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ABSTRACTPoly(lactic acid)-zinc oxide (PLA-ZnO) nanocomposites for fused filament fabrication have potential applications in the biomedical field as they combine the bio-compatibility of PLA with the antibacterial properties of ZnO. This work investigates the effects of masterbatch mixing strategy, ZnO concentration and ZnO surface treatment (silanisation) on the printability and the mechanical performance of the nanocomposites as a pre-requirement to the wider uptake of these materials. The results showed that the printability decreased as the filler loading increased. However, the surface treatment of the ZnO powder enhanced the matrix-filler interfacial interactions and reduced the thermal degradation of PLA. This ameliorated the printability and the tensile properties of the nanocomposites filled with up to 5 wt.% of ZnO. Moreover, despite the additional thermal treatment, melt-mixing prevented the degradative effect induced by the solvent used for solvent mixing. Future work will focus on assessing the antibacterial properties of the nanocomposite FFF parts.

Experimental Archaeology: Reconstruction of Material Heritage of Lithuania, Volume II, is an interesting journey back into the past by means of practical experimentations. An insightful volume that contains a collection of well-written and well-crafted essays exploring different facets of ancient life in Lithuania – such as flint tool manufacturing, leatherwork intricacies or colouring dye on clothes. There are some portions of the English translation which may need further editorial reviews.

Introduction: Stroke often leads to cognitive impairment, but its progression and influencing factors over time remain poorly understood. This study evaluates immediate post-stroke cognitive impacts and investigates the influence of concurrent factors on cognitive evolution over the first year. Patients and methods: In the STRATEGIC study, 179 patients with first symptomatic ischemic stroke underwent neuropsychological assessments within three months post-stroke, and 141 were re-evaluated at 12 months. Risk factors tested for associations with cognitive outcome included demographic variables, cardiovascular and other medical factors, and lesion characteristics. Cognitive performance was primarily measured via the Montreal Cognitive Assessment (MoCA), with domain-specific assessments for episodic memory (Free and Cued Selective Reminding Task), short-term memory (Digit Span forward), and working memory (Digit Span backward). Results: At the time of stroke, participants ranged in age from 46 to 89 years (M = 70, SD = 9.5) and 36.9% were female. Ischemic heart disease predicted cognitive non-improvement between 3 and 12 months. Atrial fibrillation and carotid stenosis were linked to changes in episodic and working memory, respectively. Moreover, female sex and lower education correlated with stagnant global cognition and episodic memory. Discussion and conclusion: Our findings underscore the important influence of cardiovascular risk factors on cognitive functional recovery after stroke. Interventions targeting these risk factors may improve cognitive prognosis and affect traditional outcome measures such as recurrent vascular events. Future trials should include cognitive measures to fully capture the potential benefits of intensive risk factor intervention.

Introduction Spinal cord stimulators (SCS) offer safe and effective pain relief. Precise lead placement is critical. Indications for lead placement include chronic pain, failed back surgery syndrome and complex regional pain syndrome (1). Hardware related complications include lead fracture and lead migration into the subdural space. Complications can also include spinal cord injury, nerve root damage or lack of desired pain control (2). We present a case of subarachnoid hemorrhage (SAH) due to SCS lead migration into the subdural space. Methods An 81‐year‐old female patient with a past medical history of heart failure, atrial fibrillation and a mechanical mitral valve, presents with a severe headache and right hemiparesis. The patient was anticoagulated with a warfarin to heparin bridge. One week prior to presentation, the patient underwent SCS placement for chronic lower back pain due to post herpetic neuralgia. She was also found to have 8/10 pain on palpation of the lumbar spine and loss of sensation in the right lower extremity. An urgent CT brain revealed a SAH in the bilateral occipital lobes, right sylvian fissure and right temporal lobe. CT angiogram was also performed and did not reveal any evidence of a cerebral aneurysm. CT of the thoracic spine revealed neurostimulator lead migration into the subdural space. Neurosurgery was consulted and subsequently removed the SCS. The patient’s hemiparesis resolved, and CT brain showed no progression of the hemorrhage. MRI brain showed no infarct. Results We propose that the combined risk of anticoagulation and lead migration into the subdural space led to the development of SAH. Conclusion In cases of a SAH, where a cerebral aneurysm or arteriovenous malformation have been excluded, other sources should be considered. We report a novel case of SAH following SCS placement.

Introduction Very little is known about how the COVID-19 pandemic has affected the health of residents and the healthcare system in Alberta, Canada. The purpose of this study is to establish an observational study to characterise the health of residents in Alberta, Canada, over time, covering a population that tested negative or positive for COVID-19 during the pandemic. The primary outcome is to characterise ‘long COVID-19’ and the health status of residents during the COVID-19 pandemic. Secondary outcomes include the estimation of the risk of and risk factors associated with adverse health outcomes and healthcare utilisation and burdens.Methods and analysis This is a population-level provincial observational study which will follow-up with Alberta residents who underwent testing for COVID-19 and completed surveys adapted from the ISARIC COVID-19 long-term follow-up survey. The survey data will be linked with medical records. Statistical analyses will be carried out to characterise ‘long COVID-19’ and the health status of residents during the pandemic. The outcomes of this study will inform strategies for primary care and rehabilitation services to prevent chronic consequences; contribute to healthcare management, interventional studies, rehabilitation and health management to reduce overall morbidity and improve long-term outcomes of COVID-19 and the COVID-19 pandemic and potentially guide a self-evaluation of a remote monitoring system to manage individuals’ health.Ethics and dissemination This study was reviewed and approved by the University of Alberta ethics committee (Study ID: Pro00112053 & Pro00113039) on 13 August 2021 and adheres to the Alberta Health Services research information management policy. Study results will be used to manage clinical care, published in peer-reviewed journals and presented at local, national and international conferences.Protocol version 6 June 2022EuroQol ID 161 015.

Abstract Introduction Remote electrical neuromodulation (REN) is a novel acute treatment of migraine. Upper arm peripheral nerves are stimulated to induce conditioned pain modulation (CPM)—an endogenous analgesic mechanism in which conditioning stimulation inhibits pain in remote body regions. The REN device (Nerivio®, Theranica Bio-Electronics LTD., Israel) is FDA-authorized for acute treatment of migraine in adults who do not have chronic migraine. The current study assessed the consistency of response over multiple migraine attacks in people with chronic migraine who are typically characterized with severe pain intensity, high disability, and less robust response to triptans. Methods This was an open-label, single-arm, dual-center study conducted on adults with chronic migraine. Participants underwent a 4-week treatment phase in which they treated their migraine headaches with the device for 45 min within 1 h of attack onset. Pain levels were recorded at baseline, 2 h, and 24 h post-treatment. Efficacy outcomes (pain relief and pain-free responses at 2 h, sustained pain relief and sustained pain-free responses at 24 h) focused on intra-individual consistency of response across multiple attacks, which was defined as response in at least 50% of the treatments. Results Forty-two participants were enrolled, and 38 participants were evaluable for analyses; 73.7% (28/38) achieved pain relief at 2 h, 26.3% (10/38) were pain-free at 2 h, 84.4% (27/32) had sustained pain relief response at 24 h and 45.0% (9/20) had sustained pain relief response at 24 h in at least 50% of their treated attacks. The effects of REN on associated symptoms and improvement in function were also consistent. The incidence of device-related adverse events was low (1.8%). Conclusions REN used for a series of migraine attacks was effective and well tolerated across attacks. REN may offer a safe and effective non-pharmacological alternative for acute treatment in patients with chronic migraine. Trial Registration ClinicalTrials.gov identifier, NCT04161807. Retrospectively registered on November 13, 2019.

Age-specific resources in human MRI mitigate processing biases that arise from structural changes across the lifespan. There are fewer age-specific resources for preclinical imaging, and they only represent developmental periods rather than adulthood. Since rats recapitulate many facets of human aging, it was hypothesized that brain volume and each tissue's relative contribution to total brain volume would change with age in the adult rat. Data from a longitudinal study of rats at 3, 5, 11, and 17 months old were used to test this hypothesis. Tissue volume was estimated from high resolution structural images using a priori information from tissue probability maps. However, existing tissue probability maps generated inaccurate gray matter probabilities in subcortical structures, particularly the thalamus. To address this issue, gray matter, white matter, and CSF tissue probability maps were generated by combining anatomical and signal intensity information. The effects of age on volumetric estimations were then assessed with mixed-effects models. Results showed that herein estimation of gray matter volumes better matched histological evidence, as compared to existing resources. All tissue volumes increased with age, and the tissue proportions relative to total brain volume varied across adulthood. Consequently, a set of rat brain templates and tissue probability maps from across the adult lifespan is released to expand the preclinical MRI community's fundamental resources.

For patients with cardiac implantable electronic devices (CIEDs), arrythmias such as atrial fibrillation (AF) can be detected and actions taken to rapidly assess and initiate treatment where appropriate. Actions include timely initiation of anticoagulation, review of blood pressure, and optimization of cholesterol/lipids to prevent unfavorable outcomes, such as stroke and other cardiovascular complications. Delays to initiating anticoagulation can have devastating consequences. We sought to implement a virtual clinic, where a pharmacist reviews patient referrals from a CIED clinic after detecting AF from the CIED. Anticoagulation choice is determined by patient-specific factors, and a shared patient–provider decision to start oral anticoagulation is made. In addition, blood pressure readings and medications are assessed with lipid-lowering therapies for optimization. A total of 315 patients have been admitted through this clinic and anticoagulated over a two-year span; in addition, 322 successful interventions were made for optimization of cardiac therapy. Rapid initiation of anticoagulation within five days of referral was likely to have reduced unfavorable outcomes, such as stroke and other cardiovascular optimizations, leading to improved patient outcomes.

Small vessel disease (SVD) is associated with cognitive impairment in older age and be implicated in vascular dementia. Post-mortem studies show proliferation of activated microglia in the affected white matter. However, the role of inflammation in SVD pathogenesis is incompletely understood and better biomarkers are needed. We hypothesized that expression of the 18 kDa translocator protein (TSPO), a marker of microglial activation, would be higher in SVD. Positron emission tomography (PET) was performed with the second-generation TSPO ligand [11C]PBR28 in 11 participants with SVD. TSPO binding was evaluated by a two-tissue compartment model, with and without a vascular binding component, in white matter hyperintensities (WMH) and normal-appearing white matter (NAWM). In post-mortem tissue, in a separate cohort of individuals with SVD, immunohistochemistry was performed for TSPO and a pan-microglial marker Iba1. Kinetic modeling showed reduced tracer volume and blood volume fraction in WMH compared with NAWM, but a significant increase in vascular binding. Vascular [11C]PBR28 binding was also increased compared with normal-appearing white matter of healthy participants free of SVD. Immunohistochemistry showed a diffuse increase in microglial staining (with Iba1) in sampled tissue in SVD compared with control samples, but with only a subset of microglia staining positively for TSPO. Intense TSPO staining was observed in the vicinity of damaged small blood vessels, which included perivascular macrophages. The results suggest an altered phenotype of activated microglia, with reduced TSPO expression, in the areas of greatest white matter ischemia in SVD, with implications for the interpretation of TSPO PET studies in older individuals or those with vascular risk factors.

Background: Studies of lesion location have been unsuccessful in identifying mappings between single brain regions and post-stroke depression (PSD). Based on studies implicating the reward system in major depressive disorder without stroke, we investigated structural correlates within this system and their associations with PSD. Methods: The study enrolled 16 healthy controls, 12 stroke patients with PSD and 34 stroke patients free of PSD. Participants underwent 3T structural and diffusion MRI. Graph theoretical measures were used to examine global topology and whole-brain connectome analyses were employed to assess differences in the interregional connectivity matrix between groups. Structural correlates specific to the reward system were examined from grey matter volumes and by reconstructing its main white matter pathways, namely the medial forebrain bundle and cingulum connections, using deterministic tractography. Fractional anisotropy (FA) was derived as a measure of microstructural organization, and extracellular free-water (FW) as a possible proxy of neuroinflammation. Results: Subnetworks of decreased FA-weighted and increased FW-weighted connectivity were observed in patients with PSD relative to healthy controls. These networks subsumed the majority of regions constituting the reward system. Within the reward system, FA and FW of major connection pathways and grey matter volume were collectively predictive of PSD, explaining 37.8% of the variance in depression severity. Conclusions: PSD is associated with grey matter volume loss, reduced FA and increased extracellular FW in the reward system, similar to features observed in major depression without stroke. Structural characterization of the reward system is a promising biomarker of vulnerability to depression after stroke.

Abstract Background Dendritic cells (DC) induce adaptive responses against foreign antigens, and play an essential role in maintaining peripheral tolerance to self-antigens. Therefore they are involved in preventing fatal autoimmunity. Selective delivery of antigens to immature DC via the endocytic DEC-205 receptor on their surface promotes antigen-specific T cell tolerance, both by recessive and dominant mechanisms. We provide evidence that the induction of antigen-specific T cell tolerance is not a unique property of CD11c+CD8+DEC-205+ DCs. Methods We employed a fusion between αDCIR2 antibodies and the highly encephalitogenic peptide 139–151 of myelin-derived proteolipid protein (PLP139–151), to target CD11c +CD8- DCs with a DEC-205−DCIR2+ phenotype in vivo, and to substantially improve clinical symptoms in the PLP139–151-induced model of experimental autoimmune encephalomyelitis (EAE). Results Consistent with previous studies targeting other cell surface receptors, EAE protection mediated by αDCIR2-PLP139–151 fusion antibody (Ab) depended on an immature state of targeted DCIR2+ DCs. The mechanism of αDCIR2-PLP139–151 mAb function included the deletion of IL-17- and IFN-γ-producing pathogenic T cells, as well as the enhancement of regulatory T (Treg) cell activity. In contrast to the effect of αDEC-205+ fusion antibodies, which involves extrathymic induction of a Foxp3+ Treg cell phenotype in naïve CD4+Foxp3- T cells, treatment of animals with DCIR2+ fusion antibodies resulted in antigen-specific activation and proliferative expansion of natural Foxp3+ Treg cells. Conclusions These results suggest that multiple mechanisms can lead to the expansion of the Treg population, depending on the DC subset and receptor targeted.

Individual differences in memory during aging are associated with the microstructure of the fornix, a bidirectional tract connecting the hippocampus with the diencephalon, basal forebrain and cortex. To investigate the origin of alterations in fornix microstructure, measurement of hippocampal subfield volumes was combined with diffusion MRI and cognitive evaluation in a new sample of 31 healthy human participants aged 50–89 years. The fornix, uncinate and parahippocampal cingulum were reconstructed using diffusion MRI tractography. Episodic memory was assessed with free and cued verbal recall, visual recognition and paired associate learning tests. Recall performance was associated with fornix microstructure and hippocampal subfield volumes. Subiculum and CA1 volumes remained positively associated with fornix microstructure when controlling for other volumes. Subiculum volume was also associated with fornix microstructure independent of age. Regression analyses showed that subiculum-fornix associations explained more variation in recall than that of CA1-fornix associations. In a multivariable regression model, age and subiculum volume were independent predictors of free recall whilst fornix microstructure and CA1 volume were not. These results suggest that age-related changes in a network that includes the subiculum and fornix are important in cognitive change in healthy aging. These results match anatomical predictions concerning the importance of hippocampal – diencephalic projections for memory.

The construction of a homing tour is known to be NP-complete. On the other hand, the Euler formula puts su cient restrictions on plane graphs that one should be able to assert the existence of such tours in some cases; in particular we focus on split Euler tours (SETs) in 3-connected, 4-regular, planar graphs (tfps). An Euler tour S in a graph G is a SET if there is a vertex v (called a half vertex of S) such that the longest portion of the tour between successive visits to v is exactly half the number of edges of G. Among other results, we establish that every tfp G having a SET S in which every vertex of G is a half vertex of S can be transformed to another tfp G′ having a SET S′ in which every vertex of G′ is a half vertex of S′ and G′ has at most one point having a face configuration of a particular class. The various results rely heavily on the structure of such graphs as determined by the Euler formula and on the construction of tfps from the octahedron. We also construct a 2-connected 4-regular planar graph that does not have a SET.

Abstract Abnormal uterine activity in pregnancy causes a range of important clinical disorders, including preterm birth, dysfunctional labour and post‐partum haemorrhage. Uterine contractile patterns are controlled by the generation of complex electrical signals at the myometrial smooth muscle plasma membrane. To identify novel targets to treat conditions associated with uterine dysfunction, we undertook a genome‐wide screen of potassium channels that are enriched in myometrial smooth muscle. Computational modelling identified Kir7.1 as potentially important in regulating uterine excitability during pregnancy. We demonstrate Kir7.1 current hyper‐polarizes uterine myocytes and promotes quiescence during gestation. Labour is associated with a decline, but not loss, of Kir7.1 expression. Knockdown of Kir7.1 by lentiviral expression of miRNA was sufficient to increase uterine contractile force and duration significantly. Conversely, overexpression of Kir7.1 inhibited uterine contractility. Finally, we demonstrate that the Kir7.1 inhibitor VU590 as well as novel derivative compounds induces profound, long‐lasting contractions in mouse and human myometrium; the activity of these inhibitors exceeds that of other uterotonic drugs. We conclude Kir7.1 regulates the transition from quiescence to contractions in the pregnant uterus and may be a target for therapies to control uterine contractility.