Introduction of Aedes aegypti mosquitoes carrying wAlbB Wolbachia sharply decreases dengue incidence in disease hotspots.

Partial replacement of resident Aedes aegypti mosquitoes with introduced mosquitoes carrying certain strains of inherited Wolbachia symbionts can result in transmission blocking of dengue and other viruses of public health importance. Wolbachia strain wAlbB is an effective transmission blocker and stable at high temperatures, making it particularly suitable for hot tropical climates. Following trial field releases in Malaysia, releases using wAlbB Ae. aegypti have become operationalized by the Malaysian health authorities. We report here on an average reduction in dengue fever of 62.4% (confidence intervals 50-71%) in 20 releases sites when compared to 76 control sites in high-rise residential areas. Importantly the level of dengue reduction increased with Wolbachia frequency, with 75.8% reduction (61-87%) estimated at 100% Wolbachia frequency. These findings indicate large impacts of wAlbB Wolbachia invasions on dengue fever incidence in an operational setting, with incidence expected to further decrease as wider areas are invaded.

Integrative GWAS and co-localisation analysis suggests novel genes associated with age-related multimorbidity.

Advancing age is the greatest risk factor for developing multiple age-related diseases. Therapeutic approaches targeting the underlying pathways of ageing, rather than individual diseases, may be an effective way to treat and prevent age-related morbidity while reducing the burden of polypharmacy. We harness the Open Targets Genetics Portal to perform a systematic analysis of nearly 1,400 genome-wide association studies (GWAS) mapped to 34 age-related diseases and traits, identifying genetic signals that are shared between two or more of these traits. Using locus-to-gene (L2G) mapping, we identify 995 targets with shared genetic links to age-related diseases and traits, which are enriched in mechanisms of ageing and include known ageing and longevity-related genes. Of these 995 genes, 128 are the target of an approved or investigational drug, 526 have experimental evidence of binding pockets or are predicted to be tractable, and 341 have no existing tractability evidence, representing underexplored genes which may reveal novel biological insights and therapeutic opportunities. We present these candidate targets for exploration and prioritisation in a web application.

Surface profile of laminated transfemoral socket fabricated with different types of reinforcement materials.

Composite materials used in the prosthetic and orthotic fields have helped improve the fabrication of sockets. Laminated sockets proved to be stronger than conventional thermoplastic sockets. The internal surface of a laminated socket plays an important role in patient comfort and is influenced by the material used to fabricate the socket. This study analyzes the internal surface profile of five different materials, that is, Dacron felt, fiberglass, Perlon stockinette, polyester stockinette, and elastic stockinette. All sockets were fabricated using an acrylic resin mix with hardener powder at a ratio of 100:3. The internal surface of the sockets was tested using the Mitutoyo SurfTest SJ-210 series for 20 trials. The overall Ra values were 2.318, 2.380, 2.682, 2.722, and 3.750 µm for fiberglass, polyester, Perlon, elastic stockinette, and Dacron felt. Dacron felt yielded the lowest Ra value, thus, producing the smoothest internal surface but requiring high skill and the correct technique during the fabrication of a laminated socket. Fiberglass is considered the best material for the internal surface despite not producing the lowest value individually but overall is the lowest and most consistent, indicating that it is easy to use to laminate prosthetic sockets.

Surface profile analysis of laminated transfemoral prosthetic socket fabricated with different ratios of epoxy resin and acrylic resin.

Acrylic and epoxy are common types of resin used in fabricating sockets. Different types of resin will affect the internal surface of a laminated socket. This paper is to determine the best combination of ratio for epoxy and acrylic resin for a laminated prosthesis socket and to evaluate the surface profile analysis of different combinations of laminated prosthetic sockets for surface roughness. Transfemoral sockets were created using various resin-to-hardener ratios of 2:1, 3:1, 3:2, 2:3, and 1:3 for epoxy resin and 100:1, 100:2, 100:3, 100:4, and 100:5 for acrylic resin. Eight layers of stockinette consisting of four elastic stockinette and four Perlon stockinette were used. A sample with a size of 4 cm × 6 cm was cut out from the socket on the lateral side below the Greater Trochanter area. The Mitutoyo Sj-210 Surface Tester stylus was run through the sample and gave the Average Surface Roughness value (Ra), Root Mean Square Roughness value (Rq), and Ten-Point Mean Roughness value (Rz). Epoxy resin shows a smoother surface compared to acrylic resin with Ra values of is 0.766 µm, 0.9716 µm, 0.9847 µm and 1.5461 µm with 3:2, 3:1, 2:1 and 2:3 ratio respectively. However, for epoxy resin with ratio 1:3, the resin does not cure with the hardener. As for acrylic resin the Ra values are 1.0086 µm, 2.362 µm, 3.372 µm, 4.762 µm and 6.074 µm with 100: 1, 100:2, 100:5, 100:4 and 100:3 ratios, respectively. Epoxy resin is a better choice in fabricating a laminated socket considering the surface produced is smoother.

Development and Performance Evaluation of an IoT-Integrated Breath Analyzer.

Although alcohol consumption may produce effects that can be beneficial or harmful, alcohol consumption prevails among communities around the globe. Additionally, alcohol consumption patterns may be associated with several factors among communities and individuals. Numerous technologies and methods are implemented to enhance the detection and tracking of alcohol consumption, such as vehicle-integrated and wearable devices. In this paper, we present a cellular-based Internet of Things (IoT) implementation in a breath analyzer to enable data collection from multiple users via a single device. Cellular technology using hypertext transfer protocol (HTTP) was implemented as an IoT gateway. IoT integration enabled the direct retrieval of information from a database relative to the device and direct upload of data from the device onto the database. A manually developed threshold algorithm was implemented to quantify alcohol concentrations within a range from 0 to 200 mcg/100 mL breath alcohol content using electrochemical reactions in a fuel-cell sensor. Two data collections were performed: one was used for the development of the model and was split into two sets for model development and on-machine validation, and another was used as an experimental verification test. An overall accuracy of 98.16% was achieved, and relative standard deviations within the range from 1.41% to 2.69% were achieved, indicating the reliable repeatability of the results. The implication of this paper is that the developed device (an IoT-integrated breath analyzer) may provide practical assistance for healthcare representatives and researchers when conducting studies involving the detection and data collection of alcohol consumption patterns.

The next-generation Open Targets Platform: reimagined, redesigned, rebuilt.

The Open Targets Platform (https://platform.opentargets.org/) is an open source resource to systematically assist drug target identification and prioritisation using publicly available data. Since our last update, we have reimagined, redesigned, and rebuilt the Platform in order to streamline data integration and harmonisation, expand the ways in which users can explore the data, and improve the user experience. The gene-disease causal evidence has been enhanced and expanded to better capture disease causality across rare, common, and somatic diseases. For target and drug annotations, we have incorporated new features that help assess target safety and tractability, including genetic constraint, PROTACtability assessments, and AlphaFold structure predictions. We have also introduced new machine learning applications for knowledge extraction from the published literature, clinical trial information, and drug labels. The new technologies and frameworks introduced since the last update will ease the introduction of new features and the creation of separate instances of the Platform adapted to user requirements. Our new Community forum, expanded training materials, and outreach programme support our users in a range of use cases.

Volume Fluctuations in Active and Nonactive Transtibial Prosthetics Users.

This study aims to evaluate the validity and reliability of the Biosculptor's Bioscanner system in capturing transtibial residual limb volume fluctuations in active and nonactive amputees during walking activity. Residual limb volume was obtained by measuring the limb circumference after amputees walked for 5 to 25 minutes for five consecutive days. The comparison of mean circumference between Bioscanner and manual measurements (i.e., tape measure) showed that the Bioscanner gave a higher estimation of circumference for the different amputees. Short-term changes in girth and volume due to an activity such as walking do not fluctuate uniformly. The results reflected as such as nonconsistence circumference change identified at different locations of the circumference profiles. Both amputees experienced a significant increase in circumference at the distal end of the limbs after 5 minutes of walking (7.35% change in nonactive and 8.83% in active amputees), and the measurement decreased as amputees walked longer. At 4-8 cm below the mid-patella tendon (pressure tolerant areas), both amputees experienced minor changes in the size of their circumference. The residual limb volume calculation resulted in the percentage difference between the two methods ranging from 2.4% to 9.3%. Pearson coefficient correlation obtained showed a high correlation between the two techniques, ranging from 0.97 to 1. The analysis of the limit of agreements showed that the majority of measurements were closed to the mean, suggesting that Bioscanner and manual techniques may be interchangeable and agree with one another. This study has implied that Bioscanner is comparable to the standard measurement method and may serve as an alternative tool in managing daily residual limb volume change.

Alcohol Consumption Patterns: A Systematic Review of Demographic and Sociocultural Influencing Factors.

BACKGROUND: Excessive alcohol consumption has negative effects not only on the drinkers' health but also on others around them. Previous studies suggest that excessive alcohol consumption can be related to a combination of factors such as age, family background, religiosity, etc. Investigating and clarifying these roots of alcohol consumption is crucial so that the right type of interventions can be designed in a specific and targeted manner. OBJECTIVES: This work was conducted as a systematic review to reveal the factors associated with alcohol consumption and to heighten the understanding of the differences among various communities and segments of the population regarding their usage of alcohol. DATA SOURCES: A systematic search of Web of Science, PubMed, ScienceDirect, and Google Scholar was performed. RESULTS: Forty-five studies were included in the review after excluding irrelevant records and duplicates. CONCLUSIONS: Alcohol consumption patterns can be associated with several factors related to communities and individuals, and our review revealed demographic factors, including age and proximity to alcohol outlets, as well as social factors, including family background, socioeconomic background, and religious influence. These findings can be used to establish a guideline for further studies in understanding alcohol consumption patterns among individuals according to their personal characteristics and sociocultural backgrounds.

Multi-ancestry Mendelian randomization of omics traits revealing drug targets of COVID-19 severity.

BACKGROUND: Recent omic studies prioritised several drug targets associated with coronavirus disease 2019 (COVID-19) severity. However, little evidence was provided to systematically estimate the effect of drug targets on COVID-19 severity in multiple ancestries. METHODS: In this study, we applied Mendelian randomization (MR) and colocalization approaches to understand the putative causal effects of 16,059 transcripts and 1608 proteins on COVID-19 severity in European and effects of 610 proteins on COVID-19 severity in African ancestry. We further integrated genetics, clinical and literature evidence to prioritise drug targets. Additional sensitivity analyses including multi-trait colocalization and phenome-wide MR were conducted to test for MR assumptions. FINDINGS: MR and colocalization prioritized four protein targets, FCRL3, ICAM5, ENTPD5 and OAS1 that showed effect on COVID-19 severity in European ancestry. One protein target, SERPINA1 showed a stronger effect in African ancestry but much weaker effect in European ancestry (odds ratio [OR] in Africans=0.369, 95%CI=0.203 to 0.668, P = 9.96 × 10-4; OR in Europeans=1.021, 95%CI=0.901 to 1.157, P = 0.745), which suggested that increased level of SERPINA1 will reduce COVID-19 risk in African ancestry. One protein, ICAM1 showed suggestive effect on COVID-19 severity in both ancestries (OR in Europeans=1.152, 95%CI=1.063 to 1.249, P = 5.94 × 10-4; OR in Africans=1.481, 95%CI=1.008 to 2.176; P = 0.045). The OAS1, SERPINA1 and ICAM1 effects were replicated using updated COVID-19 severity data in the two ancestries respectively, where alternative splicing events in OAS1 and ICAM1 also showed marginal effects on COVID-19 severity in Europeans. The phenome-wide MR of the prioritised targets on 622 complex traits provided information on potential beneficial effects on other diseases and suggested little evidence of adverse effects on major complications. INTERPRETATION: Our study identified six proteins as showing putative causal effects on COVID-19 severity. OAS1 and SERPINA1 were targets of existing drugs in trials as potential COVID-19 treatments. ICAM1, ICAM5 and FCRL3 are related to the immune system. Across the six targets, OAS1 has no reliable instrument in African ancestry; SERPINA1, FCRL3, ICAM5 and ENTPD5 showed a different level of putative causal evidence in European and African ancestries, which highlights the importance of more powerful ancestry-specific GWAS and value of multi-ancestry MR in informing the effects of drug targets on COVID-19 across different populations. This study provides a first step towards clinical investigation of beneficial and adverse effects of COVID-19 drug targets. FUNDING: No.

Whole-exome sequencing identifies rare genetic variants associated with human plasma metabolites.

Metabolite levels measured in the human population are endophenotypes for biological processes. We combined sequencing data for 3,924 (whole-exome sequencing, WES, discovery) and 2,805 (whole-genome sequencing, WGS, replication) donors from a prospective cohort of blood donors in England. We used multiple approaches to select and aggregate rare genetic variants (minor allele frequency [MAF] < 0.1%) in protein-coding regions and tested their associations with 995 metabolites measured in plasma by using ultra-high-performance liquid chromatography-tandem mass spectrometry. We identified 40 novel associations implicating rare coding variants (27 genes and 38 metabolites), of which 28 (15 genes and 28 metabolites) were replicated. We developed algorithms to prioritize putative driver variants at each locus and used mediation and Mendelian randomization analyses to test directionality at associations of metabolite and protein levels at the ACY1 locus. Overall, 66% of reported associations implicate gene targets of approved drugs or bioactive drug-like compounds, contributing to drug targets' validating efforts.

Validation of a roughness parameters for defining surface roughness of prosthetic polyethylene Pe-Lite liner.

The Biosculptor's CNC milling machine, the Biomill, offered four different surfaces machined on positive models. This study aims to adopt the surface topography method in characterizing the four different surface roughness of polyethylene Pe-Lite liner as a product of the Biomill. Three surface parameters chosen were the arithmetic average (Ra), root mean square roughness (Rq), and ten-point height (Rz). The surface parameters were used to define the four different surfaces (STANDARD, FINE, COARSE, and FAST) and then compared with the same liner material from a conventionally fabricated socket. The Ra values of the conventional liner, 8.43 µm, were determined to be in-between the Ra values of STANDARD and FAST surfaces which were 8.33 µm and 8.58 µm respectively. STANDARD surface required 43.2 min to be carved while FAST surface took almost only a third of the time compared to STANDARD surface (conventional socket takes 2-3 days). The results of this study would be one of the guidelines to the prosthetists using the Biosculptor in socket fabrication to produce sockets according to the suitable surface to cater to different requirements and levels of activity of each amputee.

Coding and regulatory variants are associated with serum protein levels and disease.

Circulating proteins can be used to diagnose and predict disease-related outcomes. A deep serum proteome survey recently revealed close associations between serum protein networks and common disease. In the current study, 54,469 low-frequency and common exome-array variants were compared to 4782 protein measurements in the serum of 5343 individuals from the AGES Reykjavik cohort. This analysis identifies a large number of serum proteins with genetic signatures overlapping those of many diseases. More specifically, using a study-wide significance threshold, we find that 2021 independent exome array variants are associated with serum levels of 1942 proteins. These variants reside in genetic loci shared by hundreds of complex disease traits, highlighting serum proteins' emerging role as biomarkers and potential causative agents of a wide range of diseases.

Acclimation of Photosynthesis to Changes in the Environment Results in Decreases of Oxidative Stress in Arabidopsis thaliana.

The dynamic acclimation of photosynthesis plays an important role in increasing the fitness of a plant under variable light environments. Since acclimation is partially mediated by a glucose-6-phosphate/phosphate translocator 2 (GPT2), this study examined whether plants lacking GPT2, which consequently have defective acclimation to increases in light, are more susceptible to oxidative stress. To understand this mechanism, we used the model plant Arabidopsis thaliana [accession Wassilewskija-4 (Ws-4)] and compared it with mutants lacking GPT2. The plants were then grown at low light (LL) at 100 µmol m-2 s-1 for 7 weeks. For the acclimation experiments, a set of plants from LL was transferred to 400 µmol m-2 s-1 conditions for 7 days. Biochemical and physiological analyses showed that the gpt2 mutant plants had significantly greater activity for ascorbate peroxidase (APX), guiacol peroxidase (GPOX), and superoxide dismutase (SOD). Furthermore, the mutant plants had significantly lower maximum quantum yields of photosynthesis (Fv/Fm). A microarray analysis also showed that gpt2 plants exhibited a greater induction of stress-related genes relative to wild-type (WT) plants. We then concluded that photosynthetic acclimation to a higher intensity of light protects plants against oxidative stress.

An open approach to systematically prioritize causal variants and genes at all published human GWAS trait-associated loci.

Genome-wide association studies (GWASs) have identified many variants associated with complex traits, but identifying the causal gene(s) is a major challenge. In the present study, we present an open resource that provides systematic fine mapping and gene prioritization across 133,441 published human GWAS loci. We integrate genetics (GWAS Catalog and UK Biobank) with transcriptomic, proteomic and epigenomic data, including systematic disease-disease and disease-molecular trait colocalization results across 92 cell types and tissues. We identify 729 loci fine mapped to a single-coding causal variant and colocalized with a single gene. We trained a machine-learning model using the fine-mapped genetics and functional genomics data and 445 gold-standard curated GWAS loci to distinguish causal genes from neighboring genes, outperforming a naive distance-based model. Our prioritized genes were enriched for known approved drug targets (odds ratio = 8.1, 95% confidence interval = 5.7, 11.5). These results are publicly available through a web portal ( http://genetics.opentargets.org ), enabling users to easily prioritize genes at disease-associated loci and assess their potential as drug targets.

A review of history of CAD/CAM system application in the production of transtibial prosthetic socket in developing countries (from 1980 to 2019).

The development of the CAD/CAM (Computer-aided design and computer-aided manufacturing) system has globally changed the fabrication and delivery of prosthetics and orthotics. Furthermore, since the introduction of CAD/CAM in the 1980s, many successful CAD/CAM system are available in the market today. However, less than 20% of amputees have access to digital fabrication technology and large portion of the amputees are from the developing countries. This review designed to examine selected studies from 1980 to 2019 on CAD/CAM systems in the production of transtibial prosthetic sockets. A review was conducted based on articles gathered from Web of Science, Pubmed and Science Direct. From the findings, 92 articles found related to CAD/CAM-derived transtibial prosthetic socket (TPS). After a further screening of the articles, 20 studies were chosen and only one study was done in a developing country. The results showed an increase interest in CAD/CAM application in Transtibial prosthetic socket (TPS) production for both developed and developing countries, yet the technology has not fully utilised in the developing countries. Factors such as resources, accessibility, knowledge-gap and lack of experienced prosthetists remain the major causes of the lack of CAD/CAM system studies. Large-scale trials are required to employ digital fabrication in the developing regions, consequently advancing the production of high-quality CAD-CAM-derived TPS where most prosthetic and orthotics are needed.

Open Targets Platform: supporting systematic drug-target identification and prioritisation.

The Open Targets Platform (https://www.targetvalidation.org/) provides users with a queryable knowledgebase and user interface to aid systematic target identification and prioritisation for drug discovery based upon underlying evidence. It is publicly available and the underlying code is open source. Since our last update two years ago, we have had 10 releases to maintain and continuously improve evidence for target-disease relationships from 20 different data sources. In addition, we have integrated new evidence from key datasets, including prioritised targets identified from genome-wide CRISPR knockout screens in 300 cancer models (Project Score), and GWAS/UK BioBank statistical genetic analysis evidence from the Open Targets Genetics Portal. We have evolved our evidence scoring framework to improve target identification. To aid the prioritisation of targets and inform on the potential impact of modulating a given target, we have added evaluation of post-marketing adverse drug reactions and new curated information on target tractability and safety. We have also developed the user interface and backend technologies to improve performance and usability. In this article, we describe the latest enhancements to the Platform, to address the fundamental challenge that developing effective and safe drugs is difficult and expensive.

Comparative study on the accuracy of Biosculptor's Bioscanner system in transtibial residual limb circumference measurement.

PURPOSE: This study aimed to examine the accuracy and validity of the Biosculptor's Bioscanner shape capturing system as a portable measuring device by analysing the changes in transtibial residual limb circumference parameters while walking. Assessment on an amputee could also allow for the clinical usability of the digital scanner to be studied. METHODS: To verify the accuracy of the system, the Bioscanner method was compared to the widely used standard anthropometric manual measurement technique (i.e., tape measure). One transtibial prosthetic user was recruited to conduct a walking activity at a normal walking pace for 5 to 15 minutes. Circumferential profiles of the participant were obtained digitally and manually during 2-5 minutes of resting walking intervals. The mean differences between the two methods were compared and percentage differences were calculated. The means were used to calculate the standard error measurement (SEM) and the 95% confidence intervals. Study of the limit of agreement between the two method was also used to validate the accuracy of Bioscanner. RESULTS: The findings showed that both measurements gave a general comparable linear pattern. The averaged results from both methods resulted in only small distinctive differences especially at circumference near the mid-patella tendon. Similarly, the pressure-sensitive areas of the limb resulted in only an average of 2.28% differences between the two measurement techniques. The system showed high reliability and SEM with <1 of 95% CI values and repeatability study gave ICC >0.9. CONCLUSIONS: Bioscanner appeared to be comparable with the standard manual method. The Biosculptor system provides the portability, fast, reliable, and high accuracy measurements of the transtibial residual limb circumference, thus, it can be considered as a valuable tool for daily measurement of amputee's residual limb and pre-prosthetic training.

Open Targets Genetics: systematic identification of trait-associated genes using large-scale genetics and functional genomics.

Open Targets Genetics (https://genetics.opentargets.org) is an open-access integrative resource that aggregates human GWAS and functional genomics data including gene expression, protein abundance, chromatin interaction and conformation data from a wide range of cell types and tissues to make robust connections between GWAS-associated loci, variants and likely causal genes. This enables systematic identification and prioritisation of likely causal variants and genes across all published trait-associated loci. In this paper, we describe the public resources we aggregate, the technology and analyses we use, and the functionality that the portal offers. Open Targets Genetics can be searched by variant, gene or study/phenotype. It offers tools that enable users to prioritise causal variants and genes at disease-associated loci and access systematic cross-disease and disease-molecular trait colocalization analysis across 92 cell types and tissues including the eQTL Catalogue. Data visualizations such as Manhattan-like plots, regional plots, credible sets overlap between studies and PheWAS plots enable users to explore GWAS signals in depth. The integrated data is made available through the web portal, for bulk download and via a GraphQL API, and the software is open source. Applications of this integrated data include identification of novel targets for drug discovery and drug repurposing.