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Objective. Detection of circulating tumor DNA (ctDNA) in cancer patients can potentially serve as a noninvasive, sensitive test of disease status. The purpose of this study was to determine the ability to detect BRAF (V600E) mutations in the plasma of patients with thyroid nodules, with the goal of distinguishing between benign and malignant nodules. Methods. Consecutive patients with thyroid nodules who consented for surgery were recruited. Plasma samples were obtained preoperatively and one month postoperatively. Quantitative PCR was used to determine the levels of the BRAF (V600E) mutation preoperatively and postoperatively. Results. A total of 109 patients were recruited. On final pathology, 38 (32.8%) patients had benign thyroid nodules, 45 (38.8%) had classical papillary thyroid cancer (PTC), 23 (19.8%) had nonclassical PTC, and 3 (2.6%) had follicular thyroid cancer. 15/109 patients had detectable BRAF (V600E) ctDNA in their preoperative samples—all of them having classical PTC. Higher T-stage and extrathyroidal extension in PTC were associated with positive BRAF (V600E) ctDNA (p<0.05). Eighty-eight pairs of preoperative and postoperative plasma samples were collected and analyzed. Of these eighty-eight paired samples, a total of 13/88 (14.8%) patients had detectable BRAF (V600E) ctDNA in their preoperative samples—all of them having classical PTC. 12 of these 13 patients had no detectable BRAF (V600E) postoperatively, while one remaining patient had a significant decline in his levels (p<0.05). Conclusion. BRAF (V600E) circulating thyroid tumor DNA can be detected in plasma and is correlated with a final diagnosis of the classical variant of PTC. Given that a postoperative drop in BRAF (V600E) ctDNA levels was observed in all cases suggests its utility as a tumor marker.

Mention the words “Easy Readers” and “Leveling” to any children’s librarian and you are sure to get a breadth of responses—from reverence to revulsion. No two librarians will feel the same way about a system. With this article, we wanted to get a birds-eye view of how children’s librarians across the country felt about leveling: if they do or don’t do it, how they feel about it, and how does it work (or not) for their library. For this article, we created a survey on Google Forms consisting of thirteen mostly multiple-choice questions, with write-in options, that we distributed to various librarian-focused Facebook groups and through the ALSC community on ALA Connect.

The superintendent is faced with the challenge of managing their image, building relationships, and utilizing their resources in such a way that they will be perceived as effective, creditable and trustworthy by their principals. Research by Chemers and Murphy (1997) found that perceptions of the leader by followers are the very foundation on which the leaders ability to influence are built. This study sought to: (1) examine the perceptions of a diverse group of principals have of their African American superintendents' leadership; (2) identify any differences that exist between the perceptions of principals of color and European American principals about their African American superintendents; and (3) examine how African American superintendents perceive their leadership in a diverse environment. Qualitative methods were used to examine the perceptions of the principals and the superintendents. Ethnic diversity was the variable used to describe principals of color and European American principals' perceptions of their African American superintendents leadership. Results of the study revealed that principals of color perceived their superintendents differently than their European American counterparts, and European American females had higher levels of trust for their African American superintendents that the European American males.

Background Identification of deleterious genetic variants using DNA sequencing data relies on increasingly detailed filtering strategies to isolate the small subset of variants that are more likely to underlie a disease phenotype. Datasets reflecting population allele frequencies of different types of variants serve as powerful filtering tools, especially in the context of rare disease analysis. While such population-scale allele frequency datasets now exist for structural variants (SVs), it remains a challenge to match SV calls between multiple datasets, thereby complicating estimates of a putative SV's population allele frequency. Results We introduce SVAFotate, a software tool that enables the annotation of SVs with variant allele frequency and related information from existing SV datasets. As a result, VCF files annotated by SVAFotate offer a variety of metrics to aid in the stratification of SVs as common or rare in the broader human population. Conclusions Here we demonstrate the use of SVAFotate in the classification of SVs with regards to their population frequency and illustrate how SVAFotate's annotations can be used to filter and prioritize SVs. Lastly, we detail how best to utilize these SV annotations in the analysis of genetic variation in studies of rare disease.

Over 36 million adults over 65 years of age experience accidental falls each year. The underlying neuromechanics (whole-body function) and driving forces behind accidental falls, as well as the effects of aging on the ability of the musculoskeletal system to adapt, are poorly understood. We evaluated differences in kinematics (lower extremity joint angles and range of motion), kinetics (ground reaction force), and electromyography (muscle co-contraction), due to changes in surface conditions during gait in 14 older adults with a history of falling and 14 young adults. We investigated the impact of challenging surfaces on musculoskeletal adaptation and compared the mechanisms of adaptation between age-groups. Older adults displayed greater hip and knee flexion and range of motion during gait, reduced initial vertical loading, and 13 % greater knee muscle co-contraction during early stance compared to young adults. Across age groups, the presence of an uneven challenging surface increased lower-limb flexion compared to an even surface. On a slick surface, older adults displayed 30 % greater ankle muscle co-contraction during early stance as compared to young adults. Older adults respond to challenging surfaces differently than their younger counterparts, employing greater flexion during early stance. This study underscores the need for determining lower-limb musculoskeletal adaptation strategies during gait and assessing how these strategies change with age, risk of accidental falls, and environmental surfaces to reduce the risk of accidental falls.

Mangrove forests provide many ecosystem services but are among the world’s most threatened ecosystems. Mangroves vary substantially according to their geomorphic and sedimentary setting; while several conceptual frameworks describe these settings, their spatial distribution has not been quantified. Here, we present a new global mangrove biophysical typology and show that, based on their 2016 extent, 40.5% (54,972 km 2 ) of mangrove systems were deltaic, 27.5% (37,411 km 2 ) were estuarine and 21.0% (28,493 km 2 ) were open coast, with lagoonal mangroves the least abundant (11.0%, 14,993 km 2 ). Mangroves were also classified based on their sedimentary setting, with carbonate mangroves being less abundant than terrigenous, representing just 9.6% of global coverage. Our typology provides a basis for future research to incorporate geomorphic and sedimentary setting in analyses. We present two examples of such applications. Firstly, based on change in extent between 1996 and 2016, we show while all types exhibited considerable declines in area, losses of lagoonal mangroves (− 6.9%) were nearly twice that of other types. Secondly, we quantify differences in aboveground biomass between mangroves of different types, with it being significantly lower in lagoonal mangroves. Overall, our biophysical typology provides a baseline for assessing restoration potential and for quantifying mangrove ecosystem service provision.

Severe respiratory infections can result in acute respiratory distress syndrome (ARDS) 1 . There are no effective pharmacological therapies that have been shown to improve outcomes for patients with ARDS. Although the host inflammatory response limits spread of and eventually clears the pathogen, immunopathology is a major contributor to tissue damage and ARDS 1 , 2 . Here we demonstrate that respiratory viral infection induces distinct fibroblast activation states, which we term extracellular matrix (ECM)-synthesizing, damage-responsive and interferon-responsive states. We provide evidence that excess activity of damage-responsive lung fibroblasts drives lethal immunopathology during severe influenza virus infection. By producing ECM-remodelling enzymes—in particular the ECM protease ADAMTS4—and inflammatory cytokines, damage-responsive fibroblasts modify the lung microenvironment to promote robust immune cell infiltration at the expense of lung function. In three cohorts of human participants, the levels of ADAMTS4 in the lower respiratory tract were associated with the severity of infection with seasonal or avian influenza virus. A therapeutic agent that targets the ECM protease activity of damage-responsive lung fibroblasts could provide a promising approach to preserving lung function and improving clinical outcomes following severe respiratory infections. Viral infection of the respiratory system induces exuberant fibroblast activity, resulting in extensive remodelling of the extracellular matrix and cytokine release, which promote immune cell infiltration of the affected area at the expense of respiratory function.

Tania Attié-Bitach and colleagues report that biallelic mutations in KIF7 , a component of the Hedgehog signaling pathway, cause hydrolethalus and acrocallosal syndromes. They also present evidence that heterozygous KIF7 mutations contribute to the allelic load and phenotypic spectrum of other cilia disorders. KIF7, the human ortholog of Drosophila Costal2, is a key component of the Hedgehog signaling pathway. Here we report mutations in KIF7 in individuals with hydrolethalus and acrocallosal syndromes, two multiple malformation disorders with overlapping features that include polydactyly, brain abnormalities and cleft palate. Consistent with a role of KIF7 in Hedgehog signaling, we show deregulation of most GLI transcription factor targets and impaired GLI3 processing in tissues from individuals with KIF7 mutations. KIF7 is also a likely contributor of alleles across the ciliopathy spectrum, as sequencing of a diverse cohort identified several missense mutations detrimental to protein function. In addition, in vivo genetic interaction studies indicated that knockdown of KIF7 could exacerbate the phenotype induced by knockdown of other ciliopathy transcripts. Our data show the role of KIF7 in human primary cilia, especially in the Hedgehog pathway through the regulation of GLI targets, and expand the clinical spectrum of ciliopathies.

Background DNA sequencing has unveiled extensive tumor heterogeneity in several different cancer types, with many exhibiting diverse subclonal populations. Identifying and tracing mutations throughout the expansion and progression of a tumor represents a significant challenge. Furthermore, prioritizing the subset of such mutations most likely to contribute to tumor evolution or that could serve as potential therapeutic targets represents an ongoing problem. Results Here, we describe OncoGEMINI, a new tool designed for exploring the complex patterns and trajectory of somatic and inherited variation observed in heterogeneous tumors biopsied over the course of treatment. This is accomplished by creating a searchable database of variants that includes tumor sampling time points and allows for filtering methods that reflect specific changes in variant allele frequencies over time. Additionally, by incorporating existing annotations and resources that facilitate the interpretation of cancer mutations (e.g., CIViC, DGIdb), OncoGEMINI enables rapid searches for, and potential identification of, mutations that may be driving subclonal evolution. Conclusions By combining relevant genomic annotations alongside specific filtering tools, OncoGEMINI provides powerful and customizable approaches that enable the quick identification of individual tumor variants that meet specified criteria. It can be applied to a wide range of tumor-derived sequence data, but is especially designed for studies with multiple samples, including longitudinal datasets. It is available under an MIT license at github.com/fakedrtom/oncogemini .

Background Phosphorylated tau (p ‐tau)217 has emerged as the optimal blood‐based biomarker for assessing Alzheimer’s disease (AD) pathology in vivo. However, the ability of p ‐tau217 to detect other neurodegenerative diseases such as chronic traumatic encephalopathy (CTE) is unknown. Methods The sample included UNITE brain bank donors with available CSF(n=145) and serum (n=89) collected postmortem. Neuropathological assessments were performed for CTE, including stages I‐IV, as well as intermediate to high likelihood of AD with NIA‐Reagan criteria, including Braak neurofibrillary tangle stage and CERAD score for neuritic plaques. CTE & AD co‐pathologies were assessed. A commercially available single molecule assay for p ‐tau217 (AlzPath) analyzed concentrations within CSF and serum. One‐way ANOVAs were performed to test for increased p ‐tau217 levels in CTE and AD compared to controls. Secondary binary and ordinal logistic regressions, adjusting for age, were conducted to test associations of CSF and serum p ‐tau217 concentrations with high stage CTE and CTE stage and AD, Braak stage, and CERAD score. Results Table 1 describes sample characteristics. p ‐tau217 concentrations in CSF and serum show no significant difference in high stage CTE compared to no or low stage CTE or between CTE stages (Figure 1). p ‐tau217 in CSF and serum was significantly greater in AD (p =<0.001, p =0.042) compared to no or low AD and significantly increased in those with CERAD score>1 compared to those with CERAD of 0 (p =<0.001, p =0.044, Figure 2). Logistic regressions showed no significant associations in CSF or serum between p ‐tau217 and CTE or CTE stage. However, CSF p ‐tau217 concentrations were positively associated with AD (OR=2.717, p =0.002), increasing Braak stage (OR=1.728, p =0.004), and with increasing CERAD score (OR=2.048, p =<.001). Increasing serum p ‐tau217 concentrations showed a trend towards an association with AD (OR=1.456, p =0.092) and with increasing CERAD score (OR=1.412, p =0.080). Conclusions Postmortem CSF and serum p ‐tau217 were significantly associated with AD. In contrast, neither CSF or serum p ‐tau217 showed associations with CTE diagnosis or severity. This suggests that p ‐tau217 may be helpful for discriminating AD from CTE. Discovery efforts are needed for development of fluid biomarkers with diagnostic utility for CTE.