Search

Cortical cell loss is a core feature of Huntington's disease (HD), beginning many years before clinical motor diagnosis, during the premanifest stage. However, it is unclear how genetic topography relates to cortical cell loss. Here, we explore the biological processes and cell types underlying this relationship and validate these using cell-specific post-mortem data. Eighty premanifest participants on average 15 years from disease onset and 71 controls were included. Using volumetric and diffusion MRI we extracted HD-specific whole brain maps where lower grey matter volume and higher grey matter mean diffusivity, relative to controls, were used as proxies of cortical cell loss. These maps were combined with gene expression data from the Allen Human Brain Atlas (AHBA) to investigate the biological processes relating genetic topography and cortical cell loss. Cortical cell loss was positively correlated with the expression of developmental genes (i.e. higher expression correlated with greater atrophy and increased diffusivity) and negatively correlated with the expression of synaptic and metabolic genes that have been implicated in neurodegeneration. These findings were consistent for diffusion MRI and volumetric HD-specific brain maps. As wild-type huntingtin is known to play a role in neurodevelopment, we explored the association between wild-type huntingtin (HTT) expression and developmental gene expression across the AHBA. Co-expression network analyses in 134 human brains free of neurodegenerative disorders were also performed. HTT expression was correlated with the expression of genes involved in neurodevelopment while co-expression network analyses also revealed that HTT expression was associated with developmental biological processes. Expression weighted cell-type enrichment (EWCE) analyses were used to explore which specific cell types were associated with HD cortical cell loss and these associations were validated using cell specific single nucleus RNAseq (snRNAseq) data from post-mortem HD brains. The developmental transcriptomic profile of cortical cell loss in preHD was enriched in astrocytes and endothelial cells, while the neurodegenerative transcriptomic profile was enriched for neuronal and microglial cells. Astrocyte-specific genes differentially expressed in HD post-mortem brains relative to controls using snRNAseq were enriched in the developmental transcriptomic profile, while neuronal and microglial-specific genes were enriched in the neurodegenerative transcriptomic profile. Our findings suggest that cortical cell loss in preHD may arise from dual pathological processes, emerging as a consequence of neurodevelopmental changes, at the beginning of life, followed by neurodegeneration in adulthood, targeting areas with reduced expression of synaptic and metabolic genes. These events result in age-related cell death across multiple brain cell types. [ABSTRACT FROM AUTHOR]

Background: The role of white matter (WM) neurodegeneration in Alzheimer's disease (AD) is poorly understood. Fine‐grained sequencing of WM neurodegeneration could provide new avenues for early diagnosis and novel disease‐modifying therapies to slow or halt AD progression. Previous approaches are limited by their coarse granularity and incomplete disease coverage. In this study, we apply event‐based disease progression modelling (DPM) (Fonteijn et al, Neuroimage, 2012), which can provide fine‐grained ordering, to estimate progression of regional WM abnormality in AD. Method: Diffusion tensor imaging (DTI) markers of WM abnormality and Freesurfer volumetric markers of grey matter (GM) atrophy were obtained from ADNI. DTI markers were hemisphere‐averaged and GM volumes were normalised by head size. Eleven WM ROIs with reported AD abnormality and 4 reference GM ROIs were selected for sequencing (abbreviations in Table 1), yielding complete data for 83 cognitively normal subjects, 40 AD patients and 102 MCI subjects. Event‐based DPM (github.com/ucl‐pond/kde_ebm) was used to estimate a data‐driven sequence of neurodegeneration and its uncertainty (positional variance), and individuals were assigned to their most likely stage (Young et al., Brain, 2014). Resampling analysis assessed the robustness of the estimated sequence. Result: Fig. 1 shows the first data‐driven sequence of WM abnormalities in AD, including positional variance, with GM abnormality events for reference. The earliest WM events are increases in mean diffusivity (MD) in CGH and axial diffusivity (AxD) in FX and BCC. Subsequently, a cascade of AxD events in corpus callosum regions precedes abnormality in other medial temporal lobe WM structures. Fig. 2 shows the sequence is relatively robust under resampling, with low positional variance and similar median positions for most ROIs. Subject staging (Fig. 3, 4) shows that the fine‐grained approach splits MCI subjects with hippocampal atrophy into those with hippocampal atrophy and those with additional increased MD in CGH. Conclusion: This study finds WM microstructural abnormality among the earliest events in AD. Early hippocampal WM abnormality and corpus callosum ordering are consistent with early memory deficits in AD and inferences from cruder group‐based comparisons. The order suggests Wallerian degeneration rather than retrogenesis is the primary driver of WM neurodegeneration in AD. [ABSTRACT FROM AUTHOR]

Background: Neurite Orientation Dispersion and Density Imaging (NODDI) provides in‐vivo indices of neurite density (NDI) and orientation dispersion (ODI) within the tissue compartment of each voxel. However, NDI and ODI are treated equally when calculating region of interest (ROI) means, despite tissue fraction (TF) varying within regions undergoing neurodegeneration. Covariation between TF and cortical NODDI measures bias these conventional means and we recommend using tissue‐weighted averages to address this. Method: In this study, we included 22 healthy controls and 33 individuals affected by Young‐Onset Alzheimer's disease (YOAD, see Table 1 for demographics) with suitable diffusion‐weighted and T1‐weighted 3T MR images. Diffusion data were corrected for eddy currents, motion and susceptibility artefacts before fitting the NODDI model to produce NDI, ODI, isotropic volume fraction (ISO) and TF maps (TF=1‐ISO). T1w images were parcellated into cortical ROIs using Geodesic Information Flow (Cardoso et al., IEEE Trans.Med.Im.; 34:1976‐1988, 2015). Five bilateral ROIs expected to undergo neurodegeneration were analysed (Precuneus, Fusiform Gyrus, Superior Parietal, Middle and Inferior Temporal cortex). ROIs were resampled into native diffusion space and two regional measures calculated: 1) conventional, unweighted NDI and ODI averages and 2) tissue‐weighted averages using voxel TF as weights. Within‐participant differences between conventional and tissue‐weighted measures were calculated. Spearman's rank tested correlations and Wilcoxon tests evaluated within‐ and between‐participant differences (Bonferroni adjusted for multiple comparisons). Result: TF positively correlated with GM volume (rs range=0.33‐0.68,p<0.05) in all ROIs except the left fusiform gyrus (rs=0.31,p=0.06) (Figure 1). YOAD individuals had lower TF than healthy controls in all ROIs (Figure 2a), and lower volumes in all ROIs except the right fusiform gyrus (W=475,p=0.27) (Figure 2b). NDI showed small positive/negative biases in six of the ten ROIs (Figure 3a), while ODI showed significant positive biases across all ROIs (Figure 3b). Biases decreased as TF increased towards its maximum of one (Figure 4a‐4b). Conclusion: Lower cortical volumes in YOAD were associated with lower TF and higher bias, suggesting a greater risk for misestimation of cortical region NODDI metrics in studies involving neurodegenerative disease. We recommend tissue‐weighted averages to account for varying intra‐regional TF in NODDI measures. [ABSTRACT FROM AUTHOR]

Background: Mapping axonal loss in young‐onset Alzheimer’s disease (YOAD) can provide a clearer picture of neurodegenerative processes. Axonal loss has been estimated using metrics derived from diffusion MRI (dMRI). However, these measures are also sensitive to myelin, thus cannot unambiguously disentangle axon loss and demyelination. Here, we address this with multi‐modal imaging, combining dMRI with magnetisation transfer saturation (MTsat) MRI, a technique sensitive specifically to myelin. Method: Neurite density index (NDI), a dMRI estimate from NODDI, relates to axon volume fraction (AVF), an axon density estimate unconfounded by myelin: AVF=(1‐MVF)(1‐FWF)NDI (Stikov et al. Neuroimage; 118:397‐405, 2015). MVF is the myelin volume fraction, an estimate of myelin density, and FWF the free water fraction from NODDI. MVF is estimated from MTsat imaging (Mohammadi et al. Frontiers in Neuroscience; 9, 9:441, 2015). Maps of AVF, MVF and NDI were computed for 21 healthy controls and 30 YOAD patients who underwent NODDI‐compatible dMRI and MTsat MRI. Tract‐based spatial statistics (TBSS) was used to map significant changes (p<0.05, FWE‐corrected) along white matter (WM) skeleton (Fig. 2, lower) of the population template. Result: Figure 1 shows the population‐averaged AVF and MVF of each point along the WM skeleton, demonstrating NDI is influenced by both AVF and MVF. While AVF and NDI correlate strongly (R2=0.46, p<5e‐10), suggesting NDI is primarily a marker of axon density, MVF also contributes to the observed NDI variation (R2=0.16, p<5e‐10). Figure 2 shows TBSS group differences in these metrics. MVF reductions in fronto‐occipital regions, indicating demyelination, overlap with NDI reductions but not AVF changes (Fig. 2A). AVF reductions in the splenium, indicating axonal loss, did not overlap with NDI changes (Fig. 2B). This demonstrates sub‐optimal specificity and sensitivity of NDI to axonal loss. Most AVF reductions; in the posterior tracts, fornix and the corpus callosum splenium, areas associated with symptoms of YOAD; were accompanied by decreased NDI. Concomitant MVF reductions occurred in posterior areas (Fig 2C). Conclusion: This study presents a multi‐modal imaging approach to disambiguate markers of axonal loss and demyelination, effects previously entangled in single modality DWI analysis. This technique may provide new insight into in vivo pathological processes in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

In its decades-long history, the Division of Blood Disorders (DBD) at CDC has evolved from a patient-focused, services-supporting entity at inception, to one of the world leaders in the practice of public health to improve the lives of people at risk for or affected by nonmalignant blood disorders. The DBD’s earliest public health activities consisted of working with care providers in a network of hemophilia treatment centers to provide AIDS risk reduction services to people with hemophilia. Because this infectious disease threat has been reduced over time as a result of the development of safer treatment products, the DBD—under the auspices of congressional appropriations guidance—has expanded its core activities to encompass blood disorders other than hemophilia, including hemoglobinopathies such as thalassemia and sickle cell disease, and Diamond Blackfan anemia. Simultaneously, in transitioning to a greater public health role, the DBD has expanded its network of partners to new consumer and professional organizations, as well as state and other federal health agencies. The DBD has also developed and maintains many surveillance and registry activities beyond the Universal Data Collection system aimed at providing a better understanding of the health status, health needs, and health-related quality of life of people with nonmalignant blood disorders. The DBD has integrated applicable components of the Essential Services of Public Health successfully to promote and advance the agenda of blood disorders in public health. [ABSTRACT FROM AUTHOR]

Structural brain networks may be reconstructed from diffusion MRI tractography data and have great potential to further our understanding of the topological organisation of brain structure in health and disease. Network reconstruction is complex and involves a series of processesing methods including anatomical parcellation, registration, fiber orientation estimation and whole-brain fiber tractography. Methodological choices at each stage can affect the anatomical accuracy and graph theoretical properties of the reconstructed networks, meaning applying different combinations in a network reconstruction pipeline may produce substantially different networks. Furthermore, the choice of which connections are considered important is unclear. In this study, we assessed the similarity between structural networks obtained using two independent state-of-the-art reconstruction pipelines. We aimed to quantify network similarity and identify the core connections emerging most robustly in both pipelines. Similarity of network connections was compared between pipelines employing different atlases by merging parcels to a common and equivalent node scale. We found a high agreement between the networks across a range of fiber density thresholds. In addition, we identified a robust core of highly connected regions coinciding with a peak in similarity across network density thresholds, and replicated these results with atlases at different node scales. The binary network properties of these core connections were similar between pipelines but showed some differences in atlases across node scales. This study demonstrates the utility of applying multiple structural network reconstrution pipelines to diffusion data in order to identify the most important connections for further study. [ABSTRACT FROM AUTHOR]

With its preference for small government and fiscal responsibility, the Tea Party movement claims to be conservative. Yet, their tactics and rhetoric belie this claim. The shrill attacks against Blacks, illegal immigrants, and gay rights are all consistent with conservatism, but suggesting that the president is a socialist bent on ruining the country, is beyond politics. This chapter shows that Richard Hofstadter's thesis about the "paranoid style" of American politics helps characterize the Tea Party's pseudo- conservatism. Through a comprehensive analysis of qualitative interviews, content analysis and public opinion data, we find that Tea Party sympathizers are not mainstream conservatives, but rather, they hold a strong sense of out-group anxiety and a concern over the social and demographic changes in America. [ABSTRACT FROM AUTHOR]

Bleeding and clotting in women is an issue that directly affects the life of every woman, child, and family worldwide. This article summarizes recent activities undertaken by the Division of Blood Disorders (DBD) at the Centers for Disease Control and Prevention (CDC) to identify risk factors through evidence-based research and surveillance to prevent complications of blood disorders in women. Specific focus is given to our efforts to improve early identification and diagnosis of blood disorders among women, improve our understanding of maternal and infant outcomes, and develop surveillance systems to monitor the prevalence and incidence of these events. [ABSTRACT FROM AUTHOR]

Improving the health of our children offers the greatest potential for improving the health of our nation. One paradigm for improving the health of children that may offer the greatest rate of return lies in improving the health of women. Throughout the complete life stages of both women and children, overall good health of women positively influences the health and wellness of our children. [ABSTRACT FROM AUTHOR]

The paper suggests that the bridging of the growing university/schools gap (resulting from a growing corpus of theory at research level) may be achieved by the use of various models which act as both teaching aids and conceptual props. In this respect it outlines some of the uses of models in school geography, while concerning itself in more detail with the use of analogue models in human geography. The rules for the valid use of such analogues are reviewed, and illustrated via the medium of a weighted chemical diffusion model to delimit spheres of influence in a given group of settlements. [ABSTRACT FROM PUBLISHER]

Abstract: Although the issue of whether sickle cell trait (SCT) is clinically benign or a significant health concern has not yet been resolved, the potential health risk to affected individuals is of vital importance and represents a tremendous challenge in protecting, promoting, and improving the health of the approximately 300 million people worldwide and 3 million people in the U.S. who possess the trait. In response to a request by the Sickle Cell Disease Association of America, in December 2009, the CDC convened a meeting of partners, stakeholders, and experts to identify the gaps in public health, clinical health services, epidemiologic research, and community-based outreach strategies and to develop an agenda for future initiatives. Through facilitated discussion and presentations in four topic areas, participants discussed pertinent issues, synthesized clinical research findings, and developed a coherent framework for establishing an agenda for future initiatives. A primary outcome of the meeting was to provide the first step of an iterative process to move toward agreement regarding appropriate counseling, care, and, potentially, treatment of people with SCT. [Copyright &y& Elsevier]

Abstract: Technologic advances in diagnostic testing, vaccinations, pathogen inactivation, and vigilant donor screening have greatly reduced the risk of transmitting pathogens through blood transfusion. Nevertheless, transfusion-related infections and fatalities continue to be reported, and emerging pathogens continue to become an increasing threat to the blood supply. This threat is even greater to patients with blood disorders, who are heavily transfused and rely on safe blood products. This article describes some of the emerging and re-emerging transfusion-transmitted pathogens that have increased in incidence in the U.S. in recent years. Peer-reviewed articles and agency websites were the sources of information. The article focuses on the treatment of hereditary blood disorders including hemophilia and thalassemia, and hereditary bone marrow failure. A coordinated approach to addressing blood safety and continued development of sensitive diagnostic testing are necessary to reduce risk in an increasingly globalized society. [Copyright &y& Elsevier]

Abstract: Nonmalignant blood disorders meet all criteria for qualifying, as a group, as a very important public health problem with serious morbidities affecting over 1 million Americans every year, not including an additional 8 million individuals suffering from anemia. Many of these conditions and the morbidities and mortalities associated with them are, to a large extent, preventable. Further, the changing demographic composition of the American population is sure to increase the number of individuals affected by these conditions. Yet, nonmalignant blood disorders have not been recognized as important public health priorities. Immediate action is needed to meet the increasing challenge of blood disorders in public health. We propose a national, comprehensive, organized, coordinated, institutionalized, sustainable public health response to blood disorders based on the three core functions and the ten essential services of public health. Immediate action needs to be taken to improve surveillance and monitoring, increase public and provider awareness, increase the use of evidence-based practices, and enhance epidemiologic research on the causes, prevention, and treatment of conditions resulting in adverse outcomes. [Copyright &y& Elsevier]

Abstract: Sickle cell disease (SCD) is a collection of inherited blood disorders that affect a substantial number of people in the U.S., particularly African Americans. People with SCD have an abnormal type of hemoglobin, Hb S, which polymerizes when deoxygenated, causing the red blood cells to become misshapen and rigid. Individuals with SCD are at higher risk of morbidity and mortality from infections, vaso-occlusive pain crises, acute chest syndrome, and other complications. Addressing the public health needs related to SCD is an important step toward improving outcomes and maintaining health for those affected by the disorder. The objective of this study was to review public health activities focusing on SCD and define the need to address it more comprehensively from a public health perspective. We found that there has been some progress in the development of SCD-related public health activities. Such activities include establishing newborn screening (NBS) for SCD with all states currently having universal NBS programs. However, additional areas needing focus include strengthening surveillance and monitoring of disease occurrence and health outcomes, enhancing adherence to health maintenance guidelines, increasing knowledge and awareness among those affected, and improving healthcare access and utilization. These and other activities discussed in this paper can help strengthen public health efforts to address SCD. [Copyright &y& Elsevier]

Background: Patients with sickle cell disease (SCD) often use emergency department services to obtain medical care. Limited information is available about emergency department use among patients with SCD.Purpose: This study assessed characteristics of emergency department visits made nationally by patients with SCD.Methods: Data from the National Hospital Ambulatory Medical Care Survey (NHAMCS) for the years 1999-2007 were analyzed. The NHAMCS is a survey of hospital emergency department and outpatient visits. Emergency department visits by patients with SCD were identified using ICD-9-CM codes, and nationally weighted estimates were calculated.Results: On average, approximately 197,333 emergency department visits were estimated to have occurred each year between 1999 and 2007 with SCD as one of the diagnoses listed. The expected source of payment was private insurance for 14%, Medicaid/State Children's Health Insurance Program for 58%, Medicare for 14%, and other/unknown for 15%. Approximately 29% of visits resulted in hospital admission; this was 37% among patients aged 0-19 years, and 26% among patients aged >/=20 years. The episode of care was indicated as a follow-up visit for 23% of the visits. Patient-cited reasons for the emergency department visit included chest pain (11%); other pain or unspecified pain (67%); fever/infection (6%); and shortness of breath/breathing problem/cough (5%), among other reasons.Conclusions: Substantial numbers of emergency department visits occur among people with SCD. The most common reason for the emergency department visits is pain symptoms. The findings of this study can help to improve health services delivery and utilization among patients with SCD. [ABSTRACT FROM AUTHOR]

Background: Hemophilia is a hereditary bleeding disorder. Its complications can result in substantial morbidity, but few efforts have been made to quantify the disease burden. Purpose: The objective of this analysis was to estimate the burden of disease due to hemophilia (A and B) in the U.S., using disability-adjusted life years (DALY). Methods: The approach taken by the WHO in its Global Burden of Disease study was followed. Assumptions were drawn from published literature, and population estimates from the U.S. Census Bureau for the Year 2007 were used. Estimations of years of life lost resulting from mortality (YLL) and years of life lost resulting from morbidity (YLD) were done separately by gender, 5-year age intervals, and severity of disease (morbidity only) with their sum representing DALYs. Disability weights were derived from the quality-of-life tool EuroQol (EQ-5D). The stability of burden estimates was tested by performing sensitivity analyses, changing one assumption at a time. Results: In the U.S. in 2007, hemophilia resulted in 110,095 DALYs, composed of 13,418 YLLs and 96,677 YLDs. Large differences between men/boys (107,346) and women/girls (2749) were observed, given that females are genetic carriers of the disorder and rarely present with disease. Sensitivity analyses revealed a relatively robust estimate with a maximum variation of 4.49%. Conclusions: This first estimate of hemophilia-related DALYs in the U.S. indicates that control of hemophilia can potentially result in a gain of 1 healthy year of life for every 2700 people in the population. [Copyright &y& Elsevier]

Cortical cell loss is a core feature of Huntington's disease (HD), beginning many years before clinical motor diagnosis, during the premanifest stage. However, it is unclear how genetic topography relates to cortical cell loss. Here, we explore the biological processes and cell types underlying this relationship and validate these using cell-specific post-mortem data. Eighty premanifest participants on average 15 years from disease onset and 71 controls were included. Using volumetric and diffusion MRI we extracted HD-specific whole brain maps where lower grey matter volume and higher grey matter mean diffusivity, relative to controls, were used as proxies of cortical cell loss. These maps were combined with gene expression data from the Allen Human Brain Atlas (AHBA) to investigate the biological processes relating genetic topography and cortical cell loss. Cortical cell loss was positively correlated with the expression of developmental genes (i.e. higher expression correlated with greater atrophy and increased diffusivity) and negatively correlated with the expression of synaptic and metabolic genes that have been implicated in neurodegeneration. These findings were consistent for diffusion MRI and volumetric HD-specific brain maps. As wild-type huntingtin is known to play a role in neurodevelopment, we explored the association between wild-type huntingtin (HTT) expression and developmental gene expression across the AHBA. Co-expression network analyses in 134 human brains free of neurodegenerative disorders were also performed. HTT expression was correlated with the expression of genes involved in neurodevelopment while co-expression network analyses also revealed that HTT expression was associated with developmental biological processes. Expression weighted cell-type enrichment (EWCE) analyses were used to explore which specific cell types were associated with HD cortical cell loss and these associations were validated using cell specific single nucleus RNAseq (snRNAseq) data from post-mortem HD brains. The developmental transcriptomic profile of cortical cell loss in preHD was enriched in astrocytes and endothelial cells, while the neurodegenerative transcriptomic profile was enriched for neuronal and microglial cells. Astrocyte-specific genes differentially expressed in HD post-mortem brains relative to controls using snRNAseq were enriched in the developmental transcriptomic profile, while neuronal and microglial-specific genes were enriched in the neurodegenerative transcriptomic profile. Our findings suggest that cortical cell loss in preHD may arise from dual pathological processes, emerging as a consequence of neurodevelopmental changes, at the beginning of life, followed by neurodegeneration in adulthood, targeting areas with reduced expression of synaptic and metabolic genes. These events result in age-related cell death across multiple brain cell types., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Pathological processes in Huntington's disease (HD) begin many years prior to symptom onset. Recently we demonstrated that in a premanifest cohort approximately 24 years from predicted disease onset, despite intact function, there was evidence of subtle neurodegeneration. Here, we use novel imaging techniques to determine whether macro- and micro-structural changes can be detected across the whole-brain in the same cohort., Methods: 62 premanifest HD (PreHD) and 61 controls from the HD Young Adult Study (HD-YAS) were included. Grey and white matter volume, diffusion weighted imaging (DWI) measures of white matter microstructure, multiparametric maps (MPM) estimating myelin and iron content from magnetization transfer (MT), proton density (PD), longitudinal relaxation (R1) and effective transverse relaxation (R2*), and myelin g-ratio were examined. Group differences between PreHD and controls were assessed; associations between all imaging metrics and disease burden and CSF neurofilament light (NfL) were also performed. Volumetric and MPM results were corrected at a cluster-wise value of familywise error (FWE) 0.05. Diffusion and g-ratio results were corrected via threshold-free cluster enhancement at FWE 0.05., Findings: We showed significantly increased R1 and R2*, suggestive of increased iron, in the putamen, globus pallidum and external capsule of PreHD participants. There was also a significant association between lower cortical R2*, suggestive of reduced myelin or iron, and higher CSF NfL in the frontal lobe and the parieto-occipital cortices. No other results were significant at corrected levels., Interpretation: Increased iron in subcortical structures and the surrounding white matter is a feature of very early PreHD. Furthermore, increases in CSF NfL were linked to microstructural changes in the posterior parietal-occipital cortex, a region previously shown to undergo some of the earliest cortical changes in HD. These findings suggest that disease related process are occurring in both subcortical and cortical regions more than 20 years from predicted disease onset., Competing Interests: Declaration of Competing Interest SJT reports grants from Wellcome Trust, grants from UK Dementia Research Institute, during the conduct of the study; other from F. Hoffmann La Roche Ltd, personal fees from F. Hoffmann La Roche Ltd, personal fees from Annexon, personal fees from PTC Therapeutics, personal fees from Takeda Pharmaceuticals Ltd, personal fees from Vertex Pharmaceuticals Incorporated., personal fees from UCB Pharma S.A, personal fees from Alnylam Pharmaceuticals Inc, personal fees from Decision Resources Group, personal fees from Genentech, personal fees from DDF Discovery Ltd, personal fees from Triplet Theraputics, personal fees from Novartis, outside the submitted work. GR reports grants from Wellcome Trust during the conduct of the study. All other authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Patients with medically-refractory focal epilepsy may be candidates for neurosurgery and some may require placement of intracranial EEG electrodes to localise seizure onset. Assessing cerebral responses to single pulse electrical stimulation (SPES) may give diagnostically useful data. SPES produces cortico-cortical evoked potentials (CCEPs), which infer effective brain connectivity. Diffusion-weighted images and tractography may be used to estimate structural brain connectivity. This combination provides the opportunity to observe seizure onset and its propagation throughout the brain, spreading contiguously along the cortex explored with electrodes, or non-contiguously. We analysed CCEPs and diffusion tractography in seven focal epilepsy patients and reconstructed the effective and structural brain networks. We aimed to assess the inter-modal similarity of the networks at a large scale across the cortex, the effective and structural connectivity of the ictal-onset zone, and investigate potential mechanisms of non-contiguous seizure spread. We found a significant overlap between structural and effective networks. Effective network CCEP amplitude, baseline variation, and outward connectivity was higher at ictal-onset zones, while structural connection strength within the ictal-onset zone tended to be higher. These findings support the concept of hyperexcitable cortex being associated with seizure generation. The high prevalence of structural and effective connections from the ictal-onset zone to sites of non-contiguous spread suggests that macroscopic structural and effective connections are plausible routes for non-contiguous seizure spread.

This report provides recommendations to improve both preconception health and care. The goal of these recommendations is to improve the health of women and couples, before conception of a first or subsequent pregnancy. Since the early 1990s, guidelines have recommended preconception care, and reviews of previous studies have assessed the evidence for interventions and documented the evidence for specific interventions. CDC has developed these recommendations based on a review of published research and the opinions of specialists from the CDC/ATSDR Preconception Care Work Group and the Select Panel on Preconception Care. The 10 recommendations in this report are based on preconception health care for the U.S. population and are aimed at achieving four goals to 1) improve the knowledge and attitudes and behaviors of men and women related to preconception health; 2) assure that all women of childbearing age in the United States receive preconception care services (i.e., evidence-based risk screening, health promotion, and interventions) that will enable them to enter pregnancy in optimal health; 3) reduce risks indicated by a previous adverse pregnancy outcome through interventions during the interconception period, which can prevent or minimize health problems for a mother and her future children; and 4) reduce the disparities in adverse pregnancy outcomes. The recommendations focus on changes in consumer knowledge, clinical practice, public health programs, health-care financing, and data and research activities. Each recommendation is accompanied by a series of specific action steps and, when implemented, can yield results within 2-5 years. Based on implementation of the recommendations, improvements in access to care, continuity of care, risk screening, appropriate delivery of interventions, and changes in health behaviors of men and women of childbearing age are expected to occur. The implementation of these recommendations will help achieve Healthy People 2010 objectives. The recommendations and action steps are a strategic plan that can be used by persons, communities, public health and clinical providers, and governments to improve the health of women, their children, and their families. Improving preconception health among the approximately 62 million women of childbearing age will require multistrategic, action-oriented initiatives.