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UNLABELLED: The two main functions of bioinformatics are the organization and analysis of biological data using computational resources. Geneious Basic has been designed to be an easy-to-use and flexible desktop software application framework for the organization and analysis of biological data, with a focus on molecular sequences and related data types. It integrates numerous industry-standard discovery analysis tools, with interactive visualizations to generate publication-ready images. One key contribution to researchers in the life sciences is the Geneious public application programming interface (API) that affords the ability to leverage the existing framework of the Geneious Basic software platform for virtually unlimited extension and customization. The result is an increase in the speed and quality of development of computation tools for the life sciences, due to the functionality and graphical user interface available to the developer through the public API. Geneious Basic represents an ideal platform for the bioinformatics community to leverage existing components and to integrate their own specific requirements for the discovery, analysis and visualization of biological data. AVAILABILITY AND IMPLEMENTATION: Binaries and public API freely available for download at http://www.geneious.com/basic, implemented in Java and supported on Linux, Apple OSX and MS Windows. The software is also available from the Bio-Linux package repository at http://nebc.nerc.ac.uk/news/geneiousonbl.

Whole-exome sequencing (WES) has been widely used for analysis of human genetic diseases, but its value for the pharmacogenomic profiling of individuals is not well studied. Initially, we performed an in-depth evaluation of the accuracy of WES variant calling in the pharmacogenes CYP2D6 and CYP2C19 by comparison with MiSeq(®) amplicon sequencing data (n = 36). This analysis revealed that the concordance rate between WES and MiSeq(®) was high, achieving 99.60% for variants that were called without exceeding the truth-sensitivity threshold (99%), defined during variant quality score recalibration (VQSR). Beyond this threshold, the proportion of discordant calls increased markedly. Subsequently, we expanded our findings beyond CYP2D6 and CYP2C19 to include more genes genotyped by the iPLEX(®) ADME PGx Panel in the subset of twelve samples. WES performed well, agreeing with the genotyping panel in approximately 99% of the selected pass-filter variant calls. Overall, our results have demonstrated WES to be a promising approach for pharmacogenomic profiling, with an estimated error rate of lower than 1%. Quality filters, particularly VQSR, are important for reducing the number of false variants. Future studies may benefit from examining the role of WES in the clinical setting for guiding drug therapy.

Abstract The tuatara ( Sphenodon punctatus )—the only living member of the reptilian order Rhynchocephalia (Sphenodontia), once widespread across Gondwana 1,2 —is an iconic species that is endemic to New Zealand 2,3 . A key link to the now-extinct stem reptiles (from which dinosaurs, modern reptiles, birds and mammals evolved), the tuatara provides key insights into the ancestral amniotes 2,4 . Here we analyse the genome of the tuatara, which—at approximately 5 Gb—is among the largest of the vertebrate genomes yet assembled. Our analyses of this genome, along with comparisons with other vertebrate genomes, reinforce the uniqueness of the tuatara. Phylogenetic analyses indicate that the tuatara lineage diverged from that of snakes and lizards around 250 million years ago. This lineage also shows moderate rates of molecular evolution, with instances of punctuated evolution. Our genome sequence analysis identifies expansions of proteins, non-protein-coding RNA families and repeat elements, the latter of which show an amalgam of reptilian and mammalian features. The sequencing of the tuatara genome provides a valuable resource for deep comparative analyses of tetrapods, as well as for tuatara biology and conservation. Our study also provides important insights into both the technical challenges and the cultural obligations that are associated with genome sequencing.

BACKGROUND: The Global COVID Vaccine Safety (GCoVS) Project, established in 2021 under the multinational Global Vaccine Data Network™ (GVDN®), facilitates comprehensive assessment of vaccine safety. This study aimed to evaluate the risk of adverse events of special interest (AESI) following COVID-19 vaccination from 10 sites across eight countries. METHODS: Using a common protocol, this observational cohort study compared observed with expected rates of 13 selected AESI across neurological, haematological, and cardiac outcomes. Expected rates were obtained by participating sites using pre-COVID-19 vaccination healthcare data stratified by age and sex. Observed rates were reported from the same healthcare datasets since COVID-19 vaccination program rollout. AESI occurring up to 42 days following vaccination with mRNA (BNT162b2 and mRNA-1273) and adenovirus-vector (ChAdOx1) vaccines were included in the primary analysis. Risks were assessed using observed versus expected (OE) ratios with 95 % confidence intervals. Prioritised potential safety signals were those with lower bound of the 95 % confidence interval (LBCI) greater than 1.5. RESULTS: Participants included 99,068,901 vaccinated individuals. In total, 183,559,462 doses of BNT162b2, 36,178,442 doses of mRNA-1273, and 23,093,399 doses of ChAdOx1 were administered across participating sites in the study period. Risk periods following homologous vaccination schedules contributed 23,168,335 person-years of follow-up. OE ratios with LBCI > 1.5 were observed for Guillain-Barré syndrome (2.49, 95 % CI: 2.15, 2.87) and cerebral venous sinus thrombosis (3.23, 95 % CI: 2.51, 4.09) following the first dose of ChAdOx1 vaccine. Acute disseminated encephalomyelitis showed an OE ratio of 3.78 (95 % CI: 1.52, 7.78) following the first dose of mRNA-1273 vaccine. The OE ratios for myocarditis and pericarditis following BNT162b2, mRNA-1273, and ChAdOx1 were significantly increased with LBCIs > 1.5. CONCLUSION: This multi-country analysis confirmed pre-established safety signals for myocarditis, pericarditis, Guillain-Barré syndrome, and cerebral venous sinus thrombosis. Other potential safety signals that require further investigation were identified.

AIM: To describe indicators of health and well-being for New Zealand secondary school students; explore changes between 2001, 2007 and 2012; and compare these findings to international estimates. METHODS: Three national health and well-being surveys of randomly selected New Zealand secondary school students were conducted. Data are presented as prevalence and variation over time (adjusted odds ratio (aOR)). Comparisons with international estimates were made with subsets of the data. RESULTS: Between 2001 and 2012, students reported reductions in cigarette use (aOR 0.27, 95% confidence interval (CI) 0.23-0.32), alcohol use (aOR 0.39, 95% CI 0.33-0.46), marijuana use (aOR 0.37, 95% CI 0.31-0.43), sexual abuse (aOR 0.52, 95% CI 0.46-0.58), fighting (aOR 0.63, 95% CI 0.55-0.73), seatbelt use (aOR 1.47, 95% CI 1.31-1.65) and risky driving behaviours (aOR 0.39, 95% CI 0.33-0.45). Positive connections to school (perception that the school cares, aOR 1.22, 95% CI 1.10-1.35; liking school, aOR 1.55, 95% CI 1.33-1.82) and family (good family relationship, aOR 1.83, 95% CI 1.70-1.97) also improved. Indicators that did not improve and compared poorly with international estimates were protected sex (condom use at last sexual intercourse, aOR 0.77, 95% CI 0.68-0.87) and healthy life-style (daily physical activity, aOR 0.88, 95% CI 0.78-0.99; overweight/obese, aOR 1.09, 95% CI 0.92-1.31). Exposure to family violence (aOR 1.37, 95% CI 1.11-1.68) and depressive symptoms (aOR 1.03, 95% CI 0.91-1.17) also did not improve. CONCLUSIONS: There have been important improvements in the health and well-being of New Zealand adolescents over a relatively short period. These findings demonstrate that population rates of adolescent risk behaviours are amenable to change. Current policy efforts should not lose momentum, while identified priority areas must be adequately resourced to ensure young people have opportunities to thrive now and in the future.

AIM: This study investigated whether multiple health-care robots could have any benefits or cause any problems in an aged care facility. METHOD: Fifty-three residents and 53 staff participated in a non-randomised controlled trial over 12 weeks. Six robots provided entertainment, communication and health-monitoring functions in staff rooms and activity lounges. These settings were compared to control settings without robots. RESULTS: There were no significant differences between groups in resident or staff outcomes, except a significant increase in job satisfaction in the control group only. The intervention group perceived the robots had more agency and experience than the control group did. Perceived agency of the robots decreased over time in both groups. Overall, we received very mixed responses with positive, neutral and negative comments. CONCLUSIONS: The robots had no major benefits or problems. Future research could give robots stronger operational roles, use more specific outcome measures, and perform cost-benefit analyses.

Single nucleotide polymorphisms (SNPs) are the most abundant type of molecular genetic marker and can be used for producing high-resolution genetic maps, marker-trait association studies and marker-assisted breeding. Large polyploid genomes such as wheat present a challenge for SNP discovery because of the potential presence of multiple homoeologs for each gene. AutoSNPdb has been successfully applied to identify SNPs from Sanger sequence data for several species, including barley, rice and Brassica, but the volume of data required to accurately call SNPs in the complex genome of wheat has prevented its application to this important crop. DNA sequencing technology has been revolutionized by the introduction of next-generation sequencing, and it is now possible to generate several million sequence reads in a timely and cost-effective manner. We have produced wheat transcriptome sequence data using 454 sequencing technology and applied this for SNP discovery using a modified autoSNPdb method, which integrates SNP and gene annotation information with a graphical viewer. A total of 4,694,141 sequence reads from three bread wheat varieties were assembled to identify a total of 38 928 candidate SNPs. Each SNP is within an assembly complete with annotation, enabling the selection of polymorphism within genes of interest.

As the proportion of people in the older age groups grows, demands on care providers increase. The ability of robotic technology to meet these demands is limited by a lack of acceptance by older people. This study investigates which tasks staff and residents in a retirement village would like a robot to assist with, as well as their attitudes towards robots and preferences for their appearance. Findings show that residents are more positive about robots than staff, and participants prefer a silver robot of 1.25 m height, with wheels and a screen on the body. Residents would most like the robot to assist with detecting falls, turning on and off appliances, lifting, cleaning, medication reminding, making phone calls and monitoring location. Making robots that fit these preferences may increase the acceptance of robotic assistants by older people.

BACKGROUND: Sodium restriction is a nonpharmacologic treatment suggested by practice guidelines for the management of patients with heart failure (HF). In this study, we synthesized the data from randomized controlled trials (RCTs) evaluating the effects of sodium restriction on clinical outcomes in patients with HF. METHODS: In this aggregate data meta-analysis, Cochrane Central, MEDLINE (Medical Literature Analysis and Retrieval System Online), Embase Ovid, and CINAHL (Cumulative Index to Nursing and Allied Health Literature) Plus databases were searched up to April 2, 2022. RCTs were included if they investigated the effects of sodium/salt restriction as compared to no restriction on clinical outcomes in patients with HF. Outcomes of interest included mortality, hospitalization, change in New York Heart Association functional class, and quality of life (QoL). RESULTS: Seventeen RCTs were identified (834 and 871 patients in intervention and control groups, respectively). Sodium restriction did not reduce the risk of all-cause death (odds ratio, 0.95 [95% CI, 0.58-1.58]), hospitalization (odds ratio, 0.84 [95% CI, 0.62-1.13]), or the composite of death/hospitalization (odds ratio, 0.88 [95% CI, 0.63-1.23]). The results were similar in different subgroups, except for the numerically lower risk of death with reduced sodium intake reported in RCTs with dietary sodium at the 2000 to 3000 mg/d range as opposed to <2000 mg/d (and in RCTs with versus without fluid restriction as a co-intervention). Among RCTs reporting New York Heart Association change, 2 RCTs (which accounted for two-thirds of the data) showed improvement in New York Heart Association class with sodium restriction. Substantial heterogeneity existed for QoL: 6 RCTs showed improvement of QoL and 4 RCTs showed no improvement of sodium restriction on QoL. CONCLUSIONS: In a meta-analysis of RCTs, sodium restriction was not associated with fewer deaths or hospitalizations in patients with HF. Dietary sodium restriction may be associated with improvements in symptoms and QoL.

Bread wheat (Triticum aestivum) is one of the most important crop plants, globally providing staple food for a large proportion of the human population. However, improvement of this crop has been limited due to its large and complex genome. Advances in genomics are supporting wheat crop improvement. We provide a variety of web-based systems hosting wheat genome and genomic data to support wheat research and crop improvement. WheatGenome.info is an integrated database resource which includes multiple web-based applications. These include a GBrowse2-based wheat genome viewer with BLAST search portal, TAGdb for searching wheat second-generation genome sequence data, wheat autoSNPdb, links to wheat genetic maps using CMap and CMap3D, and a wheat genome Wiki to allow interaction between diverse wheat genome sequencing activities. This system includes links to a variety of wheat genome resources hosted at other research organizations. This integrated database aims to accelerate wheat genome research and is freely accessible via the web interface at http://www.wheatgenome.info/.

AIM: To provide an overview of the health and well-being of sexual minority high school students in New Zealand, investigate differences between sexual minority youth (SMY) and exclusively opposite-sex-attracted youth (EOSAY), and examine changes across survey waves. METHODS: Nationally representative cross-sectional surveys were completed in 2001 (n = 9011), 2007 (n = 8002) and 2012 (n = 8167). Logistic regressions were used to examine the associations between selected outcomes and sexual attraction across survey waves. RESULTS: SMY accounted for 6% of participants in all three waves, with a greater proportion being 'out' in 2012 (P < 0.0001). SMY were more likely to work as volunteers (OR = 1.37) than EOSAY, and the majority of SMY reported good general health, liking school and having caring friends. With the exceptions of binge drinking and being driven dangerously by someone, SMY reported comparatively diminished health and well-being relative to EOSAY. Increasing proportions of SMY had depressive symptoms from 2001 (OR = 2.38) to 2012 (OR = 3.73) compared with EOSAY. There were some differences between the sexes; female SMY were less likely to report positive family relationships (OR = 0.59) and liking school (OR = 0.55), and they were more likely to have been hit (2012 OR = 1.95) than female EOSAY. Male SMY reported especially high rates of suicide attempts (2012 OR = 5.64) compared with male EOSAY. CONCLUSIONS: Health services, schools, communities and families must be more responsive to the needs of SMY to ensure that disparities are addressed.

The co-authors of this paper hereby state their intention to work together to launch the Genomic Observatories Network (GOs Network) for which this document will serve as its Founding Charter. We define a Genomic Observatory as an ecosystem and/or site subject to long-term scientific research, including (but not limited to) the sustained study of genomic biodiversity from single-celled microbes to multicellular organisms.An international group of 64 scientists first published the call for a global network of Genomic Observatories in January 2012. The vision for such a network was expanded in a subsequent paper and developed over a series of meetings in Bremen (Germany), Shenzhen (China), Moorea (French Polynesia), Oxford (UK), Pacific Grove (California, USA), Washington (DC, USA), and London (UK). While this community-building process continues, here we express our mutual intent to establish the GOs Network formally, and to describe our shared vision for its future. The views expressed here are ours alone as individual scientists, and do not necessarily represent those of the institutions with which we are affiliated.

We present a hardware-software coprocessing speech recognizer for real-time embedded applications. The system consists of a standard microprocessor and a hardware accelerator for Gaussian mixture model (GMM) emission probability calculation implemented on a field-programmable gate array. The GMM accelerator is optimized for timing performance by exploiting data parallelism. In order to avoid large memory requirement, the accelerator adopts a double buffering scheme for accessing the acoustic parameters with no assumption made on the access pattern of these parameters. Experiments on widely used benchmark data show that the real-time factor of the proposed system is 0.62, which is about three times faster than the pure software-based baseline system, while the word accuracy rate is preserved at 93.33%. As a part of the recognizer, a new adaptive beam-pruning algorithm is also proposed and implemented, which further reduces the average real-time factor to 0.54 with the word accuracy rate of 93.16%. The proposed speech recognizer is suitable for integration in various types of voice (speech)-controlled applications.

Nanodomains are intracellular foci which transduce signals between major cellular compartments. One of the most ubiquitous signal transducers, the ryanodine receptor (RyR) calcium channel, is tightly clustered within these nanodomains. Super-resolution microscopy has previously been used to visualize RyR clusters near the cell surface. A majority of nanodomains located deeper within cells have remained unresolved due to limited imaging depths and axial resolution of these modalities. A series of enhancements made to expansion microscopy allowed individual RyRs to be resolved within planar nanodomains at the cell periphery and the curved nanodomains located deeper within the interiors of cardiomyocytes. With a resolution of ∼ 15 nm, we localized both the position of RyRs and their individual phosphorylation for the residue Ser2808. With a three-dimensional imaging protocol, we observed disturbances to the RyR arrays in the nanometer scale which accompanied right-heart failure caused by pulmonary hypertension. The disease coincided with a distinct gradient of RyR hyperphosphorylation from the edge of the nanodomain toward the center, not seen in healthy cells. This spatial profile appeared to contrast distinctly from that sustained by the cells during acute, physiological hyperphosphorylation when they were stimulated with a β-adrenergic agonist. Simulations of RyR arrays based on the experimentally determined channel positions and phosphorylation signatures showed how the nanoscale dispersal of the RyRs during pathology diminishes its intrinsic likelihood to ignite a calcium signal. It also revealed that the natural topography of RyR phosphorylation could offset potential heterogeneity in nanodomain excitability which may arise from such RyR reorganization.

The blood-brain barrier (BBB) consists of specialized cells that tightly regulate the in- and outflow of molecules from the blood to brain parenchyma, protecting the brain's microenvironment. If one of the BBB components starts to fail, its dysfunction can lead to a cascade of neuroinflammatory events leading to neuronal dysfunction and degeneration. Preliminary imaging findings suggest that BBB dysfunction could serve as an early diagnostic and prognostic biomarker for a number of neurological diseases. This review aims to provide clinicians with an overview of the emerging field of BBB imaging in humans by answering three key questions: (1. Disease) In which diseases could BBB imaging be useful? (2. Device) What are currently available imaging methods for evaluating BBB integrity? And (3. Distribution) what is the potential of BBB imaging in different environments, particularly in resource limited settings? We conclude that further advances are needed, such as the validation, standardization and implementation of readily available, low-cost and non-contrast BBB imaging techniques, for BBB imaging to be a useful clinical biomarker in both resource-limited and well-resourced settings.

Domain-specific visual languages support high-level modeling for a wide range of application domains. However, building tools to support such languages is very challenging. We describe a set of key conceptual requirements for such tools and our approach to addressing these requirements, a set of visual language-based metatools. These support definition of metamodels, visual notations, views, modeling behaviors, design critics, and model transformations and provide a platform to realize target visual modeling tools. Extensions support collaborative work, human-centric tool interaction, and multiplatform deployment. We illustrate application of the metatoolset on tools developed with our approach. We describe tool developer and cognitive evaluations of our platform and our exemplar tools, and summarize key future research directions.

A quarter of patients with medullary thyroid carcinoma (MTC) have germline mutations in the RET proto-oncogene indicating MEN2. Therefore genetic testing is recommended for all patients presenting with MTC. Approximately 40% of MTCs have somatic RET mutations. Somatic mutations in the RAS genes are the next most common driver mutations and appear to be mutually exclusive with germline RET mutation. The single most common somatic RAS mutation is HRASQ61R (c.182A>G), reported in 4.6% to 11% of all MTCs. Mutation-specific immunohistochemistry (IHC) initially developed to identify the NRASQ61R mutation in melanoma (clone SP174) has proven highly sensitive and specific. Because the amino acid sequences for the HRAS and NRAS proteins at codon 61 are identical, we postulated that SP174 IHC would also identify the somatic HRASQ61R mutation. IHC with SP174 was performed on a tissue microarray of 68 patients with MTC including 13 (22.8%) with molecularly confirmed MEN2. Seven (10.3%) MTCs demonstrated positive staining. Six of these patients had already undergone germline RET mutation testing as part of clinical care and were all confirmed to be wild type, excluding the diagnosis of MEN2. All SP174 immunohistochemically positive MTCs were proven to have HRASQ61R mutation (and lack KRASQ61R and NRASQ61R) by Sanger sequencing. All MEN2 patients showed negative staining. We conclude that IHC with SP174 is highly specific for the HRASQ61R mutation in MTC. Because current data suggest that this mutation is mutually exclusive with germline RET mutation, IHC may also have a role in triaging formal genetic testing for MEN2.

It is well known that when a wireless power transfer system bifurcates, the maximum power transfer capability reduces significantly. This research proposes a dynamic zero voltage switching (ZVS) controller to track the middle ZVS operation curve so as to maintain the peak power potential the system can deliver. A prototype wireless power transfer system has been developed, and it has found that the system can deliver 10 W power required to drive an implantable heart pump with a reduced input voltage, increased coil separation and improved end‐to‐end power efficiency.

BACKGROUND: Relationships between right ventricular (RV) and left ventricular (LV) shape and function may be useful in determining optimal timing for pulmonary valve replacement in patients with repaired tetralogy of Fallot (rTOF). However, these are multivariate and difficult to quantify. We aimed to quantify variations in biventricular shape associated with pulmonary regurgitant volume (PRV) in rTOF using a biventricular atlas. METHODS: In this cross-sectional retrospective study, a biventricular shape model was customized to cardiovascular magnetic resonance (CMR) images from 88 rTOF patients (median age 16, inter-quartile range 11.8-24.3 years). Morphometric scores quantifying biventricular shape at end-diastole and end-systole were computed using principal component analysis. Multivariate linear regression was used to quantify biventricular shape associations with PRV, corrected for age, sex, height, and weight. Regional associations were confirmed by univariate correlations with distances and angles computed from the models, as well as global systolic strains computed from changes in arc length from end-diastole to end-systole. RESULTS: PRV was significantly associated with 5 biventricular morphometric scores, independent of covariates, and accounted for 12.3% of total shape variation (p < 0.05). Increasing PRV was associated with RV dilation and basal bulging, in conjunction with decreased LV septal-lateral dimension (LV flattening) and systolic septal motion towards the RV (all p < 0.05). Increased global RV radial, longitudinal, circumferential and LV radial systolic strains were significantly associated with increased PRV (all p < 0.05). CONCLUSION: A biventricular atlas of rTOF patients quantified multivariate relationships between left-right ventricular morphometry and wall motion with pulmonary regurgitation. Regional RV dilation, LV reduction, LV septal-lateral flattening and increased RV strain were all associated with increased pulmonary regurgitant volume. Morphometric scores provide simple metrics linking mechanisms for structural and functional alteration with important clinical indices.

BACKGROUND: Though it is believed the switch from whole cell to acellular pertussis vaccine has contributed to the resurgence of pertussis disease, few studies have evaluated vaccine effectiveness (VE) and duration of protection provided by an acellular vaccine schedule including three primary doses but no toddler-age dose. We assessed this schedule in New Zealand (NZ), a setting with historically high rates of pertussis disease, and low but recently improved immunisation coverage. We further evaluated protection following the preschool-age booster dose. METHODS: We performed a nested case-control study using national-level healthcare data. Hospitalised and non-hospitalised pertussis was detected among children 6weeks to 7years of age between January 2006 and December 2013. The NZ National Immunisation Register provided vaccination status for cases and controls. Conditional logistic regression was used to calculate dose-specific VE with duration of immunity examined by stratifying VE into ages aligned with the immunisation schedule. RESULTS: VE against pertussis hospitalisation was 93% (95% confidence interval [CI]: 87, 96) following three doses among infants aged 5-11months who received three compared to zero doses. This protection was sustained through children's fourth birthdays (VE⩾91%). VE against non-hospitalised pertussis was also sustained after three doses, from 86% (95% CI: 80, 90) among 5-11month olds to 84% (95% CI: 80, 88) among 3-year-olds. Following the first booster dose at 4years of age, the protective VE of 93% (95% CI: 90, 95) among 4-year-olds continued through 7years of age (VE⩾91%). CONCLUSIONS: We found a high level of protection with no reduction in VE following both the primary course and the first booster dose. These findings support a 3-dose primary course of acellular vaccine with no booster dose until 4years of age.