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Introduction: Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide and is characterised by progressive loss of dopaminergic neurons in the midbrain. Neuronal death is often accompanied by the formation of Lewy bodies, large perinuclear inclusion bodies primarily composed of misfolded [alpha]-synuclein. Accumulation of misfolded proteins is a central paradigm in the progression of neurodegeneration and results primarily from the dysregulation of protein homeostasis. The unfolded protein response (UPR) of the endoplasmic reticulum (ER) plays a central role in protein homeostasis, along with ER-phagy, a specific form of autophagy. Dysregulation of the UPR and ER-phagy have recently been linked to neurodegeneration, though their specific role in PD remains unknown. [...], Thesis (PhD Doctorate), Doctor of Philosophy (PhD), School of Environment and Sc, Science, Environment, Engineering and Technology, Full Text

Objective We conducted a survey-based discrete-choice experiment (DCE) to understand the test features that drive women's preferences for prenatal genomic testing, and explore variation across countries. Methods Five test attributes were identified as being important for decision-making through a literature review, qualitative interviews and quantitative scoring exercise. Twelve scenarios were constructed in which respondents choose between two invasive tests or no test. Women from eight countries who delivered a baby in the previous 24 months completed a DCE presenting these scenarios. Choices were modeled using conditional logit regression analysis. Results Surveys from 1239 women (Australia: n = 178; China: n = 179; Denmark: n = 88; Netherlands: n = 177; Singapore: n = 90; Sweden: n = 178; UK: n = 174; USA: n = 175) were analyzed. The key attribute affecting preferences was a test with the highest diagnostic yield (p < 0.01). Women preferred tests with short turnaround times (p < 0.01), and tests reporting variants of uncertain significance (VUS; p < 0.01) and secondary findings (SFs; p < 0.01). Several country-specific differences were identified, including time to get a result, who explains the result, and the return of VUS and SFs. Conclusion Most women want maximum information from prenatal genomic tests, but our findings highlight country-based differences. Global consensus on how to return uncertain results is not necessarily realistic or desirable.

Objective: We conducted a survey-based discrete-choice experiment (DCE) to understand the test features that drive women's preferences for prenatal genomic testing, and explore variation across countries. Methods: Five test attributes were identified as being important for decision-making through a literature review, qualitative interviews and quantitative scoring exercise. Twelve scenarios were constructed in which respondents choose between two invasive tests or no test. Women from eight countries who delivered a baby in the previous 24 months completed a DCE presenting these scenarios. Choices were modeled using conditional logit regression analysis. Results: Surveys from 1239 women (Australia: n = 178; China: n = 179; Denmark: n = 88; Netherlands: n = 177; Singapore: n = 90; Sweden: n = 178; UK: n = 174; USA: n = 175) were analyzed. The key attribute affecting preferences was a test with the highest diagnostic yield (p < 0.01). Women preferred tests with short turnaround times (p < 0.01), and tests reporting variants of uncertain significance (VUS; p < 0.01) and secondary findings (SFs; p < 0.01). Several country-specific differences were identified, including time to get a result, who explains the result, and the return of VUS and SFs. Conclusion: Most women want maximum information from prenatal genomic tests, but our findings highlight country-based differences. Global consensus on how to return uncertain results is not necessarily realistic or desirable.

Objective: To compare the effectiveness of an animation against two leaflets with and without images, in educating young people about genome sequencing (GS). Methods: An experimental survey with three assessment points (pre- intervention [T1], post – intervention [T2], 6-week follow-up [T3]). Participants (N = 606) were randomly assigned to receive one of three educational interventions; animation (n = 212); leaflet with images (n = 197); or leaflet with text only (n = 197). Measures of objective and subjective knowledge were completed at T1 (N = 606), T2 (N = 606) and T3 (N = 459). Measures of attitudes, intentions and beliefs towards GS and satisfaction with intervention were completed at T2 only. Results: The type of educational intervention young people received had no significant impact on their objective or subjective knowledge at both T2 and T3 (all p > .05), nor did the educational intervention type affect their attitudes, intentions and beliefs towards GS at T2 (p > .05). However, participant satisfaction was significantly higher in the animation group than the leaflet groups (p < .001). Conclusion: Animations and leaflets are both effective ways to deliver genomic education to young people, but the animations lead to higher satisfaction. Practice implications: Different individuals may find different modes of educational resources more accessible than others. Therefore a range of resources should ideally be made available to patients.

Jason E Pope,1 Michael A Fishman,2 Joshua A Gunn,3 Bradley M Cotten,3 Melissa M Hill,3 Timothy R Deer4 1Evolve Restorative Center, Santa Rosa, CA, USA; 2Center for Interventional Pain and Spine, Lancaster, PA, USA; 3Ethos Research and Development, LLC, Newport, KY, USA; 4The Spine and Nerve Center of the Virginias, Charleston, WV, USACorrespondence: Jason E PopeEvolve Restorative Center, Santa Rosa, CA, USATel +1844 527-7369Email jepope@evolverestorativecenter.carePurpose: Discovery and validation of pragmatic biomarkers represent significant advancements in the field of pain management. Evaluating relationships between objective biomarkers and patient-reported outcomes (PROs) is an effective way to gain mechanistic insight into the potential role of biochemistry in chronic pain. The aim of this study was to validate the Foundation Pain Index (FPI) by evaluating associations between deranged biochemical function and PROMIS-29 domains in individuals living with chronic pain.Patients and Methods: PROMIS-29 scores and FPI test results were obtained from 298 patients with chronic pain in this retrospective, observational study. Statistical analysis was performed using clinical test data to evaluate relationships between deranged biochemical function and quality of life measures across 8 universal domains.Results: FPI scores significantly associated with multiple PROMIS-29 domains including physical function, impact score, fatigue, pain interference, and depression (P < 0.05). Moreover, specific analytes that comprise the FPI significantly correlated with PROMIS-29 domains, including 5-hydroxyindolacetic acid (pain interference, physical function, and pain impact scores), hydroxymethylglutarate (physical function), homocysteine (pain impact scores), kynurenic acid (pain interference and physical function), and quinolinic acid (physical function) (P < 0.05).Conclusion: Cross-validation of the FPI with PROMIS-29 domains further supports the role of deranged biochemic

Objectives: To conduct qualitative interviews with healthcare providers working in different countries to understand their experiences of dealing with uncertain results from prenatal chromosome microarray analysis (CMA) and exome sequencing (ES). Methods: Semi-structured interviews with 31 healthcare providers who report or return prenatal CMA and/or ES results (clinicians, genetic counsellors and clinical scientists) in six countries with differing healthcare systems; Australia (4), Denmark (5), Netherlands (6), Singapore (4), Sweden (6) and United Kingdom (6). The topic guide explored the main sources of uncertainty and their management. Results: There was variation in reporting practices both between and across countries for variants of uncertain significance, however, there was broad agreement on reporting practices for incidental findings. There was also variation in who decides what results are reported (clinical scientists or clinicians). Technical limitations and lack of knowledge (to classify variants and of prenatal phenotypes) were significant challenges, as were turnaround times and lack of guidelines. Conclusion: Health professionals around the globe are dealing with similar sources of uncertainty, but managing them in different ways, Continued dialogue with international colleagues on ways of managing uncertain results is important to compare and contrast the benefits and limitations of the different approaches.

Exome sequencing (ES) enhanced the diagnostic yield of genetic testing, but has also increased the possibility of uncertain findings. Prenatal ES is increasingly being offered after a fetal abnormality is detected through ultrasound. It is important to know how to handle uncertainty in this particularly stressful period. This systematic review aimed to provide a comprehensive overview of guidelines available for addressing uncertainty related to prenatal chromosomal microarray (CMA) and ES. Ten uncertainty types associated with prenatal ES and CMA were identified and defined by an international multidisciplinary team. Medline (all) and Embase were systematically searched. Laboratory scientists, clinical geneticists, psychologists, and a fetal medicine specialist screened the papers and performed the data extraction. Nineteen papers were included. Recommendations generally emphasized the importance of trio analysis, clinical information, data sharing, validation and re-analysis, protocols, multidisciplinary teams, genetic counselling, whether to limit the possible scope of results, and when to report particular findings. This systematic review helps provide a vocabulary for uncertainties, and a compass to navigate uncertainties. Prenatal CMA and ES guidelines provide a strong starting point for determining how to handle uncertainty. Gaps in guidelines and recommendations were identified and discussed to provide direction for future research and policy making.

The Boost Brittle Bones Before Birth (BOOSTB4) clinical trial is investigating the safety and efficacy of transplanting fetal derived mesenchymal stromal cells (MSCs) prenatally and/or in early postnatal life to treat severe Osteogenesis Imperfecta (OI). This study aimed to explore stakeholder views to understand perceived benefits or concerns, identify ethical issues and establish protocols for support and counselling. Semi-structured qualitative interviews were conducted with three groups; 1. Adults affected with OI, with and without children, and parents of children affected with OI; 2. Health professionals who work with patients with OI; 3. Patient advocates from relevant patient support groups. Interviews were digitally recorded, transcribed verbatim and analysed using thematic analysis. Interviews with 56 participants revealed generally positive views towards using fetal MSC transplantation to treat OI. Early treatment was considered advantageous for preventing fractures and reducing severity and could bring psychological benefits for parents. Common concerns were procedure safety, short/long-term side effects and whether transplantation would be effective. Difficulties inherent in decision-making were frequently discussed, as treatment efficacy is unknown and, by necessity, parents will make decisions at a time when they are vulnerable. Support needs may differ where there is a family history of OI compared to an unexpected diagnosis of OI. Explaining fetal MSC transplantation in a way that all parents can understand, clear expectation setting, psychological support and time for reflection during the decision-making process will be crucial to allow parents to make informed decisions about participation in the BOOSTB4 clinical trial.

Background: Workplace health interventions incorporating qualitative and quantitative components (mixed methods) within a Participatory Action Research approach can increase understanding of contextual issues ensuring realistic interventions which influence health behaviour. Mixed methods research teams, however, face a variety of challenges at the methodological and expertise levels when designing actions and interventions. Addressing these challenges can improve the team’s functionality and lead to higher quality health outcomes. In this paper we reflect on the data collection, implementation and data analysis phases of a mixed methods workplace health promotion project and discuss the challenges which arose within our multidisciplinary team. Methods: This project used mixed methods within a Participatory Action Research approach to address workers’ sun safety behaviours in 14 outdoor workplaces in Queensland, Australia, and elucidate why certain measures succeeded (or failed) at the worker and management level. The project integrated qualitative methods such as policy analysis and interviews, with a range of quantitative methods – including worker surveys, ultraviolet radiation (UVR) exposure measurement, and implementation cost analyses. Results: The research team found the integration of qualitative and quantitative analyses within the Participatory Action Research process to be challenging and a cause of tensions. This had a negative impact on the data analysis process and reporting of results, and the complexity of qualitative analysis was not truly understood by the quantitative team. Once all researchers recognised qualitative and quantitative data would be equally beneficial to the Participatory Action Research process, methodological bias was overcome to a degree to which the team could work cooperatively. Conclusions: Mixed methods within a Participatory Action Research approach may allow a research team to discuss,reflect and

This literature review was undertaken to inform a settings based health promotion research project, conducted by a public health research team at the Queensland University of Technology (QUT). The aim of this project is to identify how transport workplaces can support their truck drivers to access healthy food options and increase physical activity. Truck drivers in Australia are at increased risk of numerous chronic diseases, in part due to the restrictions placed upon them by the environment in which they work. Barriers to good health through adequate nutrition and physical activity are the result of a complex interaction between government regulations, corporate policies, the built environment and individual factors. Few interventions target this population in a meaningful and sustainable way, though evidence exists for interventions which can be translated into truck drivers working environment.

The HIV-1 gp120-gp41 complex, which mediates viral fusion and cellular entry, undergoes rapid evolution within its external glycan shield to enable escape from neutralizing antibody (NAb). Understanding how conserved protein determinants retain functionality in the context of such evolution is important for their evaluation and exploitation as potential drug and/ or vaccine targets. In this study, we examined how the conserved gp120-gp41 association site, formed by the N- and Cterminal segments of gp120 and the disulfide-bonded region (DSR) of gp41, adapts to glycan changes that are linked to neutralization sensitivity. To this end, a DSR mutant virus (K601D) with defective gp120-association was sequentially passaged in peripheral blood mononuclear cells to select suppressor mutations. We reasoned that the locations of suppressors point to structural elements that are functionally linked to the gp120-gp41 association site. In culture 1, gp120 association and viral replication was restored by loss of the conserved glycan at Asn136 in V1 (T138N mutation) in conjunction with the L494I substitution in C5 within the association site. In culture 2, replication was restored with deletion of the N139INN sequence, which ablates the overlapping Asn141-Asn142-Ser-Ser potential N-linked glycosylation sequons in V1, in conjunction with D601N in the DSR. The 136 and 142 glycan mutations appeared to exert their suppressive effects by altering the dependence of gp120-gp41 interactions on the DSR residues, Leu593, Trp596 and Lys601. The 136 and/or 142 glycan mutations increased the sensitivity of HIV-1 pseudovirions to the glycan-dependent NAbs 2G12 and PG16, and also pooled IgG obtained from HIV-1-infected individuals. Thus adjacent V1 glycans allosterically modulate the distal gp120- gp41 association site. We propose that this represents a mechanism for functional adaptation of the gp120-gp41 association site to an evolving glycan shield in a setting of NAb sel

Eyewitnesses are a vital part of the Criminal Justice System, thus their reliability is critical. The current research aimed to establish whether training can improve memory recall, and investigate the impact of time delay on memory for crime scenes. Fifty-six undergraduates were allocated to one of three training groups (untrained, attention trained, attention and memory trained) and then viewed three crime scene images whilst receiving relevant training instructions. A further ten crime scenes were viewed for five seconds each. A recognition memory test was administered either immediately (n = 30) or after seven days (n = 26). Eye fixations were recorded to assess the relationship between viewing behaviour and later recall. The findings highlighted the negative impact of time delay on recall (p < 0.001). Training affected accuracy, but not as predicted. The untrained group and the attention and memory trained group both scored significantly higher than the group trained in attention only (p = 0.004 and p = 0.001 respectively). Fixation count, but not duration, was linked to accuracy of recall (p < 0.001) but this did not differ across training group. It was concluded that training can influence eyewitness memory but more investigation is required.

The bias of A-rich codons in HIV-1 pol is thought to be a record of hypermutations in viral genomes that lack biological functions. Bioinformatic analysis predicted that A-rich sequences are generally associated with minimal local RNA structures. Using codon modifications to reduce the amount of A-rich sequences within HIV-1 genomes, we have reduced the flexibility of RNA sequences in pol to analyze the functional significance of these A-rich ‘structurally poor’ RNA elements in HIV-1 pol. Our data showed that codon modification of HIV-1 sequences led to a suppression of virus infectivity by 5–100-fold, and this defect does not correlate with, viral entry, viral protein expression levels, viral protein profiles or virion packaging of genomic RNA. Codon modification of HIV-1 pol correlated with an enhanced dimer stability of the viral RNA genome, which was associated with a reduction of viral cDNA synthesis both during HIV-1 infection and in a cell free reverse transcription assay. Our data provided direct evidence that the HIV-1 A-rich pol sequence is not merely an evolutionary artifact of enzyme-induced hypermutations, and that HIV-1 has adapted to rely on A-rich RNA sequences to support the synthesis of viral cDNA during reverse transcription, highlighting the utility of using ‘structurally poor’ RNA domains in regulating biological process.

The full-length human immunodeficiency virus type 1 (HIV-1) mRNA encodes two precursor polyproteins, Gag and GagProPol. An infrequent ribosomal frameshifting event allows these proteins to be synthesized from the same mRNA in a predetermined ratio of 20 Gag proteins for each GagProPol. The RNA frameshift signal consists of a slippery sequence and a hairpin stem-loop whose thermodynamic stability has been shown in in vitro translation systems to be critical to frameshifting efficiency. In this study we examined the frameshift region of HIV-1, investigating the effects of altering stem-loop stability in the context of the complete viral genome and assessing the role of the Gag spacer peptide p1 and the GagProPol transframe (TF) protein that are encoded in this region. By creating a series of frameshift region mutants that systematically altered the stability of the frameshift stem-loop and the protein sequences of the p1 spacer peptide and TF protein, we have demonstrated the importance of stem-loop thermodynamic stability in frameshifting efficiency and viral infectivity. Multiple changes to the amino acid sequence of p1 resulted in altered protein processing, reduced genomic RNA dimer stability, and abolished viral infectivity. The role of the two highly conserved proline residues in p1 (position 7 and 13) was also investigated. Replacement of the two proline residues by leucines resulted in mutants with altered protein processing and reduced genomic RNA dimer stability that were also noninfectious. The unique ability of proline to confer conformational constraints on a peptide suggests that the correct folding of p1 may be important for viral function.

Microbial mats are complex, layered microbial communities dominated by cyanobacteria. Mats have been used successfully in the bioremediation of Pb, Cd, Cu, Zn, and Mn contaminated water. This study investigated the possible removal through reduction of soluble U( VI) present in the ionic complexed form in the presence of highly carbonated waters (240 mg/L) by microbial mats. Mats developed in the Bioremediation Laboratory at Clark Atlanta University were used in batch and water column studies. Preliminary studies showed optimum uranium uptake was produced by a 1:1:1 ratio of whole microbial mats, predominately cyanobacteria, and two bacterial groups isolated from the mats: Rhodospeudomonas and a mixed anaerobe group, dominated by sulfur reducers. X-ray absorption near-edge structure spectroscopy (XANES) revealed U(VI) was reduced to U(IV). Uranium removal rate was dependent on temperature, nutrients available, photosynthetic and reducing conditions, and amount of bacterial material per volume of solution.