Genetic topography and cortical cell loss in Huntington's disease link development and neurodegeneration.

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.

Altered iron and myelin in premanifest Huntington's Disease more than 20 years before clinical onset: Evidence from the cross-sectional HD Young Adult Study.

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.

Structural and effective connectivity in focal epilepsy.

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.

Correction: Emergency Department Visits and Inpatient Admissions Associated with Priapism among Males with Sickle Cell Disease in the United States, 2006-2010.

[This corrects the article DOI: 10.1371/journal.pone.0153257.].

Risk of venous thromboembolism occurrence among adults with selected autoimmune diseases: a study among a U.S. cohort of commercial insurance enrollees.

OBJECTIVE: This study assessed the risk of venous thromboembolism (VTE) among privately insured adults in the U.S. with one or more of the following autoimmune diseases: autoimmune hemolytic anemia (AIHA), immune thrombocytopenic purpura (ITP), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). MATERIALS AND METHODS: Using the Truven Health MarketScan® Databases, patients 18-64 years of age with a diagnosis of AIHA, ITP, RA, or SLE in 2007 and a sex and age-group matched comparison group of enrollees were followed up through 2010 to identify VTE events. Survival curve and Cox proportional hazards analyses were conducted to assess differences between groups. RESULTS: Among patients with AIHA, ITP, RA, or SLE, or >1 of these diseases, the risk of at least one VTE event was 19.74, 7.72, 4.90, 9.89, and 13.35 per 1,000 person-years, respectively; among the comparison group, the risk was 1.91 per 1,000 person-years. The adjusted hazard ratios (aHRs) for VTE among patients with AIHA, ITP, RA, or SLE, or >1 of these diseases (when compared with the comparison group) tended to decline over follow-up time; at 1year, the aHRs were 6.30 (95% confidence interval [CI]: 4.44-8.94), 2.95 (95% CI: 2.18-4.00), 2.13 (95% CI: 1.89-2.40), 4.68 (95% CI: 4.10-5.33), and 5.11 (95% CI: 4.26-6.14), respectively. CONCLUSION: Having AIHA, ITP, RA, or SLE, or >1 of these diseases was associated with an increased likelihood of a VTE event. More research is necessary to develop better understanding of VTE occurrence among people with autoimmune diseases.

Consensus between pipelines in structural brain networks.

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.

Meeting the emerging public health needs of persons with blood disorders.

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.

Sickle cell disease: the need for a public health agenda.

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.

Public health implications of sickle cell trait: a report of the CDC meeting.

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.

Factors affecting the willingness of counselors to integrate preconception care into sexually transmitted disease clinics.

BACKGROUND: The high rate of unintended pregnancy is an immediate barrier to providing preconception care (PCC). Failure to deliver additional PCC messages at sexually transmitted disease (STD) clinics might represent a major missed opportunity to target women at increased risk for unintended pregnancy for behaviors that also put them at risk for adverse pregnancy outcomes. METHODS: Using a survey questionnaire, we assessed perceptions of PCC and factors influencing the willingness of STD counselors to integrate PCC as an intervention service provided by the STD clinics of 140 STD counselors. We used a cross-sectional design and selected survey participants with a minimum of 2 years' experience in providing HIV pretest and posttest counseling and syphilis interviewing using a nonprobability, purposive sample. RESULTS: The level of occupational responsibility and the amount of time available seemed to affect counselor perceptions of the importance of PCC and whether it should be integrated as an intervention service provided by STD clinics. Findings suggested that, although most STD counselors reported that PCC was an important issue, there was significant variation in the perception of whether PCC should be delivered at STD clinics. CONCLUSION: STD counselors perceived PCC to be an important intervention service that can be delivered at STD clinics. Additional study is needed to identify factors that might affect full integration into the STD clinic setting.

Developing a public health research agenda for women with blood disorders.

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.

The public health response to blood disorders.

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.

Assessing emerging infectious threats to blood safety for the blood disorders community.

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.

Burden of disease resulting from hemophilia in the U.S.

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.

Emergency department visits made by patients with sickle cell disease: a descriptive study, 1999-2007.

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.

Improving women's health for the sake of our children.

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.

Recommendations to improve preconception health and health care--United States. A report of the CDC/ATSDR Preconception Care Work Group and the Select Panel on Preconception Care.

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.