Dolutegravir in pregnant mice is associated with increased rates of fetal defects at therapeutic but not at supratherapeutic levels

BACKGROUND: Dolutegravir (DTG) is a preferred regimen for all people with HIV including pregnant women, but its effects on the fetus are not fully understood. Periconceptional exposure to DTG has been associated with increased rates of neural tube defects (NTDs), although it is unknown whether this is a causal relationship. This has led to uncertainty around the use of DTG in women of reproductive potential. METHODS: Pregnant C57BL/6J mice were randomly allocated to control (water), 1x-DTG (2.5 mg/kg-peak plasma concentration ~3000 ng/ml - therapeutic level), or 5x-DTG (12.5 mg/kg-peak plasma concentration ~12,000 ng/ml - supratherapeutic level), once daily from gestational day 0.5 until sacrifice. DTG was administered with 50 mg/kg tenofovir+33.3 mg/kg emtricitabine. Fetal phenotypes were determined, and maternal and fetal folate levels were quantified by mass-spectrometry. FINDINGS: 352 litters (91 control, 150 1x-DTG, 111 5x-DTG) yielding 2776 fetuses (747 control, 1174 1x-DTG, 855 5x-DTG) were assessed. Litter size and viability rates were similar between groups. Fetal and placenta weights were lower in the 1x-DTG vs. control. Placental weight was higher in the 5x-DTG vs. control. Five NTDs were observed, all in the 1x-DTG group. Fetal defects, including microphthalmia, severe edema, and vascular/bleeding defects were more frequent in the 1x-DTG group. In contrast, defect rates in the 5x-DTG were similar to control. Fetal folate levels were similar between control and 1x-DTG, but were significantly higher in the 5x-DTG group. INTERPRETATION: Our findings support a causal relationship of DTG at therapeutic doses with increased risk for fetal defects, including NTDs at a rate that is similar that reported in the Tsepamo study for women exposed to DTG-based ART from conception. The non-monotonic dose-response relationship between DTG and fetal anomalies could explain the previous lack of fetal toxicity findings from pre-clinical DTG studies. The fetal folate levels suggest that DTG is unlikely to be an inhibitor of folate uptake. FUNDING: This project has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN275201800001I

Use of mixed methods designs in substance research: a methodological necessity in Nigeria

The utility of mixed methods (qualitative and quantitative) is becoming increasingly accepted in health sciences, but substance studies are yet to substantially benefit from such utilities. While there is a growing number of mixed methods alcohol articles concerning developed countries, developing nations are yet to embrace this method. In the Nigerian context, the importance of mixed methods research is yet to be acknowledged. This article therefore, draws on alcohol studies to argue that mixed methods designs will better equip scholars to understand, explore, describe and explain why alcohol consumption and its related problems are increasing in Nigeria. It argues that as motives for consuming alcohol in contemporary Nigeria are multiple, complex and evolving, mixed method approaches that provide multiple pathways for proffering solutions to problems should be embraced

Search for Exotic Strange Quark Matter in High Energy Nuclear Reactions

We report on a search for metastable positively and negatively charged states of strange quark matter in Au+Pb reactions at 11.6 A GeV/c in experiment E864. We have sampled approximately six billion 10% most central Au+Pb interactions and have observed no strangelet states (baryon number A < 100 droplets of strange quark matter). We thus set upper limits on the production of these exotic states at the level of 1-6 x 10^{-8} per central collision. These limits are the best and most model independent for this colliding system. We discuss the implications of our results on strangelet production mechanisms, and also on the stability question of strange quark matter.Comment: 21 pages, 9 figures, to be published in Nuclear Physics A (Carl Dover memorial edition

The role of pandemic planning in the management of COVID-19 in England from an infection prevention and control perspective: results of a national survey.

ObjectivesThis national survey aimed to explore how existing pandemic preparedness plans (PPP) accounted for the demands placed on infection prevention and control (IPC) services in acute and community settings in England during the first wave of the COVID-19 pandemic.Study designThis was a cross-sectional survey of IPC leaders working within National Health Service Trusts or clinical commissioning groups/integrated care systems in England.MethodsThe survey questions related to organisational COVID-19 preparedness pre-pandemic and the response provided during the first wave of the pandemic (January to July 2020). The survey ran from September to November 2021, and participation was voluntary.ResultsIn total, 50 organisations responded. Seventy-one percent (n = 34/48) reported having a current PPP in December 2019, with 81% (n = 21/26) indicating their plan was updated within the previous 3 years. Around half of IPC teams were involved in previous testing of these plans via internal and multi-agency tabletop exercises. Successful aspects of pandemic planning were identified as command structures, clear channels of communication, COVID-19 testing, and patient pathways. Key deficiencies were lack of personal protective equipment, difficulties with fit testing, keeping up to date with guidance, and insufficient staffing.ConclusionsPandemic plans need to consider the capability and capacity of IPC services to ensure they can contribute their critical knowledge and expertise to the pandemic response. This survey provides a detailed evaluation of how IPC services were impacted during the first wave of the pandemic and identifies key areas, which need to be included in future PPP to better manage the impact on IPC services

An opinion paper: emphasis on white muscle development and growth to improve farmed fish flesh quality

Due to rapid depletion of wild stocks, the necessity to cultivate fish is eminent. Current fish farming practices seek to improve flesh quality. The notion that white muscles are the main target of the fishing industry is emphasized. A novel approach is suggested based on the development of white muscles in wild fish from eggs to adults. A compilation of facts about white muscle structure, function and ontogeny is followed by an account of the changes in swimming behaviour and performance related to the use of white muscle during growth from larva to adult. Ecological data narrate early swimming performance with white muscle development and growth, unveiling some of the important natural selection factors eliminating weak swimmers and poor growers from the breeding stock. A comparison between fish culture practise and natural conditions reveals fundamental differences. New approaches following wild breeding processes promise several important advantages regarding the quality of white muscle

Formation of Supermassive Black Holes

Evidence shows that massive black holes reside in most local galaxies. Studies have also established a number of relations between the MBH mass and properties of the host galaxy such as bulge mass and velocity dispersion. These results suggest that central MBHs, while much less massive than the host (~ 0.1%), are linked to the evolution of galactic structure. In hierarchical cosmologies, a single big galaxy today can be traced back to the stage when it was split up in hundreds of smaller components. Did MBH seeds form with the same efficiency in small proto-galaxies, or did their formation had to await the buildup of substantial galaxies with deeper potential wells? I briefly review here some of the physical processes that are conducive to the evolution of the massive black hole population. I will discuss black hole formation processes for `seed' black holes that are likely to place at early cosmic epochs, and possible observational tests of these scenarios.Comment: To appear in The Astronomy and Astrophysics Review. The final publication is available at http://www.springerlink.co

Reimagining pheromone signalling in the model nematode Caenorhabditis elegans

Caenorhabditis elegans is an important, widely used developmental and genetic model. A pheromone has long been known to cause juvenile developmental arrest in C. elegans, a phenomenon that is common among nematodes more widely. Many novel effects of this pheromone are now being discovered—most recently, that exogenous supply of this pheromone controls adult worms reproduction. Here, we suggest that to properly understand and interpret these phenomena, C. elegans natural ecology must be considered, about which rather little is known. With this perspective, we suggest that C. elegans pheromone signalling evolves very locally, such that there are different dialects of pheromone signalling among ecological communities and among kin groups, and we also argue that pheromone signals may also evolve to be manipulative and dishonest. New approaches must be undertaken to study these phenomena in C. elegans. While model systems have been tremendously important tools in modern biological research, taking account of their natural history is necessary, and key, to properly understand and interpret laboratory-based discoveries.understand and interpret laboratory-based discoveries

Rose Bengal sensitized bilayered photoanode of nano-crystalline TiO–CeO for dye-sensitized solar cell application

There are two traditional ways to read Kant’s claim that every event necessarily has a cause: the weaker every-event some-cause (WCP) and the stronger same-cause same-effect (SCP) causal principles. The debate on whether and where he subscribes to the SCP has focused on the Analogies in the Critique of Pure Reason (Guyer, Allison, and Watkins) and on the Metaphysical Foundations of Natural Science (Friedman). By analysing the arguments and conclusions of both the Analogies and the Postulates, as well as the two Latin principles non datur casus and non datur fatum that summarise their results, I will argue that the SCP is actually demonstrated in the Postulates section of the First Critique

A study of lymph node ratio in stage IV colorectal cancer

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background: The finding of metastasis in colorectal cancer, stage IV disease, has a major impact on prognosis and treatment strategy. Known important factors include the extent of the metastasis and the patients &apos; performance status. The lymph node factors are of known importance in earlier cancer stages but less described in metastatic disease. The aim of the study was to evaluate lymph node status and ratio as prognostic markers in stage IV colorectal cancer. Methods: The study was retrospective and assessing all patients operated, with bowel resection, for an initial stage IV colorectal cancer during 1999–2003 (n = 136). Basic demographic data as well as given treatment was assessed. The Lymph node ratio (LNR), the quota between the number of lymph node metastasis and assessed lymph nodes, was calculated. LNR groups were created by ratio thirds, 3 equally sized groups. The analysis was made by LNR group and by eligibility for chemotherapy with cancer specific survival as outcome parameter. Results: The median survival (CSS) for the entire group was 431 days with great variability. For the patients eligible for chemotherapy it ranged from 791 days in LNR-group 1 to 433 days for th