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Abstract Background Kiwifruit (Actinidia spp.) are a relatively new, but economically important crop grown in many different parts of the world. Commercial success is driven by the development of new cultivars with novel consumer traits including flavor, appearance, healthful components and convenience. To increase our understanding of the genetic diversity and gene-based control of these key traits in Actinidia, we have produced a collection of 132,577 expressed sequence tags (ESTs). Results The ESTs were derived mainly from four Actinidia species (A. chinensis, A. deliciosa, A. arguta and A. eriantha) and fell into 41,858 non redundant clusters (18,070 tentative consensus sequences and 23,788 EST singletons). Analysis of flavor and fragrance-related gene families (acyltransferases and carboxylesterases) and pathways (terpenoid biosynthesis) is presented in comparison with a chemical analysis of the compounds present in Actinidia including esters, acids, alcohols and terpenes. ESTs are identified for most genes in color pathways controlling chlorophyll degradation and carotenoid biosynthesis. In the health area, data are presented on the ESTs involved in ascorbic acid and quinic acid biosynthesis showing not only that genes for many of the steps in these pathways are represented in the database, but that genes encoding some critical steps are absent. In the convenience area, genes related to different stages of fruit softening are identified. Conclusion This large EST resource will allow researchers to undertake the tremendous challenge of understanding the molecular basis of genetic diversity in the Actinidia genus as well as provide an EST resource for comparative fruit genomics. The various bioinformatics analyses we have undertaken demonstrates the extent of coverage of ESTs for genes encoding different biochemical pathways in Actinidia.

Patients with rare conditions such as cardiac amyloidosis (CA) are difficult to identify, given the similarity of disease manifestations to more prevalent disorders. The deployment of approved therapies for CA has been limited by delayed diagnosis of this disease. Artificial intelligence (AI) could enable detection of rare diseases. Here we present a pipeline for CA detection using AI models with electrocardiograms (ECG) or echocardiograms as inputs. These models, trained and validated on 3 and 5 academic medical centers (AMC) respectively, detect CA with C-statistics of 0.85-0.91 for ECG and 0.89-1.00 for echocardiography. Simulating deployment on 2 AMCs indicated a positive predictive value (PPV) for the ECG model of 3-4% at 52-71% recall. Pre-screening with ECG enhance the echocardiography model performance at 67% recall from PPV of 33% to PPV of 74-77%. In conclusion, we developed an automated strategy to augment CA detection, which should be generalizable to other rare cardiac diseases.

Virtual chemistry laboratory modules were investigated as a potential learning resource that complements traditional in-person experiments. In collaboration with a high school instructor, we designed two interactive modules, "Rates of Reaction" and "Models of Organic Molecules," which became part of a previously reported online chemistry platform referred to as LabLessons. High school students took advantage of these modules to reinforce their knowledge of specific chemistry concepts and prepare themselves for the corresponding lab experiments. Students and the instructor were surveyed after their use of the two modules, providing feedback on the module designs and effectiveness. Survey results as well as academic performance suggest that independent learning through modules had an overall positive impact on learning when used in conjunction with traditional methods.

Purpose: The aim of this study was to compare word-initial and word-final consonant cluster productions in young children who speak African American English (AAE) and compare their productions to what we know about cluster productions in children who speak Mainstream American English (MAE), in order to minimize misdiagnosis of speech sound disorders. Method: Twenty-two children (ages 2;10-5;4 [years;months]) labeled pictures whose names contained at least one consonant cluster in word-initial and/or word-final position. Most two-element clusters of English were sampled, the majority in two or more words. The participants' responses were transcribed using a consensus transcription procedure. Each cluster attempt was analyzed for its similarity with MAE. Results: Percentage matching scores were significantly higher for word-initial than word-final clusters. Word-final clusters produced as singletons were significantly more common than word-final cluster substitutions. However, word-initial cluster substitutions were significantly more common than word-initial clusters produced as singletons. Word-initial cluster mismatches were consistent with markedness theory and the sonority sequencing principle (SSP). By contrast, word-final cluster mismatches were not consistent with the SSP, while the voicing generalization seen in adult speakers of AAE was evident. Conclusion: Culturally and linguistically appropriate assessment of phonological development in children who speak AAE requires an understanding of the contrastive and noncontrastive features exemplified in their consonant cluster productions.

Abstract Background Mutations in several potassium channel subunits have been associated with rare forms of atrial fibrillation. In order to explore the role of potassium channels in inherited typical forms of the arrhythmia, we have screened a cohort of patients from a referral clinic for mutations in the channel subunit genes implicated in the arrhythmia. We sought to determine if mutations in KCNJ2 and KCNE1-5 are a common cause of atrial fibrillation. Methods Serial patients with lone atrial fibrillation or atrial fibrillation with hypertension were enrolled between June 1, 2001 and January 6, 2005. Each patient underwent a standardized interview and physical examination. An electrocardiogram, echocardiogram and blood sample for genetic analysis were also obtained. Patients with a family history of AF were screened for mutations in KCNJ2 and KCNE1-5 using automated sequencing. Results 96 patients with familial atrial fibrillation were enrolled. Eighty-three patients had lone atrial fibrillation and 13 had atrial fibrillation and hypertension. Patients had a mean age of 56 years at enrollment and 46 years at onset of atrial fibrillation. Eighty-one percent of patients had paroxysmal atrial fibrillation at enrollment. Unlike patients with an activating mutation in KCNQ1, the patients had a normal QTc interval with a mean of 412 ± 42 ms. Echocardiography revealed a normal mean ejection fraction of 62.0 ± 7.2 % and mean left atrial dimension of 39.9 ± 7.0 mm. A number of common polymorphisms in KCNJ2 and KCNE1-5 were identified, but no mutations were detected. Conclusion Mutations in KCNJ2 and KCNE1-5 rarely cause typical atrial fibrillation in a referral clinic population.

Abstract Background Vascular disease is a feature of aging, and coronary vascular events are a major source of morbidity and mortality in rare premature aging syndromes. One such syndrome is caused by mutations in the lamin A/C (LMNA) gene, which also has been implicated in familial insulin resistance. A second gene related to premature aging in man and in murine models is the KLOTHO gene, a hypomorphic variant of which (KL-VS) is significantly more common in the first-degree relatives of patients with premature coronary artery disease (CAD). We evaluated whether common variants at the LMNA or KLOTHO genes are associated with rigorously defined premature CAD. Methods We identified 295 patients presenting with premature acute coronary syndromes confirmed by angiography. A control group of 145 patients with no evidence of CAD was recruited from outpatient referral clinics. Comprehensive haplotyping of the entire LMNA gene, including the promoter and untranslated regions, was performed using a combination of TaqMan® probes and direct sequencing of 14 haplotype-tagging single nucleotide polymorphisms (SNPs). The KL-VS variant of the KLOTHO gene was typed using restriction digest of a PCR amplicon. Results Two SNPs that were not in Hardy Weinberg equilibrium were excluded from analysis. We observed no significant differences in allele, genotype or haplotype frequencies at the LMNA or KLOTHO loci between the two groups. In addition, there was no evidence of excess homozygosity at the LMNA locus. Conclusion Our data do not support the hypothesis that premature CAD is associated with common variants in the progeroid syndrome genes LMNA and KLOTHO.

Abstract Background There are numerous ethical challenges that can impact patients and families in the health care setting. This paper reports on the results of a study conducted with a panel of clinical bioethicists in Toronto, Ontario, Canada, the purpose of which was to identify the top ethical challenges facing patients and their families in health care. A modified Delphi study was conducted with twelve clinical bioethicist members of the Clinical Ethics Group of the University of Toronto Joint Centre for Bioethics. The panel was asked the question, what do you think are the top ten ethical challenges that Canadians may face in health care? The panel was asked to rank the top ten ethical challenges throughout the Delphi process and consensus was reached after three rounds. Discussion The top challenge ranked by the group was disagreement between patients/families and health care professionals about treatment decisions. The second highest ranked challenge was waiting lists. The third ranked challenge was access to needed resources for the aged, chronically ill, and mentally ill. Summary Although many of the challenges listed by the panel have received significant public attention, there has been very little attention paid to the top ranked challenge. We propose several steps that can be taken to help address this key challenge.

Abstract Background Prior studies attempting to improve end-of-life care have focused on specific outcomes deemed important to healthcare providers, with disappointing results. Improvement may be best achieved by identifying concerns important to individual patients, communicating the patients' concerns to the treating medical team, and repeating the process frequently until all concerns are addressed. Our objective was to conduct a preliminary evaluation of this innovative patient-centred quality improvement strategy. Methods Initial interviews elicited participants' ideas for improvement, which were then fed back to health care providers by the study investigator. A rapid-cycle change model ensured frequent reassessment and continued feedback. The study involved 36 seriously ill, hospitalized patients on teaching general medical inpatient units of a tertiary care hospital. The main outcome measure was participants' ratings of satisfaction within different domains of care on follow-up interviews. Results The proportion of participants who rated various aspects of their care as "excellent" or "very good" on initial interview was 72% for overall care, 64% for symptom control, 66% for level of support, and 75% for discussions about life sustaining treatments. Patients and families identified many actionable steps for improvement such as; better control of pain and shortness of breath, better access to physicians and medical information, more help with activities of daily living, improving the patient's environment, and shorter waits for nursing care, diagnosis, and treatment. Following feedback to the clinical team, participants reported improvement in overall care (32%), symptom control (44%), and support (40%). Only a minority had further discussions about life sustaining treatments. Conclusion A patient-centred approach using rapid-cycle change was feasible and shows promise for improving the quality of end-of-life care. It should be evaluated on a larger sample in a controlled trial.

We use new and existing nannofossil, palynological, and microfossil biostratigraphic data in conjunction with lithologic and geophysical logs from four wells to establish a series of sequence-stratigraphic events in the Mesozoic-Cenozoic of the Laurentian Subbasin of offshore Newfoundland, eastern Canada. Well biostratigraphic events are integrated with reflection seismic in the area to correlate regional seismic stratigraphic surfaces. The four wells are: Bandol-1, Emerillon C-56, East Wolverine G-37, and Heron H-73. We extend the event stratigraphic scheme previously developed for the Scotian Margin, offshore Nova Scotia, into new areas to the east along the southern Grand Banks, where we recognize four new well-log sequence stratigraphic events, and we modify the definition of a previously recognized regional surface. The new and modified regional surfaces are the Early Albian Unconformity, the Late Bathonian Maximum Flooding Surface (MFS), the Late Bajocian MFS (renamed from Bathonian/Bajocian MFS), the ?Bajocian/Toarcian Unconformity, and the Late Pliensbachian MFS. We recognize the 'Avalon Unconformity' and 'Base-Tertiary Unconformity' of previous studies as amalgamations of multiple smaller-scale unconformities and refine their age in the studied wells. A major improvement over our earlier Scotian Margin event schemes is the extension of the event stratigraphy into the Early Jurassic using a suite of marine biostratigraphic markers. We compare the Early Jurassic event scheme to Deep Sea Drilling Project Site 547B on the conjugate Moroccan Margin to better constrain potential source rock intervals and the early history of the central Atlantic Ocean. Nous utilisons des donn es biostratigraphiques sur les microfossiles, des donn es palynologiques et des donn es sur les nanofossiles, nouvelles et existantes, conjointement avec des diagraphies lithologiques et g ophysiques de quatre puits pour d finir une s rie de ph nom nes stratigraphiques s quentiels de la tranche du M sozo que-C nozo que du sous-bassin Laurentien au large des c tes de Terre-Neuve, dans l'est du Canada. Les ph nom nes biostratigraphiques des puits sont int gr s la sismique r flexion dans le secteur aux fins d'une corr lation des surfaces stratigraphiques sismiques r gionales. Les quatre puits en question sont les puits Bandol-1, Emerillon C-56, East Wolverine G-37 et Heron H-73. Nous largissons le plan stratigraphique des ph nom nes pr c demment cr pour la marge de Scotian, au large des c tes de la Nouvelle- cosse, aux nouveaux secteurs l'est le long de la zone m ridionale des Grands bancs, o nous reconnaissons quatre nouveaux ph nom nes stratigraphiques s quentiels dans les diagraphies des puits et nous modifions la d finition d'une surface r gionale ant rieurement reconnue. Les nouvelles surfaces r gionales modifi es sont la discordance de l'Albien pr coce, la surface d'inondation maximale (SIM) du Bathonien tardif, la SIM du Bajocien tardif (SIM du Bathonien/Bajocien rebaptis e), la discordance bajocienne?/toarcienne et la SIM du Pliensbachien tardif. Nous reconnaissons la << discordance d'Avalon >> et la << discordance de base-tertiaire >> d' tudes ant rieures en tant que regroupements de plusieurs discordances d' chelle plus modeste et nous d terminons leur ge de fa on plus pr cise dans les puits tudi s. Une am lioration notable par rapport nos plans ant rieurs des ph nom nes survenus dans la marge de Scotian est l' largissement de la stratigraphie des ph nom nes au cours du Jurassique pr coce au moyen de rep res stratigraphiques marins. Nous comparons le plan des ph nom nes du Jurassique pr coce au site 547B du projet de forage en eau profonde sur la marge marocaine conjugu e pour mieux limiter les intervalles ventuels de roche m re et les d buts de l'oc an Atlantique central., INTRODUCTION The Scotian Margin Play Fairway Analysis (PFA) project was a multidisciplinary study (under the auspices of the Offshore Energy Technology Research Association of Nova Scotia; OERA 2011) that examined [...]

Appropriate use and interpretation of serological tests for assessments of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure, infection and potential immunity require accurate data on assay performance. We conducted a head-to-head evaluation of ten point-of-care-style lateral flow assays (LFAs) and two laboratory-based enzyme-linked immunosorbent assays to detect anti-SARS-CoV-2 IgM and IgG antibodies in 5-d time intervals from symptom onset and studied the specificity of each assay in pre-coronavirus disease 2019 specimens. The percent of seropositive individuals increased with time, peaking in the latest time interval tested (>20 d after symptom onset). Test specificity ranged from 84.3% to 100.0% and was predominantly affected by variability in IgM results. LFA specificity could be increased by considering weak bands as negative, but this decreased detection of antibodies (sensitivity) in a subset of SARS-CoV-2 real-time PCR-positive cases. Our results underline the importance of seropositivity threshold determination and reader training for reliable LFA deployment. Although there was no standout serological assay, four tests achieved more than 80% positivity at later time points tested and more than 95% specificity.

BackgroundInitiating screening at an earlier age based on cancer family history is one of the primary recommended strategies for the prevention and detection of early-onset colorectal cancer (EOCRC), but data supporting the effectiveness of this approach are limited. The authors assessed the performance of family history-based guidelines for identifying individuals with EOCRC.MethodsThe authors conducted a population-based, case-control study of individuals aged 40 to 49 years with (2473 individuals) and without (772 individuals) incident CRC in the Colon Cancer Family Registry from 1998 through 2007. They estimated the sensitivity and specificity of family history-based criteria jointly recommended by the American Cancer Society, the US Multi-Society Task Force on CRC, and the American College of Radiology in 2008 for early screening, and the age at which each participant could have been recommended screening initiation if these criteria had been applied.ResultsFamily history-based early screening criteria were met by approximately 25% of cases (614 of 2473 cases) and 10% of controls (74 of 772 controls), with a sensitivity of 25% and a specificity of 90% for identifying EOCRC cases aged 40 to 49 years. Among 614 individuals meeting early screening criteria, 98.4% could have been recommended screening initiation at an age younger than the observed age of diagnosis.ConclusionsOf CRC cases aged 40 to 49 years, 1 in 4 met family history-based early screening criteria, and nearly all cases who met these criteria could have had CRC diagnosed earlier (or possibly even prevented) if earlier screening had been implemented as per family history-based guidelines. Additional strategies are needed to improve the detection and prevention of EOCRC for individuals not meeting family history criteria for early screening.

Background:Serological tests are crucial tools for assessments of SARS-CoV-2 exposure, infection and potential immunity. Their appropriate use and interpretation require accurate assay performance data. Method:We conducted an evaluation of 10 lateral flow assays (LFAs) and two ELISAs to detect anti-SARS-CoV-2 antibodies. The specimen set comprised 128 plasma or serum samples from 79 symptomatic SARS-CoV-2 RT-PCR-positive individuals; 108 pre-COVID-19 negative controls; and 52 recent samples from individuals who underwent respiratory viral testing but were not diagnosed with Coronavirus Disease 2019 (COVID-19). Samples were blinded and LFA results were interpreted by two independent readers, using a standardized intensity scoring system. Results:Among specimens from SARS-CoV-2 RT-PCR-positive individuals, the percent seropositive increased with time interval, peaking at 81.8-100.0% in samples taken >20 days after symptom onset. Test specificity ranged from 84.3-100.0% in pre-COVID-19 specimens. Specificity was higher when weak LFA bands were considered negative, but this decreased sensitivity. IgM detection was more variable than IgG, and detection was highest when IgM and IgG results were combined. Agreement between ELISAs and LFAs ranged from 75.7-94.8%. No consistent cross-reactivity was observed. Conclusion:Our evaluation showed heterogeneous assay performance. Reader training is key to reliable LFA performance, and can be tailored for survey goals. Informed use of serology will require evaluations covering the full spectrum of SARS-CoV-2 infections, from asymptomatic and mild infection to severe disease, and later convalescence. Well-designed studies to elucidate the mechanisms and serological correlates of protective immunity will be crucial to guide rational clinical and public health policies.

Plasticity of cancer metabolism can be a major obstacle to efficient targeting of tumour-specific metabolic vulnerabilities. Here, we identify the compensatory mechanisms following the inhibition of major pathways of central carbon metabolism in c-MYC-induced liver tumours. We find that, while inhibition of both glutaminase isoforms (Gls1 and Gls2) in tumours considerably delays tumourigenesis, glutamine catabolism continues, owing to the action of amidotransferases. Synergistic inhibition of both glutaminases and compensatory amidotransferases is required to block glutamine catabolism and proliferation of mouse and human tumour cells in vitro and in vivo. Gls1 deletion is also compensated for by glycolysis. Thus, co-inhibition of Gls1 and hexokinase 2 significantly affects Krebs cycle activity and tumour formation. Finally, the inhibition of biosynthesis of either serine (Psat1-KO) or fatty acid (Fasn-KO) is compensated for by uptake of circulating nutrients, and dietary restriction of both serine and glycine or fatty acids synergistically suppresses tumourigenesis. These results highlight the high flexibility of tumour metabolism and demonstrate that either pharmacological or dietary targeting of metabolic compensatory mechanisms can improve therapeutic outcomes.

This paper explores haptic, affective, sensory and relational interconnections between a child (Erik) and objects, materials and a researcher-practitioner (Christina) at a nursery school in Manchester, United Kingdom (UK). In doing so, it draws upon a Post-humanist theoretical framework. Observational material was collected over the period of a school year. The discussion involves a diffractive three-way 'thinking together' conversation between the authors about what emerges as we attempt to listen to Erik's voices. Improvisation in moments of physical sensation and action with objects, materials and Christina becomes a vehicle for tentative openings and immanent possibilities for all enfolded in the encounter. These are entangled, however, with national and international neoliberal expectations regarding literacy, numeracy and school readiness. We conclude that 'dissenting from within' is a necessary ethical practice if we are to offer something more optimistic for children's becomings than acquiescence in the development of human economic capital.