Recent Population Studies Research Articles

Abstract P416: RAAS Profiling in Human Pre-eclampsia Reveals Distinct Aldosterone Phenotypes

Background: Mechanisms underlying the development of pre-eclampsia in humans are not well-understood. Activation of the RAAS with markedly increased secretion of aldosterone is a key feature of normotensive pregnancy, and thought to be impaired in pre-eclampsia. The purpose of our study was to perform RAAS profiling in pre-eclampsia, where we hypothesized reduced concentrations of aldosterone in serum of patients with pre-eclampsia compared to pregnant patients without pre-eclampsia. Methods: This is a case-control study of 50 patients with pre-eclampsia and 50 gestational age-matched controls. Clinical characteristics (blood pressure, biochemical laboratory values) and blood samples were collected upon enrollment, and maternal and fetal outcomes were collected at delivery. Blood samples were analyzed for angiotensin I, angiotensin II, and aldosterone by LC-MS/MS using RAAS-Triple A. All patients have been recruited, and preliminary data are available for the cases. Results: The mean gestational age of pre-eclampsia cases was 27.9 + 6.2 weeks. RAAS profiling revealed two distinct subpopulations, where 35 patients had concentrations of aldosterone in serum that were characteristically low for pre-eclampsia: below 204 pmol/L, with median and interquartile range (IQR) of 120.0 and 35.0 – 132.2 pmol/L, and an aldosterone to angiotensin II ratio (AA2-R) of 1.05 (compared to previously published results where the median and IQR of aldosterone in pregnant women at 28 weeks was 724.8 and 376.6 – 1197 pmol/L, and median AA2-R of 4.15). In contrast, 15 patients had aldosterone concentrations more characteristic of normal pregnancy, with a median and IQR of 589.8 and 402.2– 769.6 pmol/L, and median AA2-R of 4.8). For comparison, a recent population study of non-pregnant adults determined median and IQR of aldosterone concentrations of 93 and 57.9 – 153.9 pmol/L using RAAS Triple-A. Conclusions: These data suggest two distinct phenotypes of pre-eclampsia based on RAAS profiling. Consistent with previous literature, our data indicate that pre-eclampsia is predominately characterized by reduced secretion of aldosterone, where concentrations are comparable to non-pregnant individuals. In contrast, we report that approximately one-third of patients with pre-eclampsia have elevated concentrations of aldosterone expected for pregnancy, suggesting multiple mechanisms for pre-eclampsia in humans defined by the presence or absence of elevated aldosterone secretion.

Determining the baryon impact on the matter power spectrum with galaxy clusters

ABSTRACT The redistribution of baryonic matter in massive haloes through processes like active galactic nuclei feedback and star formation leads to a suppression of the matter power spectrum on small scales. This redistribution can be measured empirically via the gas and stellar mass fractions in galaxy clusters, and leaves imprints on their electron density profiles. We constrain two semi-analytical baryon correction models with a compilation of recent Bayesian population studies of galaxy groups and clusters sampling a mass range above ∼3 × 1013 M⊙, and with cluster gas density profiles derived from deep, high-resolution X-ray observations. We are able to fit all the considered observational data, but highlight some anomalies in the observations. The constraints allow us to place precise, physically informed priors on the matter power spectrum suppression. At a scale of k = 1 h Mpc−1 we find a suppression of $0.042^{+0.012}_{-0.014}$ ($0.049^{+0.016}_{-0.012}$), while at k = 3 h Mpc−1 we find $0.184^{+0.026}_{-0.031}$ ($0.179^{+0.018}_{-0.020}$), depending on the model used. In our fiducial setting, we also predict at 97.5 per cent credibility, that at scales k < 0.37 h Mpc−1 baryon feedback impacts the matter power less than 1 per cent. This puts into question if baryon feedback is the driving factor for the discrepancy between cosmic shear and primary CMB results. We independently confirm results on this suppression from small-scale cosmic shear studies, while we exclude some hydro-dynamical simulations with too strong and too weak baryonic feedback. Our empirical prediction of the power spectrum suppression shows that studies of galaxy groups and clusters will be instrumental in unlocking the cosmological constraining power of future cosmic shear experiments like Euclid and Rubin-LSST, and invites further investigation of the baryon correction models.

A Napaac Survey to Understand Practices in Diagnosis and Treatment of Children with Moderate Aplastic Anemia

Among patients with acquired aplastic anemia, approximately 20% do not meet current classification as severe based on established criteria that reflect blood counts and marrow cellularity. For patients with moderate aplastic anemia (MAA), there is no set of defined diagnostic criteria, or clear standard-of-care for management. Little is known about the natural history of spontaneous recovery versus progression to severe bone marrow failure (BMF), response to conventional immunosuppressive treatment (IST), or evolution to myelodysplasia (MDS). Thus, institutional and individual practice can range from observation to immunosuppression or hematopoietic stem cell transplantation (HSCT). Recent studies of this patient population have begun to identify individuals harboring pathogenic mutations in genes known to cause BMF. To better understand population characteristics and management practices for patients with MAA, a survey was conducted through the North American Pediatric Aplastic Anemia Consortium (NAPAAC), consisting of 52 centers with expertise in BMF across North America. A total of 65 surveys were completed by pediatric hematology-oncology providers (55 attending physicians, 5 nurse practitioners and 5 fellows). Across all groups, there was marked variability of the MAA definition. Cytopenias were the defining criteria for diagnosis, including ANC<1000 cells/ul (79%), platelets <100K cells/ul (43%), and anemia for age (47%). In contrast, bone marrow hypocellularity (<50% cellularity) was considered by less than half (48%) of the respondents to be necessary for diagnosis. The combination of hypocellular bone marrow plus two cytopenias was considered the most common diagnostic definition of MAA (60% of participants). Although genetic testing has begun to transform diagnosis for many hematological diseases and can alter treatment decisions for pediatric BMF disorders, only 51% currently consider next generation sequencing (NGS) and 4% consider whole exome/whole genome sequencing as part of the initial work-up for MAA. Conventional cytogenetics and FISH are used more frequently in the initial work-up (86% and 73%, respectively). The two main triggers for treatment were dependence on red blood cell- (92%) or platelet (87%) transfusions, followed by persistent cytopenias (54%) and cytogenetic abnormalities (53%). Where available, acquired somatic variants triggered treatment in 30% of responses. Interestingly, infections were a less frequent trigger for treatment (35%). The most common management approaches were observation with transfusions (79%), single agent thrombopoietin receptor agonists (71%) or ATG+Cyclosporine based immune suppressive therapy (IST, 61%). Progression to severe aplastic anemia (SAA, 97%), myelodysplastic syndrome (MDS, 97%), or refractoriness to IST (61%) were the most common indications for HSCT.Availability of a matched sibling donor (MSD, 12%) was an infrequent indication for HSCT. A growing body of work, albeit largely in adult patients, suggests that patients with MAA represent a heterogenous group of individuals, some with genetic predisposition to BMF and inherent risk of myelodysplastic evolution. We identified that half of the responding NAPAAC practitioners use NGS panels routinely, suggesting a need for increased awareness to consider this work-up at initial diagnosis. Future studies are important to determine the yield of standard NGS testing, as the diagnosis of inherited BMF syndromes alter the strategy for long term surveillance of patients and genetic counseling for the family, as well as the use of related donor HSCT. We observed variability regarding the diagnostic criteria and management of children with MAA by providers who are members of NAPAAC. The heterogeneous responses to our survey suggest the need to establish management guidelines for uniform work-up and treatment, and to facilitate research of this understudied population. PC, LO: contributed equally as first authors. PK, JD: contributed equally as senior authors

The effect of stress on the thyroid morphofunctional status (literature review)

The article is a literature review on the effect of stress on the thyroid morphofunctional status. The article provides the results of research regarding the effect of various stressors on the thyroid functional state. It also discusses the mechanisms of immune system dysfunction under the influence of stressors that cause autoimmune disorders. The pathophysiological connection between the action of stress hormones and thyroid hormones is described, which consists in changes in the functional state of the thyroid gland depending on the stage of stress. The article also analyzes recent multifactorial population studies on the association of elevated cortisol levels, hyperinsulinemia, hyperleptinemia, and increased neoplastic proliferative activity. The dyshormonal etiology of insulin resistance is based on hypersensitivity due to various factors, which is based on catecholaminergic and serotonergic dysregulatory pathology. As a result, hypercortisolemia occurs. Also, in response to a chronic increase in cortisol level, the expression of leptin increases. Hyperinsulinemia and hyperleptinemia develop under the influence of hypercortisolemia. Patients with obesity, dyslipidemia, hyperleptinemia, hyperinsulinemia have increased level of insulin-like growth factor-1 and other growth factors that participate in the vascular wall remodeling and in the mechanisms of stimulation of the division of various types of cells. There are isolated studies indicating an increased incidence of nodular goiter in people with a negative metabolic phenotype. The presence of hyperinsulinemia and hyperleptinemia can be a crucial marker of the boundary between physiological cell division and neoplastic proliferative activity. Insulin-like growth factor-1 plays a significant role in the regulation of cell proliferation and apoptosis in terms of energy metabolism and depends on the type of eating behavior. Chronic stress changes eating behavior. Therefore, in this difficult historical period for Ukraine, it is important to study both clinical and pathogenetic aspects of hormonal, immunological, metabolic changes that occur in the body under the influence of chronic stress and contribute to the development of thyroid pathology.

The Spectrum of the Heterozygous Effect in Biallelic Mendelian Diseases-The Symptomatic Heterozygote Issue.

Heterozygous carriers of pathogenic/likely pathogenic variants in autosomal recessive disorders seem to be asymptomatic. However, in recent years, an increasing number of case reports have suggested that mild and unspecific symptoms can occur in some heterozygotes, as symptomatic heterozygotes have been identified across different disease types, including neurological, neuromuscular, hematological, and pulmonary diseases. The symptoms are usually milder in heterozygotes than in biallelic variants and occur "later in life". The status of symptomatic heterozygotes as separate entities is often disputed, and alternative diagnoses are considered. Indeed, often only a thin line exists between dual, dominant, and recessive modes of inheritance and symptomatic heterozygosity. Interestingly, recent population studies have found global disease effects in heterozygous carriers of some genetic variants. What makes the few heterozygotes symptomatic, while the majority show no symptoms? The molecular basis of this phenomenon is still unknown. Possible explanations include undiscovered deep-splicing variants, genetic and environmental modifiers, digenic/oligogenic inheritance, skewed methylation patterns, and mutational burden. Symptomatic heterozygotes are rarely reported in the literature, mainly because most did not undergo the complete diagnostic procedure, so alternative diagnoses could not be conclusively excluded. However, despite the increasing accessibility to high-throughput technologies, there still seems to be a small group of patients with mild symptoms and just one variant of autosomes in biallelic diseases. Here, we present some examples, the current state of knowledge, and possible explanations for this phenomenon, and thus argue against the existing dominant/recessive classification.

Moderate body lipid accumulation in mice attenuated benzene-induced hematotoxicity via acceleration of benzene metabolism and clearance

Recent population and animal studies have revealed a correlation between fat content and the severity of benzene-induced hematologic toxicity. However, the precise impact of lipid deposition on benzene-induced hematotoxicity and the underlying mechanisms remain unclear. In this study, we established a mouse model with moderate lipid accumulation by subjecting the mice to an 8-week high-fat diet (45% kcal from fat, HFD), followed by 28-day inhalation of benzene at doses of 0, 1, 10, and 100 ppm. The results showed that benzene exposure caused a dose-dependent reduction of peripheral white blood cell (WBC) counts in both diet groups. Notably, this reduction was less pronounced in the HFD-fed mice, suggesting that moderate lipid accumulation mitigates benzene-related hematotoxicity. To investigate the molecular basis for this effect, we performed bioinformatics analysis of high-throughput transcriptome sequencing data, which revealed that moderate lipid deposition alters mouse metabolism and stress tolerance towards xenobiotics. Consistently, the expression of key metabolic enzymes, such as Cyp2e1 and Gsta1, were upregulated in the HFD-fed mice upon benzene exposure. Furthermore, we utilized a real-time exhaled breath detection technique to monitor exhaled benzene metabolites, and the results indicated that moderate lipid deposition enhanced metabolic activation and increased the elimination of benzene metabolites. Collectively, these findings demonstrate that moderate lipid deposition confers reduced susceptibility to benzene-induced hematotoxicity in mice, at least in part, by accelerating benzene metabolism and clearance.

Vanadium exposure exacerbates allergic airway inflammation and remodeling through triggering reactive oxidative stress.

Metal components of environmental PM2.5 are associated with the exacerbation of allergic diseases like asthma. In our recent hospital-based population study, exposure to vanadium is shown to pose a significant risk for current asthma, but the causal relationship and its underlying molecular mechanisms remain unclear. We sought to determine whether vanadium co-exposure can aggravate house dust mite (HDM)-induced allergic airway inflammation and remodeling, as well as investigate its related mechanisms. Asthma mouse model was generated by using either vanadium pentoxide (V2O5) or HDM alone or in combination, in which the airway inflammation and remodeling was investigated. The effect of V2O5 co-exposure on HDM-induced epithelial-derived cytokine release and oxidative stress (ROS) generation was also examined by in vitro analyses. The role of ROS in V2O5 co-exposure-induced cytokine release and airway inflammation and remodeling was examined by using inhibitors or antioxidant. Compared to HDM alone, V2O5 co-exposure exacerbated HDM-induced airway inflammation with increased infiltration of inflammatory cells and elevated levels of Th1/Th2/Th17 and epithelial-derived (IL-25, TSLP) cytokines in the bronchoalveolar lavage fluids (BALFs). Intriguingly, V2O5 co-exposure also potentiated HDM-induced airway remodeling. Increased cytokine release was further supported by in vitro analysis in human bronchial epithelial cells (HBECs). Mechanistically, ROS, particularly mitochondrial-derived ROS, was significantly enhanced in HBECs after V2O5 co-exposure as compared to HDM challenge alone. Inhibition of ROS with its inhibitor N-acetyl-L-cysteine (NAC) and mitochondrial-targeted antioxidant MitoTEMPO blocked the increased epithelial release caused by V2O5 co-exposure. Furthermore, vitamin D3 as an antioxidant was found to inhibit V2O5 co-exposure-induced increased airway epithelial cytokine release and airway remodeling. Our findings suggest that vanadium co-exposure exacerbates epithelial ROS generation that contribute to increased allergic airway inflammation and remodeling.

Vanadium exposure exacerbates allergic airway inflammation and remodeling through triggering reactive oxidative stress

BackgroundMetal components of environmental PM2.5 are associated with the exacerbation of allergic diseases like asthma. In our recent hospital-based population study, exposure to vanadium is shown to pose a significant risk for current asthma, but the causal relationship and its underlying molecular mechanisms remain unclear.ObjectiveWe sought to determine whether vanadium co-exposure can aggravate house dust mite (HDM)-induced allergic airway inflammation and remodeling, as well as investigate its related mechanisms.MethodsAsthma mouse model was generated by using either vanadium pentoxide (V2O5) or HDM alone or in combination, in which the airway inflammation and remodeling was investigated. The effect of V2O5 co-exposure on HDM-induced epithelial-derived cytokine release and oxidative stress (ROS) generation was also examined by in vitro analyses. The role of ROS in V2O5 co-exposure-induced cytokine release and airway inflammation and remodeling was examined by using inhibitors or antioxidant.ResultsCompared to HDM alone, V2O5 co-exposure exacerbated HDM-induced airway inflammation with increased infiltration of inflammatory cells and elevated levels of Th1/Th2/Th17 and epithelial-derived (IL-25, TSLP) cytokines in the bronchoalveolar lavage fluids (BALFs). Intriguingly, V2O5 co-exposure also potentiated HDM-induced airway remodeling. Increased cytokine release was further supported by in vitro analysis in human bronchial epithelial cells (HBECs). Mechanistically, ROS, particularly mitochondrial-derived ROS, was significantly enhanced in HBECs after V2O5 co-exposure as compared to HDM challenge alone. Inhibition of ROS with its inhibitor N-acetyl-L-cysteine (NAC) and mitochondrial-targeted antioxidant MitoTEMPO blocked the increased epithelial release caused by V2O5 co-exposure. Furthermore, vitamin D3 as an antioxidant was found to inhibit V2O5 co-exposure-induced increased airway epithelial cytokine release and airway remodeling.ConclusionsOur findings suggest that vanadium co-exposure exacerbates epithelial ROS generation that contribute to increased allergic airway inflammation and remodeling.

PL-4: INSIGHTS INTO MOLECULAR MECHANISMS OF HYPERTENSION FROM HUMAN GENETICS

Identification and investigation of rare patients with extreme forms of high and low blood pressure has led to the identification of specific genes whose mutation results in these outlier phenotypes. These rare mutations converge on genes that mediate or regulate the renal reabsorption of Na-Cl. Mutations that increase or decrease renal salt reabsorption respectively increase or decrease blood pressure. Mutations that cause hypertension include gain of function mutations in subunits of the epithelial Na+ channel (ENaC) and in any of eight genes that cause constitutive activity of ENaC by its stimulation via its major regulator, the mineralocorticoid receptor, the target of aldosterone signaling; these increase salt reabsorption in the distal nephron. Conversely, mutations that cause hypotension include loss of function mutations in ENaC subunits, but also mutations the thiazide-sensitive Na-Cl cotransporter (NCC) or a K+ channel required for cotransporter function that act in the distal convoluted tubule (DCT), or mutations in the Na-K-2Cl cotransporter as well as K+ and Cl- channels expressed in the thick ascending limb of Henle that are required for normal Na-Cl reabsorption in this nephron segment. ENaC, the Na-Cl cotransporter and the Na-K-2Cl cotransporter, as well as the mineralocorticoid receptor are all commonly used targets for treatment of hypertension and/or diuresis. In addition to these genes, genetic studies also identified a previously unrecognized pathway that regulates the balance between renal salt reabsorption and K+ secretion. Mutations in the kinases WNK1 or WNK4, or genes that mediate their degradation via ubiquitylation, CUL3 and KLHL3 cause hypertension with hyperkalemia. Activity of WNK1 and WNK4 stimulates activation of NCC promoting Na-Cl reabsorption in the DCT, reducing Na-Cl- delivery distally, thereby limiting ENaC activity and limiting K+ secretion in the distal nephron. Conversely, hyperkalemia inhibits WNK activity, promoting distal Na-Cl delivery and maximizing K+ secretion. Angiotensin II signaling promotes WNK activity, increasing Na-Cl reabsorption in the DCT and inhibiting K+ secretion, while hyperkalemia appears to inhibit WNK activity, providing distal Na+ delivery that is used to drive K+ secretion. The importance of this pathway is that it can explain the mechanism by which increased dietary K+ lowers blood pressure. Both reduced dietary salt intake and increased dietary K+ can reduce blood pressure in controlled settings, and recent large population studies have shown that increased dietary K+ and reduced Na-Cl intake not only lower blood pressure but reduce the incidence of cardiovascular disease and death.

From inflation to black hole mergers and back again: Gravitational-wave data-driven constraints on inflationary scenarios with a first-principle model of primordial black holes across the QCD epoch

Recent population studies have searched for a subpopulation of primordial black holes (PBHs) in the gravitational-wave (GW) events so far detected by LIGO/Virgo/KAGRA (LVK), in most cases adopting a phenomenological PBH mass distribution. When deriving such population from first principles in the standard scenario, however, the equation of state of the Universe at the time of PBH formation may strongly affect the PBH abundance and mass distribution, which ultimately depend on the power spectrum of cosmological perturbations. Here we improve on previous population studies on several aspects: (i) we adopt state-of-the-art PBH formation models describing the collapse of cosmological perturbations across the QCD epoch; (ii) we perform the first Bayesian multi-population inference on GW data including PBHs and directly using power spectrum parameters instead of phenomenological distributions; (iii) we critically confront the PBH scenario with LVK phenomenological models describing the GWTC-3 catalog both in the neutron-star and in the BH mass ranges, also considering PBHs as subpopulation of the total events. Our results confirm that LVK observations prevent the majority of the dark matter to be in the form of stellar mass PBHs. We find that the best fit PBH model can comprise a small fraction of the total events, in particular it can naturally explain events in the mass gaps. If the lower mass-gap event GW190814 is interpreted as a PBH binary, we predict that LVK should detect up to a few subsolar mergers and one to $\approx 30$ lower mass gap events during the upcoming O4 and O5 runs. Finally, mapping back the best-fit power spectrum into an ultra slow-roll inflationary scenario, we show that the latter predicts detectable PBH mergers in the LVK band, a stochastic GW background detectable by current and future instruments, and may include the entirety of dark matter in asteroid-mass PBHs.

Entrainment of endangered sturgeon by a large water diversion: Rescue, enumeration, and conservation opportunities

AbstractThe Bonnet Carre' Spillway diverts water from the Mississippi River through a floodway into brackish Lake Pontchartrain to reduce river stages at New Orleans and prevent flood damage. Pallid Sturgeon Scaphirhynchus albus, a federally listed species under the Endangered Species Act, and Shovelnose Sturgeon Scaphirhynchus platorynchus, listed under the Similarity of Appearance rule, are entrained through the spillway structure and become trapped in the canals and shallow lakes. The two species of sturgeon were identified according to a suite of morphomeristic characters, not genetically, and were therefore noted as either Shovelnose Sturgeon or presumed Pallid Sturgeon. Rescue efforts were undertaken to return the entrained sturgeon back into the Mississippi River. This article describes the environmental and operational conditions that influence entrainment risk, catch, and potential impacts on the population. Five openings and corresponding rescue operations occurred between 2008 and 2019 after each spillway closure. A total of 70 days with a crew number ranging from 6 to 12 were expended to collect 57 Pallid Sturgeon, four of which were dead, and 362 Shovelnose Sturgeon, 83 of which were dead, after the five openings that spanned 240 total days. More sturgeon were entrained at higher water temperatures, with a greater number of bays opened for longer durations. Recovery of sturgeon is initially high but over time declines as sturgeon are depleted from the floodway, stranded in isolated waterbodies in the floodway, and/or displaced further downstream into Lake Pontchartrain during longer openings. Sturgeon that cannot find their way back to the floodway are unlikely to be rescued. Recent population studies indicate that only a small proportion of the Lower Mississippi River total population is entrained. However, this does not take into account those individuals entrained but not captured and the potential impacts if more frequent openings of the structure were to continue in the future. Conservation recommendations are provided to increase catch efficiency and recovery of the endangered sturgeon.

Physical activities and risk of neurodegenerative diseases: A two-sample Mendelian randomization study.

ObjectivesPhysical activity (PA) is considered beneficial in slowing the progression and improving the neurodegenerative disease prognosis. However, the association between PA and neurodegenerative diseases remains unknown. In this study, we conducted a two-sample Mendelian randomization (MR) analysis to estimate the causal association between PA phenotypes and neurodegenerative diseases.Materials and methodsGenetic variants robustly associated with PA phenotypes, used as instrumental variables, were extracted from public genome-wide association study (GWAS) summary statistics. Neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and Alzheimer’s disease (AD), were considered outcomes. GWAS information was also obtained from the most recent large population study of individuals with European ancestry. Multiple MR methods, pleiotropy tests and sensitivity analyses were performed to obtain a robust and valid estimation.ResultsWe found a positive association between moderate-to-vigorous physical activities and ALS based on the inverse variance weighted MR analysis method (OR: 2.507, 95% CI: 1.218–5.160, p = 0.013). The pleiotropy test and sensitivity analysis confirmed the robustness and validity of these MR results. No causal effects of PA phenotypes were found on PD and AD.ConclusionOur study indicates a causal effect of PA on the risk of neurodegenerative diseases. Genetically predicted increases in self-reported moderate-to-vigorous PA participation could increase the risk of ALS in individuals of European ancestry. Precise and individualized prescriptions of physical activity should be provided to the elderly population.

Skin autofluorescence as tool for cardiovascular and diabetes risk prediction.

Advanced glycation endproducts (AGE) have an important role in the development of chronic complications in diabetes mellitus and in renal failure. Skin autofluorescence (SAF) is a simple noninvasive optical technique to estimate AGE levels in the dermis. SAF increases with age, but rises more rapidly in diabetes and renal failure, and is also associated with, and a predictor of their complications. In recent large population studies, SAF is a strong predictor of development of type 2 diabetes (T2D), and in persons with known diabetes of its complications. SAF also predicts new cardiovascular disease (CVD) and mortality not only in individuals with known type 2 diabetes but also in the general population. SAF is a simple, powerful and independent predictor for development of type 2 diabetes (T2D), and also for cardiovascular disease and mortality in both persons with diabetes, and in the general population.

Neonatal stroke surveillance study protocol in the United Kingdom and Republic of Ireland.

Neonatal stroke is a devastating condition that causes brain injury in babies and often leads to lifelong neurological impairment. Recent prospective population studies of neonatal stroke are lacking. Neonatal strokes are different from those in older children and adults. A better understanding of its aetiology, current management, and outcomes could reduce the burden of this rare condition. The study aims to explore the incidence and 2 year outcomes of neonatal stroke across an entire population in the UK and Republic of Ireland. This is an active national surveillance study using a purpose-built integrated case notification-data collection online platform. Over a 13 month period, with a potential 6 month extension, clinicians will notify neonatal stroke cases presenting in the first 90 days of life electronically via the online platform monthly. Clinicians will complete a primary questionnaire via the platform detailing clinical information, including neuroimaging, for analysis and classification. An outcome questionnaire will be sent at 2 years of age via the platform. Appropriate ethics and regulatory approvals have been received. The neonatal stroke study represents the first multinational population surveillance study delivered via a purpose-built integrated case notification-data collection online platform and data safe haven, overcoming the challenges of setting up the study.

Influence of Perfluoroalkyl Substances on Occurrence of Coronavirus Disease 2019.

Epidemiologic evidence indicates exposure to polyfluoroalkyl substances (PFAS) influences immunosuppression, with diminished vaccination response. The relationship between PFAS blood levels and coronavirus disease 2019 (COVID-19) occurrence by age warrants further examination. This assessment identified blood PFAS exposure levels in discrete populations. Recent PFAS population studies summarizing age and gender results were identified and included. Geographically corresponding COVID-19 incidence data were determined for selected counties in North Carolina (NC) and Ohio (OH), and the state of New Jersey (NJ). Centers for Disease Control and Prevention COVID-19 databases were accessed for national incidence data by age groupings. We assessed associations between blood PFAS concentrations, COVID-19 incidence rates, and key demographic characteristics, within subpopulations. COVID-19 incidence counts and blood PFAS concentration were obtained for each age group, along with estimated U.S. Census total population. A general trend observed is higher PFAS levels in older age groups. Younger age groups contained fewer COVID-19 cases. Global COVID-19 mortality is highest in elderly populations with hospitalization and death greatly increasing from age 50. PFAS exposures occurring early in life may cause deleterious health effects later in life, including decreased antibody response and reduced disease resistance. Highest levels of both PFAS exposure and COVID-19 were found in the oldest populations. While this does not determine causality, such associations should help promote further study.

Far-ultraviolet to FIR Spectral-energy Distribution Modeling of the Stellar Formation History of the M31 Bulge

Abstract M31 is being surveyed at far- and near-ultraviolet with the UVIT telescope on AstroSat. The central bulge of M31 was observed in the N279N (275–280 nm), N219M (200–240 nm), F172M (160–185 nm), F169M (145–175 nm), and F148W (120–180 nm) filters. These images are made publicly available here. The UVIT data are supplemented with Sloan Digital Sky Survey data in optical, Spitzer data in near-infrared and Herschel data in mid- and far-infrared. The resulting far-ultraviolet to IR spectral-energy distributions for the bulge and for 10 subregions, are modeled using combinations of simple stellar populations and with CIGALE models. We find a dominant old (10–12 Gyr) metal-rich ([Z/H] ∼ 0.3) population and a younger (600 Myr) solar abundance ([Z/H] ∼ 0) population throughout the bulge. For the innermost 120″ we find an additional very young (25 Myr) metal-poor ([Z/H] ∼ −0.7) population. The results are consistent with the most recent stellar population studies of the bulge, which find the two populations for the whole bulge and a third young population in the innermost bulge.

Evaluation of BCG Vaccination and Plasma Amyloid: A Prospective, Pilot Study with Implications for Alzheimer's Disease.

BCG vaccine has been used for 100 years to prevent tuberculosis. Not all countries, including the United States, adopted the initial World Health Organization recommendation to use BCG. Moreover, many Western countries that had routinely used BCG have discontinued its use. Recent population studies demonstrate lower prevalence of Alzheimer’s disease (AD) in countries with high BCG coverage. Intravesicular instillation of BCG is also used to treat bladder cancer that has not invaded the bladder muscle wall and has been shown to reduce recurrence. Several retrospective studies of bladder cancer patients demonstrated that BCG treatment was associated with a significantly reduced risk of developing AD. Plasma amyloid β assessment has become a fertile area of study for an AD biomarker that is predictive of a positive amyloid PET scan. Mass spectrometry-based plasma amyloid 42/40 ratio has proven to be accurate and robust, and when combined with age and ApoE, is shown to accurately predict current and future brain amyloid status. These parameters, amyloid 42/40 ratio, age and ApoE genotype are incorporated into an Amyloid Probability Score (APS)–a score that identifies low, intermediate or high risk of having a PET scan positive for cerebral amyloid. Community recruitment was used for this open-label pilot study. Forty-nine BCG-naïve, immunocompetent individuals completed our study: prior to BCG prime and boost, as determined by the APS, 34 had low risk (APS 0–35), 5 had intermediate risk (APS 36–57) and 10 had high risk (APS 58–100). The APS range for the participant group was 0 to 94. Follow-up plasma amyloid testing 9 months after vaccination revealed a reduction in the APS in all the risk groups: low risk group (p = 0. 37), intermediate risk group (p = 0.13) and the high-risk group (statistically significant, p = 0.016). Greater benefit was seen in younger participants and those with the highest risk. The small number of participants and the nascent status of plasma amyloid testing will rightfully temper embracement of these results. However, both the favorable direction of change after BCG as well as the utility of the APS—a valuable surrogate AD biomarker—may prompt a definitive large-scale multicenter investigation of BCG and AD risk as determined by plasma amyloid peptide ratios and APS.

Evaluation of Two Methods for Quantification of Glycosaminoglycan Biomarkers in Newborn Dried Blood Spots from Patients with Severe and Attenuated Mucopolysaccharidosis Type II.

All newborn screening (NBS) for mucopolysaccharidosis-I and -II (MPS-I and MPS-II) is carried out via the measurement of α-iduronidase (IDUA) and iduronate-2-sulfatase (IDS) enzymatic activity, respectively, in dried blood spots (DBS). The majority of low enzyme results are due to pseudodeficiencies, and data from recent MPS-II population screenings and studies from the Mayo Clinic show that the false positive rate can be dramatically reduced by the inclusion of a second-tier analysis of glycosaminoglycans (GAGs) in DBS as part of NBS. In the present study, which focused on MPS-II, we obtained newborn DBS from 17 patients with severe MPS-II, 1 with attenuated MPS-II, and 6 patients with various IDS pseudodeficiencies. These samples were submitted to two different GAG mass spectrometry analyses in a comparative study: (1) internal disaccharide biomarkers and (2) endogenous biomarkers. For both of these methods, the biomarker levels in six patients with pseudodeficiencies were below the range measured in MPS-II patients. One patient with attenuated MPS-II was not distinguishable from severe disease patients, but all MPS-II patients were distinguishable from the reference range using both methods. The minimal differential factor (lowest GAG marker level in MPS-II samples divided by highest level in the reference range of 60 random newborns) was 3.01-fold for the internal disaccharide method. The endogenous biomarker method demonstrated an improved minimum differential of 5.41-fold. The minimum differential factors between MPS-II patients and patients with pseudodeficiencies for the internal disaccharide and endogenous biomarker methods were 3.77-fold and 2.06-fold, respectively. This study supports use of the second-tier GAG analysis of newborn DBS, especially the endogenous disaccharide method, as part of NBS to reduce the false positive rate.

A review of current knowledge about the importance of iodine among women of child-bearing age and healthcare professionals.

Iodine is required for thyroid hormone synthesis and fetal neurogenesis. Recent population studies in the United Kingdom (UK) have found iodine deficiency among schoolgirls, women of child-bearing age and pregnant women. This review explores knowledge and awareness of iodine among women of child-bearing age and healthcare professionals (HCPs) in the UK, set within a global context. We aimed to identify gaps in iodine knowledge in the current UK setting of iodine deficiency without iodine fortification and where iodine is not included in antenatal guidelines. The search terms 'iodine knowledge' and 'iodine awareness' were used to identify relevant papers. Iodine knowledge is poor among women of child-bearing age in the UK according to four studies using questionnaires and qualitative methods. They were unsure of dietary sources of iodine and were not consistently provided with relevant information from HCPs during clinical care. Midwives have been recognised as the main providers of dietary information during pregnancy and, although they recognised the importance of their role in providing nutrition advice, they did not feel equipped to do so and lacked confidence in addressing nutritional concerns. Globally, there was a similar lack of knowledge, however, this was somewhat improved by the inclusion of iodine in antenatal care guidelines. Midwives' knowledge of iodine was poor, as was knowledge among women of child-bearing age. Improved HCP knowledge and effective communication of information to pregnant women and women planning to conceive may help to improve iodine status which is of particular concern in pregnancy.

Characterization of Changes and Driver Microbes in Gut Microbiota During Healthy Aging Using A Captive Monkey Model

Recent population studies have significantly advanced our understanding of how age shapes the gut microbiota. However, the actual role of age could be inevitably confounded due to the complex and variable environmental factors in human populations. A well-controlled environment is thus necessary to reduce undesirable confounding effects, and recapitulate age-dependent changes in the gut microbiota of healthy primates. Herein we performed 16S rRNA gene sequencing, characterized the age-associated gut microbial profiles from infant to elderly crab-eating macaques reared in captivity, and systemically revealed the lifelong dynamic changes of the primate gut microbiota. While the most significant age-associated taxa were mainly found as commensals such as Faecalibacterium, the abundance of a group of suspicious pathogens such as Helicobacter was exclusively increased in infants, underlining their potential role in host development. Importantly, topology analysis indicated that the network connectivity of gut microbiota was even more age-dependent than taxonomic diversity, and its tremendous decline with age could probably be linked to healthy aging. Moreover, we identified key driver microbes responsible for such age-dependent network changes, which were further linked to altered metabolic functions of lipids, carbohydrates, and amino acids, as well as phenotypes in the microbial community. The current study thus demonstrates the lifelong age-dependent changes and their driver microbes in the primate gut microbiota, and provides new insights into their roles in the development and healthy aging of their hosts.