Standalone portable xenon-129 hyperpolariser for multicentre clinical magnetic resonance imaging of the lungs

ObjectivesDesign and build a portable xenon-129 (¹²⁹Xe) hyperpolariser for clinically accessible ¹²⁹Xe lung MRI.MethodsThe polariser system consists of six main functional components: (i) a laser diode array and optics; (ii) a B₀ coil assembly; (iii) an oven containing an optical cell; (iv) NMR and optical spectrometers; (v) a gas-handling manifold; and (vi) a cryostat within a permanent magnet. All components run without external utilities such as compressed air or three-phase electricity, and require just three mains sockets for operation. The system can be manually transported in a lightweight van and rapidly installed on a small estates footprint in a hospital setting.ResultsThe polariser routinely provides polarised ¹²⁹Xe for routine clinical lung MRI. To test the concept of portability and rapid deployment, it was transported 200 km, installed at a hospital with no previous experience with the technology and ¹²⁹Xe MR images of a diagnostic quality were acquired the day after system transport and installation.ConclusionThis portable ¹²⁹Xe hyperpolariser system could form the basis of a cost-effective platform for wider clinical dissemination and multicentre evaluation of ¹²⁹Xe lung MR imaging.Advances in knowledgeOur work successfully demonstrates the feasibility of multicentre clinical ¹²⁹Xe MRI with a portable hyperpolariser system.     

ADAM12s in maternal serum as a potential marker of pre-eclampsia

OBJECTIVE: To examine whether maternal serum ADAM12s, a potential first- and second-trimester marker of fetal aneuploidy and fetal growth, had altered concentrations in the first or second trimester of pregnancies subsequently developing pre-eclampsia. METHODS: ADAM12s was measured by a time-resolved fluoroimmunoassay developed by PerkinElmer Life Science. Maternal serum samples from women taking part in early first-trimester aneuploidy screening in whom the pregnancy resulted in pre-eclampsia (64) were identified from a cohort of 4,390 singleton pregnancies in which uterine artery Doppler mean Pulsatility Index (PI) had been measured at 22-24 weeks. From amongst those cases delivering a normal term infant with birth weight greater than the 10th centile for gestational age 240 cases were selected as gestational age-matched controls. A second study group consisting of maternal serum taken at 22-24 weeks at the time of uterine artery Doppler in a group of 12 women developing pre-eclampsia were compared with 86 matched controls from a previously studied cohort of 24 cases and 144 controls. Serum ADAM12s concentrations were converted to multiple of the median (MoM) to take account of gestational age variation. RESULTS: First-trimester maternal serum ADAM12s levels in women who developed pre-eclampsia were reduced with a median MoM of 0.71 which was further reduced in those delivering prior to 35 weeks (0.50). At the 5th centile of normal (0.48 MoM) ADAM12s identified 27% of cases with pre-eclampsia and 47% of those with early pre-eclampsia. Combining ADAM12s with PAPP-A from a previous study only resulted in a further 1% increase in detection of all women developing pre-eclampsia. However combining ADAM12s with mean PI increased the detection rate to 66%. In the second trimester at 22-24 weeks the maternal serum ADAM12s levels were increased in those women developing pre-eclampsia compared to controls (709 vs 486 ug/L, p = 0.045). CONCLUSION: ADAM12s in addition to being a potential marker of aneuploidy may also be a marker of pre-eclampsia. Further studies are required to see if this can improve on the clinical discrimination already provided by PAPP-A in the early first trimester.     

Exploring how pregnant women in a remote northern community select a delivery location

ObjectiveTo explore the perspectives and preferences of pregnant women receiving prenatal care in a rural community regarding delivery location.DesignExploratory qualitative research project.SettingThe La Ronge Medical Clinic in northern Saskatchewan.ParticipantsPregnant women of any parity aged 18 years or older who attended the clinic for prenatal care from March 1, 2018, to March 31, 2019, were invited to participate. The closest obstetric and surgical services are 240 km away.MethodsThis project was undertaken using semistructured interviews. The interviews were audiorecorded, transcribed, and analyzed using an inductive thematic analysis, taking into consideration both saturation and analyst triangulation. The investigators and researchers on this project were family medicine residents and faculty in a remote medical clinic.Main findingsThe factors that played a substantial role in influencing the patients’ decisions regarding delivery location included access to medical services, proximity to home community, perceptions of medical care providers, and some unique features of local hospitals. The participants largely believed they maintained their autonomy in selecting their preferred delivery location while seeking input from their prenatal care providers and families.ConclusionPregnant women in this rural community consider many factors when deciding on their delivery location. These findings can be taken into consideration by physicians when discussing with their rural patients the risks and benefits of delivery in both rural and urban centres. Barriers to local delivery should be addressed, while maintaining a woman’s autonomy to choose where she gives birth.     

Exploring the Utility of Recombinant Snake Venom Serine Protease Toxins as Immunogens for Generating Experimental Snakebite Antivenoms

Snakebite is a neglected tropical disease that causes high rates of global mortality and morbidity. Although snakebite can cause a variety of pathologies in victims, haemotoxic effects are particularly common and are typically characterised by haemorrhage and/or venom-induced consumption coagulopathy. Despite polyclonal antibody-based antivenoms being the mainstay life-saving therapy for snakebite, they are associated with limited cross-snake species efficacy, as there is often extensive toxin variation between snake venoms, including those used as immunogens for antivenom production. This restricts the therapeutic utility of any antivenom to certain geographical regions. In this study, we explored the feasibility of using recombinantly expressed toxins as immunogens to stimulate focused, pathology-specific, antibodies in order to broadly counteract specific toxins associated with snakebite envenoming. Three snake venom serine proteases (SVSP) toxins, sourced from geographically diverse and medically important viper snake venoms, were successfully expressed in HEK293F mammalian cells and used for murine immunisation. Analyses of the resulting antibody responses revealed that ancrod and RVV-V stimulated the strongest immune responses, and that experimental antivenoms directed against these recombinant SVSP toxins, and a mixture of the three different immunogens, extensively recognised and exhibited immunological binding towards a variety of native snake venoms. While the experimental antivenoms showed some reduction in abnormal clotting parameters stimulated by the toxin immunogens and crude venom, specifically reducing the depletion of fibrinogen levels and prolongation of prothrombin times, fibrinogen degradation experiments revealed that they broadly protected against venom- and toxin-induced fibrinogenolytic functional activities. Overall, our findings further strengthen the case for the use of recombinant venom toxins as supplemental immunogens to stimulate focused and desirable antibody responses capable of neutralising venom-induced pathological effects, and therefore potentially circumventing some of the limitations associated with current snakebite therapies.     

The impact of depression on mothers’ neural processing of their adolescents’ affective behavior

Depression affects neural processing of emotional stimuli and could, therefore, impact parent–child interactions. However, the neural processes with which mothers with depression process their adolescents’ affective interpersonal signals and how this relates to mothers’ parenting behavior are poorly understood. Mothers with and without depression (N = 64 and N = 51, respectively; M_age = 40 years) from low-income families completed an interaction task with their adolescents (M_age = 12.8 years), which was coded for both individuals’ aggressive, dysphoric, positive and neutral affective behavior. While undergoing fMRI, mothers viewed video clips from this task of affective behavior from their own and an unfamiliar adolescent. Relative to non-depressed mothers, those with depression showed more aggressive and less positive affective behavior during the interaction task and more activation in the bilateral insula, superior temporal gyrus and striatum but less in the lateral prefrontal cortex while viewing aggressive and neutral affect. Findings were comparable for own and unfamiliar adolescents’ affect. Heightened limbic, striatal and sensory responses were associated with more aggressive and dysphoric parenting behavior during the interactions, while reduced lateral prefrontal activation was associated with less positive parenting behavior. These results highlight the importance of depressed mothers’ affective information processing for understanding mothers’ behavior during interactions with their adolescents.     

Aerobic exercise elicits clinical adaptations in myotonic dystrophy type 1 patients independently of pathophysiological changes

BackgroundMyotonic dystrophy type 1 (DM1) is a complex life-limiting neuromuscular disorder characterized by severe skeletal muscle atrophy, weakness, and cardiorespiratory defects. Exercised DM1 mice exhibit numerous physiological benefits that are underpinned by reduced CUG foci and improved alternative splicing. However, the efficacy of physical activity in patients is unknown.MethodsEleven genetically diagnosed DM1 patients were recruited to examine the extent to which 12 weeks of cycling can recuperate clinical and physiological metrics. Furthermore, we studied the underlying molecular mechanisms through which exercise elicits benefits in skeletal muscle of DM1 patients.RESULTSDM1 was associated with impaired muscle function, fitness, and lung capacity. Cycling evoked several clinical, physical, and metabolic advantages in DM1 patients. We highlight that exercise-induced molecular and cellular alterations in patients do not conform with previously published data in murine models and propose a significant role of mitochondrial function in DM1 pathology. Finally, we discovered a subset of small nucleolar RNAs (snoRNAs) that correlated to indicators of disease severity.ConclusionWith no available cures, our data support the efficacy of exercise as a primary intervention to partially mitigate the clinical progression of DM1. Additionally, we provide evidence for the involvement of snoRNAs and other noncoding RNAs in DM1 pathophysiology.Trial registrationThis trial was approved by the HiREB committee (no. 7901) and registered under ClinicalTrials.gov ({"type":"clinical-trial","attrs":{"text":"NCT04187482","term_id":"NCT04187482"}}NCT04187482).FundingNeil and Leanne Petroff. Canadian Institutes of Health Research Foundation (no. 143325).