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Purpose: The United Kingdom’s European Union membership referendum, which marked the end of UK membership in the European Union, created much uncertainty amongst those British and European business practitioners who were accustomed to conducting trade with partners across The North Sea. This exogenous threat to business was subsequently compounded by another serious threat: the COVID-19 pandemic. Knowing that business-to-business (B2B) relationships are particularly important for the success of small- and medium-sized enterprises (SMEs), and that exogenous threats in the business environment can threaten these relationships, the purpose of this study is to examine whether frequent contact and social exchanges between partners on a range of topics, during threatening times, are positively linked to the relationship qualities of trust, satisfaction, and commitment.Methodology/approach: Guided by an explorative, expert interview with a Danish SME owner-manager (OM) who has a great deal of experience conducting business with UK partners, a questionnaire was developed to examine two variables which seemingly play central roles with regard to supporting business relationships during threatening times: contact frequency (how often partners are in contact), and contact scope (how often B2B partners talk together about topics which are social in nature). The questionnaire was administered to 193 Danish SME owners and managers who had British business partners at the time of the BREXIT referendum and the COVID-19 pandemic. Findings: The questionnaire revealed a positive relationship between contact frequency and relationship satisfaction and commitment, as well as a positive relationship between contact scope and relationship commitment. However, no significant relationships were found between contact frequency nor contact scope, on the one hand, and the level of trust between business partners on the other.Research implications: This study has underscored the usefulness of studying social exchanges, and not just information exchanges, as they are an important, relationship-strengthening aspect of B2B communication. Indeed, while the central role played by informational exchanges in building quality relationships, including trusting relationships, is well-documented, this study increases our understanding of the value of social exchanges to business relationship quality; in particular, their noteworthy link to B2B partners’ willingness to go to great lengths to maintain relationships during challenging times. Practical implications: Our findings indicate that simply being in contact with B2B partners and speaking about topics that are not directly related to business is not, on its own, a sufficient means of establishing trusting relationships; however, it is nonetheless worthwhile to take the time to nurture personal relationships with B2B partners. Just a modest amount of contact is positively related to relationship satisfaction, as well as relationship commitment, which can be crucial when unforeseen and threatening times inevitably arise in the business environment. Contribution of the paper: Besides enhancing our understanding of the value of frequent and social exchanges in terms of relationship quality, this paper also illustrates a useful means of studying social aspects of business relationships, which are notoriously difficult to study. This is accomplished via a questionnaire study in which respondents are asked to concretely reflect upon and report on the frequency and nature of their contact with specific B2B partners.

Adequate lymphadenectomy during gastroesophageal junction (GEJ) cancer resection is essential, because lymph node (LN) metastasis correlates with increased recurrence risk. Fluorescence lymphography with indocyanine green (ICG) has been used for LN mapping in several surgical specialties; however, reports on GEJ cancer are lacking. Therefore, we investigated whether intraoperative ICG lymphography could facilitate LN harvest during robot-assisted resection of GEJ cancer.Patients scheduled for robot-assisted resection of GEJ cancer were included, and outcomes were compared with historical controls. After intraoperative endoscopic submucosal ICG injection, standard D1 + LN dissection was performed under white light. Then, near-infrared (NIR) fluorescence imaging was activated, and each LN dissection area was re-examined. Any tissue within the D1 + field exhibiting distinctly increased ICG fluorescence compared with background tissue was dissected and sent for pathology review.We included 70 patients between June 2020 and October 2021. Three cases were aborted due to disseminated disease, and two were converted to open resection and excluded from the analysis. Additional tissue was dissected after NIR review in 34 of 65 (52%) patients. We dissected 43 fluorescent tissue samples, and after pathology review, 30 were confirmed LNs; none were metastatic. The median number of LNs harvested per patient (34, interquartile range [IQR] = 26-44) was not significantly different from that harvested from historical controls (32, IQR = 24-45; p = 0.92), nor were there any differences between these two groups in the duration of surgery, intraoperative blood loss, or comprehensive complication scores (p = 0.12, p = 0.46, and p = 0.41, respectively).Intraoperative NIR lymphography with ICG may aid LN detection during robot-assisted resection of GEJ cancer without increasing surgical risk. Although NIR lymphography may facilitate LN dissection, none of the LN removed after the NIR review was metastatic. Hence, it remains uncertain whether NIR lymphography will improve oncological outcomes.

Amyotrophic lateral sclerosis (ALS) involves progressive motor neuron loss, leading to paralysis and death typically within 3–5 years of diagnosis. Dysfunctional astrocytes may contribute to disease and glial cell line-derived neurotrophic factor (GDNF) can be protective. Here we show that human neural progenitor cells transduced with GDNF (CNS10-NPC-GDNF) differentiated to astrocytes protected spinal motor neurons and were safe in animal models. CNS10-NPC-GDNF were transplanted unilaterally into the lumbar spinal cord of 18 ALS participants in a phase 1/2a study (NCT02943850). The primary endpoint of safety at 1 year was met, with no negative effect of the transplant on motor function in the treated leg compared with the untreated leg. Tissue analysis of 13 participants who died of disease progression showed graft survival and GDNF production. Benign neuromas near delivery sites were common incidental findings at post-mortem. This study shows that one administration of engineered neural progenitors can provide new support cells and GDNF delivery to the ALS patient spinal cord for up to 42 months post-transplantation.

Generation of thick megabreccias along carbonate platforms apparently relies on the establishment of overpressured zones in the margin and upper slope deposits (particularly during relative sea-level lowstands), but the main triggering mechanism is thought to be seismic tremors. Here, we present a detailed sedimentological analysis of carbonate density-flow deposits south and north of the Mattinata Fault, a major strike-slip fault zone in the Gargano Promontory (Italy). The analysis shows that in the southern sector the deposits of Albian–Cenomanian age (Monte S. Angelo Formation) are made up predominantly of thick and amalgamated debrites (megabreccias), whereas some 25 km to the north they are composed predominantly of prograding high-density turbidites. Moreover, detailed analysis of Maastrichtian slope deposits (Monte Acuto Limestones) from the southern sector shows that they make up a N–S-prograding system of coalesced lobes composed of high-density turbidites and subordinate debrites. We infer that preconditional factors (e.g., platform progradation, tectonic oversteepening, and high pore pressures in the margin and upper-slope deposits) for triggering the density flows varied along strike of the platform, but the main controlling factors were the activity of the prominent strike-slip Mattinata Fault and the propagation of tremor energy to its near- and far-field regions: large earthquakes triggered thick (up to 40 m) and amalgamated Albian–Cenomanian debrites in proximity (south of) to the fault, whereas the subdued effect of the tremors triggered thinner debrites (5–10 m) and rock falls in the far-field region north of the fault. Moreover, predominantly high-density turbidite deposits were emplaced in the far-field region during lower-magnitude earthquakes. During the Maastrichtian the thick succession of high-density turbidites and scattered thick debrites south of and adjacent to the Mattinata Fault may record an overall quiescent period of the fault. The results are of relevance for understanding the spatiotemporal distribution of density-flow deposition along carbonate platforms in tectonically active regions—in particular with respect to the activity of large strike-slip faults.

Contains fulltext : 291174.pdf (Publisher’s version ) (Open Access) Background: Cannabinoids have been suggested to alleviate frequently experienced symptoms of reduced mental well-being such as anxiety and depression. Mental well-being is an important subdomain of health-related quality of life (HRQoL). Reducing symptoms and maintaining HRQoL are particularly important in malignant primary brain tumor patients, as treatment options are often noncurative and prognosis remains poor. These patients frequently report unprescribed cannabinoid use, presumably for symptom relieve. As studies on brain tumor patients specifically are lacking, we performed a meta-analysis of the current evidence on cannabinoid efficacy on HRQoL and mental well-being in oncological and neurological patients. Methods: We performed a systematic PubMed, PsychINFO, Embase, and Web of Science search according to PRISMA guidelines on August 2 and 3, 2021. We included randomized controlled trials (RCTs) that assessed the effects of tetrahydrocannabinol (THC) or cannabidiol (CBD) on general HRQoL and mental well-being. Pooled effect sizes were calculated using Hedges g. Risk of bias of included studies was assessed using Cochrane's Risk of Bias tool. Results: We included 17 studies: 4 in oncology and 13 in central nervous system (CNS) disease. Meta-analysis showed no effect of cannabinoids on general HRQoL (g=-0.02 confidence interval [95% CI -0.11 to 0.06]; p=0.57) or mental well-being (g=-0.02 [95% CI -0.16 to 0.13]; p=0.81). Conclusions: RCTs in patients with cancer or CNS disease showed no effect of cannabinoids on HRQoL or mental well-being. However, studies were clinically heterogeneous and since many glioma patients currently frequently use cannabinoids, future studies are necessary to evaluate its value in this specific population. 01 februari 2023

Background Securing sufficient blood perfusion to the anastomotic area after low-anterior resection is a crucial factor in preventing anastomotic leakage (AL). Intra-operative indocyanine green fluorescent imaging (ICG-FI) has been suggested as a tool to assess perfusion. However, knowledge of inter-observer variation among surgeons in the interpretation of ICG-FI is sparse. Our primary objective was to evaluate inter-observer variation among surgeons in the interpretation of bowel blood-perfusion assessed visually by ICG-FI. Our secondary objective was to compare the results both from the visual assessment of ICG and from computer-based quantitative analyses of ICG-FI between patients with and without the development of AL. Method A multicenter study, including patients undergoing robot-assisted low anterior resection with stapled anastomosis. ICG-FI was evaluated visually by the surgeon intra-operatively. Postoperatively, recorded videos were anonymized and exchanged between centers for inter-observer evaluation. Time to visibility (TTV), time to maximum visibility (TMV), and time to wash-out (TWO) were visually assessed. In addition, the ICG-FI video-recordings were analyzed using validated pixel analysis software to quantify blood perfusion. Results Fifty-five patients were included, and five developed clinical AL. Bland–Altman plots (BA plots) demonstrated wide inter-observer variation for visually assessed fluorescence on all parameters (TTV, TMV, and TWO). Comparing leak-group with no-leak group, we found no significant differences for TTV: Hazard Ratio; HR = 0.82 (CI 0.32; 2.08), TMV: HR = 0.62 (CI 0.24; 1.59), or TWO: HR = 1.11 (CI 0.40; 3.11). In the quantitative pixel analysis, a lower slope of the fluorescence time-curve was found in patients with a subsequent leak: median 0.08 (0.07;0.10) compared with non-leak patients: median 0.13 (0.10;0.17) (p = 0.04). Conclusion The surgeon’s visual assessment of the ICG-FI demonstrated wide inter-observer variation, there were no differences between patients with and without AL. However, quantitative pixel analysis showed a significant difference between groups. Trial Registration ClinicalTrials.gov Identifier: NCT04766060.

Background: Bronchoscopy is an essential procedure in the diagnosis and treatment of pulmonary diseases. However, the literature suggests that distractions affect the quality of bronchoscopy and affect inexperienced doctors more than experienced. Objectives: The objective of the study was as follows: does simulation-based bronchoscopy training with immersive virtual reality (iVR) improve the doctors’ ability to handle distractions and thereby increase the quality, measured in procedure time, structured progression score, diagnostic completeness (%), and hand motor movements of a diagnostic bronchoscopy in a simulated scenario. Exploratory outcomes were heart rate variability and a cognitive load questionnaire (Surg-TLX). Methods: Participants were randomized. The intervention group practiced in an iVR environment with a head-mounted display (HMD) while using the bronchoscopy simulator, while the control group trained without the HMD. Both groups were tested in the iVR environment using a scenario with distractions. Results: 34 participants completed the trial. The intervention group scored significantly higher in diagnostic completeness (100 i.q.r. 100–100 vs. 94 i.q.r. 89–100, p value = 0.03) and structured progress (16 i.q.r. 15–18 vs. 12 i.q.r. 11–15, p value 0.03) but not in procedure time (367 s standard deviation [SD] 149 vs. 445 s SD 219, p value = 0.06) or hand motor movements (−1.02 i.q.r. −1.03–[−1.02] versus −0.98 i.q.r. −1.02–[–0.98], p value = 0.27). The control group had a tendency toward a lower heart rate variability (5.76 i.q.r. 3.77–9.06 vs. 4.12 i.q.r. 2.68–6.27, p = 0.25). There was no significant difference in total Surg-TLX points between the two groups. Conclusion: iVR simulation training increases the quality of diagnostic bronchoscopy in a simulated scenario with distractions compared with conventional simulation-based training.

Background: Stem cell products are increasingly entering early stage clinical trials for treating retinal degeneration. The field is learning from experience about comparability of cells proposed for preclinical and clinical use. Without this, preclinical data supporting translation to a clinical study might not adequately reflect the performance of subsequent clinical-grade cells in patients. Methods: Research- grade human neural progenitor cells (hNPC) and clinical-grade hNPC (termed CNS10-NPC) were injected into the subretinal space of the Royal College of Surgeons (RCS) rats, a rodent model for retinitis pigmentosa (RP); An IND-enabling study with CNS10-NPC was perform in the same rodent model; Finally, surgical methodology for subretinal cell delivery in the clinic was optimized in large animal model-Yucatan minipig. Results: Both research grade hNPC and clinical-grade hNPC (termed CNS10-NPC) can survive and provide functional and morphological protection in a dose-dependent fashion in the RCS rats and defined the optimal cell dose used for an investigational new drug (IND) enabling study. Grafted CNS10-NPC migrated from the injection site without differentiation into retinal cell phenotypes. Additionally, CNS10-NPC showed long-term survival, safety and efficacy in a toxicity and tumorigenicity study, with no observed cell overgrowth even at the maximum deliverable dose. Finally, using a large animal model-Yucatan minipig, which has eye size comparable to the human, we optimized the surgical methodology for subretinal cell delivery in the clinic. Conclusions: These extensive studies supported an approved IND and the translation of CNS10-NPC to an ongoing Phase 1/2a clinical trial (NCT04284293) for the treatment of retinitis pigmentosa.

The success of preventing colorectal cancer relies on the expertise of the colonoscopists. Studies suggest that the retraction technique is a powerful indicator of expertise in distinguishing endoscopists with various adenoma detection rates (ADRs). We aimed to develop a retraction technique score and explore the correlation between endoscopists' retraction technique and their ADRs.In a prospective, multicenter study, 8 colonoscopist nurses and physicians with various ADRs were included. Data from patients admitted for a colonoscopy, as part of the Danish nationwide screening program, were gathered directly from the Olympus ScopeGuide system (UPD-3; Olympus Optical, Tokyo, Japan) providing XYZ-coordinates from the coils along the length of the colonoscope. Motor skill measures were developed based on tip retraction, retraction efficiency, and retraction distance. The principal component analysis was used to study the association among the 3 measures and the historical ADR to create a combined score, the colonoscopy retraction score (CoRS).Three hundred thirty-three recordings were analyzed. We demonstrated a significant and strong correlation between CoRS and ADR (.90, P .01). Conversely, withdrawal time did not correlate significantly with ADR (.33, P = .42). In procedures without polypectomies or biopsy sampling, a significant and strong correlation was found between CoRS and ADR (.88, P .01) and between withdrawal time and ADR (.75, P = .03).This study presents a novel, real-time computerized and unbiased assessment tool for colonoscopy withdrawal. CoRS strongly correlated with ADR with and without therapeutic interventions during withdrawal and could be used to ensure quality instead of minimal withdrawal time. (Clinical trial registration number: NCT03587935.).

The data that support the findings of this study are openly available in Zenodo at https://doi.org/10.5281/zenodo (7373223) This article introduces and describes the integrated energy system of the Low Emission Oil and Gas Open reference platform. It is a hypothetical case meant to represent a typical oil and gas installation in the North Sea. The aim of this detailed specification is to serve as an open reference case where all the information about it can be publicly shared, facilitating benchmarking and collaboration. The relevance of this reference case of an off-grid energy system is not limited to the oil and gas industry, since it can also be seen as a special kind of electrical micro grid. The remote offshore location makes it especially relevant for studying offshore wind power and ocean energy sources like wave power. The specification has an emphasis on the energy system and electrical configuration, but also includes a basic description of the oil field and processing system. The intention is that it will serve as a basis for energy system studies and relating power system stability analyses regarding the integration of renewable energy sources. This allows for comparisons of a base case with different design modifications, new operational planning methods, power management strategies and control concepts. Examples of possible modifications are the replacement of gas turbines by wind turbines, addition of energy storage systems, a more variable operation of loads etc. The last part of the article demonstrates the behaviour of the reference platform implemented in two software tools: one for operational planning and one for dynamic power system analyses.

Urological injuries can occur in patients with pelvic fractures. Treatment recommendations lack solid evidence and is often pragmatical. There is a continuous need to describe short- and long-term morbidity following lower urinary tract trauma.To describe incidence, diagnosis, treatment, and morbidity following lower urinary tract injuries in pelvic fractures.Retrospective study including patients with pelvic, including acetabular, fractures admitted to a Level I Trauma Centre covering 2.8 million citizens between 2009 and 2020. Outcome measurements comprised primary management, treatment trajectory, short- and long-term complications and outcomes.A total of 39 (5%) patients with pelvic fractures had concomitant urethral and/or bladder injuries, and one patient with an acetabular fracture had a bladder injury. The management of urethral injuries varied vastly, and complete urethral ruptures were associated with severe short- and long-term complications. Only one patient with bladder injury experienced severe long-term complications.Management of lower urinary tract injuries in patients with major pelvic fractures remains a major challenge. Special attention should be focused on urethral injuries where we uncovered an unsystematic treatment and follow-up even in a highly experienced centre, although this is also attributed to complicated multidisciplinary patient trajectories. There is a continuous need to reduce long-term complications following urethral trauma which should be addressed in multicenter studies.

The aim of this study was to examine whether collagenase producing bacteria could be detected, in fluid collected from chest tubes, before clinical presentation of anastomotic leakage after esophageal resection.We conducted a prospective single-center study of patients who underwent resection of the gastroesophageal junction. All patients had a chest tube placed in the pleural cavity perioperatively. Drain fluid was collected and cultured from the first post-operative day and at time of routine removal of the drain (days 3-5).From January 2018 to July 2019, a total of 84 patients were included in the study. Twenty (36%) patients experienced severe complications with a Clavien-Dindo score of 3b-5. Eleven (13%) patients were diagnosed with anastomotic leakage which occurred after 8 days (mean, range 2-13). Twenty patients (24%) had drain samples with significant growth of microbes. Among the 11 patients with anastomotic leakage, we found 2 with microbe growth at POD 2 and POD 4, the remaining 9 samples were negative (p = 0.638). Thirty-day mortality rate was zero.Cultured fluid from the pleural cavity of asymptomatic patients following esophageal resection did not indicate a significant association with anastomotic leakage.

Staphylococcus aureus nasal carriage increases risk of infection and has been associated with lifestyle behavior and biological host characteristics. We used social network analysis to evaluate whether contacts have the same S. aureus genotype, or whether contagiousness is an indirect effect of contacts sharing the same lifestyle or characteristics. The Fit Futures 1 study collected data on social contact among 1038 first level students in the same high school district in Norway. S. aureus persistent carriage was determined from two nasal swab cultures and genotype from spa-typing of a positive throat swab culture. Bootstrap, t-tests, logistic regression, and autocorrelation were used to evaluate social network influence on host risk factors and S. aureus carriage. Both persistent carriage and spa-type were transmitted in the social network (p, 37 pages, 9 figures, 10 tables

Comparing, sharing, and shielding children's biological and biographical data in genetic databases and on Facebook are central moves when geneticists and families search for diagnoses for children with rare diseases. Based on ethnographic fieldwork in Denmark, we show that the work of linking children carrying the same genetic mutations forges new sibling-like forms of relatedness between them. With the concept of 'datasociality', we add new layers to 'biosociality' by capturing the ways in which biological information is increasingly mediated by digital and algorithmic processes in the genomic era. In the process of both sharing data and securing anonymity, unrelated children become related through qualities of otherness.

Fungi in the sooty blotch and flyspeck (SBFS) complex blemish fruit and reduce the market value of fresh-market apples. In 2010, apples were collected from 16 orchards in northern Spain that had received few to no fungicide sprays. SBFS colonies with the subtending cuticle were excised, pressed, and shipped to Ames, Iowa, United States, for isolation. A total of 213 sequences were aligned after a portion of the rRNA was amplified with primer pair VG9/LR5, and two regions were sequenced with primer pairs ITS1/ITS4 and LROR/LR5. Distance and parsimony analyses of the 28S gene sequences were used to compare the collection with previously isolated SBFS species. Most isolates (89%) were within the subclass Dothideomycetes, order Capnodiales. Within this order, the predominant genus was Schizothyrium (anamorph Zygophiala) (86 isolates), including S. pomi, Z. cryptogama, Z. cylindrica, and two previously undescribed putative species. Also widely prevalent were Microcyclosporella mali (45 isolates), four Microcyclospora spp. (36 isolates), and four Stomiopeltis-like putative species (34 isolates). Seven isolates were within the Eurotiomycetes. Twenty-five putative species were delineated using the ITS sequences and morphological characterization. These included 11 species previously named and reported as members of the SBFS complex, two putative SBFS species that were previously reported but have not yet been described, and 12 newly detected putative SBFS species. The findings add substantially to knowledge of the taxonomic diversity of this ectophytic fungal assemblage in Europe. [Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .

The Atlantic Nino is one of the most important patterns of interannual tropical climate variability, but how climate change will influence this pattern is not well known due to large climate model biases. Here we show that state-of-the-art climate models robustly predict a weakening of Atlantic Ninos in response to global warming, mainly due to a decoupling of subsurface and surface temperature variations as the upper equatorial Atlantic Ocean warms. This weakening is predicted by most (>80%) models in the Coupled Model Intercomparison Project Phases 5 and 6 under the highest emission scenarios. Our results indicate a reduction in variability by the end of the century by 14%, and as much as 24-48% when accounting for model errors using a simple emergent constraint analysis. Such a weakening of Atlantic Nino variability will potentially impact climate conditions and the skill of seasonal predictions in many regions. The Atlantic Nino is an important mode of tropical climate variability, but how it reacts to climate change is not well known due to model biases. Here the authors show a robust weakening of the Atlantic Nino of up to 24-48% under high emissions until the end of the century.

BACKGROUND: Allan-Herndon-Dudley syndrome (AHDS) is a severe psychomotor disability disorder that also manifests characteristic abnormal thyroid hormone (TH) levels. AHDS is caused by inactivating mutations in monocarboxylate transporter 8 (MCT8), a specific TH plasma membrane transporter widely expressed in the central nervous system (CNS). MCT8 mutations cause impaired transport of TH across brain barriers, leading to insufficient neural TH supply. There is currently no successful therapy for the neurological symptoms. Earlier work has shown that intravenous (IV), but not intracerebroventricular adeno-associated virus serotype 9 (AAV9) -based gene therapy given to newborn Mct8 knockout (Mct8(−/y)) male mice increased triiodothyronine (T(3)) brain content and partially rescued TH-dependent gene expression, suggesting a promising approach to treat this neurological disorder. METHODS: The potential of IV delivery of AAV9 carrying human MCT8 was tested in the well-established Mct8(−/y)/Organic anion-transporting polypeptide 1c1 (Oatp1c1)(−/ −) double knockout (dKO) mouse model of AHDS, which, unlike Mct8(−/y) mice, displays both neurological and TH phenotype. Further, as the condition is usually diagnosed during childhood, treatment was given intravenously to P30 mice and psychomotor tests were carried out blindly at P120–P140 after which tissues were collected and analyzed. RESULTS: Systemic IV delivery of AAV9-MCT8 at a juvenile stage led to improved locomotor and cognitive functions at P120–P140, which was accompanied by a near normalization of T(3) content and an increased response of positively regulated TH-dependent gene expression in different brain regions examined (thalamus, hippocampus, and parietal cortex). The effects on serum TH concentrations and peripheral tissues were less pronounced, showing only improvement in the serum T(3)/reverse T(3) (rT(3)) ratio and in liver deiodinase 1 expression. CONCLUSION: IV administration of AAV9, carrying the human MCT8, to juvenile dKO mice manifesting AHDS has long-term beneficial effects, predominantly on the CNS. This preclinical study indicates that this gene therapy has the potential to ameliorate the devastating neurological symptoms in patients with AHDS.

Hematopoietic aging is marked by a loss of regenerative capacity and skewed differentiation from hematopoietic stem cells (HSC) leading to impaired blood production. Signals from the bone marrow (BM) niche tailor blood production, but the contribution of the old niche to hematopoietic aging remains unclear. Here, we characterize the inflammatory milieu that drives both niche and hematopoietic remodeling. We find decreased numbers and functionality of osteoprogenitors (OPr) at the endosteum and expansion of central marrow LepR+ mesenchymal stromal cells (MSC-L) associated with deterioration of the sinusoidal vasculature, which together create a degraded and inflamed old BM niche. Niche inflammation, in turn, drives chronic activation of emergency myelopoiesis pathways in old HSCs and multipotent progenitors (MPP), which promotes myeloid differentiation and hinders hematopoietic regeneration. Moreover, we show how production of IL- 1b by the damaged endosteum acts in trans to drive the proinflammatory nature of the central marrow with damaging consequences for the old blood system. Remarkably, niche deterioration, HSC dysfunction, and defective regeneration can all be ameliorated by blocking IL-1 signaling. Our results demonstrate that targeting IL-1 as a key mediator of niche inflammation is a tractable strategy to improve blood production during aging.

BACKGROUND Left ventricular hypertrophy (LVH) and vitamin D deficiency have been linked to hypertension (HTN) and cardiovascular disease, particularly in African Americans (AAs). Our objective was to determine if the addition of vitamin D to antihypertensive therapy would lead to greater regression of LV mass index (LVMI) as determined by cardiac magnetic resonance (CMR) after 1 year in vitamin D deficient AA patients with uncontrolled HTN and LVH. METHODS This study was a randomized, double-blind, placebo-controlled, single-center study. AA patients with HTN (systolic blood pressure [BP] >160 mm Hg), increased LVMI, and vitamin D deficiency ( RESULTS At 1 year, there were no statistical differences between the vitamin D and placebo groups in LVMI (−14.1 ± 14.6 vs. −16.9 ± 13.1 g/m2; P = 0.34) or systolic BP (−25.6 ± 32.1 vs. −25.7 ± 25.6 mm Hg; P = 0.99) reduction, respectively. Serum vitamin D levels increased significantly in the vitamin D group compared with placebo (12.7 ± 2.0 vs. 1.8 ± 8.2 ng/ml; P < 0.001). CONCLUSIONS In this high-risk cohort of AAs we did not find an association between vitamin D supplementation and differential regression of LVMI or reduction in systolic BP. However, our study suffered from a small sample size with low statistical power precluding a definitive conclusion on the therapeutic benefit of vitamin D in such patients. CLINICAL TRIALS REGISTRATION Trial Number NCT01360476. Full trial protocol is available from corresponding author.

Parkinson’s disease is a devastating motor disorder involving the aberrant aggregation of the synaptic protein synuclein (aSyn) and degeneration of the nigrostriatal dopaminergic tract. We previously showed that proSAAS, a small secreted chaperone protein widely expressed in neurons within the brain, is able to block aSyn-induced dopaminergic cytotoxicity in primary nigral neuron cultures. We show here that coinjection of proSAAS-encoding lentivirus profoundly reduced the motor asymmetry caused by unilateral nigral AAV-mediated human aSyn overexpression. This positive functional outcome was accompanied by significant amelioration of the human aSyn-induced loss of both nigral tyrosine hydroxylase-positive cells and striatal tyrosine hydroxylase-positive terminals, demonstrating clear proSAAS-mediated protection of the nigro-striatal tract. ProSAAS overexpression also reduced the content of human aSyn protein in both the nigra and striatum and reduced the loss of tyrosine hydroxylase protein in both regions. Since proSAAS is a secreted protein, we tested the possibility that proSAAS is able to block the transsynaptic spread of aSyn from the periphery to the central nervous system, increasingly recognized as a potentially significant pathological mechanism. The number of human aSyn-positive neurites in the pons and caudal midbrain of mice following administration of human aSyn-encoding AAV into the vagus nerve was considerably reduced in mice coinjected with proSAAS-encoding AAV, supporting proSAAS-mediated blockade of transsynaptic aSyn transmission. We suggest that proSAAS may represent a promising target for therapeutic development in Parkinson’s disease.SignificanceThis paper describes two independent avenues of research that both provide support for the in vivo neuroprotective function of this small chaperone protein. In the first approach, we show that proSAAS overexpression provides remarkably effective protection against dopaminergic neurotoxicity in a rat model of Parkinson’s disease. This conclusion is supported both by three independent assays of motor function as well as by quantitative analysis of surviving dopaminergic neurons in brain areas involved in the control of motor function. In the second line of research, we show that in mice, the spread of human synuclein across synapses can be blunted by proSAAS overexpression.

Gram-positive bacteria are some of the earliest known life forms, diverging from gram-negative bacteria 2 billion years ago. These organisms utilize sortase enzymes to attach proteins to their peptidoglycan cell wall, a structural feature that distinguishes the two types of bacteria. The transpeptidase activity of sortases make them an important tool in protein engineering applications, e.g., in sortase-mediated ligations or sortagging. However, due to relatively low catalytic efficiency, there are ongoing efforts to create better sortase variants for these uses. Here, we use bioinformatics tools, principal component analysis and ancestral sequence reconstruction, in combination with protein biochemistry, to analyze natural sequence variation in these enzymes. Principal component analysis on the sortase superfamily distinguishes previously described classes and identifies regions of relatively high sequence variation in structurally-conserved loops within each sortase family, including those near the active site. Using ancestral sequence reconstruction, we determined sequences of ancestral Staphylococcus and Streptococcus Class A sortase proteins. Enzyme assays revealed that the ancestral Streptococcus enzyme is relatively active and shares similar sequence variation with other Class A Streptococcus sortases. Taken together, we highlight how natural sequence variation can be utilized to investigate this important protein family, arguing that these and similar techniques may be used to discover or design sortases with increased catalytic efficiency and/or selectivity for sortase-mediated ligation experiments.

The kidney plays a key role in the correction of systemic acid-base imbalances. Central for this regulation are the intercalated cells in the distal nephron, which secrete acid or base into the urine. How these cells sense acid-base disturbances is a long-standing question. Intercalated cells exclusively express the Na+-dependent Cl −/HCO3 − exchanger AE4 (Slc4a9). Here we show that AE4-deficient mice exhibit a major dysregulation of acid-base balance. By combining molecular, imaging, biochemical and integrative approaches, we demonstrate that AE4-deficient mice are unable to sense and appropriately correct metabolic alkalosis and acidosis. Mechanistically, a lack of adaptive base secretion via the Cl −/HCO3 − exchanger pendrin (Slc26a4) is the key cellular cause of this derailment. Our findings identify AE4 as an essential part of the renal sensing mechanism for changes in acid-base status.

Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Horizon Introduction There is a growing interest in the use of accelerometers and sensors embedded in implantable cardioverter-defibrillators (ICDs) for monitoring patient activity. Despite evidence regarding the potential clinical value of device-measured activity (D-PA), the validity of these measurements has not yet been established. Objective To assess the validity of device-measured activity against a research-grade, widely validated wearable accelerometer. Methods This is a subanalysis of the ongoing multicenter, prospective SafeHeart study. Raw accelerometry data was continuously sampled at 50Hz from a wrist-worn accelerometer (GENEActiv) during 12 months. Days with at least 22 hours of wear time were used to create summary measures of time in activity, daily active volume and total slow walking steps. These measures were compared to D-PA harmonised as percentage of active time per day, from four different ICD vendors’ remote transmission data, using linear mixed effect models. Results Wearable and device-measured activity data in 51 ICD patients rendered 1228 days (mean 24 days ±19) with both wearable and device-measured activity data. There were significant differences between wearable and device-measured accelerometery in the average time active per day (Table 1). For two vendors significant associations between D-PA, daily active volume, and total slow walking steps were observed. Also, associations between D-PA and daily active time and moderate vigorous physical activity were found in a third vendor. For the fourth vendor no association between any wearable activity metric and D-PA was found. Inter-patient differences accounted for 73.1% of the total variance in D-PA. Conclusion Results demonstrate substantial differences in device-measured activity measurements compared to research-grade activity data. This has implications for the utility and generalizability of D-PA as clinical parameter.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The LOOP Study was funded by Innovation Fund Denmark [grant number 12-1352259], The Research Foundation for the Capital Region of Denmark, The Danish Heart Foundation [grant number 11-04-R83-A3363-22625], Aalborg University Talent Management Program, Arvid Nilssons Fond, Skibsreder Per Henriksen, R og Hustrus Fond, the European Union’s Horizon 2020 program [grant number 847770], Læge Sophus Carl Emil Friis og hustru Olga Doris Friis’ Legat, and an unrestricted grant from Medtronic. Background It is well known that atrial fibrillation (AF) confers a substantially increased risk of ischemic stroke, but data on health benefits from AF screening are scarce. The newly proposed MVP risk score combining the duration, voltage and morphology of P-wave has been demonstrated to be predictive of AF and might therefore also be useful in risk-stratifying individuals for AF screening and subsequent treatment. Purpose The present study sought to examine MVP risk score and its P-wave components for prediction of AF screening effects. Methods The LOOP Study randomized AF-naïve individuals aged 70-90 years with additional stroke risk factors to either continuous AF screening with implantable loop recorder (ILR) and subsequent anticoagulation initiation upon detection of AF episode ≥6 minutes, or usual care. In this secondary analysis, the LOOP participants with a baseline 12-lead electrocardiogram (ECG) suitable for P-wave measurement were included. Results Of 5759 participants included, 265 (4.6%) had had ischemic stroke during follow-up: 213 (4.9%) of 4311 in the control group versus 64 (3.6%) of 1448 in the ILR group. Among the participants in the control group, a significantly increased risk of ischemic stroke was observed for MVP score 5-6 versus score 0-2 (hazard ratio (HR) 1.66 [95% confidence interval (CI): 1.01-2.75]) and for the presence of interatrial block (IAB) versus no IAB (HR 1.85 [95% CI: 1.19-2.86]), whereas a P-wave voltage in lead I (PWVI) 110 versus ≤110 ms). Compared with usual care, ILR screening did not significantly reduce the stroke risk regardless of MVP risk score, PWD, PWVI, or IAB pattern at baseline. Conclusions In an elderly population with additional stroke risk factors, both the P-wave parameters and the combined MVP risk score based on 12-lead ECG were associated with ischemic stroke, but these did not successfully demonstrate an association with effects of AF screening on stroke prevention.

Rebuilding one’s social network is essential to long-term social recovery from a substance-use problem. Despite this awareness, studies are needed for showing how people in long-term social recovery describe their networks and what they perceive as important in developing these networks. This study has sought to investigate (i) how people in long-term social recovery from substance-use problems describe their social networks and (ii) what they experience as key factors in developing their networks. We interviewed seventeen participants in long-term social recovery and mapped out their person-centred networks. Most of the participants were satisfied with their social networks, although some felt their networks were small and wanted more friends in the future. The qualitative thematic content analysis suggested that rebuilding networks was experienced as a demanding, anxiety-filled, long-term process. Access to social arenas, prolonged time spent with others and identification with and recognition from others were key to developing social networks. We argue that there is a need for tailored assistance and long-term support for people in long-term recovery to help them cope with the stresses of entering new social arenas, overcome societal stigma and develop social networks.