for obstetric conditions

The first clinical trials of gene therapy in the 1990s offered the promise of a new paradigm for the treatment of genetic diseases. Over the decades that followed the challenges and setbacks which gene therapy faced often overshadowed any successes. Despite this, recent years have seen cause for renewed optimism. In 2012 Glybera™, an adeno-associated viral vector expressing lipoprotein lipase, became the first gene therapy product to receive marketing authorisation in Europe, with a licence to treat familial lipoprotein lipase deficiency. This followed the earlier licensing in China of two gene therapies: Gendicine™ for head and neck squamous cell carcinoma and Oncorine™ for late-stage nasopharyngeal cancer. By this stage over 1800 clinical trials had been, or were being, conducted worldwide, and the therapeutic targets had expanded far beyond purely genetic disorders. So far no trials of gene therapy have been carried out in pregnancy, but an increasing understanding of the molecular mechanisms underlying obstetric diseases means that it is likely to have a role to play in the future. This review will discuss how gene therapy works, its potential application in obstetric conditions and the risks and limitations associated with its use in this setting. It will also address the ethical and regulatory issues that will be faced by any potential clinical trial of gene therapy during pregnancy

Longitudinal Observation of Treatment Patterns and Outcomes for Patients with Fibromyalgia: 12‐Month Findings from the REFLECTIONS Study

Objective To describe 12‐month treatment patterns and outcomes for patients starting a new medication for fibromyalgia in routine clinical practice. Design and Outcome Measures Data from 1,700 patients were collected at baseline and 1, 3, 6, and 12 months. Repeated measures and P oisson regression models controlling for demographic, clinical, and baseline outcomes were used to assess changes in health outcomes ( B rief P ain I nventory severity and interference, S heehan D isability S cale, F ibromyalgia I mpact Q uestionnaire), satisfaction, and economic factors for patients who initiated on pregabalin (214, 12.6%), duloxetine (264, 15.5%), milnacipran (134, 7.9%), or tricyclic antidepressants (66, 3.9%). Sensitivity analyses were run using propensity‐matched cohorts. Results Patients started on 145 unique drugs for fibromyalgia, and over 75% of patients took two or more medications concurrently for fibromyalgia at each time point assessed. Overall, patients showed improvement on the four health outcomes, with few differences across medication cohorts. At baseline, patients reported annual averages of 20.3 visits for outpatient care, 27.7 missed days of work, and 32.6 days of care by an unpaid caregiver. The duloxetine and milnacipran (vs pregabalin or tricyclic antidepressant) cohorts had fewer outpatient visits during the 12‐month study. Patients reported satisfaction with overall treatment and their fibromyalgia medication (46.0% and 42.8%, respectively). Conclusions In this real‐world setting, patients with fibromyalgia reported modest improvements, high resource, and medication use, and were satisfied with the care they received. Cohort differences were difficult to discern because of the high rates of drug discontinuation and concomitant medication use over the 12‐month study period.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/100168/1/pme12168.pd

Water Restrictions and Water Use: An Analysis of Water Restriction Effects in Norfolk County

This paper aims to determine what effect water restrictions in Norfolk County, Massachusetts have on residential water usage. Using data from the Massachusetts Department of Environmental Protection, this paper analyzes subsequent municipal water usage within and across towns after water restrictions, both mandatory and voluntary, are implemented. Accounting for town fixed effects, the results indicate that for some towns, water restrictions do in fact have a significant impact on decreasing water usage

Vegetation response to invasive Tamarix control in southwestern U.S. rivers: a collaborative study including 416 sites

Most studies assessing vegetation response following control of invasive Tamarix trees along southwestern U.S. rivers have been small in scale (e.g., river reach), or at a regional scale but with poor spatial-temporal replication, and most have not included testing the effects of a now widely used biological control. We monitored plant composition following Tamarix control along hydrologic, soil, and climatic gradients in 244 treated and 172 reference sites across six U.S. states. This represents the largest comprehensive assessment to date on the vegetation response to the four most common Tamarix control treatments. Biocontrol by a defoliating beetle (treatment 1) reduced the abundance of Tamarix less than active removal by mechanically using hand and chain-saws (2), heavy machinery (3) or burning (4). Tamarix abundance also decreased with lower temperatures, higher precipitation, and follow-up treatments for Tamarix resprouting. Native cover generally increased over time in active Tamarix removal sites, however, the increases observed were small and was not consistently increased by active revegetation. Overall, native cover was correlated to permanent stream flow, lower grazing pressure, lower soil salinity and temperatures, and higher precipitation. Species diversity also increased where Tamarix was removed. However, Tamarix treatments, especially those generating the highest disturbance (burning and heavy machinery), also often promoted secondary invasions of exotic forbs. The abundance of hydrophytic species was much lower in treated than in reference sites, suggesting that management of southwestern U.S. rivers has focused too much on weed control, overlooking restoration of fluvial processes that provide habitat for hydrophytic and floodplain vegetation. These results can help inform future management of Tamarix-infested rivers to restore hydrogeomorphic processes, increase native biodiversity and reduce abundance of noxious species

Individual Differences in Influenceability and Anti-Influenceability

Using a dispositional strategy, two studies investigated individual differences in three types of influenceability and two types of anti-influenceability. Study 1 replicated the majority of consistent results found in Robinson and Ickes (2016) of different personality traits being predictive of different forms of influenceability. Individuals who reported more instances of self-jeopardizing influenceability tended to (1) have an external locus of control, (2) be more other-directed, (3) have a weaker sense of self, and (4) be more prone to dispositional emotional contagion. Individuals who were prone to susceptibility to peer pressure tended to be (1) low in social desirability, (2) more other-directed, and (3) high self-monitors. Individuals who reported more instances of emotional contagion behaviors were prone to be (1) higher in dispositional emotional contagion, (2) lower in social desirability, and (3) female. Study 2 investigated dispositional determinants of two types of anti-influenceability: independence and self-jeopardizing anti-influenceability. Individuals who reported more instances of independence tended to be (1) higher in psychological reactance, (2) lower in social desirability, and (3) male. Individuals who reported higher rates of self-jeopardizing anti-influenceability were more likely to (1) reject authority, (2) be prone to psychological reactance, (3) be male, and possibly be higher in authoritarianism in certain circumstances. The author argues that extreme forms of influenceability and anti-influenceability can result in negative outcomes for the individuals who possess these qualities, and that dispositional studies can contribute to identifying these individuals. Future research can build upon the framework identified in the current studies, with the goal of intervening prior to negative long-term consequences

Maternal serum retinol and B-carotene concentrations and neonatal bone mineralisation: Results from the Southampton Women's Survey cohort

Background: studies in older adults and animals have suggested contrasting relations between bone health and different vitamin A compounds. To our knowledge, the associations between maternal vitamin A status and offspring bone development have not previously been elucidated.Objective: we examined the associations between maternal serum retinol and ?-carotene concentrations during late pregnancy and offspring bone mineralization assessed at birth with the use of dual-energy X-ray absorptiometry.Design: in the Southampton Women’s Survey mother-offspring birth cohort, maternal health, lifestyle, and diet were assessed prepregnancy and at 11 and 34 wk of gestation. In late pregnancy, maternal serum retinol and ?-carotene concentrations were measured. Offspring total body bone mineral density (BMD), bone mineral content (BMC), and bone area (BA) were measured within 2 wk after birth.Results: in total, 520 and 446 mother-offspring pairs had measurements of maternal serum retinol and ?-carotene, respectively. Higher maternal serum retinol in late pregnancy was associated with lower offspring total body BMC (? = ?0.10 SD/SD; 95% CI: ?0.19, ?0.02; P = 0.020) and BA (? = ?0.12 SD/SD; 95% CI: ?0.20, ?0.03; P = 0.009) but not BMD. Conversely, higher maternal serum ?-carotene concentrations in late pregnancy were associated with greater total body BMC (? = 0.12 SD/SD; 95% CI: 0.02, 0.21; P = 0.016) and BA (? = 0.12 SD/SD; 95% CI: 0.03, 0.22; P = 0.010) but not BMD.Conclusions: maternal serum retinol and ?-carotene concentrations had differing associations with offspring bone size and growth at birth: retinol was negatively associated with these measurements, whereas ?-carotene was positively associated. These findings highlight the need for further investigation of the effects of maternal retinol and carotenoid status on offspring bone developmen

Nitrogen isotopic evidence for deglacial changes in nutrient supply in the eastern equatorial Pacific

The Eastern Equatorial Pacific (EEP) is a high nutrient–low chlorophyll region of the ocean. Downcore nitrogen isotope records from the EEP have been previously interpreted as a direct reflection of changes in nutrient consumption. However, the observed changes in sedimentary δ15N since the last glacial maximum have no coherent relationship with export productivity or an inferred variation in the iron‐to‐nitrate ratio of the surface waters. Rather, downcore N isotope records in the EEP strongly resemble changes in the extent of water column denitrification as recorded in nearby sedimentary δ15N records along the western margin of the Americas. This similarity is attributed to the overprinting of the N isotopic composition of nitrate in the EEP through the advection of nitrate westward from the margins in the subsurface. A local nitrogen isotope record of changes in the degree of nutrient consumption is extracted from the bulk sedimentary record by subtracting two different sedimentary δ15N records of denitrification changes from two new EEP δ15N records (TR163‐22 and ODP Site 1240). The denitrification records used are from 1) the Central American margin (ODP Site 1242) and 2) the South American margin (GeoB7139‐2). The degree of consumption in the surface waters declines rapidly from elevated values during the last glacial maximum to a pair of minima around 15 and 11–13 ka, and finally it increases into the Holocene. The derived EEP nitrogen isotope record indicates that the regional peak in export productivity occurred when the supply of nutrients exceeded the apparently high demand. The influx of nutrients during the deglaciation is attributed to the resumption of intense overturning in the Southern Ocean and the release of sequestered CO2 and nutrient‐rich, O2 poor waters from the deep ocean. This has important implications for understanding the glacial‐interglacial scale variation in intermediate water suboxia and water column denitrification

The genomes of two key bumblebee species with primitive eusocial organization

Background: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. Results: We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. Conclusions: These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation