The viability and acceptability of a Virtual Wound Care Command Centre in Australia.

The objective of this study was to assess the viability and acceptability of an innovative Virtual Wound Care Command Centre where patients in the community, and their treating clinicians, have access to an expert wound specialist service that comprises a digitally enabled application for wound analysis, decision-making, remote consultation, and monitoring. Fifty-one patients with chronic wounds from 9 centres, encompassing hospital services, outpatient clinics, and community nurses in one metropolitan and rural state in Australia, were enrolled and a total of 61 wounds were analysed over 7 months. Patients received, on average, an occasion of service every 4.4 days, with direct queries responded to in a median time of 1.5 hours. During the study period, 26 (42.6%) wounds were healed, with a median time to healing of 66 (95% CI: 56-88) days. All patients reported high satisfaction with their wound care, 86.4% of patients recommended the Virtual Wound Care Command Centre with 84.1% of patients reporting the digital wound application as easy to use. Potential mean travel savings of $99.65 for rural patients per visit were recognised. The data revealed that the Virtual Wound Care Command Centre was a viable and acceptable patient-centred expert wound consultation service for chronic wound patients in the community.

Plasma p-tau181, p-tau217, and other blood-based Alzheimer's disease biomarkers in a multi-ethnic, community study.

INTRODUCTION: Blood-based Alzheimer's disease (AD) biomarkers provide opportunities for community studies and across ethnic groups. We investigated blood biomarker concentrations in the Washington Heights-Inwood Columbia Aging Project (WHICAP), a multi-ethnic community study of aging and dementia. METHODS: We measured plasma amyloid beta (Aß)40, Aß42, total tau (t-tau), phosphorylated tau (p-tau)181, and p-tau217, and neurofilament light chain (NfL) in 113 autopsied participants (29% with high AD neuropathological changes) and in 300 clinically evaluated individuals (42% with clinical AD). Receiver operating characteristics were used to evaluate each biomarker. We also investigated biomarkers as predictors of incident clinical AD. RESULTS: P-tau181, p-tau217, and NfL concentrations were elevated in pathologically and clinically diagnosed AD. Decreased Aß42/Aß40 ratio and increased p-tau217 and p-tau181 were associated with subsequent AD diagnosis. DISCUSSION: Blood-based AD biomarker concentrations are associated with pathological and clinical diagnoses and can predict future development of clinical AD, providing evidence that they can be incorporated into multi-ethnic, community-based studies.

Plasma phospho-tau181 increases with Alzheimer's disease clinical severity and is associated with tau- and amyloid-positron emission tomography.

INTRODUCTION: We examined and compared plasma phospho-tau181 (pTau181) and total tau: (1) across the Alzheimer's disease (AD) clinical spectrum; (2) in relation to brain amyloid ß (Aß) positron emission tomography (PET), tau PET, and cortical thickness; and (3) as a screening tool for elevated brain Aß. METHODS: Participants included 172 cognitively unimpaired, 57 mild cognitively impaired, and 40 AD dementia patients with concurrent Aß PET (Pittsburgh compound B), tau PET (AV1451), magnetic resonance imaging, plasma total tau, and pTau181. RESULTS: Plasma total tau and pTau181 levels were higher in AD dementia patients than those in cognitively unimpaired. Plasma pTau181 was more strongly associated with both Aß and tau PET. Plasma pTau181 was a more sensitive and specific predictor of elevated brain Aß than total tau and was as good as, or better than, the combination of age and apolipoprotein E (APOE). DISCUSSION: Plasma pTau181 may have utility as a biomarker of AD pathophysiology and as a noninvasive screener for elevated brain Aß.

Genomic structure and expression of the human serotonin 2A receptor gene (HTR2A) locus: identification of novel HTR2A and antisense (HTR2A-AS1) exons.

BACKGROUND: The serotonin 2A receptor is widely implicated in genetic association studies and remains an important drug target for psychiatric, neurological, and cardiovascular conditions. RNA sequencing redefined the architecture of the serotonin 2A receptor gene (HTR2A), revealing novel mRNA transcript isoforms utilizing unannotated untranslated regions of the gene. Expression of these untranslated regions is modulated by common single nucleotide polymorphisms (SNPs), namely rs6311. Previous studies did not fully capture the complexity of the sense- and antisense-encoded transcripts with respect to novel exons in the HTR2A gene locus. Here, we comprehensively catalogued exons and RNA isoforms for both HTR2A and HTR2A-AS1 using RNA-Seq from human prefrontal cortex and multiple mouse tissues. We subsequently tested associations between expression of newfound gene features and common SNPs in humans. RESULTS: We find that the human HTR2A gene spans ~66 kilobases and consists of 7, rather than 4 exons. Furthermore, the revised human HTR2A-AS1 gene spans ~474 kilobases and consists of 18, rather than 3 exons. Three HTR2A exons directly overlap with HTR2A-AS1 exons, suggesting potential for complementary nucleotide interactions. The repertoire of possible mouse Htr2a splice isoforms is remarkably similar to humans and we also find evidence for overlapping sense-antisense transcripts in the same relative positions as the human transcripts. rs6311 and SNPs in high linkage disequilibrium are associated with HTR2A-AS1 expression, in addition to previously described associations with expression of the extended 5' untranslated region of HTR2A. CONCLUSIONS: Our proposed HTR2A and HTR2A-AS1 gene structures dramatically differ from current annotations, now including overlapping exons on the sense and anti-sense strands. We also find orthologous transcript isoforms expressed in mice, providing opportunities to elucidate the biological roles of the human isoforms using a model system. Associations between rs6311 and expression of HTR2A and HTR2A-AS1 suggest this polymorphism is capable of modulating the expression of the sense or antisense transcripts. Still unclear is whether these SNPs act directly on the expression of the sense or antisense transcripts and whether overlapping exons are capable of interacting through complimentary base-pairing. Additional studies are necessary to determine the extent and nature of interactions between the SNPs and the transcripts prior to interpreting these findings in the context of phenotypes associated with HTR2A.

Levels of tau protein in plasma are associated with neurodegeneration and cognitive function in a population-based elderly cohort.

INTRODUCTION: Tau protein levels in plasma may be a marker of neuronal damage. We examined associations between plasma tau levels and Alzheimer's disease (AD)-related magnetic resonance imaging (MRI) and positron emission tomography (PET) neuroimaging measures among nondemented individuals. METHODS: Participants included 378 cognitively normal (CN) and 161 mild cognitive impairment (MCI) individuals enrolled in the Mayo Clinic Study of Aging with concurrent neuropsychological measures and amyloid PET, fluorodeoxyglucose PET, and MRI. Baseline plasma tau levels were measured using the Quanterix Simoa-HD1 tau assay. RESULTS: Plasma tau levels were higher in MCI compared with CN (4.34 vs. 4.14 pg/mL, P = .078). In regression models adjusted for age, gender, education, and APOE, higher plasma tau was associated with worse memory performance (b = -0.30, P = .02) and abnormal cortical thickness in an AD signature region (odds ratio = 1.80, P = .018). DISCUSSION: Plasma tau is associated with cortical thickness and memory performance. Longitudinal studies will better elucidate the associations between plasma tau, neurodegeneration, and cognition.

The Viability and Acceptability of a Virtual Wound Care Command Centre in Australia.

The objective of this study was to assess the viability and acceptability of an innovative Virtual Wound Care Command Centre where patients in the community, and their treating clinicians, have access to an expert wound specialist service that comprises a digital wound application (app) for wound analysis, decision-making, remote consultation, and monitoring. Fifty-one patients with chronic (42.6%) wounds were healed, with a median time to healing of 66 (95% CI: 56-88) days. All patients reported high satisfaction with their wound care, 86.4% of patients recommended the Virtual Wound Care Command Centre with 84.1% of patients reporting the app as easy to use. The data revealed that the Virtual Wound Care Command Centre was a viable and acceptable patient-centred expert wound consultation service for chronic wound patients in the community.

Neuron densities vary across and within cortical areas in primates.

The numbers and proportion of neurons in areas and regions of cortex were determined for a single cortical hemisphere from two prosimian galagos, one New World owl monkey, one Old World macaque monkey, and one baboon. The results suggest that there is a common plan of cortical organization across the species examined here and also differences that suggest greater specializations in the Old World monkeys. In all primates examined, primary visual cortex (V1) was the most neuron-dense cortical area and the secondary visual areas had higher-than-average densities. Primary auditory and somatosensory areas tended to have high densities in the Old World macaque and baboon. Neuronal density varies less across cortical areas in prosimian galagos than in the Old World monkeys. Thus, cortical architecture varies greatly within and across primate species, but cell density is greater in cortex devoted to the early stages of sensory processing.

The Collaborative Cross, a community resource for the genetic analysis of complex traits.

The goal of the Complex Trait Consortium is to promote the development of resources that can be used to understand, treat and ultimately prevent pervasive human diseases. Existing and proposed mouse resources that are optimized to study the actions of isolated genetic loci on a fixed background are less effective for studying intact polygenic networks and interactions among genes, environments, pathogens and other factors. The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way we approach human health and disease.

Mechanism of action deconvolution of the small-molecule pathological tau aggregation inhibitor Anle138b.

BACKGROUND: A key histopathological hallmark of Alzheimer's disease (AD) is the presence of neurofibrillary tangles of aggregated microtubule-associated protein tau in neurons. Anle138b is a small molecule which has previously shown efficacy in mice in reducing tau aggregates and rescuing AD disease phenotypes. METHODS: In this work, we employed bioinformatics analysis-including pathway enrichment and causal reasoning-of an in vitro tauopathy model. The model consisted of cultured rat cortical neurons either unseeded or seeded with tau aggregates derived from human AD patients, both of which were treated with Anle138b to generate hypotheses for its mode of action. In parallel, we used a collection of human target prediction models to predict direct targets of Anle138b based on its chemical structure. RESULTS: Combining the different approaches, we found evidence supporting the hypothesis that the action of Anle138b involves several processes which are key to AD progression, including cholesterol homeostasis and neuroinflammation. On the pathway level, we found significantly enriched pathways related to these two processes including those entitled "Superpathway of cholesterol biosynthesis" and "Granulocyte adhesion and diapedesis". With causal reasoning, we inferred differential activity of SREBF1/2 (involved in cholesterol regulation) and mediators of the inflammatory response such as NFKB1 and RELA. Notably, our findings were also observed in Anle138b-treated unseeded neurons, meaning that the inferred processes are independent of tau pathology and thus represent the direct action of the compound in the cellular system. Through structure-based ligand-target prediction, we predicted the intracellular cholesterol carrier NPC1 as well as NF-κB subunits as potential targets of Anle138b, with structurally similar compounds in the model training set known to target the same proteins. CONCLUSIONS: This study has generated feasible hypotheses for the potential mechanism of action of Anle138b, which will enable the development of future molecular interventions aiming to reduce tau pathology in AD patients.

Functional coding variation in recombinant inbred mouse lines reveals multiple serotonin transporter-associated phenotypes.

The human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT, SLC6A4) figures prominently in the etiology and treatment of many prevalent neurobehavioral disorders including anxiety, alcoholism, depression, autism, and obsessive-compulsive disorder (OCD). Here, we use naturally occurring polymorphisms in recombinant inbred (RI) lines to identify multiple phenotypes associated with altered SERT function. The widely used mouse strain C57BL/6J, harbors a SERT haplotype defined by 2 nonsynonymous coding variants [Gly-39 and Lys-152 (GK)]. At these positions, many other mouse lines, including DBA/2J, encode, respectively, Glu-39 and Arg-152 (ER haplotype), amino acids found also in hSERT. Ex vivo synaptosomal 5-HT transport studies revealed reduced uptake associated with the GK variant, a finding confirmed by in vitro heterologous expression studies. Experimental and in silico approaches using RI lines (C57BL/6J x DBA/2J = BXD) identify multiple anatomical, biochemical, and behavioral phenotypes specifically impacted by GK/ER variation. Among our findings are several traits associated with alcohol consumption and multiple traits associated with dopamine signaling. Further bioinformatic analysis of BXD phenotypes, combined with biochemical evaluation of SERT knockout mice, nominates SERT-dependent 5-HT signaling as a major determinant of midbrain iron homeostasis that, in turn, dictates iron-regulated DA phenotypes. Our studies provide an example of the power of coordinated in vitro, in vivo, and in silico approaches using mouse RI lines to elucidate and quantify the system-level impact of gene variation.

Nutcracker syndrome: A case report and review of the literature.

Background: Nutcracker syndrome (NS) is an uncommon condition resulting from the compression of the left renal vein (LRV) between the aorta and superior mesenteric artery (SMA), resulting in symptoms such as flank pain and hematuria. Case presentation: We present the case of a 30-year-old woman complaining of abdominal pain who was found to have nutcracker syndrome and treated with endovascular stenting of the left renal vein. Discussion: We review the literature related to endovascular treatment of NS with focus on the distribution of the sizes of stents and rates of stent migration. Conclusion: NC is a rare condition requiring a high index of suspicion for diagnosis. Endovascular treatment is a reasonable option, but its limitations must be considered.

Using Transparent Soils to Observe Soil Liquefaction and Fines Migration.

The cyclic liquefaction of soils and associated mud-pumping can lead to costly repairs of roads, railways, and other heavy-haul infrastructure. Over the last decade, several laboratory studies have been conducted to investigate these phenomena, but, due to the opacity of soil, the typical experimental observations of cyclic liquefaction have been limited to post-test observations of fine movement and the data of water pressures and soil settlements. In this paper, we show how partially transparent soil models can be used to provide the visualization of a moving saturation front and that fully transparent models can be used to observe fine migration during the cycling loading of a soil column. The changing saturation degree was tracked using a correlation between the degree of saturation, soil transparency, and grayscale image values, while particle movements of fines and larger particles were measured using a small number of fluorescent particles and particle tracking velocimetry. Another innovation of the work was in using mixtures of ethyl benzoate and ethanol as a low-viscosity pore fluid with the refractive index matching the fused silica soil particles. The benefits and challenges of these visualization tests are discussed.

A human tau seeded neuronal cell model recapitulates molecular responses associated with Alzheimer's disease.

Cellular models recapitulating features of tauopathies are useful tools to investigate the causes and consequences of tau aggregation and the identification of novel treatments. We seeded rat primary cortical neurons with tau isolated from Alzheimer's disease brains to induce a time-dependent increase in endogenous tau inclusions. Transcriptomics of seeded and control cells identified 1075 differentially expressed genes (including 26 altered at two time points). These were enriched for lipid/steroid metabolism and neuronal/glial cell development genes. 50 genes were correlated with tau inclusion formation at both transcriptomic and proteomic levels, including several microtubule and cytoskeleton-related proteins such as Tubb2a, Tubb4a, Nefl and Snca. Several genes (such as Fyn kinase and PTBP1, a tau exon 10 repressor) interact directly with or regulate tau. We conclude that this neuronal model may be a suitable platform for high-throughput screens for target or hit compound identification and validation.

Cross-Sectional Exploration of Plasma Biomarkers of Alzheimer's Disease in Down Syndrome: Early Data from the Longitudinal Investigation for Enhancing Down Syndrome Research (LIFE-DSR) Study.

With improved healthcare, the Down syndrome (DS) population is both growing and aging rapidly. However, with longevity comes a very high risk of Alzheimer's disease (AD). The LIFE-DSR study (NCT04149197) is a longitudinal natural history study recruiting 270 adults with DS over the age of 25. The study is designed to characterize trajectories of change in DS-associated AD (DS-AD). The current study reports its cross-sectional analysis of the first 90 subjects enrolled. Plasma biomarkers phosphorylated tau protein (p-tau), neurofilament light chain (NfL), amyloid ß peptides (Aß1-40, Aß1-42), and glial fibrillary acidic protein (GFAP) were undertaken with previously published methods. The clinical data from the baseline visit include demographics as well as the cognitive measures under the Severe Impairment Battery (SIB) and Down Syndrome Mental Status Examination (DS-MSE). Biomarker distributions are described with strong statistical associations observed with participant age. The biomarker data contributes to understanding DS-AD across the spectrum of disease. Collectively, the biomarker data show evidence of DS-AD progression beginning at approximately 40 years of age. Exploring these data across the full LIFE-DSR longitudinal study population will be an important resource in understanding the onset, progression, and clinical profiles of DS-AD pathophysiology.

High-throughput multiplexed transcript analysis yields enhanced resolution of 5-hydroxytryptamine 2C receptor mRNA editing profiles.

RNA editing is a post-transcriptional modification in which adenosine residues are converted to inosine (adenosine-to-inosine editing). Commonly used methodologies to quantify RNA editing levels involve either direct sequencing or pyrosequencing of individual cDNA clones. The limitations of these methods lead to a small number of clones characterized in comparison to the number of mRNA molecules in the original sample, thereby producing significant sampling errors and potentially erroneous conclusions. We have developed an improved method for quantifying RNA editing patterns that increases sequence analysis to an average of more than 800,000 individual cDNAs per sample, substantially increasing accuracy and sensitivity. Our method is based on the serotonin 2C receptor (5-hydroxytryptamine(2C); 5HT(2C)) transcript, an RNA editing substrate in which up to five adenosines are modified. Using a high-throughput multiplexed transcript analysis, we were able to quantify accurately the expression of twenty 5HT(2C) isoforms, each representing at least 0.25% of the total 5HT(2C) transcripts. Furthermore, this approach allowed the detection of previously unobserved changes in 5HT(2C) editing in RNA samples isolated from different inbred mouse strains and dissected brain regions, as well as editing differences in alternatively spliced 5HT(2C) variants. This approach provides a novel and efficient strategy for large-scale analyses of RNA editing and may prove to be a valuable tool for uncovering new information regarding editing patterns in specific disease states and in response to pharmacological and physiological perturbation, further elucidating the impact of 5HT(2C) RNA editing on central nervous system function.

Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer's disease.

Cerebrospinal fluid (CSF) p-tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer's disease (AD), reflecting abnormal tau metabolism in the brain. Here we investigate the performance of CSF p-tau217 as a biomarker of AD in comparison to p-tau181. In the Swedish BioFINDER cohort (n = 194), p-tau217 shows stronger correlations with the tau positron emission tomography (PET) tracer [18F]flortaucipir, and more accurately identifies individuals with abnormally increased [18F]flortaucipir retention. Furthermore, longitudinal increases in p-tau217 are higher compared to p-tau181 and better correlate with [18F]flortaucipir uptake. P-tau217 correlates better than p-tau181 with CSF and PET measures of neocortical amyloid-ß burden and more accurately distinguishes AD dementia from non-AD neurodegenerative disorders. Higher correlations between p-tau217 and [18F]flortaucipir are corroborated in an independent EXPEDITION3 trial cohort (n = 32). The main results are validated using a different p-tau217 immunoassay. These findings suggest that p-tau217 might be more useful than p-tau181 in the diagnostic work up of AD.

Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobar degeneration.

With the potential development of new disease-modifying Alzheimer's disease (AD) therapies, simple, widely available screening tests are needed to identify which individuals, who are experiencing symptoms of cognitive or behavioral decline, should be further evaluated for initiation of treatment. A blood-based test for AD would be a less invasive and less expensive screening tool than the currently approved cerebrospinal fluid or amyloid ß positron emission tomography (PET) diagnostic tests. We examined whether plasma tau phosphorylated at residue 181 (pTau181) could differentiate between clinically diagnosed or autopsy-confirmed AD and frontotemporal lobar degeneration. Plasma pTau181 concentrations were increased by 3.5-fold in AD compared to controls and differentiated AD from both clinically diagnosed (receiver operating characteristic area under the curve of 0.894) and autopsy-confirmed frontotemporal lobar degeneration (area under the curve of 0.878). Plasma pTau181 identified individuals who were amyloid ß-PET-positive regardless of clinical diagnosis and correlated with cortical tau protein deposition measured by 18F-flortaucipir PET. Plasma pTau181 may be useful to screen for tau pathology associated with AD.

Meta-Analysis of the Alzheimer's Disease Human Brain Transcriptome and Functional Dissection in Mouse Models.

We present a consensus atlas of the human brain transcriptome in Alzheimer's disease (AD), based on meta-analysis of differential gene expression in 2,114 postmortem samples. We discover 30 brain coexpression modules from seven regions as the major source of AD transcriptional perturbations. We next examine overlap with 251 brain differentially expressed gene sets from mouse models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus tau pathology and reveal age- and sex-dependent expression signatures for disease progression. Human coexpression modules enriched for neuronal and/or microglial genes broadly overlap with mouse models of AD, Huntington's disease, amyotrophic lateral sclerosis, and aging. Other human coexpression modules, including those implicated in proteostasis, are not activated in AD models but rather following other, unexpected genetic manipulations. Our results comprise a cross-species resource, highlighting transcriptional networks altered by human brain pathophysiology and identifying correspondences with mouse models for AD preclinical studies.

RNA editing of the serotonin 2C receptor and expression of Galpha(q) protein: genetic mouse models do not support a role for regulation or compensation.

The serotonin 2C (5-HT(2C)) receptor undergoes RNA editing at five bases in a region of the pre-mRNA encoding the second intracellular loop, generating many unique 5-HT(2C) receptor isoforms. Mechanisms regulating in vivo expression of different edited 5-HT(2C) receptor isoforms are poorly understood, as are the adaptive consequences of variation in editing profiles. Recent findings suggest a putative relationship between expression levels of Galpha(q/11) protein and the degree of editing of 5-HT(2C) receptor transcripts. To elucidate the potential regulatory or adaptive role of Galpha(q/11) protein levels, we quantified editing of 5-HT(2C) receptor RNA transcripts in Galpha(q) null mice and protein levels of Galpha(q) and Galpha(11) in transgenic male mice solely expressing either the non-edited (INI) or the fully edited (VGV) isoforms of the 5-HT(2C) receptor. Pyrosequencing of RNA isolated from amygdaloid cortex in Galpha(q) null and wild-type mice revealed no significant differences in 5-HT(2C) receptor mRNA editing profiles. Cortical tissue from INI/y, VGV/y, and wild-type mice was assayed for expression of Galpha(q) and Galpha(11) subunits by Western blotting. No differences in signal density between wild-type and INI/y or VGV/y groups were found, indicating equivalent levels of Galpha(q) and Galpha(11) protein. Together, these data do not support a causal or compensatory relationship between 5-HT(2C) receptor RNA editing and G(q) protein levels.

Heritable variation of ERBB2 and breast cancer risk.

Amplification of the epithelial growth factor receptor gene ERBB2 (HER2, NEU) in breast cancer is associated with a poor clinical prognosis. In mammary gland development, this receptor plays a role in ductal and lobuloalveolar differentiation. We conducted a systematic investigation of the role of genetic variation of the ERBB2 gene in breast cancer risk in a study of 842 histologically confirmed invasive breast cancer cases and 1,108 controls from the Shanghai Breast Cancer Study. We observed that the ERBB2 gene resides within a locus of high linkage disequilibrium, composed of three major ancestral haplotypes in the study population. These haplotypes are marked by simple tandem repeat and single nucleotide polymorphisms, including the missense variants I655V and P1170A. We observed a risk-modifying effect of a highly polymorphic simple tandem repeat within an evolutionarily conserved region, 4.4 kb upstream from the ERBB2 transcription start site. Under a dominant genetic model, the age-adjusted odds ratio was 1.74 (95% confidence interval, 1.27-2.37). Its association with breast cancer, and with breast cancer stratified by histology, by histologic grade, and by stage, remained significant after correction for multiple comparisons. In contrast, we observed no association of ERBB2 single nucleotide polymorphism haplotypes with breast cancer predisposition.