Invasion and Amplification of Endogenous Retroviruses in Dasyuridae Marsupial Genomes.

Retroviruses are an ancient viral family that have globally coevolved with vertebrates and impacted their evolution. In Australia, a continent that has been geographically isolated for millions of years, little is known about retroviruses in wildlife, despite the devastating impacts of a retrovirus on endangered koala populations. We therefore sought to identify and characterize Australian retroviruses through reconstruction of endogenous retroviruses from marsupial genomes, in particular the Tasmanian devil due to its high cancer incidence. We screened 19 marsupial genomes and identified over 80,000 endogenous retrovirus fragments which we classified into eight retrovirus clades. The retroviruses were similar to either Betaretrovirus (5/8) or Gammaretrovirus (3/8) retroviruses, but formed distinct phylogenetic clades compared to extant retroviruses. One of the clades (MEBrv 3) lost an envelope but retained retrotranspositional activity, subsequently amplifying throughout all Dasyuridae genomes. Overall, we provide insights into Australian retrovirus evolution and identify a highly active endogenous retrovirus within Dasyuridae genomes.

ChillsDB: A Gold Standard for Aesthetic Chills Stimuli.

We introduce ChillsDB the first validated database of audiovisual stimuli eliciting aesthetic chills (goosebumps, psychogenic shivers) in a US population. To discover chills stimuli "in the wild", we devised a bottom-up, ecologically-valid method consisting in searching for mentions of the emotion' somatic markers in user comments throughout social media platforms (YouTube and Reddit). We successfully captured 204 chills-eliciting videos of three categories: music, film, and speech. We then tested the top 50 videos in the database on 600+ participants and validated a gold standard of 10 stimuli with a 0.9 probability of generating chills. All ChillsDB tools and data are fully available on GitHub for researchers to be able to contribute and perform further analysis.

Impacts of fast production of afucosylated antibodies and Fc mutants in ExpiCHO-S™ for enhancing FcγRIIIa binding and NK cell activation.

This study has employed mammalian transient expression systems to generate afucosylated antibodies and antibody Fc mutants for rapid candidate screening in discovery and early development. While chemical treatment with the fucose analogue 2-fluoro-peracetyl-fucose during transient expression only partially produced antibodies with afucosylated N-glycans, the genetic inactivation of the FUT8 gene in ExpiCHO-S™ by CRISPR/Cas9 enabled the transient production of fully afucosylated antibodies. Human IgG1 and murine IgG2a generated by the ExpiCHOfut8KO cell line possessed a 8-to-11-fold enhanced FcγRIIIa binding activity in comparison with those produced by ExpiCHO-S™. The Fc mutant S239D/S298A/I332E produced by ExpiCHO-S™ had an approximate 2-fold higher FcγRIIIa affinity than that of the afucosylated wildtype molecule, although it displayed significantly lower thermal-stability. When the Fc mutant was produced in the ExpiCHOfut8KO cell line, the resulting afucosylated Fc mutant antibody had an additional approximate 6-fold increase in FcγRIIIa binding affinity. This synergistic effect between afucosylation and the Fc mutations was further verified by a natural killer (NK) cell activation assay. Together, these results have not only established an efficient large-scale transient CHO system for rapid production of afucosylated antibodies, but also confirmed a cooperative impact between afucosylation and Fc mutations on FcγRIIIa binding and NK cell activation.

Multi-center prospective population pharmacokinetic study and the performance of web-based individual dose optimization application of intravenous vancomycin for adults in Hong Kong: A study protocol.

A recent consensus guideline recommends migrating the therapeutic drug monitoring practice for intravenous vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infection from the traditional trough-based approach to the Bayesian approach based on area under curve to improve clinical outcomes. To support the implementation of the new strategy for hospitals under Hospital Authority, Hong Kong, this study is being proposed to (1) estimate and validate a population pharmacokinetic model of intravenous vancomycin for local adults, (2) develop a web-based individual dose optimization application for clinical use, and (3) evaluate the performance of the application by comparing the treatment outcomes and clinical satisfaction against the traditional approach. 300 adult subjects prescribed with intravenous vancomycin and not on renal replacement therapy will be recruited for population pharmacokinetic model development and validation. Sex, age, body weight, serum creatinine level, intravenous vancomycin dosing records, serum vancomycin concentrations etc. will be collected from several electronic health record systems maintained by Hospital Authority. Parameter estimation will be performed using non-linear mixed-effect modeling techniques. The web-based individual dose optimization application is based on a previously reported application and is built using R and the package shiny. Data from another 50 subjects will be collected during the last three months of the study period and treated as informed by the developed application and compared against historical control for clinical outcomes. Since the study will incur extra blood-taking procedures from patients, informed consent is required. Other than that, recruited subjects should receive medical treatments as usual. Identifiable patient data will be available only to site investigators and clinicians in each hospital. The study protocol and informed consent forms have been approved by the Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee (reference number: NTEC-2021-0215) and registered at the Chinese Clinical Trial Registry (registration number: ChiCTR2100048714).

Aesthetic chills cause an emotional drift in valence and arousal.

Aesthetic chills are an embodied peak emotional experience induced by stimuli such as music, films, and speeches and characterized by dopaminergic release. The emotional consequences of chills in terms of valence and arousal are still debated and the existing empirical data is conflicting. In this study, we tested the effects of ChillsDB, an open-source repository of chills-inducing stimuli, on the emotional ratings of 600+ participants. We found that participants experiencing chills reported significantly more positive valence and greater arousal during the experience, compared to participants who did not experience chills. This suggests that the embodied experience of chills may influence one's perception and affective evaluation of the context, in favor of theoretical models emphasizing the role of interoceptive signals such as chills in the process of perception and decision-making. We also found an interesting pattern in the valence ratings of participants, which tended to harmonize toward a similar mean after the experiment, though initially disparately distributed. We discuss the significance of these results for the diagnosis and treatment of dopaminergic disorders such as Parkinson's, schizophrenia, and depression.

Revealing the uncharacterised diversity of amphibian and reptile viruses.

Amphibians and non-avian reptiles represent a significant proportion of terrestrial vertebrates, however knowledge of their viruses is not proportional to their abundance. Many amphibians and reptiles have strict habitual environments and localised populations and are vulnerable to viral outbreaks and potential elimination as a result. We sought to identify viruses that were hidden in amphibian and reptile metatranscriptomic data by screening 235 RNA-sequencing datasets from a 122 species covering 25 countries. We identified 26 novel viruses and eight previously characterised viruses from fifteen different viral families. Twenty-five viruses had RNA genomes with identity to Arteriviridae, Tobaniviridae, Hantaviridae, Rhabdoviridae, Astroviridae, Arenaviridae, Hepeviridae, Picornaviridae, Orthomyxoviridae, Reoviridae, Flaviviridae and Caliciviridae. In addition to RNA viruses, we also screened datasets for DNA viral transcripts, which are commonly excluded from transcriptomic analysis. We identified ten DNA viruses with identity to Papillomaviridae, Parvoviridae, Circoviridae and Adomaviridae. With the addition of these viruses, we expand the global amphibian and reptile virome and identify new potentially pathogenic viruses that could challenge populations. We speculate that amphibian viruses often have simpler genomes than those in amniotes, as in the case of the Secondpapillomavirinae and Orthomyxoviridae viruses identified in this study. In addition, we find evidence of inter-family recombination in RNA viruses, and we also identify new members of the recombinant Adomaviridae family. Overall, we provide insights into the uncharacterised diversity of amphibian and reptile viruses with the aim of improving population management, treatment and conservation into the future.

Ancient viral integrations in marsupials: a potential antiviral defence.

Marsupial viruses are understudied compared to their eutherian mammal counterparts, although they may pose severe threats to vulnerable marsupial populations. Genomic viral integrations, termed 'endogenous viral elements' (EVEs), could protect the host from infection. It is widely known past viral infections and EVEs play an active role in antiviral defence in invertebrates and plants. This study aimed to characterise actively transcribed EVEs in Australian marsupial species, because they may play an integral role in cellular defence against viruses. This study screened publicly available RNA sequencing data sets (n = 35) and characterised 200 viral transcripts from thirteen Australian marsupial species. Of the 200 transcripts, 188 originated from either Bornaviridae, Filoviridae, or Parvoviridae EVEs. The other twelve transcripts were from putative active infections from members of the Herpesviridae and Anelloviridae, and Hepadnaviridae. EVE transcripts (n = 188) were mapped to marsupial genomes (where available, n = 5/13) to identify the genomic insertion sites. Of the 188 transcripts, 117 mapped to 39 EVEs within the koala, bare-nosed wombat, tammar wallaby, brushtail possum, and Tasmanian devil genomes. The remaining eight animals had no available genome (transcripts n = 71). Every marsupial has Bornaviridae, Filoviridae, and Parvoviridae EVEs, a trend widely observed in eutherian mammals. Whilst eutherian bornavirus EVEs are predominantly nucleoprotein-derived, marsupial bornavirus EVEs demonstrate a surprising replicase gene bias. We predicted these widely distributed EVEs were conserved within marsupials from ancient germline integrations, as many were over 65 million years old. One bornavirus replicase EVE, present in six marsupial genomes, was estimated to be 160 million years old, predating the American-Australian marsupial split. We considered transcription of these EVEs through small non-coding RNA as an ancient viral defence. Consistent with this, in koala small RNA sequence data sets, we detected Bornaviridae replicase and Filoviridae nucleoprotein produced small RNA. These were enriched in testis tissue, suggesting they could protect marsupials from vertically transmitted viral integrations.

Discovery of Novel Viruses Associated With the Invasive Cane Toad (Rhinella marina) in Its Native and Introduced Ranges.

Cane toads (Rhinella marina) are notoriously successful invaders: from 101 individuals brought to Australia in 1935, poisonous toads now cover an area >1.2 million km2 with adverse effects on native fauna. Despite extensive research on the role of macroparasites in cane toad invasion, viral research is lagging. We compared viral prevalence and diversity between toads in their native range (French Guiana, n=25) and two introduced ranges: Australia (n=151) and Hawai'i (n=10) with a metatranscriptomic and metagenomic approach combined with PCR screening. Australian toads almost exclusively harbor one of seven viruses detected globally. Rhimavirus-A (Picornaviridae) exhibited low genetic diversity and likely actively infected 9% of sampled Australian toads extending across ~2,000km of Northern Australia and up to the current invasion front. In native range cane toads, we identified multiple phylogenetically distinct viruses (Iridoviridae, Picornaviridae, Papillomaviridae, and Nackedna-like virus). None of the same viruses was detected in both ranges, suggesting that Australian cane toads have largely escaped the viral infection experienced by their native range counterparts. The novel native range viruses described here are potential biocontrol agents, as Australian toads likely lack prior immunological exposure to these viruses. Overall, our evidence suggests that there may be differences between viruses infecting cane toads in their native vs. introduced ranges, which lays the groundwork for further studies on how these viruses have influenced the toads' invasion history.

Choices in hemodialysis therapies: variants, personalized therapy and application of evidence-based medicine.

The extent of removal of the uremic toxins in hemodialysis (HD) therapies depends primarily on the dialysis membrane characteristics and the solute transport mechanisms involved. While designation of 'flux' of membranes as well toxicity of compounds that need to be targeted for removal remain unresolved issues, the relative role, efficiency and utilization of solute removal principles to optimize HD treatment are better delineated. Through the combination and intensity of diffusive and convective removal forces, levels of concentrations of a broad spectrum of uremic toxins can be lowered significantly and successfully. Extended clinical experience as well as data from several clinical trials attest to the benefits of convection-based HD treatment modalities. However, the mode of delivery of HD can further enhance the effectiveness of therapies. Other than treatment time, frequency and location that offer clinical benefits and increase patient well-being, treatment- and patient-specific criteria may be tailored for the therapy delivered: electrolytic composition, dialysate buffer and concentration and choice of anticoagulating agent are crucial for dialysis tolerance and efficacy. Evidence-based medicine (EBM) relies on three tenets, i.e. clinical expertise (i.e. doctor), patient-centered values (i.e. patient) and relevant scientific evidence (i.e. science), that have deviated from their initial aim and summarized to scientific evidence, leading to tyranny of randomized controlled trials. One must recognize that practice patterns as shown by Dialysis Outcomes and Practice Patterns Study and personalization of HD care are the main driving force for improving outcomes. Based on a combination of the three pillars of EBM, and particularly on bedside patient-clinician interaction, we summarize what we have learned over the last 6 decades in terms of best practices to improve outcomes in HD patients. Management of initiation of dialysis, vascular access, preservation of kidney function, selection of biocompatible dialysers and use of dialysis fluids of high microbiological purity to restrict inflammation are just some of the approaches where clinical experience is vital in the absence of definitive scientific evidence. Further, HD adequacy needs to be considered as a broad and multitarget approach covering not just the dose of dialysis provided, but meeting individual patient needs (e.g. fluid volume, acid-base, blood pressure, bone disease metabolism control) through regular assessment-and adjustment-of a series of indicators of treatment efficiency. Finally, in whichever way new technologies (i.e. artificial intelligence, connected health) are embraced in the future to improve the delivery of dialysis, the human dimension of the patient-doctor interaction is irreplaceable. Kidney medicine should remain 'an art' and will never be just 'a science'.

Participating in Complementary and Integrative Health Approaches Is Associated With Veterans' Patient-reported Outcomes Over Time.

BACKGROUND: Veterans Affairs is dedicated to providing a Whole Health approach to care, including offering complementary and integrative health (CIH) approaches to Veterans. OBJECTIVE: The objective of this study was to examine the association of CIH participation with Veterans' patient-reported outcomes over time. RESEARCH DESIGN: A survey of patient-reported outcomes at 5 timepoints: baseline, 2, 4, 6, and 12 months. SUBJECTS: Veterans participating in any type of CIH approach at 2 Veterans Affairs medical centers. MEASURES: Mixed hierarchical models with repeated variables were used to test the hypothesis that participating in any CIH approach would be associated with Veterans' overall physical/mental health [Patient-Reported Outcomes Measurement Information System 28 (PROMIS 28)], pain intensity, perceived stress (Perceived Stress Scale-4), and engagement in their care (Patient Activation Measure-13), controlling for age, male sex, site, participation in other CIH approaches, and surveys completed. RESULTS: We received 401 surveys from 119 Veterans (72% male, age range: 29-85 y) across all timepoints. Yoga participation was related to decreases in perceived stress (P<0.001), while tai chi participation was associated with improvements in overall PROMIS 28 physical and mental health functioning (P<0.02). Specific types of CIH were associated with significant improvements in PROMIS 28 subscales: meditation participation with physical functioning at 2, 6, and 12 months; tai chi participation with anxiety at 2 and 6 months, and ability to participate in social role activities at 2 months. No CIH approach was associated with Veterans' pain or engagement in their care. CONCLUSION: As specific CIH approaches are associated with improvements in patient-reported outcomes, clinicians, Veterans, and family members may use this information in discussions of nonpharmacological options to address health and well-being.

Precursors to non-invasive clinical dengue screening: Multivariate signature analysis of in-vivo diffuse skin reflectance spectroscopy on febrile patients in Malaysia.

Dengue diagnostics have come a long way. Attempts at breaking away from lab-oriented dengue detection, such as NS1 antigen, IgM or IgG antibodies detection have extensively received numerous coverage. As a result, rapid detection tests (RDTs) have started to gain inroads in medical practice. Rapid detection tests notwithstanding, analysis of blood serum is still a relatively complicated task. This includes the necessity of phlebotomy, centrifugation for blood serum, and other reagent-based tests. Therefore, a non-invasive method of dengue detection was considered. In this study, we present the utility of diffuse reflectance skin spectroscopy (bandwidth of 200-2500nm) on the forearm during the triaging period for dengue screening potential. This is performed with multivariate analysis of 240 triaged febrile/suspected dengue patients. The data is then scrutinized for its clinical validity to be included as either confirmed or probable dengue, or a control group. Based on discriminant analysis of several data normalization models, we can predict the patients' clinical dengue-positivity at ranges of accuracy between ~93-98% depending on mode of the data, with a probably optimal sensitivity and specificity to the clinical diagnosis of ~89% and ~100% respectively. From the outcomes of this study, we recommend further trials with cautious optimism. With these findings, it is hoped that the elusive non-invasive detection of tropical diseases may gain platform in the near future.

Selecting slip resistant winter footwear for personal support workers.

BACKGROUND: Falls are among the leading causes of occupational injuries for workers exposed to outdoor winter conditions such as Personal Support Workers (PSWs). Slip resistant footwear is known to reduce the risk of falls, however, it is difficult to predict how well a particular boot will perform prior to purchasing them. Our recently developed Maximum Achievable Angle (MAA) test can be used to rate footwear objectively to address this gap. OBJECTIVE: To rate the slip resistance of a selection of winter footwear that meets the needs and preferences of PSWs. METHODS: We selected 40 representative types of footwear based on survey results from 677 PSWs and applied our MAA test to rate slip resistance. RESULTS: Comfort and slip resistance were rated the most important features for selecting winter footwear. Of the 40 types of footwear tested, six were found to have a good slip resistance on ice. CONCLUSION: The vast majority of winter footwear that meet the needs and preferences of PSWs, perform poorly on ice. Therefore, PSWs should consult our website (ratemytreads.com) for selecting appropriate footwear that will keep them safe in the winter.

Recombinant GII.P16/GII.4 Sydney 2012 Was the Dominant Norovirus Identified in Australia and New Zealand in 2017.

For the past two decades, norovirus pandemic variants have emerged every 3⁻5 years, and dominate until they are replaced by alternate strains. However, this scenario changed in 2016 with the co-circulation of six prevalent viruses, three of which possessed the pandemic GII.4 Sydney 2012 capsid. An increased number of institutional gastroenteritis outbreaks were reported within the Oceania region in mid-2017. This study identified emerging noroviruses circulating in Australia and New Zealand in 2017 to assess the changing dynamics of the virus infection. RT-PCR-based methods, next generation sequencing, and phylogenetic analyses were used to genotype noroviruses from both clinical and wastewater samples. Antigenic changes were observed between the capsid of pandemic Sydney 2012 variant and the two new Sydney recombinant viruses. The combination of these antigenic changes and the acquisition of a new ORF1 through recombination could both facilitate their ongoing persistence in the population. Overall, an increased prevalence of GII.P16/GII.4 Sydney 2012 viruses was observed in 2017, replacing the GII.P16/GII.2 recombinant that dominated in the region at the end of 2016. This shift in strain dominance was also observed in wastewater samples, demonstrating the reliability of wastewater as a molecular surveillance tool.

Potential Therapeutic Agents for Feline Calicivirus Infection.

Feline calicivirus (FCV) is a major cause of upper respiratory tract disease in cats, with widespread distribution in the feline population. Recently, virulent systemic diseases caused by FCV infection has been associated with mortality rates up to 50%. Currently, there are no direct-acting antivirals approved for the treatment of FCV infection. Here, we tested 15 compounds from different antiviral classes against FCV using in vitro protein and cell culture assays. After the expression of FCV protease-polymerase protein, we established two in vitro assays to assess the inhibitory activity of compounds directly against the FCV protease or polymerase. Using this recombinant enzyme, we identified quercetagetin and PPNDS as inhibitors of FCV polymerase activity (IC50 values of 2.8 µM and 2.7 µM, respectively). We also demonstrate the inhibition of FCV protease activity by GC376 (IC50 of 18 µM). Using cell culture assays, PPNDS, quercetagetin and GC376 did not display antivirals effects, however, we identified nitazoxanide and 2'-C-methylcytidine (2CMC) as potent inhibitors of FCV replication, with EC50 values in the low micromolar range (0.6 µM and 2.5 µM, respectively). In conclusion, we established two in vitro assays that will accelerate the research for FCV antivirals and can be used for the high-throughput screening of direct-acting antivirals.

Five opportunities for healthcare leaders to better support person- and family-centred care in long-term care settings.

The benefits of Person- and Family-Centred Care (PFCC) are well documented, and many healthcare organizations have expressed their commitment to take this approach. Yet, it can be a difficult endeavour, with common barriers identified at the point-of-care, organizational and system levels. We implemented a PFCC education program with healthcare leaders, providers, and support staff working in home, community, and long-term care organizations across Canada. Focus groups were then conducted with almost 200 workshop participants and 20 long-term care home residents and family members. Five key opportunities for healthcare leaders to better support the provision of PFCC were revealed. In this article, specific recommendations from focus group participants for addressing each of these five opportunities are provided. These findings can assist healthcare leaders to proactively ensure the supports and processes are in place to enable staff to provide care in a more person- and family-centred way.

Acculturative stress as a moderator for international student drinking behaviors and alcohol use consequences.

Drinking behaviors and alcohol use consequences can have a major effect on well-being in college student populations. Little research has addressed how the unique acculturative stress experiences of international students may affect their alcohol use and consequences. This study examined acculturative stress as a moderator of the relationship between international student drinking behaviors and alcohol use consequences. Data were collected from 175 international students and analyzed using hierarchal regression analysis to assess the moderating effect of acculturative stress. Acculturative stress moderated the relationship between alcohol use and related consequences such that the relationship was stronger among those with higher levels of acculturative stress. Efforts to alleviate acculturative stress experiences of this population may help decrease alcohol use consequences.

Discovery of Highly Potent Liver X Receptor ß Agonists.

Introducing a uniquely substituted phenyl sulfone into a series of biphenyl imidazole liver X receptor (LXR) agonists afforded a dramatic potency improvement for induction of ATP binding cassette transporters, ABCA1 and ABCG1, in human whole blood. The agonist series demonstrated robust LXRß activity (>70%) with low partial LXRα agonist activity (<25%) in cell assays, providing a window between desired blood cell ABCG1 gene induction in cynomolgus monkeys and modest elevation of plasma triglycerides for agonist 15. The addition of polarity to the phenyl sulfone also reduced binding to the plasma protein, human α-1-acid glycoprotein. Agonist 15 was selected for clinical development based on the favorable combination of in vitro properties, excellent pharmacokinetic parameters, and a favorable lipid profile.

The Invisible Wound: Moral Injury and Its Impact on the Health of Operation Enduring Freedom/Operation Iraqi Freedom Veterans.

Many veterans are now returning from Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) deployments with physical and mental health problems. However, there are few studies that examine the impact of moral injury on both physical and mental well-being. This study examines the impact of moral injury on self-reported general physical health, general mental health, post-traumatic stress disorder symptoms, and depression symptoms. Cross-sectional data were collected at as part of a pilot study at the New Jersey Veteran Affairs. 100 OEF/OIF veterans recruited at the New Jersey Veteran Affairs completed the paper questionnaire. We found that moral injury and combat experiences positively predicted post-traumatic stress disorder scores. Seeing the aftermath of battle and moral injury were negatively associated with mental well-being and positively associated with depression. Physical health status was negatively associated with depression. Spirituality and moral injury were negatively associated with physical health, whereas age was positively associated with physical health. Moral injury plays an important role in both physical and mental health outcomes for OEF/OIF veterans, but it is often not addressed in health care. These results underline the need for an approach to veterans' health care that includes discussion of existential and moral issues since they may impact health outcomes for many service members.

Rare presentation of small bowel intussusception in childhood.

Small bowel intussusception complicated simultaneously by volvulus in an older child is rare but clinically significant, necessitating urgent operative management. We report a local case of jejuno-jejunal intussusception complicated by volvulus and bowel infarction in a 9-year-old Chinese girl, with diagnosis made on preoperative computed tomography and confirmed at laparotomy. An intestinal polyp as the lead point for intussusception was identified operatively.