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IntroductionPostoperative delirium in older people may result from the interaction between intrinsic brain vulnerability (e.g. neurodegeneration) and precipitating factors (e.g. surgery induced cytokines). Intrinsic brain vulnerability may be overt (e.g. Alzheimer's disease) or preclinical. In cognitively intact older people presenting for surgery, identification of preclinical neurodegeneration using bedside tools could aid postoperative delirium risk stratification. Thinning of the circumpapillary retinal nerve fibre layer thickness is associated with neurodegenerative disorders e.g. Alzheimer's disease. We propose that thinning of the retinal nerve fibre layer may be present some older people with postoperative delirium due to preclinical neurodegeneration, albeit to a lesser extent than in overt dementia.ObjectivesThe primary objective: Feasibility of acquiring usable retinal images with the hand-held optical coherence device, at the bedside of older, hip fracture surgery patients. Secondary objective: Comparison of the circumpapillary retinal nerve fibre layer thickness between people who did/did not have postoperative delirium. Proportion of exclusions due to retinal pathology.MethodFeasibility study involving 30, cognitively intact, older people recovering from hip fracture surgery. Retinal images were obtained using the hand-held optical coherence tomography device at the participants' bedside. Imaging was deferred in participants who had postoperative delirium.ResultsRetinal images that could be assessed for circumpapillary retinal nerve fibre layer thickness were obtained in 26 participants (22 no postoperative delirium, 4 postoperative delirium). The mean circumpapillary retinal nerve fibre layer thickness was lower in the participants who had postoperative delirium compared to those who did not experience postoperative delirium (Mean (95% CI) of 76.50 (62.60-90.40) vs 89.19 (85.41-92.97) respectively).ConclusionRetinal imaging at the patient's bedside, using hand-held OCT is feasible. Our data suggests that the circumpapillary retinal nerve fibre layer may be thinner in older people who experience postoperative delirium compared to those who do not. Further studies are required.

Currently early diagnosis of malignant lesions at the periphery of lung parenchyma requires guidance of the biopsy needle catheter from the bronchoscope into the smaller peripheral airways via harmful X-ray radiation. Previously, we developed an image-guided system, iMTECH which uses electromagnetic tracking and although it increases the precision of biopsy collection and minimizes the use of harmful X-ray radiation during the interventional procedures, it only traces the tip of the biopsy catheter leaving the remaining catheter untraceable in real time and therefore increasing image registration error. To address this issue, we developed a shape sensing guidance system containing a fiber-Bragg grating (FBG) catheter and an artificial intelligence (AI) software, AIrShape to track and guide the entire biopsy instrument inside the lung airways, without radiation or electromagnetic navigation. We used a FBG fiber with one central and three peripheral cores positioned at 120° from each other, an array of 25 draw tower gratings with 1cm/3nm spacing, 2 mm grating length, Ormocer-T coating, and a total outer diameter of 0.2 mm. The FBG fiber was placed in the working channel of a custom made three-lumen catheter with a tip bending mechanism (FBG catheter). The AIrShape software determines the position of the FBG catheter by superimposing its position to the lung airway center lines using an AI algorithm. The feasibility of the FBG system was tested in an anatomically accurate lung airway model and validated visually and with the iMTECH platform. The results prove a viable shape-sensing hardware and software navigation solution for flexible medical instruments to reach the peripheral airways. During future studies, the feasibility of FBG catheter will be tested in pre-clinical animal models.

Public health measures to reduce COVID-19 transmission include masking in public places, physical distancing, staying home when ill, avoiding high-risk locations, using a contact tracing app, and being willing to take a COVID-19 vaccine. However, adoption of these measures varies greatly. We aimed to improve health messaging to increase adherence to public health behaviours to reduce COVID-19 transmission by: 1) determining attitudes towards public health measures and current behaviours; 2) identifying barriers to following public health measures; and, 3) identifying public health communication strategies. We recruited participants from a random panel of 3000 phone numbers across Alberta to fill a predetermined quota: age (18-29; 30-59; 60+ years), geographic location (urban; rural), and whether they had school-age children. Two researchers coded and themed all transcripts. We performed content analysis and in-depth thematic analysis. Nine focus groups were conducted with 2-8 participants/group in August-September, 2020. Several themes were identified: 1) importance of public health measures; 2) compliance with public health measures; 3) critiques of public health messaging; and 4) suggestions for improving public health messaging. Physical distancing and masking were seen as more important than using a contact tracing app. There were mixed views around willingness to take COVID-19 vaccine. Current public health messaging was perceived as conflicting. Participants felt that consistent messaging and using social media to reach younger people would be helpful. In conclusion, these findings provide insights that can be used to inform targeted (e.g., by age, current behaviour) public health communications to encourage behaviors that reduce COVID-19 transmission.

BACKGROUND:Distal flap necrosis is a frequent complication of perforator flaps. Advances in nanotechnology offer exciting new therapeutic approaches. Anti-inflammatory and neo-angiogenic properties of certain metal oxides within the nanoparticles, including bioglass and ceria, may promote flap survival. Here, we explore the ability of various nanoparticle formulations to increase flap survival in a rat model. MATERIALS AND METHODS:A 9 x 3 cm dorsal flap based on the posterior thigh perforator was raised in 32 Lewis rats. They were divided in 4 groups and treated with different nanoparticle suspensions: I-saline (control), II-Bioglass, III-Bioglass/ceria and IV-Zinc-doped strontium-substituted bioglass/ceria. On post-operative day 7, planimetry and laser Doppler analysis were performed to assess flap survival and various samples were collected to investigate angiogenesis, inflammation and toxicity. RESULTS:All nanoparticle-treated groups showed a larger flap survival area as compared to the control group (69.9%), with groups IV (77,3%) and II (76%) achieving statistical significance. Blood flow measurements by laser Doppler analysis showed higher perfusion in the nanoparticle-treated flaps. Tissue analysis revealed higher number of blood vessels and increased VEGF expression in groups II and III. The cytokines CD31 and MCP-1 were decreased in groups II and IV. CONCLUSIONS:Bioglass-based nanoparticles exert local anti-inflammatory and neo-angiogenic effects on the distal part of a perforator flap, increasing therefore its survival. Substitutions in the bioglass matrix and trace metal doping allow for further tuning of regenerative activity. These results showcase the potential utility of these nanoparticles in the clinical setting.

BACKGROUND:Renal dysfunction and anaemia are common in patients with acute heart failure (HF). It is not known whether their combined presence has additive prognostic value. We investigated their prognostic value separately and in combination, on prognosis in acute HF patients. Furthermore, we examined whether the improvement in prognosis was comparable between patients with and without renal dysfunction. METHODS AND RESULTS:This prospective registry includes 1783 patients admitted to the (Intensive) Coronary Care Unit for acute HF in the period of 1985-2008. The outcome measure was the composite of all-cause mortality, heart transplantation and left ventricular assist device implantation. In patients without renal dysfunction, anemia was associated with worse 30-day outcome (HR 2.91; [95% CI 1.69-5.00]), but not with 10-year outcome (HR 1.13 [95% CI 0.93-1.37]). On the contrary, anemia was found to influence prognosis in patients with renal dysfunction, both at 30 days (HR 1.93 [95% CI 1.33-2.80]) and at 10 years (HR 1.27 [95% CI 1.10-1.47]). Over time, the 10-year survival rate improved in patients with preserved renal function (HR 0.73 [95% CI 0.55-0.97]), but not in patients with renal dysfunction. CONCLUSION:The long-term prognosis of acute HF patients with a preserved renal function was found to have improved significantly. However, the prognosis of patients with renal dysfunction did not change. Anemia was a strong prognosticator for short-term outcome in all patients. In patients with renal dysfunction, anemia was also associated with impaired long-term prognosis.

BACKGROUND:The interaction between genetic and environmental factors is crucial to multiple sclerosis (MS) pathogenesis. Human Endogenous Retroviruses (HERVs) are endogenous viral elements of the human genome whose expression is associated with MS. OBJECTIVE:To perform a systematic review and meta-analysis and to assess qualitative and quantitative evidence on the expression of HERV families in MS patients. METHODS:Medline, Embase and the Cochrane Library were searched for published studies on the association of HERVs and MS. Meta-analysis was performed on the HERV-W family. Odds Ratio (OR) and 95% confidence interval (CI) were calculated for association. RESULTS:43 reports were extracted (25 related to HERV-W, 13 to HERV-H, 9 to HERV-K, 5 to HRES-1 and 1 to HER-15 family). The analysis showed an association between expression of all HERV families and MS. For HERV-W, adequate data was available for meta-analysis. Results from meta-analyses of HERV-W were OR = 22.66 (95%CI 6.32 to 81.20) from 4 studies investigating MSRV/HERV-W (MS-associated retrovirus) envelope mRNA in peripheral blood mononuclear cells, OR = 44.11 (95%CI 12.95 to 150.30) from 6 studies of MSRV/HERV-W polymerase mRNA in serum/plasma and OR = 6.00 (95%CI 3.35 to 10.74) from 4 studies of MSRV/HERV-W polymerase mRNA in CSF. CONCLUSIONS:This systematic review and meta-analysis shows an association between expression of HERVs, and in particular the HERV-W family, and MS.

The importance of the process of Neolithization for the genetic make-up of European populations has been hotly debated, with shifting hypotheses from a demic diffusion (DD) to a cultural diffusion (CD) model. In this regard, ancient DNA data from the Balkan Peninsula, which is an important source of information to assess the process of Neolithization in Europe, is however missing. In the present study we show genetic information on ancient populations of the South-East of Europe. We assessed mtDNA from ten sites from the current territory of Romania, spanning a time-period from the Early Neolithic to the Late Bronze Age. mtDNA data from Early Neolithic farmers of the Starčevo Criş culture in Romania (Cârcea, Gura Baciului and Negrileşti sites), confirm their genetic relationship with those of the LBK culture (Linienbandkeramik Kultur) in Central Europe, and they show little genetic continuity with modern European populations. On the other hand, populations of the Middle-Late Neolithic (Boian, Zau and Gumelniţa cultures), supposedly a second wave of Neolithic migration from Anatolia, had a much stronger effect on the genetic heritage of the European populations. In contrast, we find a smaller contribution of Late Bronze Age migrations to the genetic composition of Europeans. Based on these findings, we propose that permeation of mtDNA lineages from a second wave of Middle-Late Neolithic migration from North-West Anatolia into the Balkan Peninsula and Central Europe represent an important contribution to the genetic shift between Early and Late Neolithic populations in Europe, and consequently to the genetic make-up of modern European populations.

SerpinB2 (PAI-2), a member of the clade B family of serine protease inhibitors, is one of the most upregulated proteins following cellular stress. Originally described as an inhibitor of urokinase plasminogen activator, its predominant cytoplasmic localisation suggests an intracellular function. SerpinB2 has been reported to display cytoprotective properties in neurons and to interact with intracellular proteins including components of the ubiquitin-proteasome system (UPS). In the current study we explored the potential role of SerpinB2 as a modulator of proteotoxic stress. Initially, we transiently transfected wild-type SerpinB2 and SerpinB2-/- murine embryonic fibroblasts (MEFs) with Huntingtin exon1-polyglutamine (fused C-terminally to mCherry). Inclusion body formation as result of Huntingtin aggregation was evident in the SerpinB2 expressing cells but significantly impaired in the SerpinB2-/- cells, the latter concomitant with loss in cell viability. Importantly, recovery of the wild-type phenotype and cell viability was rescued by retroviral transduction of SerpinB2 expression. SerpinB2 modestly attenuated Huntingtin and amyloid beta fibril formation in vitro and was able to bind preferentially to misfolded proteins. Given the modest chaperone-like activity of SerpinB2 we tested the ability of SerpinB2 to modulate UPS and autophagy activity using a GFP reporter system and autophagy reporter, respectively. Activity of the UPS was reduced and autophagy was dysregulated in SerpinB2-/- compared to wild-type MEFs. Moreover, we observed a non-covalent interaction between ubiquitin and SerpinB2 in cells using GFP-pulldown assays and bimolecular fluorescence complementation. We conclude that SerpinB2 plays an important role in proteostasis as its loss leads to a proteotoxic phenotype associated with an inability to compartmentalize aggregating proteins and a reduced capacity of the UPS.

Coordinate based meta-analysis (CBMA) is used to find regions of consistent activation across fMRI and PET studies selected for their functional relevance to a hypothesis. Results are clusters of foci where multiple studies report in the same spatial region, indicating functional relevance. Contrast meta-analysis finds regions where there are consistent differences in activation pattern between two groups. The activation likelihood estimate methods tackle these problems, but require a specification of uncertainty in foci location: the full width half max (FWHM). Results are sensitive to FWHM. Furthermore, contrast meta-analysis requires correction for multiple statistical tests. Consequently it is sensitive only to very significant localised differences that produce very small p-values, which remain significant after correction; subtle diffuse differences between the groups can be overlooked. In this report we redefine the FWHM parameter, by analogy with a density clustering algorithm, and provide a method to estimate it. The FWHM is modified to account for the number of studies in the analysis, and represents a substantial change to the CBMA philosophy that can be applied to the current algorithms. Consequently we observe more reliable detection of clusters when there are few studies in the CBMA, and a decreasing false positive rate with larger study numbers. By contrast the standard definition (FWHM independent of the number of studies) is demonstrated to paradoxically increase the false positive rate as the number of studies increases, while reducing ability to detect true clusters for small numbers of studies. We also provide an algorithm for contrast meta-analysis, which includes a correction for multiple correlated tests that controls for the proportion of false clusters expected under the null hypothesis. Furthermore, we detail an omnibus test of difference between groups that is more sensitive than contrast meta-analysis when differences are diffuse. This test is useful where contrast meta-analysis is unrevealing.

To investigate the effects of inotropic agents on parameters of tissue perfusion in patients with cardiogenic shock.Thirty patients with cardiogenic shock were included. Patients received dobutamine, enoximone, or norepinephrine. We performed hemodynamic measurements at baseline and after titration of the inotropic agent until cardiac index (CI) ≥ 2.5 L.min-1.m(-2) or mixed-venous oxygen saturation (SvO2) ≥ 70% (dobutamine or enoximone), and mean arterial pressure (MAP) ≥ 70 mmHg (norepinephrine). As parameters of tissue perfusion, we measured central-peripheral temperature gradient (delta-T) and sublingual perfused capillary density (PCD). All patients reached predefined therapeutic targets. The inotropes did not significantly change delta-T. Dobutamine did not change PCD. Enoximone increased PCD (9.1 [8.9-10.2] vs. 11.4 [8.4-13.9] mm.mm(-2); p10.3 mm.mm(-2); mortality 72% vs. 17%, p = 0.003).This study demonstrates the effects of commonly used inotropic agents on parameters of tissue perfusion in patients with cardiogenic shock. Despite hemodynamic optimization, tissue perfusion was not sufficiently restored in most patients. In these patients, mortality was high. Interventions directed at improving microcirculation may eventually help bridging the gap between improved hemodynamics and dismal patient outcome in cardiogenic shock.

Coordinate based meta-analysis (CBMA) is widely used to find regions of consistent activation across fMRI studies that have been selected for their functional relevance to a given hypothesis. Only reported coordinates (foci), and a model of their spatial uncertainty, are used in the analysis. Results are clusters of foci where multiple studies have reported in the same spatial region, indicating functional relevance. There are several published methods that perform the analysis in a voxel-wise manner, resulting in around 10(5) statistical tests, and considerable emphasis placed on controlling the risk of type 1 statistical error. Here we address this issue by dramatically reducing the number of tests, and by introducing a new false discovery rate control: the false cluster discovery rate (FCDR). FCDR is particularly interpretable and relevant to the results of CBMA, controlling the type 1 error by limiting the proportion of clusters that are expected under the null hypothesis. We also introduce a data diagnostic scheme to help ensure quality of the analysis, and demonstrate its use in the example studies. We show that we control the false clusters better than the widely used ALE method by performing numerical experiments, and that our clustering scheme results in more complete reporting of structures relevant to the functional task.

Episodic memory impairment is a common but poorly-understood phenomenon in multiple sclerosis (MS). We aim to establish the relative contributions of reduced integrity of components of the extended hippocampal-diencephalic system to memory performance in MS patients using quantitative neuroimaging.34 patients with relapsing-remitting MS and 24 healthy age-matched controls underwent 3 T MRI including diffusion tensor imaging and 3-D T1-weighted volume acquisition. Manual fornix regions-of-interest were used to derive fornix fractional anisotropy (FA). Normalized hippocampal, mammillary body and thalamic volumes were derived by manual segmentation. MS subjects underwent visual recall, verbal recall, verbal recognition and verbal fluency assessment. Significant differences between MS patients and controls were found for fornix FA (0.38 vs. 0.46, means adjusted for age and fornix volume, P

We propose and validate a multivariate classification algorithm for characterizing changes in human intracranial electroencephalographic data (iEEG) after learning motor sequences. The algorithm is based on a Hidden Markov Model (HMM) that captures spatio-temporal properties of the iEEG at the level of single trials. Continuous intracranial iEEG was acquired during two sessions (one before and one after a night of sleep) in two patients with depth electrodes implanted in several brain areas. They performed a visuomotor sequence (serial reaction time task, SRTT) using the fingers of their non-dominant hand. Our results show that the decoding algorithm correctly classified single iEEG trials from the trained sequence as belonging to either the initial training phase (day 1, before sleep) or a later consolidated phase (day 2, after sleep), whereas it failed to do so for trials belonging to a control condition (pseudo-random sequence). Accurate single-trial classification was achieved by taking advantage of the distributed pattern of neural activity. However, across all the contacts the hippocampus contributed most significantly to the classification accuracy for both patients, and one fronto-striatal contact for one patient. Together, these human intracranial findings demonstrate that a multivariate decoding approach can detect learning-related changes at the level of single-trial iEEG. Because it allows an unbiased identification of brain sites contributing to a behavioral effect (or experimental condition) at the level of single subject, this approach could be usefully applied to assess the neural correlates of other complex cognitive functions in patients implanted with multiple electrodes.

Animal studies have shown that sequenced patterns of neuronal activity may be replayed during sleep. However, the existence of such replay in humans has not yet been directly demonstrated. Here we studied patients who exhibit overt behaviors during sleep to test whether sequences of movements trained during the day may be spontaneously reenacted by the patients during sleep. We recruited 19 sleepwalkers (who displayed complex and purposeful behaviors emerging from non REM sleep), 20 patients with REM sleep behavior disorder (who enacted their dreams in REM sleep) and 18 healthy controls. Continuous video sleep recordings were performed during sleep following intensive training on a sequence of large movements (learned during a variant of the serial reaction time task). Both patient groups showed learning of the intensively trained motor sequence after sleep. We report the re-enactment of a fragment of the recently trained motor behavior during one sleepwalking episode. This study provides, to our knowledge, the first evidence of a temporally-structured replay of a learned behavior during sleep in humans. Our observation also suggests that the study of such sleep disorders may provide unique and critical information about cognitive functions operating during sleep.

The JAK2 V617F mutation present in over 95% of Polycythemia Vera patients and in 50% of Essential Thrombocythemia and Primary Myelofibrosis patients renders the kinase constitutively active. In the absence of a three-dimensional structure for the full-length protein, the mechanism of activation of JAK2 V617F has remained elusive. In this study, we used functional mutagenesis to investigate the involvement of the JH2 alphaC helix in the constitutive activation of JAK2 V617F. We show that residue F595, located in the middle of the alphaC helix of JH2, is indispensable for the constitutive activity of JAK2 V617F. Mutation of F595 to Ala, Lys, Val or Ile significantly decreases the constitutive activity of JAK2 V617F, but F595W and F595Y are able to restore it, implying an aromaticity requirement at position 595. Substitution of F595 to Ala was also able to decrease the constitutive activity of two other JAK2 mutants, T875N and R683G, as well as JAK2 K539L, albeit to a lower extent. In contrast, the F595 mutants are activated by erythropoietin-bound EpoR. We also explored the relationship between the dimeric conformation of EpoR and several JAK2 mutants. Since residue F595 is crucial to the constitutive activation of JAK2 V617F but not to initiation of JAK2 activation by cytokines, we suggest that small molecules that target the region around this residue might specifically block oncogenic JAK2 and spare JAK2 wild-type.

SerpinB2 (PAI-2), a member of the clade B family of serine protease inhibitors, is one of the most upregulated proteins following cellular stress. Originally described as an inhibitor of urokinase plasminogen activator, its predominant cytoplasmic localisation suggests an intracellular function. SerpinB2 has been reported to display cytoprotective properties in neurons and to interact with intracellular proteins including components of the ubiquitin-proteasome system (UPS). In the current study we explored the potential role of SerpinB2 as a modulator of proteotoxic stress. Initially, we transiently transfected wild-type SerpinB2 and SerpinB2-/- murine embryonic fibroblasts (MEFs) with Huntingtin exon1-polyglutamine (fused C-terminally to mCherry). Inclusion body formation as result of Huntingtin aggregation was evident in the SerpinB2 expressing cells but significantly impaired in the SerpinB2-/- cells, the latter concomitant with loss in cell viability. Importantly, recovery of the wild-type phenotype and cell viability was rescued by retroviral transduction of SerpinB2 expression. SerpinB2 modestly attenuated Huntingtin and amyloid beta fibril formation in vitro and was able to bind preferentially to misfolded proteins. Given the modest chaperone-like activity of SerpinB2 we tested the ability of SerpinB2 to modulate UPS and autophagy activity using a GFP reporter system and autophagy reporter, respectively. Activity of the UPS was reduced and autophagy was dysregulated in SerpinB2-/- compared to wild-type MEFs. Moreover, we observed a non-covalent interaction between ubiquitin and SerpinB2 in cells using GFP-pulldown assays and bimolecular fluorescence complementation. We conclude that SerpinB2 plays an important role in proteostasis as its loss leads to a proteotoxic phenotype associated with an inability to compartmentalize aggregating proteins and a reduced capacity of the UPS.