Early Window Research Articles

Early life critical windows of metal exposure associated with whole brain white matter changes in children

BACKGROUND AND AIM: The brain white matter (WM) connects gray matter regions into functional networks and is critical for human cognition and behavior. Early-life exposure to metals may impact fetal WM development. Most environmental studies consider single exposures, potentially missing the combined effects of mixtures. In addition, the developmental timing of exposure may be as important as the dose. Little is known about critical windows to nutritive and toxicant metal mixtures on the developing brain. In this study, we investigated associations between early life exposure to a mixture of metals and whole brain white matter in children. METHODS: In preliminary analysis of 30 subjects (6-10 years; 19 females) enrolled in a neuroimaging follow-up visit of the ongoing Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study, we estimated weekly early life exposure (12th gestation week through one year of age) to 10 nutritive and toxicant metals (Mn, Zn, Pb, Mg, Li, Ca, Cr, Cu, Sr, Ba) in deciduous teeth using laser ablation-inductively coupled plasma-mass spectrometry. Whole brain WM microstructure integrity was estimated using fractional anisotropy (FA) from diffusion tensor imaging (DTI) acquired in a 3T Siemens scanner. We used lagged weighted quantile sum (lWQS) regression to estimate a time-varying mixture effect of multiple metals on whole brain FA. Models were adjusted for age. RESULTS:We observe a potential critical window to metal exposure during the postnatal period (0 - 13 weeks) showing positive association with whole brain FA. This association is driven mainly by Li, Mg, and Ca. Negative associations were not detected. CONCLUSIONS:WM microstructure integrity may demonstrate a postnatal critical window to essential elements. These results may help understand the role of exposure timing in driving neurodevelopmental effects, thereby pointing to future optimal, efficient, and properly timed public health interventions. KEYWORDS: Neurodevelopmental outcomes, Mixtures analysis, Mixtures

Pre-implantation alcohol exposure induces lasting sex-specific DNA methylation programming errors in the developing forebrain

BackgroundPrenatal alcohol exposure is recognized for altering DNA methylation profiles of brain cells during development, and to be part of the molecular basis underpinning Fetal Alcohol Spectrum Disorder (FASD) etiology. However, we have negligible information on the effects of alcohol exposure during pre-implantation, the early embryonic window marked with dynamic DNA methylation reprogramming, and on how this may rewire the brain developmental program.ResultsUsing a pre-clinical in vivo mouse model, we show that a binge-like alcohol exposure during pre-implantation at the 8-cell stage leads to surge in morphological brain defects and adverse developmental outcomes during fetal life. Genome-wide DNA methylation analyses of fetal forebrains uncovered sex-specific alterations, including partial loss of DNA methylation maintenance at imprinting control regions, and abnormal de novo DNA methylation profiles in various biological pathways (e.g., neural/brain development).ConclusionThese findings support that alcohol-induced DNA methylation programming deviations during pre-implantation could contribute to the manifestation of neurodevelopmental phenotypes associated with FASD.

Exploring environmental and storage factors affecting sensory, physical and chemical attributes of six southern highbush blueberry cultivars

Blueberry (Vaccinium spp.) is a specialty crop with expanding production and consumption worldwide. Southern Highbush Blueberries (SHB) require few chilling hours and include early-ripening cultivars which can be harvested in an early market window making the crop more profitable for growers in sub-tropical regions. To expand the marketability of the crop, fruit breeders are seeking to meet the current demand for fruit quality. To this end, this study gathered sensory measurements (firmness, sweetness, sourness, blueberry flavor, green flavor and off-flavors), chemical (pH, titratable acidity and soluble solids concentration), and physical attributes (compression force) on six SHB cultivars, in order to understand how fruit quality traits are affected by environmental conditions such as storage duration, year and harvest date. Differences across environmental conditions for all attributes were observed. Indigocrisp and Keecrisp were the firmest cultivars and maintained firmness over time in storage. Additionally, Indigocrisp was the sweetest and had the most blueberry and green flavors among the cultivars. On the other hand, Arcadia was the softest, as measured by sensory and compression force, but varied with year and harvest. Arcadia and Emerald were the least sweet and most sour of the cultivars, and Endura and Patrecia were intermediate for all sensory attributes. In general, sensory descriptors were well explained by instrumental measurements. Variations across seasons and storage were inconsistent among cultivars, but Indigocrisp was the most stable cultivar for the quality traits evaluated. In the end, all fruit quality traits assayed in this study were influenced by environmental conditions throughout the season.

Transcriptomic profiling of Gh/Igf system reveals a prompted tissue-specific differentiation and novel hypoxia responsive genes in gilthead sea bream

A customized PCR-array was used for the simultaneous gene expression of the Gh/Igf system and related markers of muscle growth, and lipid and energy metabolism during early life stages of gilthead sea bream (60–127 days posthatching). Also, transcriptional reprogramming by mild hypoxia was assessed in fingerling fish with different history trajectories on O2 availability during the same time window. In normoxic fish, the expression of almost all the genes in the array varied over time with a prompted liver and muscle tissue-specific differentiation, which also revealed temporal changes in the relative expression of markers of the full gilthead sea bream repertoire of Gh receptors, Igfs and Igf-binding proteins. Results supported a different contribution through development of ghr and igf subtypes on the type of action of GH via systemic or direct effects at the local tissue level. This was extensive to Igfbp1/2/4 and Igfbp3/5/6 clades that clearly evolved through development as hepatic and muscle Igfbp subtypes, respectively. This trade-off is however very plastic to cope changes in the environment, and ghr1 and igfbp1/3/4/5 emerged as hypoxic imprinting genes during critical early developmental windows leading to recognize individuals with different history trajectories of oxygen availability and metabolic capabilities later in life.

A glimpse into the early window of muscle unloading.

A glimpse into the early window of muscle unloading.

Mobile Interventional Stroke Teams Improve Outcomes in the Early Time Window for Large Vessel Occlusion Stroke.

Endovascular thrombectomy for large vessel occlusion stroke is a time-sensitive intervention. The use of a Mobile Interventional Stroke Team (MIST) traveling to Thrombectomy Capable Stroke Centers to perform endovascular thrombectomy has been shown to be significantly faster with improved discharge outcomes, as compared with the drip-and-ship (DS) model. The effect of the MIST model stratified by time of presentation has yet to be studied. We hypothesize that patients who present in the early window (last known well of ≤6 hours) will have better clinical outcomes in the MIST model. The NYC MIST Trial and a prospectively collected stroke database were assessed for patients undergoing endovascular thrombectomy from January 2017 to February 2020. Patients presenting in early and late time windows were analyzed separately. The primary end point was the proportion with a good outcome (modified Rankin Scale score of 0-2) at 90 days. Secondary end points included discharge National Institutes of Health Stroke Scale and modified Rankin Scale. Among 561 cases, 226 patients fit inclusion criteria and were categorized into MIST and DS cohorts. Exclusion criteria included a baseline modified Rankin Scale score of >2, inpatient status, or fluctuating exams. In the early window, 54% (40/74) had a good 90-day outcome in the MIST model, as compared with 28% (24/86) in the DS model (P<0.01). In the late window, outcomes were similar (35% versus 41%; P=0.77). The median National Institutes of Health Stroke Scale at discharge was 5.0 and 12.0 in the early window (P<0.01) and 5.0 and 11.0 in the late window (P=0.11) in the MIST and DS models, respectively. The early window discharge modified Rankin Scale was significantly better in the MIST model (P<0.01) and similar in the late window (P=0.41). The MIST model in the early time window results in better 90-day outcomes compared with the DS model. This may be due to the MIST capturing high-risk fast progressors at an earlier time point. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03048292.

Relationship between weight retention at 6 weeks postpartum and the risk of large-for-gestational age birth in a second pregnancy in China: a retrospective cohort study

ObjectiveWe aimed to investigate the association between weight retention at 6 weeks postpartum after the first pregnancy and large-for-gestational age (LGA) risk in a subsequent pregnancy.Study designA retrospective cohort study.SettingA...

Rapid and stable mobilization of CD8+ T cells by SARS-CoV-2 mRNA vaccine

SARS-CoV-2 spike mRNA vaccines1–3 mediate protection from severe disease as early as ten days after prime vaccination3, when neutralizing antibodies are hardly detectable4–6. Vaccine-induced CD8+ T cells may therefore be the main mediators of protection at this early stage7,8. The details of their induction, comparison to natural infection, and association with other arms of vaccine-induced immunity remain, however, incompletely understood. Here we show on a single-epitope level that a stable and fully functional CD8+ T cell response is vigorously mobilized one week after prime vaccination with bnt162b2, when circulating CD4+ T cells and neutralizing antibodies are still weakly detectable. Boost vaccination induced a robust expansion that generated highly differentiated effector CD8+ T cells; however, neither the functional capacity nor the memory precursor T cell pool was affected. Compared with natural infection, vaccine-induced early memory T cells exhibited similar functional capacities but a different subset distribution. Our results indicate that CD8+ T cells are important effector cells, are expanded in the early protection window after prime vaccination, precede maturation of other effector arms of vaccine-induced immunity and are stably maintained after boost vaccination.

Endovascular Treatment Effect Diminishes With Increasing Thrombus Perviousness: Pooled Data From 7 Trials on Acute Ischemic Stroke.

Thrombus perviousness estimates residual flow along a thrombus in acute ischemic stroke, based on radiological images, and may influence the benefit of endovascular treatment for acute ischemic stroke. We aimed to investigate potential endovascular treatment (EVT) effect modification by thrombus perviousness. We included 443 patients with thin-slice imaging available, out of 1766 patients from the pooled HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke trials) data set of 7 randomized trials on EVT in the early window (most within 8 hours). Control arm patients (n=233) received intravenous alteplase if eligible (212/233; 91%). Intervention arm patients (n=210) received additional EVT (prior alteplase in 178/210; 85%). Perviousness was quantified by thrombus attenuation increase on admission computed tomography angiography compared with noncontrast computed tomography. Multivariable regression analyses were performed including multiplicative interaction terms between thrombus attenuation increase and treatment allocation. In case of significant interaction, subgroup analyses by treatment arm were performed. Our primary outcome was 90-day functional outcome (modified Rankin Scale score), resulting in an adjusted common odds ratio for a one-step shift towards improved outcome. Secondary outcomes were mortality, successful reperfusion (extended Thrombolysis in Cerebral Infarction score, 2B–3), and follow-up infarct volume (in mL). Increased perviousness was associated with improved functional outcome. After adding a multiplicative term of thrombus attenuation increase and treatment allocation, model fit improved significantly (P=0.03), indicating interaction between perviousness and EVT benefit. Control arm patients showed significantly better outcomes with increased perviousness (adjusted common odds ratio, 1.2 [95% CI, 1.1–1.3]). In the EVT arm, no significant association was found (adjusted common odds ratio, 1.0 [95% CI, 0.9–1.1]), and perviousness was not significantly associated with successful reperfusion. Follow-up infarct volume (12% [95% CI, 7.0–17] per 5 Hounsfield units) and chance of mortality (adjusted odds ratio, 0.83 [95% CI, 0.70–0.97]) decreased with higher thrombus attenuation increase in the overall population, without significant treatment interaction. Our study suggests that the benefit of best medical care including alteplase, compared with additional EVT, increases in patients with more pervious thrombi.

Lower Devonian (Pragian–Emsian) land plants from Alexandra: an early window into the diversity of Victorian flora from southeastern Australia

Numerous fragmentary plant fossils are described from the Lower Devonian outcrops near Alexandra, Victoria, southeastern Australia. These outcrops include Eglinton Cutting and two road cuttings on Mount Pleasant and Halls Flat roads previously examined by Isabel Cookson in 1935. Most plants are preserved as iron-stained impressions or coalified compressions lacking internal anatomy in fine-grained sandstone and siltstone. The vast majority of specimens examined proved to be little more than naked fragmentary axes often distributed seemingly randomly; it is the exceptions to these that are examined herein. Most of these specimens belong to the zosterophylls and isolated axes with emergences suggestive of a Gosslingiaceae affinity. Significantly, one specimen attributable to Cooksonia Lang, 1937, renalioid-like sporangia and specimens with isolated sporangia with emergences are recorded for the first time from Victoria. A discussion follows examining the possible reasons for the differences between the Alexandra and Walhalla assemblages, and it is postulated that the differing palaeocurrents indicate the terrestrial sources were from opposite directions. This easterly source for the Walhalla assemblage suggests a subaerial environment may have existed on the eastern side of the Melbourne Zone during the deposition of the Norton Gully Sandstone, earlier than the fluvial deposits of the Middle Devonian Cathedral Beds. Fearghus R. McSweeney FGS [ tidal75@gmail.com ], School of Science, RMIT University, Swanston Street, Melbourne 3000, Australia; Jeff Shimeta [ jeff.shimeta@rmit.edu.au ], School of Science, RMIT University, Swanston Street, Melbourne 3000, Australia; John St. J. S. Buckeridge FGS [ john.buckeridge@rmit.edu.au ], Earth & Oceanic Systems Group, RMIT University, GPO Box 2476.

Current Scope of Online Ophthalmology Education and Curriculum Impact Due to COVID-19

Abstract Objective Abrupt changes in ophthalmology education caused by the COVID-19 pandemic have resulted in novel online curriculum development. The aims of this study were to identify (1) the scope of online curricula implemented both prior to and during the COVID-19 pandemic; (2) perception of educators on these online modalities; and (3) early lessons from online implementation that may guide future curricular planning. Methods Implementation of online curricula was evaluated by using a national online survey of Ophthalmology Directors of Medical Student Education (DMSE) via Qualtrics software. Participants Medical Student Educators of the Association of University Professors of Ophthalmology (AUPO) were surveyed. Results Fifty responses were collected, representing a 64.9% response rate. Prior to the COVID-19 pandemic, 44% of institutions had no online components in their courses, but 78.3% of institutions reported increasing online components in response to the pandemic. Required courses were significantly associated both with having implemented online components before the pandemic and implementing online-only versions of these courses in response to the pandemic. The three most popular modalities used for online teaching were lectures, interactive cases, and problem-based learning, with a median satisfaction of 4.0, 4.32, and 4.35, (out of five) respectively. The least popular modalities used were online teaching of physical exam skills and telemedicine, both with a median satisfaction of 2.5. Median overall educator satisfaction with online teaching was four (out of five). The most common weakness related to online teaching was the lack of effective physical exam skills training. Conclusion Our data demonstrate that most institutions successfully shifted their ophthalmology curriculum to a virtual and online version in response to the COVID-19 pandemic. DMSEs adapted quickly, transitioning in-person clinical courses, and extracurricular activities to online formats. Overall, educator satisfaction with online curricula was high. Integration of online curricula provides the opportunity to enrich institutional curriculums and overcome limitations imposed by decreasing curriculum time. This study reveals an early window into the utilization, strengths, and weaknesses of online ophthalmology education, which can serve as a guiding point to enhance ophthalmology curriculum development.

Surgical Evacuation of Intracerebral Hemorrhage: The Potential Importance of Timing.

Surgical Evacuation of Intracerebral Hemorrhage: The Potential Importance of Timing.

P38-MAPK-mediated translation regulation during early blastocyst development is required for primitive endoderm differentiation in mice

Successful specification of the two mouse blastocyst inner cell mass (ICM) lineages (the primitive endoderm (PrE) and epiblast) is a prerequisite for continued development and requires active fibroblast growth factor 4 (FGF4) signaling. Previously, we identified a role for p38 mitogen-activated protein kinases (p38-MAPKs) during PrE differentiation, but the underlying mechanisms have remained unresolved. Here, we report an early blastocyst window of p38-MAPK activity that is required to regulate ribosome-related gene expression, rRNA precursor processing, polysome formation and protein translation. We show that p38-MAPK inhibition-induced PrE phenotypes can be partially rescued by activating the translational regulator mTOR. However, similar PrE phenotypes associated with extracellular signal-regulated kinase (ERK) pathway inhibition targeting active FGF4 signaling are not affected by mTOR activation. These data indicate a specific role for p38-MAPKs in providing a permissive translational environment during mouse blastocyst PrE differentiation that is distinct from classically reported FGF4-based mechanisms.

A fossil terrestrial fauna from Tobène (Senegal) provides a unique early Pliocene window in western Africa

Early Pliocene hominin evolutionary scenarios proposed to date mostly rely on paleontological investigations from eastern Africa. Filling major geographical gaps in the fossil record could potentially invalidate these scenarios and stimulate development of improved theories. Based on published literature, no Pliocene fossil of continental vertebrates have been discovered in Western Africa and the situation is only slightly better in central and northern Africa. Here, we expand the Pliocene vertebrate continental fossil record to western Africa with the description of the Tobène fauna, a new fossiliferous Neogene locality from Senegal. We describe a diversity of large mammals, including at least ten taxa based on fragmentary remains recovered from alluvial channel deposits. Estimation based on weathering events and biochronology suggests an early Pliocene age. Most of these mammalian taxa were widely distributed over the African continent during the early Pliocene. Possible faunal correlations with eastern African localities call for continent-wide paleontological investigations.***************

A Characterization of the Effects of Minocycline Treatment During Adolescence on Structural, Metabolic, and Oxidative Stress Parameters in a Maternal Immune Stimulation Model of Neurodevelopmental Brain Disorders.

BackgroundMinocycline (MIN) is a tetracycline with antioxidant, anti-inflammatory, and neuroprotective properties. Given the likely involvement of inflammation and oxidative stress (IOS) in schizophrenia, MIN has been proposed as a potential adjuvant treatment in this pathology. We tested an early therapeutic window, during adolescence, as prevention of the schizophrenia-related deficits in the maternal immune stimulation (MIS) animal model.MethodsOn gestational day 15, Poly I:C or vehicle was injected in pregnant Wistar rats. A total 93 male offspring received MIN (30 mg/kg) or saline from postnatal day (PND) 35–49. At PND70, rats were submitted to the prepulse inhibition test. FDG-PET and T2-weighted MRI brain studies were performed at adulthood. IOS markers were evaluated in frozen brain tissue.ResultsMIN treatment did not prevent prepulse inhibition test behavioral deficits in MIS offspring. However, MIN prevented morphometric abnormalities in the third ventricle but not in the hippocampus. Additionally, MIN reduced brain metabolism in cerebellum and increased it in nucleus accumbens. Finally, MIN reduced the expression of iNOS (prefrontal cortex, caudate-putamen) and increased the levels of KEAP1 (prefrontal cortex), HO1 and NQO1 (amygdala, hippocampus), and HO1 (caudate-putamen).ConclusionsMIN treatment during adolescence partially counteracts volumetric abnormalities and IOS deficits in the MIS model, likely via iNOS and Nrf2–ARE pathways, also increasing the expression of cytoprotective enzymes. However, MIN treatment during this peripubertal stage does not prevent sensorimotor gating deficits. Therefore, even though it does not prevent all the MIS-derived abnormalities evaluated, our results suggest the potential utility of early treatment with MIN in other schizophrenia domains.

3D model related to the publication: A fossil terrestrial fauna from Tobène (Senegal) provides a unique early Pliocene window in western Africa

3D model related to the publication: A fossil terrestrial fauna from Tobène (Senegal) provides a unique early Pliocene window in western Africa

The effectiveness of continuous respiratory rate monitoring in predicting hypoxic and pyrexic events: a retrospective cohort study

Respiratory rate (RR) is routinely used to monitor patients with infectious, cardiac and respiratory diseases and is a component of early warning scores used to predict patient deterioration. However, it is often measured visually with considerable bias and inaccuracy. Objectives. Firstly, to compare distribution and accuracy of electronically measured RR (EMRR) and visually measured RR (VMRR). Secondly, to determine whether, and how far in advance, continuous electronic RR monitoring can predict oncoming hypoxic and pyrexic episodes in infectious respiratory disease. Approach. A retrospective cohort study analysing the difference between EMRR and VMRR was conducted using patient data from a large tertiary hospital. Cox proportional hazards models were used to determine whether continuous, EMRR measurements could predict oncoming hypoxic (SpO2 < 92%) and pyrexic (temperature >38 °C) episodes. Main results. Data were gathered from 34 COVID-19 patients, from which a total of 3445 observations of VMRR (independent of Hawthorne effect), peripheral oxygen saturation and temperature and 729 117 observations of EMRR were collected. VMRR had peaks in distribution at 18 and 20 breaths per minute. 70.9% of patients would have had a change of treatment during their admission based on the UK’s National Early Warning System if EMRR was used in place of VMRR. An elevated EMRR was predictive of hypoxic (hazard ratio: 1.8 (1.05–3.07)) and pyrexic (hazard ratio: 9.7 (3.8–25)) episodes over the following 12 h. Significance. Continuous EMRR values are systematically different to VMRR values, and results suggest it is a better indicator of true RR as it has lower kurtosis, higher variance, a lack of peaks at expected values (18 and 20) and it measures a physiological component of breathing directly (abdominal movement). Results suggest EMRR is a strong marker of oncoming hypoxia and is highly predictive of oncoming pyrexic events in the following 12 h. In many diseases, this could provide an early window to escalate care prior to deterioration, potentially preventing morbidity and mortality.

Exploiting an early immunological window of opportunity in COVID-19

Substantial advances in COVID-19 therapeutics have been made over the past year. Highly effective vaccines now exist to reduce a vaccinated person's risk of developing symptomatic disease and progressing to require hospital admission. For patients who are being treated in hospital and require supplemental oxygen, dexamethasone improves survival,1 with an additional benefit from tocilizumab if systemic inflammation is present.2 However, there remains an unmet need for therapeutic interventions that inhibit disease progression in symptomatic people in the community and prevent hospital admission.

Early-life oxytocin attenuates the social deficits induced by caesarean-section delivery in the mouse

The oxytocin (OXT) system has been strongly implicated in the regulation of social behaviour and anxiety, potentially contributing to the aetiology of a wide range of neuropathologies. Birth by Caesarean-section (C-section) results in alterations in microbiota diversity in early-life, alterations in brain development and has recently been associated with long-term social and anxiety-like behaviour deficits. In this study, we assessed whether OXT intervention in the early postnatal period could reverse C-section-mediated effects on behaviour, and physiology in early life and adulthood. Following C-section or per vaginum birth, pups were administered with OXT (0.2 or 2 μg/20 μl; s.c.) or saline daily from postnatal days 1–5. We demonstrate that early postnatal OXT treatment has long-lasting effects reversing many of the effects of C-section on mouse behaviour and physiology. In early-life, high-dose OXT administration attenuated C-section-mediated maternal attachment impairments. In adulthood, low-dose OXT restored social memory deficits, some aspects of anxiety-like behaviour, and improved gastrointestinal transit. Furthermore, as a consequence of OXT intervention in early life, OXT plasma levels were increased in adulthood, and dysregulation of the immune response in C-section animals was attenuated by both doses of OXT treatment. These findings indicate that there is an early developmental window sensitive to manipulations of the OXT system that can prevent lifelong behavioural and physiological impairments associated with mode of birth.

Perinatal exposure to tetracycline contributes to lasting developmental effects on offspring

BackgroundFor more than 30 years, the tetracycline on/off system of inducible gene expression has been leveraged to study disease mechanisms across many research areas, especially that of metabolism and neuroscience. This system requires acute or chronic exposure to tetracycline derivatives, such as doxycycline, to manipulate gene expression in a temporal and tissue-specific manner, with exposure often being restricted to gestational and early developmental windows. Despite evidence showing that early life antibiotic exposure has adverse effects on gut microbiota, metabolism, physiology, immunity and behavior, little is known regarding the lasting impact of doxycycline treatment on relevant outcomes in experimental offspring.ResultsTo examine the hypothesis that early life doxycycline exposure produces effects on offspring growth, behavior, and gut microbiota, we employed the most commonly used method for tetracycline on/off system by administering a low dose of doxycycline (0.5 mg/ml) in the drinking water to C57Bl/6J and C57BL/6J:129S1/SvImJ dams from embryonic day 15.5 to postnatal day 28. Developmental exposure to low dose doxycycline resulted in significant alterations to growth trajectories and body weight in both strains, which persisted beyond cessation of doxycycline exposure. Developmental doxycycline exposure influenced offspring bacterial community assembly in a temporal and sex-specific manner. Further, gut microbiota composition failed to recover by adulthood, suggesting a lasting imprint of developmental antibiotic exposure.ConclusionsOur results demonstrated that early life doxycycline exposure shifts the homeostatic baseline of prior exposed animals that may subsequently impact responses to experimental manipulations. These results highlight the gut microbiota as an important factor to consider in systems requiring methods of chronic antibiotic administration during pregnancy and critical periods of postnatal development.