High frequency of TTK mutations in microsatellite-unstable colorectal cancer and evaluation of their effect on spindle assembly checkpoint

Frameshift mutations frequently accumulate in microsatellite-unstable colorectal cancers (MSI CRCs) typically leading to downregulation of the target genes due to nonsense-mediated messenger RNA decay. However, frameshift mutations that occur in the 3' end of the coding regions can escape decay, which has largely been ignored in previous works. In this study, we characterized nonsense-mediated decay-escaping frameshift mutations in MSI CRC in an unbiased, genome wide manner. Combining bioinformatic search with expression profiling, we identified genes that were predicted to escape decay after a deletion in a microsatellite repeat. These repeats, located in 258 genes, were initially sequenced in 30 MSI CRC samples. The mitotic checkpoint kinase TTK was found to harbor decay-escaping heterozygous mutations in exon 22 in 59% (105/179) of MSI CRCs, which is notably more than previously reported. Additional novel deletions were found in exon 5, raising the mutation frequency to 66%. The exon 22 of TTK contains an A(9)-G(4)-A(7) locus, in which the most common mutation was a mononucleotide deletion in the A(9) (c.2560delA). When compared with identical non-coding repeats, TTK was found to be mutated significantly more often than expected without selective advantage. Since TTK inhibition is known to induce override of the mitotic spindle assembly checkpoint (SAC), we challenged mutated cancer cells with the microtubule-stabilizing drug paclitaxel. No evidence of checkpoint weakening was observed. As a conclusion, heterozygous TTK mutations occur at a high frequency in MSI CRCs. Unexpectedly, the plausible selective advantage in tumourigenesis does not appear to be related to SAC

Global methylome scores correlate with histological subtypes of colorectal carcinoma and show different associations with common clinical and molecular features

Background. The typical methylation patterns associated with cancer are hypermethylation at gene promoters and global genome hypomethylation. Aberrant CpG island hypermethylation at promoter regions and global genome hypomethylation have not been associated with histological colorectal carcinomas (CRC) subsets. Using Illumina’s 450 k Infinium Human Methylation beadchip, the methylome of 82 CRCs were analyzed, comprising different histological subtypes: 40 serrated adenocarcinomas (SAC), 32 conventional carcinomas (CC) and 10 CRCs showing histological and molecular features of microsatellite instability (hmMSI‐H), and, additionally, 35 normal adjacent mucosae. Scores reflecting the overall methylation at 250 bp, 1 kb and 2 kb from the transcription starting site (TSS) were studied. Results. SAC has an intermediate methylation pattern between CC and hmMSI‐H for the three genome locations. In addition, the shift from promoter hypermethylation to genomic hypomethylation occurs at a small sequence between 250 bp and 1 Kb from the gene TSS, and an asymmetric distribution of methylation was observed between both sides of the CpG islands (N vs. S shores). Conclusion. These findings show that different histological subtypes of CRC have a particular global methylation pattern depending on sequence distance to TSS and highlight the so far underestimated importance of CpGs aberrantly hypomethylated in the clinical phenotype of CRCs.This work was supported by two grants from Instituto de Salud Carlos III, Ministerio de Sanidad, Spain and FEDER funds (refs: PI12-1232, PI18-0144) and another from the European Union’s Horizon 2020 research and innovation program (ref. 848098

Immigration and recommended care after a suicide attempt in Europe: equity or bias?

This report describes the investigation of care recommendations in the medical system across European countries to immigrants who attempted suicide. Data from seven European countries with 8865 local and 2921 immigrant person-cases were derived from the WHO/EURO Multicentre Study on Suicidal Behaviour and ensuing MONSUE (Monitoring Suicidal Behaviour in Europe) project. The relationship between immigrant status and type of aftercare recommended was analysed with binary logistic regression, adjusting for gender, age, method of attempt and the Centre collecting the data. Clear disparities were identified in the care recommendation practices toward immigrants, compared with hosts, over and above differing policies by the European Centres

The accuracy and precision of radiostereometric analysis in monitoring tibial plateau fractures

Background and purpose: The application of radiostereometric analysis (RSA) to monitor stability of tibial plateau fractures during healing is both limited and yet to be validated. We therefore evaluated the accuracy and precision of RSA in a tibial plateau fracture model. Methods: Combinations of 3, 6, and 9 markers in a lateral condyle fracture were evaluated with reference to 6 proximal tibial arrangements. Translation and rotation accuracy was assessed with displacement-controlled stages, while precision was assessed with dynamic double examinations. A comparison of error according to marker number and arrangement was completed with 2-way ANOVA models. Results: The results were improved using more tantalum markers in each segment. In the fracture fragment, marker scatter in all axes was achieved by a circumferential arrangement (medial, anterior, and lateral) of the tantalum markers above the fixation devices. Markers placed on either side of the tibial tuberosity and in the medial aspect of the fracture split represented the proximal tibial reference segment best. Using 6 markers with this distribution in each segment, the translation accuracy (root mean square error) was less than 37 μm in all axes. The precision (95% confidence interval) was less than ± 16 μm in all axes in vitro. Rotation, tested around the x-axis, had an accuracy of less than 0.123° and a precision of ± 0.024°. Interpretation: RSA is highly accurate and precise in the assessment of lateral tibial plateau fracture fragment movement. The validation of our center's RSA system provides evidence to support future clinical RSA fracture studies.Lucian B Solomon, Aaron W Stevenson, Stuart A Callary, Thomas R Sullivan, Donald W Howie, and Mellick J Chehad

Use of the GenoType® MTBDRplus assay to assess drug resistance of Mycobacterium tuberculosis isolates from patients in rural Uganda

<p>Abstract</p> <p>Background</p> <p>Drug resistance levels and patterns among <it>Mycobacterium tuberculosis </it>isolates from newly diagnosed and previously treated tuberculosis patients in Mbarara Uganda were investigated.</p> <p>Methods</p> <p>We enrolled, consecutively, all newly diagnosed and previously treated smear-positive TB patients aged ≥ 18 years. Isolates were tested for drug resistance against rifampicin (RIF) and isoniazid (INH) using the Genotype^®MDRTBplus assay and results were compared with those obtained by the indirect proportion method on Lowenstein-Jensen media. HIV testing was performed using two rapid HIV tests.</p> <p>Results</p> <p>A total of 125 isolates from 167 TB suspects with a mean age 33.7 years and HIV prevalence of 67.9% (55/81) were analysed. A majority (92.8%) of the participants were newly presenting while only 7.2% were retreatment cases. Resistance mutations to either RIF or INH were detected in 6.4% of the total isolates. Multidrug resistance, INH and RIF resistance was 1.6%, 3.2% and 4.8%, respectively. The <it>rpoβ </it>gene mutations seen in the sample were D516V, S531L, H526Y H526 D and D516V, while one strain had a Δ1 mutation in the wild type probes. There were three strains with <it>katG </it>(codon 315) gene mutations while only one strain showed the <it>inhA </it>promoter region gene mutation.</p> <p>Conclusion</p> <p>The TB resistance rate in Mbarara is relatively low. The GenoType^®MTBDRplus assay can be used for rapid screening of MDR-TB in this setting.</p

Care-seeking behavior and out-of-pocket expenditure for sick newborns among urban poor in Lucknow, northern India: a prospective follow-up study

Background: The state of Uttar Pradesh, India accounts for one-quarter of India's neonatal deaths and 8 percent of those worldwide. More than half (52%) of these deaths occur due to infections. In order to achieve Millennium Development Goal-4 of reducing child mortality by two-thirds by the year 2015, it is important to study factors which affect neonatal health. In Uttar Pradesh there is meager data for spending on health care in general and neonates in particular. Methods: The study was conducted at an urban Reproductive and Child Health (RCH) center and a District hospital. Neonates were enrolled within 48 hours of birth and were followed-up once at 6 weeks &#177; 15 days at the OPD of the respective hospitals or at home. This study assessed (1) distribution of neonatal illnesses and different health providers sought (2) distribution of out-of-pocket expenditures by type of illness and type of health provider sought (3) socio-economic distribution of neonatal illnesses, care-seeking behavior and out-of-pocket expenditures. Per-protocol analysis was performed. Results: Five hundred and ten neonates were enrolled and 481(94.4%) were followed-up. Parents of 50.3% (242/481) neonates reported at least one symptom of illness. Of these 22.3% (107/481) neonates had illnesses with at least one reported Integrated Management of Neonatal and Childhood Illnesses (IMNCI) danger sign. Among IMNCI illnesses, point prevalence of septicemia was 6.2% and pneumonia was 5.2% while among non-IMNCI illnesses point prevalence of upper respiratory infection was 9.5%, and diarrhea was 7%. Community based non-government dispensers (NGDs) were leading health providers (37.6%). Mean monthly income of families was 2804 Indian Rupees (INR) (range: 800 to 14000; n = 510), where US$ 1 = 42 INR. Mean out-of-pocket expenditure on neonatal illness was 547.5 INR (range: 1 to 15000; n = 202) and mean out-of-pocket expenditure for hospitalization was 4993 INR (range: 41 to 15000; n = 17). All hospitalizations were for IMNCI illnesses. Neonates from lower income strata were less likely to receive any medical care (p &lt; 0.0001) and were also less likely to be seen by a Government provider (p = 0.03). Conclusion: Since more than half of the neonates have morbidity and out-of-pocket expenditure on neonatal illnesses often exceeds the family income of the lower strata of the low income group in the community, there is a need to either introduce health insurance scheme or subsidize health care for them. Also, since NGDs, half of which could be unqualified are leading health providers, qualified medical care-seeking for sick newborns should be promoted in urban Lucknow

Equity in development and access to health services in the Wild Coast of South Africa: the community view through four linked cross-sectional studies between 1997 and 2007

<p>Abstract</p> <p>Background</p> <p>After election in 1994, the South African government implemented national and regional programmes, such as the Wild Coast Spatial Development Initiative (SDI), to provoke economic growth and to decrease inequities. CIET measured development in the Wild Coast region across four linked cross-sectional surveys (1997-2007). The 2007 survey was an opportunity to look at inequities since the original 1997 baseline, and how such inequities affect access to health care.</p> <p>Methods</p> <p>The 2000, 2004 and 2007 follow-up surveys revisited the communities of the 1997 baseline. Household-level multivariate analysis looked at development indicators and access to health in the context of inequities such as household crowding, access to protected sources of water, house roof construction, main food item purchased, and perception of community empowerment. Individual multivariate models accounted for age, sex, education and income earning opportunities.</p> <p>Results</p> <p>Overall access to protected sources of water increased since the baseline (from 20% in 1997 to 50% in 2007), yet households made of mud and grass, and households who bought basics as their main food item were still less likely to have protected sources of water. The most vulnerable, such as those with less education and less water and food security, were also less likely to have worked for wages leaving them with little chance of improving their standard of living (less education OR 0.59, 95%CI 0.37-0.94; less water security OR 0.67, 95%CI 0.48-0.93; less food security OR 0.43, 95%CI 0.29-0.64). People with less income were more likely to visit government services (among men OR 0.28, 95%CI 0.13-0.59; among women OR 0.33, 95%CI 0.20-0.54), reporting decision factors of cost and distance; users of private clinics sought out better service and medication. Lower food security and poorer house construction was also associated with women visiting government rather than private health services. Women with some formal education were nearly eight times more likely than women with no education to access health services for prevention rather than curative reasons (OR 7.65, 95%CI 4.10-14.25).</p> <p>Conclusion</p> <p>While there have been some improvements, the Wild Coast region still falls well below provincial and national standards in key areas such as access to clean water and employment despite years of government-led investment. Inequities remain prominent, particularly around access to health services.</p

TRY plant trait database - enhanced coverage and open access

Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Mars 2020 Perseverance Rover Studies of the Martian Atmosphere Over Jezero From Pressure Measurements

The pressure sensors on Mars rover Perseverance measure the pressure field in the Jezero crater on regular hourly basis starting in sol 15 after landing. The present study extends up to sol 460 encompassing the range of solar longitudes from Ls ∼ 13°–241° (Martian Year (MY) 36). The data show the changing daily pressure cycle, the sol-to-sol seasonal evolution of the mean pressure field driven by the CO2 sublimation and deposition cycle at the poles, the characterization of up to six components of the atmospheric tides and their relationship to dust content in the atmosphere. They also show the presence of wave disturbances with periods 2–5 sols, exploring their baroclinic nature, short period oscillations (mainly at night-time) in the range 8–24 min that we interpret as internal gravity waves, transient pressure drops with duration ∼1–150 s produced by vortices, and rapid turbulent fluctuations. We also analyze the effects on pressure measurements produced by a regional dust storm over Jezero at Ls ∼ 155°.The UPV/EHU team (Spain) is supported by Grant PID2019-109467GB-I00 funded by 1042 MCIN/AEI/10.13039/501100011033/ and by Groups Gobierno Vasco IT1742-22. GM wants to acknowledge JPL funding from USRA Contract Number 1638782. A. Vicente-Retortillo is supported by the Spanish State Research Agency (AEI) Project No. MDM-2017-0737 Unidad de Excelencia “María de Maeztu”- Centro de Astrobiología (INTA-CSIC). Part of the research was carried out at the Jet Propulsion Laboratory, California Institute of Technology, under a contract with the National Aeronautics and Space Administration (80NM0018D0004). GM wants to acknowledge JPL funding from USRA Contract Number 1638782