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

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Tinnitus, physical activity and improved quality of life: investigation of the neural correlates of tinnitus and potential treatment options

Objectives. The objectives of the dissertation are to (1) identify the neural correlates of tinnitus distress and successful habituation, and (2) investigate any relationship between physical activity and tinnitus distress. Subjective tinnitus, commonly referred to as ringing in the ears, is the perception of a sound without an external sound source. It affects approximately 50 million adults in the United States of America, of whom 16 million seek medical attention and 2 million experience catastrophic tinnitus distress. The driving factor of tinnitus distress is not the loudness of tinnitus, but rather the negative emotional reaction to the percept. This reaction is associated with impaired quality of life, anxiety and depression. The limbic system is the focal region of the brain involved in the emotional reaction to stimuli. However, few studies have directly targeted this system to understand neural mechanisms of tinnitus distress or successful habituation. Physical activity has been correlated with improved quality of life and lower levels of anxiety and depression, but, this has not been established in the tinnitus population. Therefore, we investigated the association between physical activity and tinnitus distress. Design. To complete our objectives, we conducted three interconnected studies. In the first study, we examined functional and behavioral differences in those recently diagnosed with tinnitus compared to those who had tinnitus for a long period of time. Note that those with chronic tinnitus of long standing in our study reported lower distress levels than those with recently-diagnosed tinnitus. Second, we conducted a cross-sectional survey study to examine any relationship between physical activity and tinnitus severity. Lastly, we built upon the first two studies to investigate functional and behavioral differences in those with higher levels of tinnitus distress compared to those with lower levels of tinnitus distress, while accounting for physical activity levels. In studies 1 and 3, neural correlates of tinnitus distress were evaluated by comparing those with higher levels of tinnitus distress to those with lower levels of tinnitus distress, while they were listening to affective sounds. The reverse comparison was used to identify regions that may be associated with successful habituation. Results. In the first study, heightened response in the emotional processing system, particularly the insula, was observed in those with higher tinnitus distress compared to those with lower tinnitus severity when listening to affective sounds. Increased response in the middle frontal gyrus was observed in the reverse comparison. In the third study, we found increased response in the amygdala, another region of the emotional processing system, for the higher distress group compared to the lower distress group, and increased response in the superior and middle frontal gyrus for the opposite comparison. Those in the lower tinnitus severity group were also more active, on average, compared to those in the higher tinnitus severity group. Note that in study three, there was a more pronounced difference in tinnitus severity between groups than in study one. In the survey study, increased levels of physical activity were found to be correlated with lower levels of tinnitus severity and higher quality of life, while controlling for other demographic variables. Conclusion. The specific region of the limbic system recruited during emotional processing may determine the severity of tinnitus. Those with mild forms of tinnitus distress appeared to show enhanced engagement of the insula, whereas increased response from the amygdala may be specific to those with more severe forms of tinnitus. Successful habituation to tinnitus was associated with elevated response of frontal cortex, which may reduce amygdala response improve emotional control and lead to habituation to tinnitus. Our results suggest that physical activity may act as therapy to individuals with tinnitus by providing them with a sense of control over the percept and enhanced engagement of the frontal regions

Connectivity of precuneus to the default mode and dorsal attention networks: A possible invariant marker of long-term tinnitus

Resting state functional connectivity studies of tinnitus have provided inconsistent evidence concerning its neural bases. This may be due to differences in the methodology used, but it is also likely related to the heterogeneity of the tinnitus population. In this study, our goal was to identify resting state functional connectivity alterations that consistently appear across tinnitus subgroups. We examined two sources of variability in the subgroups: tinnitus severity and the length of time a person has had chronic tinnitus (referred to as tinnitus duration). Data for the current large-scale analysis of variance originated partly from our earlier investigations (Schmidt et al., 2013; Carpenter-Thompson et al., 2015) and partly from previously unpublished studies. Decreased correlations between seed regions in the default mode network and the precuneus were consistent across individuals with long-term tinnitus (who have had tinnitus for greater than one year), with more bothersome tinnitus demonstrating stronger decreases. In the dorsal attention network, patients with moderately severe tinnitus showed increased correlations between seeds in the network and the precuneus, with this effect also present in only some patients with mild tinnitus. The same effects were not seen in patients with mild tinnitus and tinnitus duration between 6 and 12months. Our results are promising initial steps towards identifying invariant neural correlates of tinnitus and indexing differences between subgroups. Keywords: Tinnitus, Resting state functional connectivity, fMRI, Default mode network, Dorsal attention network, Precuneu

Neural Plasticity of Mild Tinnitus: An fMRI Investigation Comparing Those Recently Diagnosed with Tinnitus to Those That Had Tinnitus for a Long Period of Time

Objectives. The aim of the study was to compare differences in neural correlates of tinnitus in adults with recent onset and others who had the disorder for longer than a year. Design. A total of 25 individuals with tinnitus were divided into groups based on the amount of time for which they had experienced tinnitus: <1 year (RTIN) or >1 year (LTIN). Subjects underwent an fMRI scan while listening to affective sounds from the International Affective Digital Sounds database. Resting state functional connectivity data were also collected. Results. The RTIN group recruited the posterior cingulate and insula to a greater extent than the LTIN group when processing affective sounds. In addition, we found that the LTIN group engaged more frontal regions when listening to the stimuli compared to the RTIN group. Lastly, we found increased correlations between the default mode network and the precuneus in RTIN patients compared to LTIN at rest. Conclusion. Our results suggest that the posterior cingulate and insula may be associated with an early emotional reaction to tinnitus in both task and resting states. Over time, tinnitus patients may recruit more frontal regions to better control their emotional response and exhibit altered connectivity in the default mode network

Neural Plasticity of Mild Tinnitus: An fMRI Investigation Comparing Those Recently Diagnosed with Tinnitus to Those That Had Tinnitus for a Long Period of Time

Objectives. The aim of the study was to compare differences in neural correlates of tinnitus in adults with recent onset and others who had the disorder for longer than a year. Design. A total of 25 individuals with tinnitus were divided into groups based on the amount of time for which they had experienced tinnitus: &lt;1 year (RTIN) or &gt;1 year (LTIN). Subjects underwent an fMRI scan while listening to affective sounds from the International Affective Digital Sounds database. Resting state functional connectivity data were also collected. Results. The RTIN group recruited the posterior cingulate and insula to a greater extent than the LTIN group when processing affective sounds. In addition, we found that the LTIN group engaged more frontal regions when listening to the stimuli compared to the RTIN group. Lastly, we found increased correlations between the default mode network and the precuneus in RTIN patients compared to LTIN at rest. Conclusion. Our results suggest that the posterior cingulate and insula may be associated with an early emotional reaction to tinnitus in both task and resting states. Over time, tinnitus patients may recruit more frontal regions to better control their emotional response and exhibit altered connectivity in the default mode network

Increased Frontal Response May Underlie Decreased Tinnitus Severity.

OBJECTIVES:The overall goal of the study was to identify functional and behavioral differences between individuals with higher tinnitus distress and individuals with lower tinnitus distress. Subsequent exploratory analyses were conducted to investigate the role physical activity may have on the observed results between high and low distress groups. The purpose of the experiment was to identify brain regions to be targeted in future intervention studies for tinnitus. DESIGN:A total of 32 individuals with varying levels of tinnitus severity were recruited from the Urbana-Champaign area. Volunteers were divided into higher tinnitus distress (HD) and lower tinnitus distress (LD) groups. Note that these groups also significantly differed based on physical activity level and were subsequently stratified into higher and lower physical activity level subgroups for exploratory analysis. While in a functional magnetic resonance imaging (fMRI) scanner, subjects listened to affective sounds classified as pleasant, neutral or unpleasant from the International Affective Digital Sounds database. RESULTS:The HD group recruited amygdala and parahippocampus to a greater extent than the LD group when listening to affective sounds. The LD group engaged frontal regions to a greater extent when listening to the affective stimuli compared to the HD group. Both higher physical activity level subgroups recruited more frontal regions, and both lower levels of physical activity subgroups recruited more limbic regions respectively. CONCLUSION:Individuals with lower tinnitus distress may utilize frontal regions to better control their emotional response to affective sounds. Our analysis also suggests physical activity may contribute to lower tinnitus severity and greater engagement of the frontal cortices. We suggest that future intervention studies focus on changes in the function of limbic and frontal regions when evaluating the efficacy of treatment. Additionally, we recommend further investigation concerning the impact of physical activity level on tinnitus distress

Default Mode, Dorsal Attention and Auditory Resting State Networks Exhibit Differential Functional Connectivity in Tinnitus and Hearing Loss

<div><p>We investigated auditory, dorsal attention, and default mode networks in adults with tinnitus and hearing loss in a resting state functional connectivity study. Data were obtained using continuous functional magnetic resonance imaging (fMRI) while the participants were at “rest” and were not performing any task. Participants belonged to one of three groups: middle-aged adults with tinnitus and mild-to-moderate high frequency hearing loss (TIN), age-matched controls with normal hearing and no tinnitus (NH), and a second control group with mild-to-moderate high frequency hearing loss without tinnitus (HL). After standard preprocessing, (a) a group independent component analysis (ICA) using 30 components and (b) a seeding-based connectivity analysis were conducted. In the group ICA, the default mode network was the only network to display visual differences between subject groups. In the seeding analysis, we found increased connectivity between the left parahippocampus and the auditory resting state network in the TIN group when compared to NH controls. Similarly, there was also an increased correlation between the right parahippocampus and the dorsal attention network when compared to HL controls. Other group differences in this attention network included decreased correlations between the seed regions and the right supramarginal gyrus in TIN patients when compared to HL controls. In the default mode network, there was a strong decrease in correlation between the seed regions and the precuneus when compared to both control groups. The findings of this study identify specific alterations in the connectivity of the default mode, dorsal attention, and auditory resting state networks due to tinnitus. The results suggest that therapies for tinnitus that mitigate the increased connectivity of limbic regions with auditory and attention resting state networks and the decreased coherence of the default mode network could be effective at reducing tinnitus-related distress.</p> </div

Average audiograms (combined values of both ears) with standard error bars.

<p>No significant differences between groups at the tested frequencies were observed (p<0.05).</p