Mechanically-flexible wafer-scale integrated-photonics fabrication platform.

The field of integrated photonics has advanced rapidly due to wafer-scale fabrication, with integrated-photonics platforms and fabrication processes being demonstrated at both infrared and visible wavelengths. However, these demonstrations have primarily focused on fabrication processes on silicon substrates that result in rigid photonic wafers and chips, which limit the potential application spaces. There are many application areas that would benefit from mechanically-flexible integrated-photonics wafers, such as wearable healthcare monitors and pliable displays. Although there have been demonstrations of mechanically-flexible photonics fabrication, they have been limited to fabrication processes on the individual device or chip scale, which limits scalability. In this paper, we propose, develop, and experimentally characterize the first 300-mm wafer-scale platform and fabrication process that results in mechanically-flexible photonic wafers and chips. First, we develop and describe the 300-mm wafer-scale CMOS-compatible flexible platform and fabrication process. Next, we experimentally demonstrate key optical functionality at visible wavelengths, including chip coupling, waveguide routing, and passive devices. Then, we perform a bend-durability study to characterize the mechanical flexibility of the photonic chips, demonstrating bending a single chip 2000 times down to a bend diameter of 0.5 inch with no degradation in the optical performance. Finally, we experimentally characterize polarization-rotation effects induced by bending the flexible photonic chips. This work will enable the field of integrated photonics to advance into new application areas that require flexible photonic chips.

Simultaneous Separation of Protactinium-230 and Uranium-230 Isotopes from a Proton-Irradiated Thorium Matrix.

The use of radioisotopes in cancer therapy is becoming increasingly important. As a potential candidate for targeted alpha therapy, 230U (t1/2 = 20.8 d), the decay daughter of 230Pa (t1/2 = 17.4 d) is currently being investigated for cancer treatment. For radioisotopes to be used in biomedicine, they must be radiochemically pure and free from carrier interference. This can be challenging given their short half-life. Thus, radiological separation methods for harvesting isotopes for use in biomedicine must be simple, fast, and capable of obtaining the required purity levels. Herein, we demonstrate a new rapid method for the separation of 230U and 230Pa from a proton-irradiated 232Th metal target and from coproduced fission products with high recovery and purity. A dual-column approach was used, in which the first column was an anion exchange (AX) column and the second column was a DGA column. The MP-1 AX resin was used for the primary separation of the three major components (U, Pa, and Th, as well as fission products), and the DGA column was used for further purification of the separated 230U. The method is simple and allows for straightforward separation of U, Pa, Th, and fission products; also, the entire process from target dissolution to shipment of 230U could be completed in 3 days with an overall 230U recovery yield of 96 ± 3%. Additionally, separated 230Pa fractions can be used to harvest ingrown 230U after initial separation.

Are teenagers 'drowning' in sports and energy drinks? The need for upstream and downstream interventions.

Sports and energy drinks are consumed regularly by adults, children and young people (CYP). The dental and wider health implications of their frequent consumption pose a challenge to dental and other health professionals alike, in particular the increasing consumption in CYP, with up to one-third drinking caffeinated energy drinks regularly. The recent popularity of products such as Prime has highlighted the role of social media and marketing on the purchasing and consumption of these drinks, particularly for CYP. This paper describes current consumption of sports and energy drinks nationally and the potential impact on general and dental health. It discusses their popularity in CYP, including purchasing habits and motivations for this age group, and the role of social media in promoting consumption. It then highlights the importance of introducing public health measures to address these factors. Finally, a key role for dental teams is proposed, with an emphasis on the importance of further research to determine the effectiveness of dietary interventions delivered by dental professionals.

Sustainability as part of a quality framework for the organisation of oral healthcare.

This paper aims to highlight to the reader that the organisation of dentistry at a system level lags behind other healthcare professions in regulation, policy, education and research. It argues that seeing sustainability as being as important as safety in oral healthcare quality would begin to rectify this. For the practitioner, it also identifies existing guidance on practising sustainably and reinforces that it does not require radical change but evidence-based care.

'The dental nurse played a vital role in helping to manage the patient': a thematic analysis of undergraduate dental students' reflective journals from outreach placements.

Introduction Community-based dental education, or 'outreach', forms a key part of dental courses in some high-income countries. Its educational benefits are well-established and once graduated, participants feel better prepared for their early career. Yet, it is less clear what students actually learn while on placements.Materials and method Qualitative document and thematic analysis of a convenience sample of anonymised dental student reflective journals (n = 51).Results The reflective journals described varied and broadly positive learning experiences. Analysis identified a number of themes of learning. Most related to the process and outcomes of care, but two key themes - dental anxiety and teamworking - were interrelated with both. Within teamworking, dental nurses appeared important in students' learning. Three process interrelated themes of learning were identified in the data. These were: tailoring your approach; communication and time; and evidence-based dentistry and minimising risk. Two broad interrelated themes relating to outcomes for patients and students were also identified: trust and confidence; and professionalism and personal development.Conclusion This research identified important and potentially transformative learning from outreach placements. This included how dental anxiety impacts patients and the dental team, the importance of teamworking, and the role of dental nurses in students' experiential learning.

Building consensus in defining and conceptualizing acceptability of healthcare: A Delphi study.

BACKGROUND: The concept of healthcare acceptability is important for nursing staff spending most of their time with patients. Nevertheless, acceptability remains confusing without a collective definition in existing literature. OBJECTIVE: This study aimed to create a consensus among experts on definition and conceptual framework of healthcare acceptability. METHODS: We conducted two rounds of Delphi surveys to collect opinions from experts on definition and conceptual framework of healthcare acceptability proposed following thematic content analysis. We calculated the consensus among experts using the modified Appraisal of Guidelines for Research & Evaluation II (AGREE II) instrument and followed the guidance on conducting and reporting Delphi studies (CREDES) best practices. RESULTS: A total of 34 experts completed two rounds of Delphi survey. The definition was validated through consensus as: "a multi-construct concept describing the nonlinear cumulative combination in parts or in whole of experienced or anticipated specific healthcare from the relevant patients/participants, communities, providers/researchers or healthcare systems' managers and policy makers' perspectives in a given context." The overall quality rating was 92.6% and 95.1% for the proposed definition and conceptual framework respectively. CONCLUSION: Opinions collected from experts provided significant insights to build a consensus on healthcare acceptability advancing public health nursing.

Integrated visible-light liquid-crystal-based phase modulators.

In this work, an integrated liquid-crystal-based phase modulator operating at visible wavelengths was developed and experimentally demonstrated. A visible-light silicon-nitride-based 300-mm-wafer foundry platform and a liquid-crystal integration process were developed to leverage the birefringence of liquid crystal to actively tune the effective index of a section of silicon-nitride waveguide and induce a phase shift over its length. The device was experimentally shown to achieve a 41π phase shift within 4.8 Vpp for a 500-µm-long modulator, which means that a 2π phase shifter would need to be only 24.4 µm long. This device is a compact and low-power solution to the challenge of integrated phase modulation in silicon nitride and paves the way for future low-power small-form-factor integrated systems at visible wavelengths.

Rock phosphate solubilization by abiotic and fungal-produced oxalic acid: reaction parameters and bioleaching potential.

Oxalic acid-producing fungi play an important role in biogeochemical transformations of rocks and minerals and possess biotechnological potential for extraction of valuable elements from primary or waste ores and other solid matrices. This research investigates the extraction of phosphate from rock phosphate (RP) by oxalic acid. Reaction parameters were derived using pure oxalic acid solutions to solubilize RP. It was found that the oxalic acid concentration was the main factor driving reaction kinetics. Excess oxalic acid could retard the reaction due to calcium oxalate encrustation on RP surfaces. However, complete P extraction was reached at stoichiometric proportions of apatite and oxalic acid. This reaction reached completion after 168 h, although most of the P (up to 75%) was released in less than 1 h. Most of the Ca released from the apatite formed sparingly soluble calcium oxalate minerals, with a predominance of whewellite over weddellite. Bioleaching of RP employing biomass-free spent culture filtrates containing oxalic acid (100 mM) produced by Aspergillus niger extracted ~ 74% of the P contained in the RP. These findings contribute to a better understanding of the reaction between apatite and oxalic acid and provide insights for potential applications of this process for biotechnological production of phosphate fertilizer.

Rapid, Phase-free Detection of Long Identity-by-Descent Segments Enables Effective Relationship Classification.

Identity-by-descent (IBD) segments are a useful tool for applications ranging from demographic inference to relationship classification, but most detection methods rely on phasing information and therefore require substantial computation time. As genetic datasets grow, methods for inferring IBD segments that scale well will be critical. We developed IBIS, an IBD detector that locates long regions of allele sharing between unphased individuals, and benchmarked it with Refined IBD, GERMLINE, and TRUFFLE on 3,000 simulated individuals. Phasing these with Beagle 5 takes 4.3 CPU days, followed by either Refined IBD or GERMLINE segment detection in 2.9 or 1.1 h, respectively. By comparison, IBIS finishes in 6.8 min or 7.8 min with IBD2 functionality enabled: speedups of 805-946× including phasing time. TRUFFLE takes 2.6 h, corresponding to IBIS speedups of 20.2-23.3×. IBIS is also accurate, inferring ≥7 cM IBD segments at quality comparable to Refined IBD and GERMLINE. With these segments, IBIS classifies first through third degree relatives in real Mexican American samples at rates meeting or exceeding other methods tested and identifies fourth through sixth degree pairs at rates within 0.0%-2.0% of the top method. While allele frequency-based approaches that do not detect segments can infer relationship degrees faster than IBIS, the fastest are biased in admixed samples, with KING inferring 30.8% fewer fifth degree Mexican American relatives correctly compared with IBIS. Finally, we ran IBIS on chromosome 2 of the UK Biobank dataset and estimate its runtime on the autosomes to be 3.3 days parallelized across 128 cores.

Crossover interference and sex-specific genetic maps shape identical by descent sharing in close relatives.

Simulations of close relatives and identical by descent (IBD) segments are common in genetic studies, yet most past efforts have utilized sex averaged genetic maps and ignored crossover interference, thus omitting features known to affect the breakpoints of IBD segments. We developed Ped-sim, a method for simulating relatives that can utilize either sex-specific or sex averaged genetic maps and also either a model of crossover interference or the traditional Poisson model for inter-crossover distances. To characterize the impact of previously ignored mechanisms, we simulated data for all four combinations of these factors. We found that modeling crossover interference decreases the standard deviation of pairwise IBD proportions by 10.4% on average in full siblings through second cousins. By contrast, sex-specific maps increase this standard deviation by 4.2% on average, and also impact the number of segments relatives share. Most notably, using sex-specific maps, the number of segments half-siblings share is bimodal; and when combined with interference modeling, the probability that sixth cousins have non-zero IBD sharing ranges from 9.0 to 13.1%, depending on the sexes of the individuals through which they are related. We present new analytical results for the distributions of IBD segments under these models and show they match results from simulations. Finally, we compared IBD sharing rates between simulated and real relatives and find that the combination of sex-specific maps and interference modeling most accurately captures IBD rates in real data. Ped-sim is open source and available from https://github.com/williamslab/ped-sim.

Rare DEGS1 variant significantly alters de novo ceramide synthesis pathway.

The de novo ceramide synthesis pathway is essential to human biology and health, but genetic influences remain unexplored. The core function of this pathway is the generation of biologically active ceramide from its precursor, dihydroceramide. Dihydroceramides have diverse, often protective, biological roles; conversely, increased ceramide levels are biomarkers of complex disease. To explore the genetics of the ceramide synthesis pathway, we searched for deleterious nonsynonymous variants in the genomes of 1,020 Mexican Americans from extended pedigrees. We identified a Hispanic ancestry-specific rare functional variant, L175Q, in delta 4-desaturase, sphingolipid 1 (DEGS1), a key enzyme in the pathway that converts dihydroceramide to ceramide. This amino acid change was significantly associated with large increases in plasma dihydroceramides. Indexes of DEGS1 enzymatic activity were dramatically reduced in heterozygotes. CRISPR/Cas9 genome editing of HepG2 cells confirmed that the L175Q variant results in a partial loss of function for the DEGS1 enzyme. Understanding the biological role of DEGS1 variants, such as L175Q, in ceramide synthesis may improve the understanding of metabolic-related disorders and spur ongoing research of drug targets along this pathway.

A QTL on chromosome 3q23 influences processing speed in humans.

Processing speed is a psychological construct that refers to the speed with which an individual can perform any cognitive operation. Processing speed correlates strongly with general cognitive ability, declines sharply with age and is impaired across a number of neurological and psychiatric disorders. Thus, identifying genes that influence processing speed will likely improve understanding of the genetics of intelligence, biological aging and the etiologies of numerous disorders. Previous genetics studies of processing speed have relied on simple phenotypes (eg, mean reaction time) derived from single tasks. This strategy assumes, erroneously, that processing speed is a unitary construct. In the present study, we aimed to characterize the genetic architecture of processing speed by using a multidimensional model applied to a battery of cognitive tasks. Linkage and QTL-specific association analyses were performed on the factors from this model. The randomly ascertained sample comprised 1291 Mexican-American individuals from extended pedigrees. We found that performance on all three distinct processing-speed factors (Psychomotor Speed; Sequencing and Shifting and Verbal Fluency) were moderately and significantly heritable. We identified a genome-wide significant quantitative trait locus (QTL) on chromosome 3q23 for Psychomotor Speed (LOD = 4.83). Within this locus, we identified a plausible and interesting candidate gene for Psychomotor Speed (Z = 2.90, P = 1.86 × 10-03 ).

An Evaluation of a Practice-Based Minor Oral Surgery Service.

AIM To report the findings of a service evaluation of an NHS practice-based minor oral surgery service. METHOD A service evaluation including a retrospective analysis of activity and outcome data and assessment of patient and practitioner satisfaction. RESULTS 623 appointments were arranged, with a mean waiting time of 43 days. Treatment provided included: surgical removal of third molars and non-third molars, surgical endodontics and other surgical and oral medicine cases (29.7%, 44.1%, 3.0% and 23.4% of cases respectively). Antibiotics were prescribed at 16.1% of treatment appointments and 1.9% required appointments for post-operative complications. All participants reported overall satisfaction with their care and strongly agreed/agreed with positive attitudinal statements about the oral surgeon's communication/information giving, technical competence and understanding and acceptance; 77.5% were seen on time and none were seen more than 15 minutes late; 87.5% felt the standard of the service was better than expected than at a hospital and none felt it was worse. Over 80 of practitioners agreed that waiting times were better than expected at a hospital, urgent problems were seen quickly and the referral process was easy and understandable. All practitioners strongly agreed/agreed they that they were happy with the service provided. CONCLUSIONS A range of minor oral surgery procedures can be provided with low complication rates, acceptable waiting times and accessibility, and high patient and referring practitioner satisfaction from a practice-based specialist oral surgery service.

Inferring Identical-by-Descent Sharing of Sample Ancestors Promotes High-Resolution Relative Detection.

As genetic datasets increase in size, the fraction of samples with one or more close relatives grows rapidly, resulting in sets of mutually related individuals. We present DRUID-deep relatedness utilizing identity by descent-a method that works by inferring the identical-by-descent (IBD) sharing profile of an ungenotyped ancestor of a set of close relatives. Using this IBD profile, DRUID infers relatedness between unobserved ancestors and more distant relatives, thereby combining information from multiple samples to remove one or more generations between the deep relationships to be identified. DRUID constructs sets of close relatives by detecting full siblings and also uses an approach to identify the aunts/uncles of two or more siblings, recovering 92.2% of real aunts/uncles with zero false positives. In real and simulated data, DRUID correctly infers up to 10.5% more relatives than PADRE when using data from two sets of distantly related siblings, and 10.7%-31.3% more relatives given two sets of siblings and their aunts/uncles. DRUID frequently infers relationships either correctly or within one degree of the truth, with PADRE classifying 43.3%-58.3% of tenth degree relatives in this way compared to 79.6%-96.7% using DRUID.

Neurodegenerative disease biomarkers Aß1-40, Aß1-42, tau, and p-tau181 in the vervet monkey cerebrospinal fluid: Relation to normal aging, genetic influences, and cerebral amyloid angiopathy.

Background: The Caribbean vervet monkey (Chlorocebus aethiops sabaeus) is a potentially valuable animal model of neurodegenerative disease. However, the trajectory of aging in vervets and its relationship to human disease is incompletely understood. Methods: To characterize biomarkers associated with neurodegeneration, we measured cerebrospinal fluid (CSF) concentrations of Aß1-40, Aß1-42, total tau, and p-tau181 in 329 members of a multigenerational pedigree. Linkage and genome-wide association were used to elucidate a genetic contribution to these traits. Results: Aß1-40 concentrations were significantly correlated with age, brain total surface area, and gray matter thickness. Levels of p-tau181 were associated with cerebral volume and brain total surface area. Among the measured analytes, only CSF Aß1-40 was heritable. No significant linkage (LOD > 3.3) was found, though suggestive linkage was highlighted on chromosomes 4 and 12. Genome-wide association identified a suggestive locus near the chromosome 4 linkage peak. Conclusions: Overall, these results support the vervet as a non-human primate model of amyloid-related neurodegeneration, such as Alzheimer's disease and cerebral amyloid angiopathy, and highlight Aß1-40 and p-tau181 as potentially valuable biomarkers of these processes.

Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees.

A major challenge in evaluating the contribution of rare variants to complex disease is identifying enough copies of the rare alleles to permit informative statistical analysis. To investigate the contribution of rare variants to the risk of type 2 diabetes (T2D) and related traits, we performed deep whole-genome analysis of 1,034 members of 20 large Mexican-American families with high prevalence of T2D. If rare variants of large effect accounted for much of the diabetes risk in these families, our experiment was powered to detect association. Using gene expression data on 21,677 transcripts for 643 pedigree members, we identified evidence for large-effect rare-variant cis-expression quantitative trait loci that could not be detected in population studies, validating our approach. However, we did not identify any rare variants of large effect associated with T2D, or the related traits of fasting glucose and insulin, suggesting that large-effect rare variants account for only a modest fraction of the genetic risk of these traits in this sample of families. Reliable identification of large-effect rare variants will require larger samples of extended pedigrees or different study designs that further enrich for such variants.

Genetic variation and gene expression across multiple tissues and developmental stages in a nonhuman primate.

By analyzing multitissue gene expression and genome-wide genetic variation data in samples from a vervet monkey pedigree, we generated a transcriptome resource and produced the first catalog of expression quantitative trait loci (eQTLs) in a nonhuman primate model. This catalog contains more genome-wide significant eQTLs per sample than comparable human resources and identifies sex- and age-related expression patterns. Findings include a master regulatory locus that likely has a role in immune function and a locus regulating hippocampal long noncoding RNAs (lncRNAs), whose expression correlates with hippocampal volume. This resource will facilitate genetic investigation of quantitative traits, including brain and behavioral phenotypes relevant to neuropsychiatric disorders.

Bioprotection of the built environment and cultural heritage.

The growth of microbial biofilms and various biomineralization phenomena can lead to the formation of stable layers and veneers on rocks known as 'rock varnishes' that can stabilize surfaces and protect from further weathering. This article describes the potential application of fungal systems for bioprotection of rock and mineral-based substrates and the evidence to support this concept of utilizing natural or engineered colonization and metabolic properties of fungi, including lichens.

Benchmarking Relatedness Inference Methods with Genome-Wide Data from Thousands of Relatives.

Inferring relatedness from genomic data is an essential component of genetic association studies, population genetics, forensics, and genealogy. While numerous methods exist for inferring relatedness, thorough evaluation of these approaches in real data has been lacking. Here, we report an assessment of 12 state-of-the-art pairwise relatedness inference methods using a data set with 2485 individuals contained in several large pedigrees that span up to six generations. We find that all methods have high accuracy (92-99%) when detecting first- and second-degree relationships, but their accuracy dwindles to <43% for seventh-degree relationships. However, most identical by descent (IBD) segment-based methods inferred seventh-degree relatives correct to within one relatedness degree for >76% of relative pairs. Overall, the most accurate methods are Estimation of Recent Shared Ancestry (ERSA) and approaches that compute total IBD sharing using the output from GERMLINE and Refined IBD to infer relatedness. Combining information from the most accurate methods provides little accuracy improvement, indicating that novel approaches, such as new methods that leverage relatedness signals from multiple samples, are needed to achieve a sizeable jump in performance.

TRAK2, a novel regulator of ABCA1 expression, cholesterol efflux and HDL biogenesis.

Aims: The recent failures of HDL-raising therapies have underscored our incomplete understanding of HDL biology. Therefore there is an urgent need to comprehensively investigate HDL metabolism to enable the development of effective HDL-centric therapies. To identify novel regulators of HDL metabolism, we performed a joint analysis of human genetic, transcriptomic, and plasma HDL-cholesterol (HDL-C) concentration data and identified a novel association between trafficking protein, kinesin binding 2 (TRAK2) and HDL-C concentration. Here we characterize the molecular basis of the novel association between TRAK2 and HDL-cholesterol concentration. Methods and results: Analysis of lymphocyte transcriptomic data together with plasma HDL from the San Antonio Family Heart Study (n = 1240) revealed a significant negative correlation between TRAK2 mRNA levels and HDL-C concentration, HDL particle diameter and HDL subspecies heterogeneity. TRAK2 siRNA-mediated knockdown significantly increased cholesterol efflux to apolipoprotein A-I and isolated HDL from human macrophage (THP-1) and liver (HepG2) cells by increasing the mRNA and protein expression of the cholesterol transporter ATP-binding cassette, sub-family A member 1 (ABCA1). The effect of TRAK2 knockdown on cholesterol efflux was abolished in the absence of ABCA1, indicating that TRAK2 functions in an ABCA1-dependent efflux pathway. TRAK2 knockdown significantly increased liver X receptor (LXR) binding at the ABCA1 promoter, establishing TRAK2 as a regulator of LXR-mediated transcription of ABCA1. Conclusion: We show, for the first time, that TRAK2 is a novel regulator of LXR-mediated ABCA1 expression, cholesterol efflux, and HDL biogenesis. TRAK2 may therefore be an important target in the development of anti-atherosclerotic therapies.