Code-based Syndromic Surveillance for Influenzalike Illness by International Classification of Diseases, Ninth Revision

ICD-9 codes collected automatically in a syndromic system are sensitive and specific in detecting outbreaks caused by respiratory viruses

Enhanced Monocyte Response and Decreased Central Memory T Cells in Children with Invasive Staphylococcus aureus Infections

Staphylococcus aureus has emerged as a significant pathogen causing severe invasive disease in otherwise healthy people. Despite considerable advances in understanding the epidemiology, resistance mechanisms, and virulence factors produced by the bacteria, there is limited knowledge of the in vivo host immune response to acute, invasive S. aureus infections. Herein, we report that peripheral blood mononuclear cells from patients with severe S. aureus infections demonstrate a distinctive and robust gene expression profile which is validated in a distinct group of patients and on a different microarray platform. Application of a systems-wide modular analysis framework reveals significant over-expression of innate immunity genes and under-expression of genes related to adaptive immunity. Simultaneous flow cytometry analyses demonstrated marked alterations in immune cell numbers, with decreased central memory CD4 and CD8 T cells and increased numbers of monocytes. CD14+ monocyte numbers significantly correlated with the gene expression levels of genes related to the innate immune response. These results demonstrate the value of applying a systems biology approach that reveals the significant alterations in the components of circulating blood lymphocytes and monocytes in invasive S. aureus infections

p53 Transactivation and the Impact of Mutations, Cofactors and Small Molecules Using a Simplified Yeast-Based Screening System

The p53 tumor suppressor, which is altered in most cancers, is a sequence-specific transcription factor that is able to modulate the expression of many target genes and influence a variety of cellular pathways. Inactivation of the p53 pathway in cancer frequently occurs through the expression of mutant p53 protein. In tumors that retain wild type p53, the pathway can be altered by upstream modulators, particularly the p53 negative regulators MDM2 and MDM4. promoter, ii) single copy, chromosomally located p53-responsive and control luminescence reporters, iii) enhanced chemical uptake using modified ABC-transporters, iv) small-volume formats for treatment and dual-luciferase assays, and v) opportunities to co-express p53 with other cofactor proteins. This robust system can distinguish different levels of expression of WT and mutant p53 as well as interactions with MDM2 or 53BP1.We found that the small molecules Nutlin and RITA could both relieve the MDM2-dependent inhibition of WT p53 transactivation function, while only RITA could impact p53/53BP1 functional interactions. PRIMA-1 was ineffective in modifying the transactivation capacity of WT p53 and missense p53 mutations. This dual-luciferase assay can, therefore, provide a high-throughput assessment tool for investigating a matrix of factors that can influence the p53 network, including the effectiveness of newly developed small molecules, on WT and tumor-associated p53 mutants as well as interacting proteins

Linking soil microbial community structure to potential carbon mineralization: A continental scale assessment of reduced tillage

Potential carbon mineralization (Cmin) is a commonly used indicator of soil health, with greater Cmin values interpreted as healthier soil. While Cmin values are typically greater in agricultural soils managed with minimal physical disturbance, the mechanisms driving the increases remain poorly understood. This study assessed bacterial and archaeal community structure and potential microbial drivers of Cmin in soils maintained under various degrees of physical disturbance. Potential carbon mineralization, 16S rRNA sequences, and soil characterization data were collected as part of the North American Project to Evaluate Soil Health Measurements (NAPESHM). Results showed that type of cropping system, intensity of physical disturbance, and soil pH influenced microbial sensitivity to physical disturbance. Furthermore, 28% of amplicon sequence variants (ASVs), which were important in modeling Cmin, were enriched under soils managed with minimal physical disturbance. Sequences identified as enriched under minimal disturbance and important for modeling Cmin, were linked to organisms which could produce extracellular polymeric substances and contained metabolic strategies suited for tolerating environmental stressors. Understanding how physical disturbance shapes microbial communities across climates and inherent soil properties and drives changes in Cmin provides the context necessary to evaluate management impacts on standardized measures of soil microbial activity

Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

SummaryWe report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCCs/PGLs), a rare tumor type. Multi-platform integration revealed that PCCs/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, and NF1). We also discovered fusion genes in PCCs/PGLs, involving MAML3, BRAF, NGFR, and NF1. Integrated analysis classified PCCs/PGLs into four molecularly defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCCs/PGLs included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine

Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations.

OBJECTIVES: To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi-national investigation of targeted prostate cancer (PCa) screening among men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes. PARTICPANTS AND METHODS: Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36-item short-form health survey (SF-36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale-Revised, risk perception and knowledge. The results of the baseline questionnaire are presented. RESULTS: A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants' perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF-36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status. CONCLUSION: This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer-specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support to men seeking PCa screening

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The Lancet Global Health Commission on Global Eye Health: vision beyond 2020

Eye health and vision have widespread and profound implications for many aspects of life, health, sustainable development, and the economy. Yet nowadays, many people, families, and populations continue to suffer the consequences of poor access to high-quality, affordable eye care, leading to vision impairment and blindness. In 2020, an estimated 596 million people had distance vision impairment worldwide, of whom 43 million were blind. Another 510 million people had uncorrected near vision impairment, simply because of not having reading spectacles. A large proportion of those affected (90%), live in low-income and middle-income countries (LMICs). However, encouragingly, more than 90% of people with vision impairment have a preventable or treatable cause with existing highly cost-effective interventions. Eye conditions affect all stages of life, with young children and older people being particularly affected. Crucially, women, rural populations, and ethnic minority groups are more likely to have vision impairment, and this pervasive inequality needs to be addressed. By 2050, population ageing, growth, and urbanisation might lead to an estimated 895 million people with distance vision impairment, of whom 61 million will be blind. Action to prioritise eye health is needed now. This Commission defines eye health as maximised vision, ocular health, and functional ability, thereby contributing to overall health and wellbeing, social inclusion, and quality of life. Eye health is essential to achieve many of the Sustainable Development Goals (SDGs). Poor eye health and impaired vision have a negative effect on quality of life and restrict equitable access to and achievement in education and the workplace. Vision loss has substantial financial implications for affected individuals, families, and communities. Although high-quality data for global economic estimates are scarce, particularly for LMICs, conservative assessments based on the latest prevalence figures for 2020 suggest that annual global productivity loss from vision impairment is approximately US$410·7 billion purchasing power parity. Vision impairment reduces mobility, affects mental wellbeing, exacerbates risk of dementia, increases likelihood of falls and road traffic crashes, increases the need for social care, and ultimately leads to higher mortality rates. By contrast, vision facilitates many daily life activities, enables better educational outcomes, and increases work productivity, reducing inequality. An increasing amount of evidence shows the potential for vision to advance the SDGs, by contributing towards poverty reduction, zero hunger, good health and wellbeing, quality education, gender equality, and decent work. Eye health is a global public priority, transforming lives in both poor and wealthy communities. Therefore, eye health needs to be reframed as a development as well as a health issue and given greater prominence within the global development and health agendas. Vision loss has many causes that require promotional, preventive, treatment, and rehabilitative interventions. Cataract, uncorrected refractive error, glaucoma, age-related macular degeneration, and diabetic retinopathy are responsible for most global vision impairment. Research has identified treatments to reduce or eliminate blindness from all these conditions; the priority is to deliver treatments where they are most needed. Proven eye care interventions, such as cataract surgery and spectacle provision, are among the most cost-effective in all of health care. Greater financial investment is needed so that millions of people living with unnecessary vision impairment and blindness can benefit from these interventions. Lessons from the past three decades give hope that this challenge can be met. Between 1990 and 2020, the age-standardised global prevalence of blindness fell by 28·5%. Since the 1990s, prevalence of major infectious causes of blindness—onchocerciasis and trachoma—have declined substantially. Hope remains that by 2030, the transmission of onchocerciasis will be interrupted, and trachoma will be eliminated as a public health problem in every country worldwide. However, the ageing population has led to a higher crude prevalence of age-related causes of blindness, and thus an increased total number of people with blindness in some regions. Despite this progress, business as usual will not keep pace with the demographic trends of an ageing global population or address the inequities that persist in each country. New threats to eye health are emerging, including the worldwide increase in diabetic retinopathy, high myopia, retinopathy of prematurity, and chronic eye diseases of ageing such as glaucoma and age-related macular degeneration. With the projected increase in such conditions and their associated vision loss over the coming decades, urgent action is needed to develop innovative treatments and deliver services at a greater scale than previously achieved. Good eye health at the community and national level has been marginalised as a luxury available to only wealthy or urban areas. Eye health needs to be urgently brought into the mainstream of national health and development policy, planning, financing, and action. The challenge is to develop and deliver comprehensive eye health services (promotion, prevention, treatment, rehabilitation) that address the full range of eye conditions within the context of universal health coverage. Accessing services should not bring the risk of falling into poverty and services should be of high quality, as envisaged by the WHO framework for health-care quality: effective, safe, people-centred, timely, equitable, integrated, and efficient. To this framework we add the need for services to be environmentally sustainable. Universal health coverage is not universal without eye care. Multiple obstacles need to be overcome to achieve universal coverage for eye health. Important issues include complex barriers to availability and access to quality services, cost, major shortages and maldistribution of well-trained personnel, and lack of suitable, well maintained equipment and consumables. These issues are particularly widespread in LMICs, but also occur in underserved communities in high-income countries. Strong partnerships need to be formed with natural allies working in areas affected by eye health, such as non-communicable diseases, neglected tropical diseases, healthy ageing, children's services, education, disability, and rehabilitation. The eye health sector has traditionally focused on treatment and rehabilitation, and underused health promotion and prevention strategies to lessen the impact of eye disease and reduce inequality. Solving these problems will depend on solutions established from high quality evidence that can guide more effective implementation at scale. Evidence-based approaches will need to address existing deficiencies in the supply and demand. Strategic investments in discovery research, harnessing new findings from diverse fields, and implementation research to guide effective scale up are needed globally. Encouragingly, developments in telemedicine, mobile health, artificial intelligence, and distance learning could potentially enable eye care professionals to deliver higher quality care that is more plentiful, equitable, and cost-effective. This Commission did a Grand Challenges in Global Eye Health prioritisation exercise to highlight key areas for concerted research and action. This exercise has identified a broad set of challenges spanning the fields of epidemiology, health systems, diagnostics, therapeutics, and implementation. The most compelling of these issues, picked from among 3400 suggestions proposed by 336 people from 118 countries, can help to frame the future research agenda for global eye health. In this Commission, we harness lessons learned from over two decades, present the growing evidence for the life-transforming impact of eye care, and provide a thorough understanding of rapid developments in the field. This report was created through a broad consultation involving experts within and outside the eye care sector to help inform governments and other stakeholders about the path forward for eye health beyond 2020, to further the SDGs (including universal health coverage), and work towards a world without avoidable vision loss. The next few years are a crucial time for the global eye health community and its partners in health care, government, and other sectors to consider the successes and challenges encountered in the past two decades, and at the same time to chart a way forward for the upcoming decades. Moving forward requires building on the strong foundation laid by WHO and partners in VISION 2020 with renewed impetus to ultimately deliver high quality universal eye health care for all