Panitumumab Use in Metastatic Colorectal Cancer and Patterns of KRAS Testing: Results from a Europe-Wide Physician Survey and Medical Records Review

Background

From 2008–2013, the European indication for panitumumab required that patients’ tumor KRAS exon 2 mutation status was known prior to starting treatment. To evaluate physician awareness of panitumumab prescribing information and how physicians prescribe panitumumab in patients with metastatic colorectal cancer (mCRC), two European multi-country, cross-sectional, observational studies were initiated in 2012: a physician survey and a medical records review. The first two out of three planned rounds for each study are reported.

Methods

The primary objective in the physician survey was to estimate the prevalence of KRAS testing, and in the medical records review, it was to evaluate the effect of test results on patterns of panitumumab use. The medical records review study also included a pathologists’ survey.

Results

In the physician survey, nearly all oncologists (299/301) were aware of the correct panitumumab indication and the need to test patients’ tumor KRAS status before treatment with panitumumab. Nearly all oncologists (283/301) had in the past 6 months of clinical practice administered panitumumab correctly to mCRC patients with wild-type KRAS status. In the medical records review, 97.5% of participating oncologists (77/79) conducted a KRAS test for all of their patients prior to prescribing panitumumab. Four patients (1.3%) did not have tumor KRAS mutation status tested prior to starting panitumumab treatment. Approximately one-quarter of patients (85/306) were treated with panitumumab and concurrent oxaliplatin-containing chemotherapy; of these, 83/85 had confirmed wild-type KRAS status prior to starting panitumumab treatment. All 56 referred laboratories that participated used a Conformité Européenne-marked or otherwise validated KRAS detection method, and nearly all (55/56) participated in a quality assurance scheme.

Conclusions

There was a high level of knowledge amongst oncologists around panitumumab prescribing information and the need to test and confirm patients’ tumors as being wild-type KRAS prior to treatment with panitumumab, with or without concurrent oxaliplatin-containing therapy.     

Effectiveness of a primary care-based integrated mobile health intervention for stroke management in rural China (SINEMA): A cluster-randomized controlled trial

BackgroundManaging noncommunicable diseases through primary healthcare has been identified as the key strategy to achieve universal health coverage but is challenging in most low- and middle-income countries. Stroke is the leading cause of death and disability in rural China. This study aims to determine whether a primary care-based integrated mobile health intervention (SINEMA intervention) could improve stroke management in rural China.Methods and findingsBased on extensive barrier analyses, contextual research, and feasibility studies, we conducted a community-based, two-arm cluster-randomized controlled trial with blinded outcome assessment in Hebei Province, rural Northern China including 1,299 stroke patients (mean age: 65.7 [SD:8.2], 42.6% females, 71.2% received education below primary school) recruited from 50 villages between June 23 and July 21, 2017. Villages were randomly assigned (1:1) to either the intervention or control arm (usual care). In the intervention arm, village doctors who were government-sponsored primary healthcare providers received training, conducted monthly follow-up visits supported by an Android-based mobile application, and received performance-based payments. Participants received monthly doctor visits and automatically dispatched daily voice messages. The primary outcome was the 12-month change in systolic blood pressure (BP). Secondary outcomes were predefined, including diastolic BP, health-related quality of life, physical activity level, self-reported medication adherence (antiplatelet, statin, and antihypertensive), and performance in “timed up and go” test. Analyses were conducted in the intention-to-treat framework at the individual level with clusters and stratified design accounted for by following the prepublished statistical analysis plan. All villages completed the 12-month follow-up, and 611 (intervention) and 615 (control) patients were successfully followed (3.4% lost to follow-up among survivors). The program was implemented with high fidelity, and the annual program delivery cost per capita was US$24.3. There was a significant reduction in systolic BP in the intervention as compared with the control group with an adjusted mean difference: −2.8 mm Hg (95% CI −4.8, −0.9; p = 0.005). The intervention was significantly associated with improvements in 6 out of 7 secondary outcomes in diastolic BP reduction (p < 0.001), health-related quality of life (p = 0.008), physical activity level (p < 0.001), adherence in statin (p = 0.003) and antihypertensive medicines (p = 0.039), and performance in “timed up and go” test (p = 0.022). We observed reductions in all exploratory outcomes, including stroke recurrence (4.4% versus 9.3%; risk ratio [RR] = 0.46, 95% CI 0.32, 0.66; risk difference [RD] = 4.9 percentage points [pp]), hospitalization (4.4% versus 9.3%; RR = 0.45, 95% CI 0.32, 0.62; RD = 4.9 pp), disability (20.9% versus 30.2%; RR = 0.65, 95% CI 0.53, 0.79; RD = 9.3 pp), and death (1.8% versus 3.1%; RR = 0.52, 95% CI 0.28, 0.96; RD = 1.3 pp). Limitations include the relatively short study duration of only 1 year and the generalizability of our findings beyond the study setting.ConclusionsIn this study, a primary care-based mobile health intervention integrating provider-centered and patient-facing technology was effective in reducing BP and improving stroke secondary prevention in a resource-limited rural setting in China.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT03185858","term_id":"NCT03185858"}}NCT03185858.

Lijing Yan and colleagues evaluate a mobile health intervention for secondary stroke prevention in China.     

The Carboxy-Terminal Tails of Septins Cdc11 and Shs1 Recruit Myosin-II Binding Factor Bni5 to the Bud Neck in Saccharomyces cerevisiae

To facilitate large-scale functional studies in Drosophila, the Drosophila Transgenic RNAi Project (TRiP) at Harvard Medical School (HMS) was established along with several goals: developing efficient vectors for RNAi that work in all tissues, generating a genome-scale collection of RNAi stocks with input from the community, distributing the lines as they are generated through existing stock centers, validating as many lines as possible using RT–qPCR and phenotypic analyses, and developing tools and web resources for identifying RNAi lines and retrieving existing information on their quality. With these goals in mind, here we describe in detail the various tools we developed and the status of the collection, which is currently composed of 11,491 lines and covering 71% of Drosophila genes. Data on the characterization of the lines either by RT–qPCR or phenotype is available on a dedicated website, the RNAi Stock Validation and Phenotypes Project (RSVP, http://www.flyrnai.org/RSVP.html), and stocks are available from three stock centers, the Bloomington Drosophila Stock Center (United States), National Institute of Genetics (Japan), and TsingHua Fly Center (China).     

Digital Health and Shared Decision-Making in Diabetes Care – A Survey Initiative in Patients and Clinicians

ObjectiveTo assess the landscape of digital health resources in the United States, better understand the impact of the digital health on shared decision-making, and identify potential barriers and opportunities for progress in the care of persons with diabetes.MethodsThe study consisted of two phases: A qualitative phase in which one-on-one interviews were conducted virtually with 34 physicians (endocrinologists {Endos}: n = 15; primary care physicians {PCPs}: n = 19) between February 11, 2021 and February 18, 2021, and a quantitative phase in which two online, email-based surveys in the English language were conducted between April 16, 2021 and May 17, 2021: one with healthcare professionals (HCP) (n = 403: n = 200 Endos and n = 203 PCPs), and one with persons with diabetes (n = 517: patients with type 1 diabetes, n = 257; patients with type 2 diabetes, n = 260).ResultsDiabetes digital health tools were found to be helpful in shared decision-making, but leading barriers include cost, coverage, and lack of time by healthcare professionals. Among diabetes digital health tools, continuous glucose monitoring (CGM) systems were used most commonly and viewed as most effective in improving quality of life and facilitating shared decision-making. Strategies for increasing use of diabetes digital health resources included lower cost, integration into electronic health records, and increased simplicity of tools.ConclusionThis study revealed that both Endos and PCPs feel that diabetes digital health tools have an overall positive impact. Integration with telemedicine and simpler, lower cost tools with increased patient access can further facilitate shared decision-making and improved diabetes care and quality of life.     

detectIR: A Novel Program for Detecting Perfect and Imperfect Inverted Repeats Using Complex Numbers and Vector Calculation

Inverted repeats are present in abundance in both prokaryotic and eukaryotic genomes and can form DNA secondary structures – hairpins and cruciforms that are involved in many important biological processes. Bioinformatics tools for efficient and accurate detection of inverted repeats are desirable, because existing tools are often less accurate and time consuming, sometimes incapable of dealing with genome-scale input data. Here, we present a MATLAB-based program called detectIR for the perfect and imperfect inverted repeat detection that utilizes complex numbers and vector calculation and allows genome-scale data inputs. A novel algorithm is adopted in detectIR to convert the conventional sequence string comparison in inverted repeat detection into vector calculation of complex numbers, allowing non-complementary pairs (mismatches) in the pairing stem and a non-palindromic spacer (loop or gaps) in the middle of inverted repeats. Compared with existing popular tools, our program performs with significantly higher accuracy and efficiency. Using genome sequence data from HIV-1, Arabidopsis thaliana, Homo sapiens and Zea mays for comparison, detectIR can find lots of inverted repeats missed by existing tools whose outputs often contain many invalid cases. detectIR is open source and its source code is freely available at: https://sourceforge.net/projects/detectir.     

Valor pronóstico de los instrumentos de evaluación de enfermedad avanzada y de final de vida en ancianos ingresados en un centro sociosanitario

Objective

To apply 3 advanced chronic disease evaluation tools in elderly patients admitted to an intermediate and long-term care centre, and evaluate its relationship with mortality.

Accurate Assignment of Significance to Neuropeptide Identifications Using Monte Carlo K-Permuted Decoy Databases

In support of accurate neuropeptide identification in mass spectrometry experiments, novel Monte Carlo permutation testing was used to compute significance values. Testing was based on k-permuted decoy databases, where k denotes the number of permutations. These databases were integrated with a range of peptide identification indicators from three popular open-source database search software (OMSSA, Crux, and X! Tandem) to assess the statistical significance of neuropeptide spectra matches. Significance p-values were computed as the fraction of the sequences in the database with match indicator value better than or equal to the true target spectra. When applied to a test-bed of all known manually annotated mouse neuropeptides, permutation tests with k-permuted decoy databases identified up to 100% of the neuropeptides at p-value < 10⁻⁵. The permutation test p-values using hyperscore (X! Tandem), E-value (OMSSA) and Sp score (Crux) match indicators outperformed all other match indicators. The robust performance to detect peptides of the intuitive indicator “number of matched ions between the experimental and theoretical spectra” highlights the importance of considering this indicator when the p-value was borderline significant. Our findings suggest permutation decoy databases of size 1×10⁵ are adequate to accurately detect neuropeptides and this can be exploited to increase the speed of the search. The straightforward Monte Carlo permutation testing (comparable to a zero order Markov model) can be easily combined with existing peptide identification software to enable accurate and effective neuropeptide detection. The source code is available at http://stagbeetle.animal.uiuc.edu/pepshop/MSMSpermutationtesting.     

A flexible framework for multi-particle refinement in cryo-electron tomography

Cryo-electron tomography (cryo-ET) and subtomogram averaging (STA) are increasingly used for macromolecular structure determination in situ. Here, we introduce a set of computational tools and resources designed to enable flexible approaches to STA through increased automation and simplified metadata handling. We create a bidirectional interface between the Dynamo software package and the Warp-Relion-M pipeline, providing a framework for ab initio and geometrical approaches to multiparticle refinement in M. We illustrate the power of working within this framework by applying it to EMPIAR-10164, a publicly available dataset containing immature HIV-1 virus-like particles (VLPs), and a challenging in situ dataset containing chemosensory arrays in bacterial minicells. Additionally, we provide a comprehensive, step-by-step guide to obtaining a 3.4-Å reconstruction from EMPIAR-10164. The guide is hosted on https://teamtomo.org/, a collaborative online platform we establish for sharing knowledge about cryo-ET.

Employing optimal computational methodology in cryo-electron tomography is not always easy; this article provides a set of tools and a complete guide to obtaining high-resolution structures from cryo-ET data.     

Worst case scenario match analysis and contextual variables in professional soccer players: a longitudinal study

This study aimed to describe the worst-case scenarios (WCS) of professional soccer players by playing position in different durations and analyse WCS considering different contextual variables (match half, match location and match outcome). A longitudinal study was conducted in a professional soccer team. Data were collected from different WCS durations in the total distance (TD), high-speed running distance (HSRD), and sprinting distance (SPD). A mixed analysis of variance was performed to compare different WCS durations between playing positions and contextual variables, making pairwise comparisons by Bonferroni post hoc test. Positional differences were found for TD (p < 0.01, ω_p² = 0.02), HSRD (p < 0.01, ω_p² = 0.01) and SPD (p < 0.01, ω_p² = 0.02). There was a significant interaction when comparing WCS by match half in TD (F = 6.1, p < 0.01, ω_p² = 0.07) but no significant differences in HSRD (p = 0.403, ω_p² = 0) or SPD (p = 0.376, ω_p² = 0). A significant interaction was identified when comparing WCS by match location in TD (F = 51.5, p < 0.01, ω_p² = 0.14), HSRD (F = 19.15, p < 0.01, ω_p² = 0.05) and SPD (F = 8.95, p < 0.01, ω_p² = 0.01) as well as WCS by match outcome in TD (F = 36.4, p < 0.01, ω_p² = 0.08), HSRD (F = 13.6, p < 0.01, ω_p² = 0.04) and SPD (F = 7.4, p < 0.01, ω_p² = 0.02). Positional differences exist in TD, HSRD, and SPD in match-play WCS, and contextual variables such as match half, match location and match outcome have a significant impact on the WCS of professional soccer players.     

Mini-Tn7 vectors as genetic tools for single copy gene cloning in Acinetobacter baumannii

Acinetobacter baumannii is an emerging pathogen that causes serious infections with high mortality rates in immunocompromised individuals. Genetic manipulations in this medically-relevant pathogen are limited by the paucity of molecular tools. In this study, we show the application of the mini-Tn7-based single copy insertion system in A. baumannii. Mini-Tn7 elements are known to integrate at a naturally evolved, therefore presumably neutral location (intergenic region) downstream of the glmS gene (glucosamine-fructose-6-phosphate aminotransferase) in Gram-negative bacteria. We identified the site of insertion of mini-Tn7 in A. baumannii and demonstrated application of this useful cloning tool by inserting the gfp gene into the chromosome. Our work shows that mini-Tn7 elements are useful tools for genetic studies in this important pathogen.     

MOET: a web-based gene set enrichment tool at the Rat Genome Database for multiontology and multispecies analyses

Biological interpretation of a large amount of gene or protein data is complex. Ontology analysis tools are imperative in finding functional similarities through overrepresentation or enrichment of terms associated with the input gene or protein lists. However, most tools are limited by their ability to do ontology-specific and species-limited analyses. Furthermore, some enrichment tools are not updated frequently with recent information from databases, thus giving users inaccurate, outdated or uninformative data. Here, we present MOET or the Multi-Ontology Enrichment Tool (v.1 released in April 2019 and v.2 released in May 2021), an ontology analysis tool leveraging data that the Rat Genome Database (RGD) integrated from in-house expert curation and external databases including the National Center for Biotechnology Information (NCBI), Mouse Genome Informatics (MGI), The Kyoto Encyclopedia of Genes and Genomes (KEGG), The Gene Ontology Resource, UniProt-GOA, and others. Given a gene or protein list, MOET analysis identifies significantly overrepresented ontology terms using a hypergeometric test and provides nominal and Bonferroni corrected P-values and odds ratios for the overrepresented terms. The results are shown as a downloadable list of terms with and without Bonferroni correction, and a graph of the P-values and number of annotated genes for each term in the list. MOET can be accessed freely from https://rgd.mcw.edu/rgdweb/enrichment/start.html.     

A Systematic Assessment of Smartphone Tools for Suicide Prevention

BackgroundSuicide is a leading cause of death globally, and there has been a rapid growth in the use of new technologies such as mobile health applications (apps) to help identify and support those at risk. However, it is not known whether these apps are evidence-based, or indeed contain potentially harmful content. This review examines the concordance of features in publicly available apps with current scientific evidence of effective suicide prevention strategies.MethodsApps referring to suicide or deliberate self-harm (DSH) were identified on the Android and iOS app stores. Systematic review methodology was employed to screen and review app content. App features were labelled using a coding scheme that reflected the broad range of evidence-based medical and population-based suicide prevention interventions. Best-practice for suicide prevention was based upon a World Health Organization report and supplemented by other reviews of the literature.ResultsOne hundred and twenty-three apps referring to suicide were identified and downloaded for full review, 49 of which were found to contain at least one interactive suicide prevention feature. Most apps focused on obtaining support from friends and family (n = 27) and safety planning (n = 14). Of the different suicide prevention strategies contained within the apps, the strongest evidence in the literature was found for facilitating access to crisis support (n = 13). All reviewed apps contained at least one strategy that was broadly consistent with the evidence base or best-practice guidelines. Apps tended to focus on a single suicide prevention strategy (mean = 1.1), although safety plan apps provided the opportunity to provide a greater number of techniques (mean = 3.9). Potentially harmful content, such as listing lethal access to means or encouraging risky behaviour in a crisis, was also identified.DiscussionMany suicide prevention apps are available, some of which provide elements of best practice, but none that provide comprehensive evidence-based support. Apps with potentially harmful content were also identified. Despite the number of apps available, and their varied purposes, there is a clear need to develop useful, pragmatic, and multifaceted mobile resources for this population. Clinicians should be wary in recommending apps, especially as potentially harmful content can be presented as helpful. Currently safety plan apps are the most comprehensive and evidence-informed, for example, “Safety Net” and “MoodTools—Depression Aid”.     

The first,second, and third most demanding passages of play in professional soccer: a longitudinal study

The study aimed to compare the physical demands required during the first, second, and third most demanding passages (MDP) of play considering the effect of playing position, type of passage, and passage duration. A longitudinal study for three mesocycles was conducted in a professional soccer team competing in LaLiga123. Tracking systems collected total distance covered (DIS), high-speed running distance (HSRD), sprinting distance (SPD), total of high-intensity accelerations (ACC_HIGH), and total of high-intensity decelerations (DEC_HIGH). The results confirmed that a significant effect of the type of passage (first, second or third MDP of play) on DIS (F_{(1.24, 178.89)} = 115.53; p = 0.01; ηp² = 0.45), HSRD (F_{(1.35, 195.36)} = 422.82; p = 0.01; ηp² = 0.75), SPD (F_{(1.43, 206.59)} = 299.99; p = 0.01; ηp² = 0.68), ACC_HIGH (F_{(1.45, 209.38)} = 268.59; p = 0.01; ηp² = 0.65), and DEC_HIGH (F_{(1.45, 209.38)} = 324.88; p = 0.01; ηp² = 0.69) was found. In addition, a significant interaction between playing position, type and duration of the passage was observed in DIS (F_{(12.60, 453.47)} = 1.98; p = 0.02; ηp² = 0.05) and ACC_HIGH (F_{(13.99, 503.78)} = 1.92; p = 0.03; ηp² = 0.06). In conclusion, significant differences in physical demands between the first, second, and third MDP of play were observed. However, there were some cases (DIS and ACC_HIGH) in which no significant differences were found between these passages. Therefore, coaches should consider not only the magnitude of these peak intensity periods (e.g., distance covered per minute) but also the number of passages that players may experience during match play.     

Effect of Village Health Team Home Visits and Mobile Phone Consultations on Maternal and Newborn Care Practices in Masindi and Kiryandongo,Uganda: A Community-Intervention Trial

IntroductionThe World Health Organisation recommends home visits conducted by Community Health Workers (in Uganda known as Village Health Teams—VHTs) in order to improve maternal and newborn health. This study measured the effect of home visits combined with mobile phone consultations on maternal and newborn care practices.MethodIn a community intervention trial design 16 health centres in Masindi and Kiryandongo districts, Uganda were randomly and equally allocated to one of two arms: control and intervention arms. Eight control health centres received the usual maternal and newborn educational messages offered by professional health workers and eight intervention health centres that received an intervention package for maternal care and essential newborn care practices. In the intervention arm VHTs made two prenatal and one postnatal home visit to households. VHTs were provided with mobile phones to enable them make regular telephone consultations with health workers at the health centre serving the catchment area. The primary outcome was health facility delivery. Other outcomes included antenatal attendances, birth preparedness, cord and thermal care and breastfeeding practices. Analysis was by intention-to-treat.ResultsA total of 1385 pregnant women were analysed: 758 and 627 in the control and intervention arms respectively. Significant post-intervention differences were: delivery place [adjusted Odds Ratio aOR: 17.94(95%CI: 6.26–51.37); p<0.001], cord care [aOR: 3.05(95%CI: 1.81–5.12); p<0.001] thermal care [aOR: 7.58(95%CI: 2.52–22.82); p<0.001], and timely care-seeking for newborn illness [aOR: 4.93(95%CI: 1.59–15.31); p = 0.006].ConclusionVHTs can have an effect in promoting proper cord and thermal care for the newborn and improve timely care-seeking for health facility delivery and newborn illness, because they could answer questions and refer patients correctly. However, VHTs should be supported by professional health workers through the use of mobile phones.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02084680","term_id":"NCT02084680"}}NCT02084680     

Serological Prevalence of Schistosoma japonicum in Mobile Populations in Previously Endemic but Now Non-Endemic Regions of China: A Systematic Review and Meta-Analysis

Background

Schistosomiasis japonica has been resurging in certain areas of China where its transmission was previously well controlled or interrupted. Several factors may be contributing to this, including mobile populations, which if infected, may spread the disease. A wide range of estimates have been published for S. japonicum infections in mobile populations, and a synthesis of these data will elucidate the relative risk presented from these groups.

Methods

A literature search for publications up to Oct 31, 2014 on S. japonicum infection in mobile populations in previously endemic but now non-endemic regions was conducted using four bibliographic databases: China National Knowledge Infrastructure, WanFang, VIP Chinese Journal Databases, and PubMed. A meta-analysis was conducted by pooling one arm binary data with MetaAnalyst Beta 3.13. The protocol is available on PROSPERO (No. CRD42013005967).

Results

A total of 41 studies in Chinese met the inclusion criteria, covering seven provinces of China. The time of post-interruption surveillance ranged from the first year to the 31^st year. After employing a random-effects model, from 1992 to 2013 the pooled seroprevalence ranged from 0.9% (95% CI: 0.5-1.6%) in 2003 to 2.3% (95% CI: 1.5-3.4) in 1995; from the first year after the disease had been interrupted to the 31^st year, the pooled seroprevalence ranged from 0.6% (95% CI: 0.2-2.1%) in the 27th year to 4.0% (95%CI: 1.3-11.3%) in the second year. The pooled seroprevalence in mobile populations each year was significantly lower than among the residents of endemic regions, whilst four papers reported a lower level of infection in the mobile populations than in the local residents out of only 13 papers which included this data.

Conclusions

The re-emergence of S. japonicum in areas which had previously interrupted transmission might be due to other factors, although risk from re-introduction from mobile populations could not be excluded.     

A new approach for annotation of transposable elements using small RNA mapping

Transposable elements (TEs) are mobile genomic DNA sequences found in most organisms. They so densely populate the genomes of many eukaryotic species that they are often the major constituents. With the rapid generation of many plant genome sequencing projects over the past few decades, there is an urgent need for improved TE annotation as a prerequisite for genome-wide studies. Analogous to the use of RNA-seq for gene annotation, we propose a new method for de novo TE annotation that uses as a guide 24 nt-siRNAs that are a part of TE silencing pathways. We use this new approach, called TASR (for Transposon Annotation using Small RNAs), for de novo annotation of TEs in Arabidopsis, rice and soybean and demonstrate that this strategy can be successfully applied for de novo TE annotation in plants.Executable PERL is available for download from: http://tasr-pipeline.sourceforge.net/