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

Comparing Latino Community Members’ and Clinical Staff’s Perspectives on Barriers and Facilitators to Colorectal Cancer Screening

Latinos in the United States have low rates of colorectal cancer (CRC) screening even though CRC is the third leading cause of cancer death among Latinos. This qualitative study aimed to understand and compare the perspectives of clinical staff (CS) and Latino community members (LCMs) in an urban Southern California community regarding barriers and facilitators of CRC screening. Through purposive sampling, 39 LCMs (mean age: 59.4 years, 79.5% female) were recruited to participate in one of five focus groups, and 17 CS (mean age: 38.8 years, 64.7% female) were recruited to participate in semi-structured in-depth interviews, along with a demographic survey. Interviews and focus group recordings were transcribed verbatim, translated, and analyzed using direct content analysis. Demographic data were summarized using descriptive statistics. Findings suggest that CS and LCMs have both similar and opposing perspectives with regard to barriers and facilitators of CRC screening. Themes discussed included attitudes towards CRC screening, CRC knowledge, access to resources, commitments and responsibilities, social support, vicarious learning, patient-provider communication, trust, and social relationships. Study findings can be used to guide interventions and policies to improve access to CRC screening among LCMs

Association between Characteristics of National Association of Epilepsy Centers and Reported Utilization of Specific Surgical Techniques

Background and Objective Nearly one-third of persons with epilepsy will continue having seizures despite trialing multiple antiseizure medications. Epilepsy surgery may be beneficial in these cases, and evaluation at a comprehensive epilepsy center is recommended. Numerous palliative and potentially curative approaches exist, and types of surgery performed may be influenced by center characteristics. This article describes epilepsy center characteristics associated with epilepsy surgery access and volumes in the United States. Methods We analyzed National Association of Epilepsy Centers 2019 annual report and supplemental survey data obtained with responses from 206 adult epilepsy center directors and 136 pediatric epilepsy center directors in the United States. Surgical treatment volumes were compiled with center characteristics, including US Census region. We used multivariable modeling with zero-inflated Poisson regression models to present ORs and incidence rate ratios of receiving a given surgery type based on center characteristics. Results The response rate was 100% with individual element missingness less than 4% across 352 observations undergoing univariate analysis. Multivariable models included 319 complete observations. Significant regional differences were present. The rates of laser interstitial thermal therapy (LITT) were lower at centers in the Midwest (incidence rate ratio [IRR] 0.74, 95% CI 0.59–0.92; p = 0.006) and Northeast (IRR 0.77, 95% CI 0.61–0.96; p = 0.022) compared with those in the South. Conversely, responsive neurostimulation implantation rates were higher in the Midwest (IRR 1.45, 95% CI 1.1–1.91; p = 0.008) and West (IRR 1.91, 95% CI 1.49–2.44; p \u3c 0.001) compared with the South. Center accreditation level, institution type, demographics, and resources were also associated with variations in access and rates of potentially curative and palliative surgical interventions. Discussion Epilepsy surgery procedure volumes are influenced by US epilepsy center region and other characteristics. These variations may affect access to specific surgical treatments for persons with drug resistant epilepsy across the United States

Epilepsy center characteristics and geographic region influence presurgical testing in the United States

Objective: Persons with drug-resistant epilepsy may benefit from epilepsy surgery and should undergo presurgical testing to determine potential candidacy and appropriate intervention. Institutional expertise can influence use and availability of evaluations and epilepsy surgery candidacy. This census survey study aims to examine the influence of geographic region and other center characteristics on presurgical testing for medically intractable epilepsy. Methods: We analyzed annual report and supplemental survey data reported in 2020 from 206 adult epilepsy center directors and 136 pediatric epilepsy center directors in the United States. Test utilization data were compiled with annual center volumes, available resources, and US Census regional data. We used Wilcoxon rank-sum, Kruskal–Wallis, and chi-squared tests for univariate analysis of procedure utilization. Multivariable modeling was also performed to assign odds ratios (ORs) of significant variables. Results: The response rate was 100% with individual element missingness \u3c 11% across 342 observations undergoing univariate analysis. A total of 278 complete observations were included in the multivariable models, and significant regional differences were present. For instance, compared to centers in the South, those in the Midwest used neuropsychological testing (OR = 2.87, 95% confidence interval [CI] = 1.2–6.86; p =.018) and fluorodeoxyglucose–positron emission tomography (OR = 2.74, 95% CI = = 1.14–6.61; p =.025) more commonly. For centers in the Northeast (OR =.46, 95% CI =.23–.93; p =.031) and West (OR =.41, 95% CI =.19–.87; p =.022), odds of performing single-photon emission computerized tomography were lower by nearly 50% compared to those in the South. Center accreditation level, demographics, volume, and resources were also associated with varying individual testing rates. Significance: Presurgical testing for drug-resistant epilepsy is influenced by US geographic region and other center characteristics. These findings have potential implications for comparing outcomes between US epilepsy centers and may inject disparities in access to surgical treatment

Associations between testing and treatment pathways in lesional temporal or extratemporal epilepsy: A census survey of NAEC center directors

Objective: The evaluation to determine candidacy and treatment for epilepsy surgery in persons with drug-resistant epilepsy (DRE) is not uniform. Many non-invasive and invasive tests are available to ascertain an appropriate treatment strategy. This study examines expert response to clinical vignettes of magnetic resonance imaging (MRI)–positive lesional focal cortical dysplasia in both temporal and extratemporal epilepsy to identify associations in evaluations and treatment choice. Methods: We analyzed annual report data and a supplemental epilepsy practice survey reported in 2020 from 206 adult and 136 pediatric epilepsy center directors in the United States. Non-invasive and invasive testing and surgical treatment strategies were compiled for the two scenarios. We used chi-square tests to compare testing utilization between the two scenarios. Multivariable logistic regression modeling was performed to assess associations between variables. Results: The supplemental survey response rate was 100% with 342 responses included in the analyses. Differing testing and treatment approaches were noted between the temporal and extratemporal scenarios such as chronic invasive monitoring selected in 60% of the temporal scenario versus 93% of the extratemporal scenario. Open resection was the most common treatment choice; however, overall treatment choices varied significantly (p \u3c.001). Associations between non-invasive testing, invasive testing, and treatment choices were present in both scenarios. For example, in the temporal scenario stereo-electroencephalography (SEEG) was more commonly associated with fluorodeoxyglucose–positron emission tomography (FDG-PET) (odds ratio [OR] 1.85; 95% confidence interval [CI] 1.06–3.29; p =.033), magnetoencephalography (MEG) (OR 2.90; 95% CI 1.60–5.28; p = \u3c.001), high density (HD) EEG (OR 2.80; 95% CI 1.27–6.24; p =.011), functional MRI (fMRI) (OR 2.17; 95% CI 1.19–4.10; p =.014), and Wada (OR 2.16; 95% CI 1.28–3.66; p =.004). In the extratemporal scenario, choosing SEEG was associated with increased odds of neuromodulation over open resection (OR 3.13; 95% CI 1.24–7.89; p =.016). Significance: In clinical vignettes of temporal and extratemporal lesional DRE, epilepsy center directors displayed varying patterns of non-invasive testing, invasive testing, and treatment choices. Differences in practice underscore the need for comparative trials for the surgical management of DRE

‘Beating the News ’ with EMBERS: Forecasting Civil Unrest using Open Source Indicators

We describe the design, implementation, and evaluation of EMBERS, an automated, 24x7 continuous system for forecasting civil unrest across 10 countries of Latin America using open source indicators such as tweets, news sources, blogs, economic indicators, and other data sources. Unlike retrospective studies, EMBERS has been making forecasts into the future since Nov 2012 which have been (and continue to be) evaluated by an independent T&E team (MITRE). Of note, EMBERS has successfully forecast the June 2013 protests in Brazil and Feb 2014 violent protests in Venezuela. We outline the system architecture of EMBERS, individual models that leverage specific data sources, and a fusion and suppression engine that supports trading off specific evaluation criteria. EMBERS also provides an audit trail interface that enables the investigation of why specific predictions were made along with the data utilized for forecasting. Through numerous evaluations, we demonstrate the superiority of EMBERS over baserate methods and its capability to forecast significant societal happenings

Immunological Cross-Reactivity between Malaria Vaccine Target Antigen P48/45 in <i>Plasmodium vivax</i> and <i>P</i>. <i>falciparum</i> and Cross–Boosting of Immune Responses

<div><p>In general, malaria immunity has been suggested to be species specific with very little, if any, known cross-reactivity between <i>Plasmodium vivax</i> and <i>P</i>. <i>falciparum</i>, both of which are responsible for >90% of human malaria, and co-endemic in many countries. It is therefore believed that species-specific immunity may be needed to target different species of <i>Plasmodium</i>. Pfs48/45 and Pvs48/45 are well established targets in the sexual stages of the malaria parasites, and are being pursued for the development of transmission blocking vaccines. Comparison of their sequences reveals 61% and 55% identity at the DNA and protein level, respectively raising the possibility that these two target antigens might share cross-reacting epitopes. Having succeeded in expressing recombinant Pfs48/45 and Pvs48/45 proteins, we hypothesized that these proteins will not only exhibit immunological cross–reactivity but also cross-boost immune responses. Mice were immunized with purified recombinant proteins using CFA, Montanide ISA-51 and alum as adjuvants, and the sera were analyzed by ELISA, Western blotting and indirect fixed and live IFA to address the hypothesis. Our studies revealed that Pvs48/45-immune sera showed strong cross-reactivity to full length Pfs48/45 protein, and the majority of this cross reactivity was in the amino-terminal and carboxyl-terminal sub-fragments of Pfs48/45. In cross-boosting experiments Pfs48/45 and Pvs48/45 antigens were able to cross-boost each other in mouse immunization studies. Additionally we also noticed an effect of adjuvants in the overall magnitude of observed cross-reactivity. These studies may have significant implications for immunity targeting transmission of both the species of malaria parasites.</p></div

Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy

International audienceBACKGROUND Nusinersen is an antisense oligonucleotide drug that modulates pre-messenger RNA splicing of the survival motor neuron 2 (SMN2) gene. It has been developed for the treatment of spinal muscular atrophy (SMA). METHODS We conducted a multicenter, double-blind, sham-controlled, phase 3 trial of nusinersen in 126 children with SMA who had symptom onset after 6 months of age. The children were randomly assigned, in a 2: 1 ratio, to undergo intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) or a sham procedure (control group) on days 1, 29, 85, and 274. The primary end point was the least-squares mean change from baseline in the Hammersmith Functional Motor Scale-Expanded (HFMSE) score at 15 months of treatment; HFMSE scores range from 0 to 66, with higher scores indicating better motor function. Secondary end points included the percentage of children with a clinically meaningful increase from baseline in the HFMSE score (>= 3 points), an outcome that indicates improvement in at least two motor skills. RESULTS In the prespecified interim analysis, there was a least-squares mean increase from baseline to month 15 in the HFMSE score in the nusinersen group (by 4.0 points) and a least-squares mean decrease in the control group (by -1.9 points), with a significant between-group difference favoring nusinersen (least-squares mean difference in change, 5.9 points; 95% confidence interval, 3.7 to 8.1; P< 0.001). This result prompted early termination of the trial. Results of the final analysis were consistent with results of the interim analysis. In the final analysis, 57% of the children in the nusinersen group as compared with 26% in the control group had an increase from baseline to month 15 in the HFMSE score of at least 3 points (P< 0.001), and the overall incidence of adverse events was similar in the nusinersen group and the control group (93% and 100%, respectively). CONCLUSIONS Among children with later-onset SMA, those who received nusinersen had significant and clinically meaningful improvement in motor function as compared with those in the control group. (Funded by Biogen and Ionis Pharmaceuticals; CHERISH ClinicalTrials. gov number, NCT02292537.