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Abstract Aquaporin-1 (Aqp1), a water channel, has garnered significant interest for cell-based medicine and in vivo synthetic biology due to its ability to be genetically encoded to produce magnetic resonance signals by increasing the rate of water diffusion in cells. However, concerns regarding the effects of Aqp1 overexpression and increased membrane diffusivity on cell physiology have limited its widespread use as a deep-tissue reporter. In this study, we present evidence that Aqp1 generates strong diffusion-based magnetic resonance signals without adversely affecting cell viability or morphology in diverse cell lines derived from mice and humans. Our findings indicate that Aqp1 overexpression does not induce ER stress, which is frequently associated with heterologous expression of membrane proteins. Furthermore, we observed that Aqp1 expression had no detrimental effects on native biological activities, such as phagocytosis, immune response, insulin secretion, and tumor cell migration in the analyzed cell lines. These findings should serve to alleviate any lingering safety concerns regarding the utilization of Aqp1 as a genetic reporter and should foster its broader application as a noninvasive reporter for in vivo studies.

Abstract Background/objectives In healthcare research investigating complex interventions, gaps in understanding of processes can be filled by using qualitative methods alongside a quantitative approach. The aim of this mixed-methods pilot trial was to provide feasibility evidence comparing two treatment regimens for neovascular age-related macular degeneration (nAMD) to inform a future large-scale randomised controlled trial (RCT). Subjects/methods Forty-four treatment-naïve nAMD patients were followed over 24 months and randomised to one of two treatment regimens: standard care (SC) or treat and extend (T&E). The primary objective evaluated feasibility of the MATE trial via evaluations of screening logs for recruitment rates, nonparticipation and screen fails, whilst qualitative in-depth interviews with key study staff evaluated the recruitment phase and running of the trial. The secondary objective assessed changes in visual acuity and central retinal thickness (CRT) between the two treatment arms. Results The overall recruitment rate was 3.07 participants per month with a 40.8% non-participation rate, 18.51% screen-failure rate and 15% withdrawal/non-completion rate. Key themes in the recruitment phase included human factors, protocol-related issues, recruitment processes and challenges. Both treatment regimens showed a trend towards a visual acuity gain at month 12 which was not maintained at month 24, whilst CRT reduced similarly in both regimens over the same time period. These were achieved with one less treatment following a T&E regimen. Conclusion This mixed-methodology, pilot RCT achieved its pre-defined recruitment, nonparticipation and screen failure rates, thus deeming it a success. With some minor protocol amendments, progression to a large-scale RCT will be achievable.

Abstract Macular degeneration (MD) embodies a collection of disorders causing a progressive loss of central vision. Cross-sectional MRI studies have revealed structural changes in the grey and white matter in the posterior visual pathway in MD but there remains a need to understand how such changes progress over time. To that end we assessed the posterior pathway, characterising the visual cortex and optic radiations over a ~ 2-year period in MD patients and controls. We performed cross-sectional and longitudinal analysis of the former. Reduced cortical thickness and white matter integrity were observed in patients compared to controls, replicating previous findings. While faster, neither the rate of thinning in visual cortex nor the reduction in white matter integrity during the ~ 2-year period reached significance. We also measured cortical myelin density; cross-sectional data showed this was higher in patients than controls, likely as a result of greater thinning of non-myelinated tissue in patients. However, we also found evidence of a greater rate of loss of myelin density in the occipital pole in the patient group indicating that the posterior visual pathway is at risk in established MD. Taken together, our results revealed a broad decline in grey and white matter in the posterior visual pathway in bilateral MD; cortical thickness and fractional anisotropy show hints of an accelerated rate of loss also, with larger effects emerging in the occipital pole.

Abstract Tauopathies are a category of neurodegenerative diseases characterized by the presence of abnormal tau protein-containing neurofibrillary tangles (NFTs). NFTs are universally observed in aging, occurring with or without the concomitant accumulation of amyloid-beta peptide (Aβ) in plaques that typifies Alzheimer disease (AD), the most common tauopathy. Primary age-related tauopathy (PART) is an Aβ-independent process that affects the medial temporal lobe in both cognitively normal and impaired subjects. Determinants of symptomology in subjects with PART are poorly understood and require clinicopathologic correlation; however, classical approaches to staging tau pathology have limited quantitative reproducibility. As such, there is a critical need for unbiased methods to quantitatively analyze tau pathology on the histological level. Artificial intelligence (AI)-based convolutional neural networks (CNNs) generate highly accurate and precise computer vision assessments of digitized pathology slides, yielding novel histology metrics at scale. Here, we performed a retrospective autopsy study of a large cohort (n = 706) of human post-mortem brain tissues from normal and cognitively impaired elderly individuals with mild or no Aβ plaques (average age of death of 83.1 yr, range 55–110). We utilized a CNN trained to segment NFTs on hippocampus sections immunohistochemically stained with antisera recognizing abnormal hyperphosphorylated tau (p-tau), which yielded metrics of regional NFT counts, NFT positive pixel density, as well as a novel graph-theory based metric measuring the spatial distribution of NFTs. We found that several AI-derived NFT metrics significantly predicted the presence of cognitive impairment in both the hippocampus proper and entorhinal cortex (p

Category: Midfoot/Forefoot; Sports; Trauma Introduction/Purpose: Proximal fifth metatarsal fractures are a common foot injury. Previous surgical treatments have consisted of intramedullary screw fixation and a newer technique of plantar plating due to non-union and refractures seen with screw fixation. Purpose of this multi-surgeon case series study is to evaluate clinical and radiographic outcomes and complication rates after fifth metatarsal plating for proximal fifth metatarsal fractures in recreational and elite athletes. Methods: Retrospective multiple surgeon case series involving patients who underwent fifth metatarsal plantar plating for proximal fifth metatarsal fractures with a mean follow-up of 33.1 months (range, 12-52). Elite and recreational athletes were included. Demographic data, radiographic evaluation, and clinical notes were analyzed. Patient phone conversations were made to document complications outside of our electronic medical record. Results: Forty-four patients (45 fractures) were treated with plantar plating technique with a mean age of 37.3 years (range 14- 80). Five patients sustained refractures (11.1% of patients), 2 at previous fracture site, 1 through a screw hole, 1 proximal to plate, and 1 distal to plate. All refractures were treated non-operatively. No wound complications were seen. No secondary revision surgery was needed and union rate was 100% at final follow up. Conclusion: With a one year minimum follow up, plantar plating of proximal fifth metatarsal fractures is a viable option for treatment of both acute and chronic fractures as well as after failed intramedullary screw fixation with low refracture rates and without non-unions. Plantar plating allows the surgeon to have direct visualization of fracture reduction and ease of access for bone grafting. Both elite and recreational athletes can benefit from the plating technique.

Abstract Much concern exists over the role of blast-induced traumatic brain injury (TBI) in the chronic cognitive and mental health problems that develop in veterans and active duty military personnel. The brain vasculature is particularly sensitive to blast injury. The aim of this study was to characterize the evolving molecular and histologic alterations in the neurovascular unit induced by three repetitive low-energy blast exposures (3 × 74.5 kPa) in a rat model mimicking human mild TBI or subclinical blast exposure. High-resolution two-dimensional differential gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization (MALDI) mass spectrometry of purified brain vascular fractions from blast-exposed animals 6 weeks post-exposure showed decreased levels of vascular-associated glial fibrillary acidic protein (GFAP) and several neuronal intermediate filament proteins (α-internexin and the low, middle, and high molecular weight neurofilament subunits). Loss of these proteins suggested that blast exposure disrupts gliovascular and neurovascular interactions. Electron microscopy confirmed blast-induced effects on perivascular astrocytes including swelling and degeneration of astrocytic endfeet in the brain cortical vasculature. Because the astrocyte is a major sensor of neuronal activity and regulator of cerebral blood flow, structural disruption of gliovascular integrity within the neurovascular unit should impair cerebral autoregulation. Disrupted neurovascular connections to pial and parenchymal blood vessels might also affect brain circulation. Blast exposures also induced structural and functional alterations in the arterial smooth muscle layer. Interestingly, by 8 months after blast exposure, GFAP and neuronal intermediate filament expression had recovered to control levels in isolated brain vascular fractions. However, despite this recovery, a widespread vascular pathology was still apparent at 10 months after blast exposure histologically and on micro-computed tomography scanning. Thus, low-level blast exposure disrupts gliovascular and neurovascular connections while inducing a chronic vascular pathology.

Despite the recent flurry of interest in various aspects of ancient urbanism, we still know little about how much traffic flowed in and out of ancient cities, in part because of problems with using commodities as proxies for trade. This article investigates another approach, which is to estimate these flows from the built environment, concentrating on transport infrastructure such as city gates. To do this, I begin by discussing a new model for how we would expect this kind of infrastructure to expand with population, before investigating the relationship between the populations of sites and the total numbers and widths of city gates, focusing on the Greek and Roman world. The results suggest that there is indeed a systematic relationship between the estimated populations of cities and transport infrastructure, which is entirely consistent with broader theoretical and empirical expectations. This gives us a new way of exploring the connectivity and integration of ancient cities, contributing to a growing body of general theory about how settlements operate across space and time.

Industrial waste materials are increasingly being used in asphalt to improve pavement quality and reduce environmental impacts. The aim of this research was to test the pavement distress-related effects of using ground-granulated blast-furnace slag (GGBFS) as a filler in hot mix asphalt. There is potential for GGBFS to be integrated into Western Australian (WA) asphalt pavements. GGBFS was used as a replacement for the conventional hydrated lime (HL) filler used in mix designs of the Main Roads WA specifications. A control mixture (1.5% HL) was compared with three prototype mixtures containing 1.5%, 3% or 5% GGBFS instead of HL. To investigate their characteristics, we conducted wheel tracking tests, four-point bending tests, and assessments with an asphalt mixture performance tester (AMPT). The findings support the use of GGBFS in asphalt pavements. The mixture with 3% GGBFS had the best fatigue life, rutting resistance and AMPT results.