Reduced cognitive deficits after FLASH irradiation of whole mouse brain are associated with less hippocampal dendritic spine loss and neuroinflammation

Aim To evaluate the impact of ultra-rapid FLASH mouse whole brain irradiation on hippocampal dendritic spines and neuroinflammation, factors associated with cognitive impairment after brain irradiation. Methods We administered 30 Gy whole brain irradiation to C57BL6/J mice in sub-second (FLASH) vs. 240 s conventional delivery time keeping all other parameters constant, using a custom configured clinical linac. Ten weeks post-irradiation, we evaluated spatial and non-spatial object recognition using novel object location and object recognition testing. We measured dendritic spine density by tracing Golgi-stained hippocampal neurons and evaluated neuroinflammation by CD68 immunostaining, a marker of activated microglia, and expression of 10 pro-inflammatory cytokines using a multiplex immunoassay. Results At ten weeks post-irradiation, compared to unirradiated controls, conventional delivery time irradiation significantly impaired novel object location and recognition tasks whereas the same dose given in FLASH delivery did not. Conventional delivery time, but not FLASH, was associated with significant loss of dendritic spine density in hippocampal apical dendrites, with a similar non-significant trend in basal dendrites. Conventional delivery time was associated with significantly increased CD68-positive microglia compared to controls whereas FLASH was not. Conventional delivery time was associated with significant increases in 5 of 10 pro-inflammatory cytokines in the hippocampus (and non-significant increases in another 3), whereas FLASH was associated with smaller increases in only 3. Conclusion Reduced cognitive impairment and associated neurodegeneration were observed with FLASH compared to conventional delivery time irradiation, potentially through decreased induction of neuroinflammation, suggesting a promising approach to increasing therapeutic index in radiation therapy of brain tumors

A mixed-methods study of maternal health care utilisation in six referral hospitals in four sub-Saharan African countries before and during the COVID-19 pandemic

Introduction In sub-Saharan Africa, referral hospitals are important sources of key maternal health services, especially during a crisis such as the COVID-19 pandemic. This study prospectively assessed the effect of the COVID-19 pandemic on maternal health service utilisation in six large referral hospitals in Guinea, Nigeria, Tanzania and Uganda during the first year of the pandemic. Methods Mixed-methods design combining three data sources: (1) quantitative data based on routine antenatal, childbirth and postnatal care data collected March 2019–February 2021, (2) qualitative data from recurring rounds of semi-structured interviews conducted July 2020–February 2021 with 22 maternity skilled heath personnel exploring their perceptions of service utilisation and (3) timeline data of COVID-19 epidemiology, global, national and hospital-level events. Qualitative and quantitative data were analysed separately, framed based on the timeline analysis and triangulated when reporting. Results Three periods including a first wave, slow period and second wave were identified. Maternal health service utilisation was lower during the pandemic compared with the prepandemic year in all but one selected referral hospital. During the pandemic, service utilisation was particularly lower during the waves and higher or stable during the slow period. Fear of being infected in hospitals, lack of transportation, and even when available, high cost of transportation and service closures were key reasons affecting utilisation during the waves. However, community perception that the pandemic was over or insinuation by Government of the same appeared to stabilise use of referral hospitals for childbirth. Conclusion Utilisation of maternal health services across the continuum of care varied through the different periods and across countries. In crisis situations such as COVID-19, restrictions and service closures need to be implemented with consideration given to alternative options for women to access and use services. Information on measures put in place for safe hospital use should be communicated to women

A mixed-methods study of maternal health care utilisation in six referral hospitals in four sub-Saharan African countries before and during the COVID-19 pandemic.

INTRODUCTION: In sub-Saharan Africa, referral hospitals are important sources of key maternal health services, especially during a crisis such as the COVID-19 pandemic. This study prospectively assessed the effect of the COVID-19 pandemic on maternal health service utilisation in six large referral hospitals in Guinea, Nigeria, Tanzania and Uganda during the first year of the pandemic. METHODS: Mixed-methods design combining three data sources: (1) quantitative data based on routine antenatal, childbirth and postnatal care data collected March 2019-February 2021, (2) qualitative data from recurring rounds of semi-structured interviews conducted July 2020-February 2021 with 22 maternity skilled heath personnel exploring their perceptions of service utilisation and (3) timeline data of COVID-19 epidemiology, global, national and hospital-level events. Qualitative and quantitative data were analysed separately, framed based on the timeline analysis and triangulated when reporting. RESULTS: Three periods including a first wave, slow period and second wave were identified. Maternal health service utilisation was lower during the pandemic compared with the prepandemic year in all but one selected referral hospital. During the pandemic, service utilisation was particularly lower during the waves and higher or stable during the slow period. Fear of being infected in hospitals, lack of transportation, and even when available, high cost of transportation and service closures were key reasons affecting utilisation during the waves. However, community perception that the pandemic was over or insinuation by Government of the same appeared to stabilise use of referral hospitals for childbirth. CONCLUSION: Utilisation of maternal health services across the continuum of care varied through the different periods and across countries. In crisis situations such as COVID-19, restrictions and service closures need to be implemented with consideration given to alternative options for women to access and use services. Information on measures put in place for safe hospital use should be communicated to women

‘We are not going to shut down, because we cannot postpone pregnancy’: a mixed-methods study of the provision of maternal healthcare in six referral maternity wards in four sub-Saharan African countries during the COVID-19 pandemic

Introduction Referral hospitals in sub-Saharan Africa are located in crowded urban areas, which were often epicentres of the COVID-19 pandemic. This paper prospectively assesses how maternal healthcare was provided in six referral hospitals in Guinea, Nigeria, Tanzania and Uganda during the first year of the COVID-19 pandemic. Methods Mixed-methods design using three data sources: (1) qualitative data from repeated rounds of semi-structured interviews conducted between July 2020 and February 2021 with 22 maternity skilled heath personnel (SHP) on perceptions of care provision; (2) quantitative monthly routine data on caesarean section and labour induction from March 2019 to February 2021; and (3) timeline data of COVID-19 epidemiology, national and hospital-level events. Qualitative and quantitative data were analysed separately, framed based on timeline analysis, and triangulated during reporting. Results We identified three periods: first wave, slow period and second wave. The first wave was challenging for SHP given little knowledge about COVID-19, lack of infection prevention and control training, and difficulties reaching workplace. Challenges that persisted beyond the first wave were shortage of personal protective equipment and no rapid testing for women suspected with COVID-19. We noted no change in the proportion of caesarean sections during the pandemic, and a small increase in the proportion of labour inductions. All hospitals arranged isolation areas for women suspected/confirmed with COVID-19 and three hospitals provided care to women with suspected/confirmed COVID-19. Breastfeeding was not discouraged and newborns were not separated from mothers confirmed with COVID-19. Care provision was maintained through dedication of SHP, support from hospital management and remote communication between SHP. Conclusion Routine maternal care provision was maintained in referral hospitals, despite first wave challenges. Referral hospitals and SHP contributed to guideline development for pregnant women suspected/confirmed with COVID-19. Maternity SHP, women and pregnancy must always be included in priority setting when responding to health system shocks, including outbreaks

A global assessment of genetic diversity and distributions of medusozoans

Jellyfish ‘blooms’ are enigmatic due in part to poor understanding of underlying demographic causes and the geographic extent of populations. I aimed to answer two questions regarding the geographic scales of medusozoan genetic diversity: (1) do congeneric individuals found within the same regional boundary correspond with a single evolutionarily significant unit (ESU), and (2) do individuals from different geographic regions correspond to different ESUs? I used DNA barcoding of cytochrome c subunit I (COI) to estimate genetic heterogeneity in 18 medusozoan genera. I quantified the distribution of genetic variation within- and between-regions: either large marine ecosystems (LMEs) or Longhurst biogeographical provinces (Provinces). For both within- and between-region analyses, I estimated K2P pairwise sequence divergence (PSD) and total ESUs present by genus. For between-region analyses, I also estimated pairwise ΦST. Additionally, I correlated genetic and geodesic distances for three genera to establish an estimate of the geographic scales of ESUs as a continuous-scale alternative to the categorical framework explicit in definitions of LMEs and Provinces. I found that of 3,750 and 5,649 within-region comparisons 73-80% constituted a single ESU. Likewise, within-regions, ~51-67% of comparisons revealed ΦST > 0.2. I found that of 3,859 and 5,460 between-region comparisons, ~16% of comparisons have unique ESUs present between regions (LMEs and Provinces, respectively). Genetic and geodesic distances revealed patterns with life-history; meroplanktonic taxa exhibit species-level differences at 1,000 km, whereas the holoplanktonic taxon was genetically homogenous up to 17,500 km. For the majority of regions, individuals found within the same region do not correspond with a single ESU, and few taxa have unique ESUs present within LMEs or Provinces. This greater understanding of the number, distributions, and differences of ESUs allows us to develop better hypotheses about local adaptation and the causes of population dynamics for these taxa. Taxon and life-history have important effects on genetic structuring, and regional differences may elicit different dynamics. This analysis is a step toward an ecological, genetic framework through which I can begin to explore the impacts of global change elicited on, and via, medusozoan dynamics

Amphetamine stimulates movement through thalamocortical glutamate release

The ventrolateral thalamus (VL) is a primary relay point between the basal ganglia and the primary motor cortex (M1). Using dual probe microdialysis and locomotor behavior monitoring, we investigated the contribution of VL input into M1 during amphetamine (AMPH)‐stimulated monoamine release and hyperlocomotion in rats. Tetrodotoxin (10 μM) perfusion into the VL significantly lowered hyperactivity induced by AMPH (1 mg/kg i.p.). This behavioral response corresponded to reduced cortical glutamate and monoamine release. To determine which glutamate receptors the thalamocortical projections acted upon, we perfused either the α‐amino‐3‐(3‐hydroxy‐5‐methyl‐isoxazol‐4‐yl)propanoic acid (AMPA)/kainate receptor antagonist 2,3‐dihydroxy‐6‐nitro‐7‐sulfamoyl‐benzo[f]quinoxaline‐2,3‐dione (NBQX) (10 μM) or the N‐methyl‐D‐aspartic acid (NMDA) receptor antagonist (MK‐801) intracortically followed by systemic AMPH. The results show that AMPA/kainate, and to a lesser extent NMDA receptors, mediated the observed effects. As glutamate–monoamine interactions could possibly occur through local or circuit‐based mechanisms, we isolated and perfused M1 tissue ex vivo to determine the extent of local glutamate–dopamine interactions. Taken together, these results demonstrate that AMPH generates hyperlocomotive states via thalamocortical signaling and that cortical AMPA receptors are an important mediator of these effects. This study utilizes dual probe microdialysis sampling and comprehensive LC‐MS analysis to determine the effects of amphetamine (1 mg/kg i.p.) on thalamocortical neurotransmission. Using pharmacological tools such as local thalamic tetrodotoxin (TTX) perfusion and glutamate antagonist at the cortical level, we demonstrate that thalamocortical glutamate (acting primarily through cortical AMPA receptors) is an essential component in amphetamine‐induced hyperlocomotion. This study utilizes dual probe microdialysis sampling and comprehensive LC‐MS analysis to determine the effects of amphetamine (1 mg/kg i.p.) on thalamocortical neurotransmission. Using pharmacological tools such as local thalamic tetrodotoxin (TTX) perfusion and glutamate antagonist at the cortical level, we demonstrate that thalamocortical glutamate (acting primarily through cortical AMPA receptors) is an essential component in amphetamine‐induced hyperlocomotion.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102157/1/jnc12378.pd

Physical activity and atrial fibrillation: Data from wearable fitness trackers

BackgroundRegular physical activity is an important determinant of cardiovascular health and quality of life. Previous investigations examining the association between exercise and atrial fibrillation (AF) have been limited by self-reported, retrospectively collected activity data.ObjectiveThe purpose of this study was to objectively quantify differences in daily physical activity among individuals with and those without AF using electronic wearable activity trackers.MethodsDaily exercise data were directly obtained from wrist-worn activity trackers (Fitbit, San Francisco, CA) among participants in the Health eHeart (HeH) study. Average daily step count was compared between individuals with and those without AF both before and after adjusting for comorbidities. AF severity was quantified using the Atrial Fibrillation Effect on QualiTy of Life (AFEQT) survey.ResultsAmong 171,284 HeH study participants, 3333 individuals (234 with AF [7%]) submitted activity data. In unadjusted analysis, AF participants ambulated an average of 723 fewer steps per day (95% confidence interval [CI] 292-1154; P = .001) compared to individuals without AF. After adjustment for demographics and comorbid diseases, participants with AF demonstrated 591 fewer steps per day (95% CI 149-1033; P = .009). Among AF patients, AF severity was associated with less physical activity. For each single point decrease in AFEQT score (corresponding to more symptomatic AF), physical activity decreased by a mean 24 steps per day (95% CI 1-46; P = .04).ConclusionObjective, automatically collected step count data demonstrate that individuals with AF engage in significantly less average daily physical activity. In addition, worsening AF symptom severity is associated with reduced daily exercise

A mixed DNA profile controversy revisited

Semaan et al. (J Forensic Res, 2020, 11, 453) discuss a mock case “where eight different individuals [P1 through P8] could not be excluded in a mixed DNA analysis. Even though … expert DNA mixture analysis software was used.” Two of these are the true donors. The LRs reported are incorrect due to the incorrect entry of propositions into LRmix Studio. This forced the software to account for most of the alleles as drop-in, resulting in LRs 60–70 orders of magnitude larger than expected. P1, P2, P4, P5, and P8 can be manually excluded using peak heights. This has relevance when using LRmix which does not use peak heights. We extend the work using the same two reference genotypes who were the true contributors as Semaan et al. (J Forensic Res, 2020, 11, 453). We simulate three two-donor mixtures with peak heights using these two genotypes and analyze using STRmix™. For the simulated 1:1 mixture, one of the non-donors’ LRs supported him being a contributor when no conditioning was used. When considered in combination with any other potential donors (i.e., with conditioning), this non-donor was correctly eliminated. For the 3:1 mixture, all results correctly supported that the non-donors were not contributors. The low-template 4:1 mixture LRs with no conditioning showed support for all eight profiles as donors. However, the results from pair-wise conditioning showed that only the two ground truth donors had LRs supporting that they were contributors to the mixture. We recommend the use of peak heights and conditioning profiles, as this allows better sensitivity and specificity even when the persons share many alleles