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Globalization is a commonly used term to describe the rapid changes and spatial transformations that have taken place on a global scale over the past forty years. The purpose of this paper is to examine how globalization has influenced pilgrimage from a geographical perspective. This paper begins with a discussion on globalization and glocalization. Attention is then turned to the changing use of the term and practice of pilgrimage in the modern, and post-secular world. The text then discusses ten ways in which modern pilgrimage travel has changed due to globalization, including: the democratization of pilgrimage; changes in the sacred laws of hospitality; the increasing medicalization of pilgrimage; pilgrims as an unwanted guest; technology and the pilgrimage experience; the over-commodification and monetization of pilgrimage; the segmenting of pilgrimage and tourism; pilgrimage as spectacle and play; transplanted pilgrimages; and pilgrimage as a sustainable practice(?), are discussed before concluding.

I dagens Europa som preges av kompleks gjensidig avhengighet, argumenterer vi for at tette tilknytningsformer, som Norge har til EU, best kan analyseres utfra begrepet autonomi. Dette begrepet omfatter handlingsrom og er langt mer dekkende for å forstå Norges relasjon enn suverenitet og uavhengighet. Norges EU-relasjon er ikke bare tett, men kompleks og sammensatt. En slik tilknytningsform bidrar til å gjøre makt og ansvarsforhold uklare, uforutsigbare og usikre, hvilket medfører at analysene av tilknytningsformens konsekvenser best forstås ved å anvende begreper som kan gradere og skalere effekter. Artikkelen introduserer og utlegger derfor et nytt begrepsapparat forankret i autonomi, statlig så vel som individuell. Gjennom to empiriske illustrasjoner viser artikkelen hvilke begrensninger Norges forhold til EU legger på statlig autonomi, samt hvor komplisert forholdet er mellom statlig og individuell autonomi i dagens kontekst preget av kompleks (asymmetrisk) gjensidig avhengighet.

Abstract Background Syringomyelia (SM) and myxomatous mitral valve disease (MMVD) are highly prevalent in Cavalier King Charles spaniels (CKCS). Cardiac status in CKCS with and without SM is currently unknown. Objectives To investigate the association between SM and MMVD severity in CKCS and CKCS with SM with and without clinical signs of SM. Animals Fifty‐five CKCS: 40 with SM (22 symptomatic and 18 asymptomatic) and 15 without SM. Methods A combined retrospective and prospective study. MRI and echocardiography were used to diagnose SM and MMVD, respectively. The association between SM and MMVD severity (left ventricle internal diameter in diastole normalized to bodyweight [LVIDDN] and left atrium to aortic ratio [LA/Ao]) were tested using multivariable linear regression analysis adjusting for sex and age. Results Overall, no significant difference in LVIDDN and LA/Ao was found between CKCS with or without SM. However, CKCS with symptomatic SM had significantly smaller LVIDDN (1.45 [1.30‐1.50]) (median [IQR]) and LA/Ao (1.20 [1.10‐1.28]) compared to CKCS with asymptomatic SM (1.60 [1.50‐1.90] and 1.40 [1.20‐1.75]) as well as CKCS without SM (0.24 [0.03‐0.45] and 0.30 [0.05‐0.56]) (all P values

New technology has opened opportunities for research and exploration of deep-water ecosystems, highlighting deep-sea coral reefs as a rich source of novel bioactive natural products. During our ongoing investigation of the chemodiversity of the Irish deep sea and the soft coral Anthothela grandiflora, we report 12 unreported cadinene-like functionalized sesquiterpenes, anthoteibinenes F–Q. The metabolites were isolated using both bioassay- and 1H NMR-guided approaches. One-/two-dimensional NMR spectroscopy and high-resolution mass spectrometry were used for structure elucidation, while a combination of NOESY NMR experiments, GIAO NMR calculations coupled with DP4+ probabilities measures, and ECD comparisons were incorporated to propose relative and absolute configurations of the anthoteibinenes. The metabolites were screened against the Respiratory Syncytial Virus (RSV), ESKAPE pathogens, five Candida albicans strains, and one strain of C. auris.

Chemical investigation of the Antarctic sponge Suberites sp. has previously led to the identification of new suberitane derivatives, some of which show bioactivity toward respiratory syncytial virus (RSV). Our ongoing NMR-guided investigation of new specimens of the sponge resulted in the isolation of five new analogs (1–5), previously reported suberitenones A–D (6–9), and oxaspirosuberitenone (10). Suberitenone K (1) was characterized as the 8-keto derivative of 6, while three new phenols, suberitandiol (2), abeosuberitandiol (3), and furanosuberitandiol (4), and the degraded sesterterpene norsuberitenone B (5) were also found. Compound 3 displays a ring contraction while 4 has a new dihydrofuran ring. Structural characterization was achieved by a combination of NMR, HR-MS, and X-ray diffraction (XRD). Moderate activity towards RSV was reported for 9 and the new metabolite 1, with IC50 values of 15.0 μM and 39.8 μM, respectively.

Abstract Background A variant in the canine phosphodiesterase (PDE) 5A gene (PDE5A:E90K) is associated with decreased concentrations of circulating cyclic guanosine monophosphate (cGMP) and response to PDE5 inhibitor treatment. Pimobendan is a PDE inhibitor recommended for medical treatment of certain stages of myxomatous mitral valve disease (MMVD) in dogs. Hypothesis PDE5A:E90K polymorphism attenuates the inhibitory effect of pimobendan on in vitro platelet aggregation and increases basal platelet aggregation in Cavalier King Charles Spaniels (CKCS). Selected clinical variables (MMVD severity, sex, age, hematocrit, platelet count in platelet‐rich plasma [PRP], and echocardiographic left ventricular fractional shortening [LV FS]) will not show an association with results. Animals Fifty‐two privately owned CKCS with no or preclinical MMVD. Methods Using blood samples, we prospectively assessed PDE5A genotype using Sanger sequencing and adenosine diphosphate‐induced platelet aggregation response (area under the curve [AUC], maximal aggregation [MaxA], and velocity [Vel]) with and without pimobendan using light transmission aggregometry. Dogs also underwent echocardiography. Results Pimobendan inhibited platelet function as measured by AUC, MaxA, and Vel at a concentration of 10 μM (P

BackgroundAnti-CGRP-(receptor-)monoclonal antibodies (anti-CGRP(R)-mAbs) represent a novel class of drugs for migraine treatment, but their long-term cerebrovascular and cardiovascular (CV) safety warrants further examination.MethodsIn this observational cohort study we assessed the CV safety for erenumab and fremanezumab in a real-world setting during a follow-up period of at least 1 year. Patients with hypertension or CV history were excluded. We conducted ECGs and collected clinical data at treatment initiation and thereafter every 3 months, including liver and kidney function, lipid-, electrolyte-and glucose levels.ResultsAmong patients receiving erenumab (n = 101) or fremanezumab (n = 92), 3.1% (6/193) developed abnormal ECGs or CV adverse events. Of these, three (1.6%) experienced moderate to severe CV adverse events (cerebellar stroke, spontaneous coronary artery dissection, and pericarditis) and discontinued treatment. The remaining three (1.6%) developed non-threatening ECG abnormalities without physical complaints. No significant changes were observed in liver and kidney function, lipid-, electrolyte-, or glucose levels.DiscussionWe observed CV events in 1.6% of patients with 1.5-year follow-up of anti-CGRP(R)-mAbs treatment. We advise awareness regarding CV events in patients with migraine undergoing CGRP-targeted treatment, not as a confirmation of increased risk but as a proactive measure to address potential multifactorial influences.

IntroductionWe sought to determine pre-infection correlates of protection against SARS-CoV-2 post-vaccine inzfections (PVI) acquired during the first Omicron wave in the United States.MethodsSerum and saliva samples from 176 vaccinated adults were collected from October to December of 2021, immediately before the Omicron wave, and assessed for SARS-CoV-2 Spike-specific IgG and IgA binding antibodies (bAb). Sera were also assessed for bAb using commercial assays, and for neutralization activity against several SARS-CoV-2 variants. PVI duration and severity, as well as risk and precautionary behaviors, were assessed by questionnaires.ResultsSerum anti-Spike IgG levels assessed by research assay, neutralization titers against Omicron subvariants, and low home risk scores correlated with protection against PVIs after multivariable regression analysis. Commercial assays did not perform as well as research assay, likely due to their lower dynamic range.DiscussionIn the 32 participants that developed PVI, anti-Spike IgG bAbs correlated with lower disease severity and shorter duration of illness.

Abstract Background While a low-carbohydrate diet (LCD) reduces HbA1c in patients with type 2 diabetes (T2D), the associated high intake of fat may adversely affect cardiovascular risk factors. To address this, we examined the effect of a non-calorie-restricted LCD high in fat on endothelial function and markers of low-grade inflammation in T2D over 6 months. Methods In an open-label randomized controlled trial, 71 patients with T2D were randomized 2:1 to either a LCD (

Abstract Antibodies with similar amino acid sequences, especially across their complementarity-determining regions, often share properties. Finding that an antibody of interest has a similar sequence to naturally expressed antibodies in healthy or diseased repertoires is a powerful approach for the prediction of antibody properties, such as immunogenicity or antigen specificity. However, as the number of available antibody sequences is now in the billions and continuing to grow, repertoire mining for similar sequences has become increasingly computationally expensive. Existing approaches are limited by either being low-throughput, non-exhaustive, not antibody specific, or only searching against entire chain sequences. Therefore, there is a need for a specialized tool, optimized for a rapid and exhaustive search of any antibody region against all known antibodies, to better utilize the full breadth of available repertoire sequences. We introduce Known Antibody Search (KA-Search), a tool that allows for the rapid search of billions of antibody variable domains by amino acid sequence identity across either the variable domain, the complementarity-determining regions, or a user defined antibody region. We show KA-Search in operation on the $$\sim $$ ∼ 2.4 billion antibody sequences available in the OAS database. KA-Search can be used to find the most similar sequences from OAS within 30 minutes and a representative subset of 10 million sequences in less than 9 seconds. We give examples of how KA-Search can be used to obtain new insights about an antibody of interest. KA-Search is freely available at https://github.com/oxpig/kasearch .

Abstract Background Congenital heart disease (CHD) is a common and significant birth defect, frequently requiring surgical intervention. For beneficiaries of the Department of Defense, a new diagnosis of CHD may occur while living at rural duty stations. Choice of tertiary care center becomes a function of geography, referring provider recommendations, and patient preference. Methods Using billing data from the Military Health System over a 5-year period, outcomes for beneficiaries age 50 high complexity cases annually) demonstrated decreased one year mortality, but increased cost and length of stay. Conclusions Together, these findings contribute to the national conversation of rural community medicine versus regionalized subspecialty care; separation of patients between rural areas and more urban locations for initial CHD surgical care does not increase their mortality risk. In fact, traveling to high volume centers may have an associated mortality benefit.

Adult growth hormone deficiency (AGHD) is associated with an increased risk of cardiovascular (CV) disease. Long-term growth hormone (GH) trea tment could improve CV outcomes. The objective of this study was to evaluate CV disease risk in patients with AGHD who received GH replacement therapy for up to 10 years as part of NordiNet® IOS (NCT00960128) and the ANSWER Program (NCT01009905). The studies were observational, non-interventional and multicentre, monitoring l ong-term effectiveness and safety of GH treatment. NordiNet® IOS involved 23 countries (469 sites) across Europe and the Middle East. The ANSWER Program was conducted in the USA (207 sites). This analysis included patients aged 18–75 years who were GH na ïve at study entry, who had ≤10 years of GH treatment data and who could be assessed for CV risk for at least 1 follow-up year. The main outcome measure was risk of CV disea se by age 75 years, as calculated with the Multinational Cardiovascular Risk Consortium model (Brunner score) using non-high-density lipoprotein cholesterol adjusted for age, sex and CV risk factors. The results of this analysis showed that CV risk decreased gradually over the 10-year period for GH-treated patients. The risk was lower for patients treated for 2 and 7 years vs age- and sex-matched control groups (not yet started treatment) (14.51% vs 16.15%; P = 0.0105 and 13.53% vs 16.81%; P = 0.0001, respectively). This suggests that GH treatment in people with AGHD may reduce the risk of CV disease by age 75 years compared with matched controls.

Background The association between common carotid artery intima‐media thickness (CCA‐IMT) and incident carotid plaque has not been characterized fully. We therefore aimed to precisely quantify the relationship between CCA‐IMT and carotid plaque development. Methods and Results We undertook an individual participant data meta‐analysis of 20 prospective studies from the Proof‐ATHERO (Prospective Studies of Atherosclerosis) consortium that recorded baseline CCA‐IMT and incident carotid plaque involving 21 494 individuals without a history of cardiovascular disease and without preexisting carotid plaque at baseline. Mean baseline age was 56 years (SD, 9 years), 55% were women, and mean baseline CCA‐IMT was 0.71 mm (SD, 0.17 mm). Over a median follow‐up of 5.9 years (5th–95th percentile, 1.9–19.0 years), 8278 individuals developed first‐ever carotid plaque. We combined study‐specific odds ratios (ORs) for incident carotid plaque using random‐effects meta‐analysis. Baseline CCA‐IMT was approximately log‐linearly associated with the odds of developing carotid plaque. The age‐, sex‐, and trial arm–adjusted OR for carotid plaque per SD higher baseline CCA‐IMT was 1.40 (95% CI, 1.31–1.50; I2=63.9%). The corresponding OR that was further adjusted for ethnicity, smoking, diabetes, body mass index, systolic blood pressure, low‐ and high‐density lipoprotein cholesterol, and lipid‐lowering and antihypertensive medication was 1.34 (95% CI, 1.24–1.45; I2=59.4%; 14 studies; 16 297 participants; 6381 incident plaques). We observed no significant effect modification across clinically relevant subgroups. Sensitivity analysis restricted to studies defining plaque as focal thickening yielded a comparable OR (1.38 [95% CI, 1.29–1.47]; I2=57.1%; 14 studies; 17 352 participants; 6991 incident plaques). Conclusions Our large‐scale individual participant data meta‐analysis demonstrated that CCA‐IMT is associated with the long‐term risk of developing first‐ever carotid plaque, independent of traditional cardiovascular risk factors.

Marine-terminating outlet glacier terminus traces, mapped from satellite and aerial imagery, have been used extensively in understanding how outlet glaciers adjust to climate change variability over a range of timescales. Numerous studies have digitized termini manually, but this process is labor intensive, and no consistent approach exists. A lack of coordination leads to duplication of efforts, particularly for Greenland, which is a major scientific research focus. At the same time, machine learning techniques are rapidly making progress in their ability to automate accurate extraction of glacier termini, with promising developments across a number of optical and synthetic aperture radar (SAR) satellite sensors. These techniques rely on high-quality, manually digitized terminus traces to be used as training data for robust automatic traces. Here we present a database of manually digitized terminus traces for machine learning and scientific applications. These data have been collected, cleaned, assigned with appropriate metadata including image scenes, and compiled so they can be easily accessed by scientists. The TermPicks data set includes 39 060 individual terminus traces for 278 glaciers with a mean of 136 ± 190 and median of 93 of traces per glacier. Across all glaciers, 32 567 dates have been digitized, of which 4467 have traces from more than one author, and there is a duplication rate of 17 %. We find a median error of ∼ 100 m among manually traced termini. Most traces are obtained after 1999, when Landsat 7 was launched. We also provide an overview of an updated version of the Google Earth Engine Digitization Tool (GEEDiT), which has been developed specifically for future manual picking of the Greenland Ice Sheet.

Abstract Background Obesity is strongly associated with the development of cardiovascular disease (CVD). However, the heterogenous nature of obesity in CVD-risk is still poorly understood. We aimed to explore novel CVD biomarkers and their possible association with presumed unhealthy obesity, defined as hospitalized subjects with obesity (HO). Methods Ninety-two proteins associated with CVD were analyzed in 517 (mean age 67 ± 6 years; 33.7% women) individuals with obesity (BMI ≥30 kg/m2) from the Malmö Preventive Project cohort, using a proximity extension array technique from the Olink CVD III panel. Individuals with at least one recorded hospitalization for somatic disease prior to study baseline were defined as HO phenotypes. Associations between proteins and HO (n = 407) versus non-hospitalized subjects with obesity (NHO, n = 110), were analyzed using multivariable binary logistic regression, adjusted for traditional risk factors. Results Of 92 analyzed unadjusted associations between biomarkers and HO, increased levels of two proteins were significant at a false discovery rate

Impaired mitochondrial function in liver tissue may contribute to the pathogenesis and disease progression of nonalcoholic fatty liver disease (NAFLD). Here the authors report that patients with obesity have lower mitochondrial capacity in adipose tissues but higher capacity in the liver, without overall associations to NAFLD severity, and that bariatric surgery increases hepatic mitochondrial respiration and mitochondrial biogenesis.

Background: Nationally representative, household-based, health-related surveys are an invaluable source of health information, but face implementation challenges. In sub-Saharan Africa, these challenges are exacerbated when surveys include the collection of biological specimens. In this study, we describe the potential implementation challenges identified during field practice leading up to the 2020 Zambia Population-based HIV Impact Assessment (ZAMPHIA) survey, and explore the role of two crises on community mistrust of, and apprehension to, participate in the survey. Methods: Using focus group methodology to better understand the influence of crises on ZAMPHIA participation, we conducted 12 focus group discussions (FGDs) in five districts across two provinces. FGDs were conducted with three purposively sampled study groups: recognized household heads, community leaders, and young adults aged 18-24 years. We used reflexive thematic analysis to develop themes from across the FGDs. Results: We identified two key themes: the ever-present threat a stranger posed to the community is enhanced by crises, and endorsement of community awareness through sensitization can mitigate outsider challenges in medical research. Conclusion: We argue that these crises emphasized underlying mistrust that can only be addressed with substantial investment in community engagement efforts to build trust and partnership in medical research endeavors. Our findings underline the importance of prioritizing community engagement through substantial investment in varied and extensive approaches to sensitization to facilitate community engagement toward community acceptance of ZAMPHIA and similar studies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies decay but persist 6 months postvaccination; lower levels of neutralizing titers persist against Delta than wild-type virus. Of 227 vaccinated healthcare workers tested, only 2 experienced outpatient symptomatic breakthrough infections, despite 59/227 exhibiting serologic evidence of SARS-CoV-2 infection, defined as presence of nucleocapsid protein antibodies.

Abstract Proteases play a major role in many vital physiological processes. Trypsin-like serine proteases (TLPs), in particular, are paramount in proteolytic cascade systems such as blood coagulation and complement activation. The structural topology of TLPs is highly conserved, with the trypsin fold comprising two β-barrels connected by a number of variable surface-exposed loops that provide a surprising capacity for functional diversity and substrate specificity. To expand our understanding of the roles these loops play in substrate and co-factor interactions, we employ a systematic methodology akin to the natural truncations and insertions observed through evolution of TLPs. The approach explores a larger deletion space than classical random or directed mutagenesis. Using FVIIa as a model system, deletions of 1–7 amino acids through the surface exposed 170 loop, a vital allosteric regulator, was introduced. All variants were extensively evaluated by established functional assays and computational loop modelling with Rosetta. The approach revealed detailed structural and functional insights recapitulation and expanding on the main findings in relation to 170 loop functions elucidated over several decades using more cumbersome crystallization and single deletion/mutation methodologies. The larger deletion space was key in capturing the most active variant, which unexpectedly had a six-amino acid truncation. This variant would have remained undiscovered if only 2–3 deletions were considered, supporting the usefulness of the methodology in general protease engineering approaches. Our findings shed further light on the complex role that surface-exposed loops play in TLP function and supports the important role of loop length in the regulation and fine-tunning of enzymatic function throughout evolution.

Abstract Epidemiological data suggest that exercise training protects from cancer independent of BMI. Here, we aimed to elucidate mechanisms involved in voluntary wheel running-dependent control of tumor growth across chow and high-fat diets. Access to running wheels decreased tumor growth in B16F10 tumor-bearing on chow (− 50%) or high-fat diets (− 75%, p

Summary: Background: High-sensitivity Troponin T (hsTnT), a biomarker of cardiomyocyte overload and injury, relates to aortic valve replacement (AVR) and mortality in severe aortic stenosis (AS). However, its prognostic value remains unknown in asymptomatic patients with AS. We aimed to investigate if an hsTnT level >14 pg/mL (above upper limit of normal 99th percentile) is associated with echocardiographic AS-severity, subsequent AVR, ischaemic coronary events (ICE), and mortality in asymptomatic patients with non-severe AS. Methods: In this post-hoc sub-analysis of the multicentre, randomised, double-blind, placebo-controlled SEAS trial (ClinicalTrials.gov, NCT00092677), we included asymptomatic patients with mild to moderate-severe AS. We ascertained baseline and 1-year hsTnT concentrations and examined the association between baseline levels and the risk of the primary composite endpoint, defined as the first event of all-cause mortality, isolated AVR (without coronary artery bypass grafting (CABG)), or ICE. Multivariable regressions and competing risk analyses examined associations of hsTnT level >14 pg/mL with clinical correlates and 5-year risk of the primary endpoint. Findings: Between January 6, 2003, and March 4, 2004, a total of 1873 patients were enrolled in the SEAS trial, and 1739 patients were included in this post-hoc sub-analysis. Patients had a mean (SD) age of 67.5 (9.7) years, 61.0% (1061) were men, 17.4% (302) had moderate-severe AS, and 26.0% (453) had hsTnT level >14 pg/mL. The median hsTnT difference from baseline to 1-year was 0.8 pg/mL (IQR, −0.4 to 2.3). In adjusted linear regression, log(hsTnT) did not correlate with echocardiographic AS severity (p = 0.36). In multivariable Cox regression, a hsTnT level >14 pg/mL vs. hsTnT ≤14 pg/mL was associated with an increased risk of the primary composite endpoint (HR, 1.41; 95% CI, 1.18–1.70; p = 0.0002). In a competing risk model of first of the individual components of the primary endpoint, a hsTnT level >14 pg/mL was associated with ICE risk (HR 1.71; 95% CI, 1.23–2.38; p = 0.0013), but not with isolated AVR (p = 0.064) or all-cause mortality (p = 0.49) as the first event. Interpretation: hsTnT level is within the reference range (≤14 pg/mL) in 3 out of 4 non-ischaemic patients with asymptomatic mild-to-moderate AS and remains stable during a 1-year follow-up regardless of AS-severity. An hsTnT level >14 pg/mL was mainly associated with subsequent ICE, which suggest that hsTnT concentration is primarily a risk marker of subclinical coronary atherosclerotic disease. Funding: Merck & Co., Inc., the Schering-Plough Corporation, the Interreg IVA program, Roche Diagnostics Ltd., and Gangstedfonden. Open access publication fee funding provided by prof. Olav W. Nielsen and Department of Cardiology, Bispebjerg University Hospital, Denmark.

Whooping cranes (Grus americana) are naturally seasonal breeders and rely on wetland habitats throughout the annual cycle. However, captive cranes are commonly housed in dry outdoor pens, which may lack key environmental stimuli that in turn compromise reproduction. Our study sought to first, assess seasonal patterns of reproductive hormones in successful versus non-successful bird pairs and second, determine endocrine responses to alterations in enclosure environments. Fecal samples were collected from eight crane pairs year-round for 3 consecutive years, once a week during non-breeding season and three times a week during the breeding season. During Year 1, all pairs were housed in traditional dry pens, whereas during January of Year 2 all pairs were moved to either new dry pens (control, n = 4) or ponded pens (wetland, n = 4) and remained in the same pen until the end of the study. Fecal samples were assessed for gonadal (year-round) and adrenal (breeding season only) hormones. Estrogen and progestagen metabolite concentrations were low during non-breeding season in all females. However, as birds transition into a breeding season, gonadal hormone concentrations significantly increased (p

Purpose People with disabilities are less active and experience increased burden of disease compared to those without disabilities. Leisure time physical activity (LTPA) participation is strongly related to improved health in all populations. Despite this, research with amputees focuses heavily on prosthetic design and function, leaving amputees an under-represented population in LTPA and motivation research. This study explored the lived experiences of motivation to engage in LTPA among amputees. Method Interpretative phenomenological analysis (IPA) approach, influenced by understandings of embodiment and Self-Determination Theory (SDT), was used. Six people with lower extremity, acquired amputations created a photo-diary of their motivations to be active and participated in two in-depth interviews each. Results Study findings suggest motivations to be active among amputees are primarily influenced by personal relationships. Barriers, facilitators, and processes to be active provided insight into how LTPA participation may be affected by more than motivation. Embodiment was experienced as bodily integration of the prosthesis. Conclusions There is evidence that the relationship between motivation and participation is not direct, but influenced by facilitators, barriers, and processes to be active. The results suggest strategies to increase activity among amputees by emphasizing LTPA with others, improving the built environment, and ensuring prosthesis fit.

Abstract Background The neurotransmitter serotonin (5‐HT) affects valvular degeneration and dogs with myxomatous mitral valve disease (MMVD) exhibit alterations in 5‐HT signaling. In Maltese dogs, 3 single nucleotide polymorphisms (SNPs) in the 5‐HT transporter (SERT) gene are suggested to associate with MMVD. Hypothesis/Objectives Determine the association of SERT polymorphisms on MMVD severity and serum 5‐HT concentration in Cavalier King Charles Spaniels (CKCS). Additionally, investigate the association between selected clinical and hematologic variables and serum 5‐HT and assess the correlation between HPLC and ELISA measurements of serum 5‐HT. Animals Seventy‐one CKCS (42 females and 29 males; 7.8 [4.7;9.9] years (median [Q1;Q3])) in different MMVD stages. Methods This prospective study used TaqMan genotyping assays to assess SERT gene polymorphisms. Neurotransmitter concentrations were assessed by HPLC and ELISA. Results TaqMan analyses identified none of the selected SERT polymorphisms in any of the CKCS examined. Serum 5‐HT was associated with platelet count (P

Abstract Background SARS-CoV-2 is a recently emerged pandemic coronavirus (CoV) capable of causing severe respiratory illness. However, a significant number of infected people present as asymptomatic or pauci-symptomatic. In this prospective assessment of at-risk healthcare workers (HCWs) we seek to determine whether pre-existing antibody or T cell responses to previous seasonal human coronavirus (HCoV) infections affect immunological or clinical responses to SARS-CoV-2 infection or vaccination. Methods A cohort of 300 healthcare workers, confirmed negative for SARS-CoV-2 exposure upon study entry, will be followed for up to 1 year with monthly serology analysis of IgM and IgG antibodies against the spike proteins of SARS-CoV-2 and the four major seasonal human coronavirus - HCoV-OC43, HCoV-HKU1, HCoV-229E, and HCoV-NL63. Participants will complete monthly questionnaires that ask about Coronavirus Disease 2019 (COVID-19) exposure risks, and a standardized, validated symptom questionnaire (scoring viral respiratory disease symptoms, intensity and severity) at least twice monthly and any day when any symptoms manifest. SARS-CoV-2 PCR testing will be performed any time participants develop symptoms consistent with COVID-19. For those individuals that seroconvert and/or test positive by SARS-CoV-2 PCR, or receive the SARS-CoV-2 vaccine, additional studies of T cell activation and cytokine production in response to SARS-CoV-2 peptide pools and analysis of Natural Killer cell numbers and function will be conducted on that participant’s cryopreserved baseline peripheral blood mononuclear cells (PBMCs). Following the first year of this study we will further analyze those participants having tested positive for COVID-19, and/or having received an authorized/licensed SARS-CoV-2 vaccine, quarterly (year 2) and semi-annually (years 3 and 4) to investigate immune response longevity. Discussion This study will determine the frequency of asymptomatic and pauci-symptomatic SARS-CoV-2 infection in a cohort of at-risk healthcare workers. Baseline and longitudinal assays will determine the frequency and magnitude of anti-spike glycoprotein antibodies to the seasonal HCoV-OC43, HCoV-HKU1, HCoV-229E, and HCoV-NL63, and may inform whether pre-existing antibodies to these human coronaviruses are associated with altered COVID-19 disease course. Finally, this study will evaluate whether pre-existing immune responses to seasonal HCoVs affect the magnitude and duration of antibody and T cell responses to SARS-CoV-2 vaccination, adjusting for demographic covariates.

Abstract The potentially fatal cardiovascular effects of hypoglycaemia are not well understood and large animal models of the counter-regulatory responses and cardiovascular consequences of insulin-induced hypoglycaemia are needed to understand the mechanisms in humans. The aim of this study was to develop a human-like minipig model of hypoglycaemia including healthy and diabetic pigs to investigate endocrine, electrocardiographic and platelet effects. Hypoglycaemia was induced using a hyperinsulinaemic, hypoglycaemic clamp and an insulin bolus protocol. Plasma glucose, glucagon, C-peptide, insulin, epinephrine and platelet aggregation responses were measured before, during and after hypoglycaemia. Continuous electrocardiographic recordings were obtained. Hypoglycaemia at a plasma glucose concentration of 0.8–1.0 mM in the clamp induced 25-fold increase in epinephrine and sixfold and threefold increase in glucagon for healthy and diabetic pigs, respectively. The hypoglycaemic clamp induced QTc-interval prolongation and increase in cardiac arrhythmias. In the bolus approach, the non-diabetic group reached plasma glucose target of 1.5 mM and QTc-interval was prolonged after insulin injection, but before glucose nadir. The diabetic group did not reach hypoglycaemic target, but still demonstrated QTc-interval prolongation. These results demonstrate effects of hyperinsulinaemic hypoglycaemia closely resembling human physiology, indicating the minipig as a translational animal model of counter-regulatory endocrine and myocardial effects of hypoglycaemia.

Abstract Aims The epidemiological association between diabetes and cardiovascular disease is well established, but the pathophysiological link is complex and multifactorial. We investigated seven proteins, previously linked to incident diabetes mellitus, and their association with cardiovascular disease and mortality. Methods and results Plasma samples from 1713 individuals from the Swedish population‐based Malmö Preventive Project (mean age 67.4 ± 6.0 years; 29.1% women) were analysed with a proximity extension assay panel. Seven proteins [scavenger receptor cysteine rich type 1 protein M130 (CD163), fatty acid‐binding protein 4 (FABP4), plasminogen activator inhibitor 1 (PAI), insulin‐like growth factor‐binding protein 2 (IGFB2), cathepsin D (CTSD), galectin‐4 (GAL4), and paraoxonase‐3 (PON3)] previously shown to be associated with incident diabetes were analysed for associations with all‐cause mortality (ACM), cardiovascular mortality (CVM), incident coronary events (CEs), and incident heart failure (HF). After exclusion of prevalent cases of respective outcome, proteins that met Bonferroni‐corrected significance were analysed in multivariable Cox regression models. Significant associations were identified between five proteins [GAL4 (hazard ratio; 95% confidence interval: 1.17–1.41), CTSD (1.15–1.37), CD163 (1.09–1.30), IGFBP2 (1.05–1.30), and FABP4 (1.04–1.29)] and ACM and four proteins [GAL4 (1.38–1.56), CTSD (1.14–1.43), CD163 (1.09–1.36), and IGFBP2 (1.03–1.35)] with CVM. Three proteins [GAL4 (1.14–1.57), CTSD (1.12–1.50), and FABP4 (1.05–1.55)] were significantly associated with incident CE and two [GAL4 (1.03–1.54) and CTSD (1.01–1.46)] were associated with incident HF after adjusting for traditional risk factors including N‐terminal pro‐brain natriuretic peptide. Conclusions In a general Swedish population, four proteins previously shown to be associated with diabetes were associated with ACM and CVM. Three proteins were associated with incident CE. Finally, GAL4 and CTSD displayed novel associations with incident HF and were the only proteins associated with all outcomes.

Purpose: The objective of this study was to test if combining antecedent systolic blood pressure (SBP) with traditional risk factors and hypertension-mediated organ damage (HMOD) improves risk stratification for subsequent cardiovascular disease. Materials and methods: 1910 subjects participated in this study. Antecedent SBP was defined as the average of measurements obtained in 1982 and in 1987. Current SBP was obtained in 1993. HMOD were examined in 1993. HMOD was defined as either atherosclerotic plaque(s), increased pulse wave velocity, increased urine albumin creatinine ratio (above the 90th percentile) or left ventricular hypertrophy. Major adverse cardiovascular events (MACE) including myocardial infarction, cerebrovascular disease, heart failure and arrhythmia were obtained from national registries. Results: Subjects were divided into two age categories: a middle-aged group (aged 41 or 51) and an older group (aged 61 or 71). From 1993 to 2010, 425 events were observed. In multivariable analysis with both current and antecedent SBP adjusted for traditional risk factors, current SBP was associated with each measure of HMOD whilst antecedent SBP was not significantly associated with urine albumin creatinine ratio in the older group, LVMI in the middle-aged group, or the presence of plaque in any of the age groups (all p > 0.15). When current and antecedent SBP were evaluated together, current SBP was not associated with MACE in the middle-aged subgroup [HR = 1.09 (0.96–1.22), p = 0.18] but remained associated with MACE in the older subgroup [HR = 1.21 (1.10–1.34), p

Abstract GtxA, a leukotoxic RTX-toxin, has been proposed a main virulence factor of Gallibacterium anatis. To evaluate the impact of GtxA during infection, we experimentally infected laying hens with a G. anatis wild-type (WT) strain and its isogenic gtxA deletion mutant (ΔgtxA), respectively, and monitored the birds during a 6 day period. Birds inoculated with ΔgtxA had significantly reduced gross lesions and microscopic changes compared to the birds inoculated with the WT strain. To assess the host response further, we quantified the expression of pro-inflammatory cytokines and apoptosis genes by RT-qPCR. In the ovarian tissue, the expression levels of IL-4 and TNF-α were significantly lower in the ΔgtxA group compared to the WT group, while IL-6 and IL-10 levels appeared similar in the two groups. In the spleen tissue of ΔgtxA infected chickens, IL-4 expression was also lower compared to the WT infected chickens. The results indicated that GtxA plays a key role in an acute cytokine-mediated Th2-like response against G. anatis infection in the ovary tissue. The pro-inflammatory response in the ovary tissue of birds inoculated with ΔgtxA mutant was thus significantly lower than the wild-type response. This was, at least partly, supported by the apoptosis gene expression levels, which were significantly higher in the ΔgtxA mutant compared to the wild-type infected chickens. In conclusion, GtxA clearly plays an important role in the pathogenesis of G. anatis infections in laying hens. Further investigations into the specific factors regulating the host response is however needed to provide a more complete understanding of the bacteria-host interaction.

To assess whether anthropometric measures (body mass index [BMI], waist-hip ratio [WHR], and estimated fat mass [EFM]) are independently associated with major adverse cardiovascular events (MACE), and to assess their added prognostic value compared with serum total-cholesterol. The study population comprised 109,509 individuals (53% men) from the MORGAM-Project, aged 19–97 years, without established cardiovascular disease, and not on antihypertensive treatment. While BMI was reported in all, WHR and EFM were reported in ∼52,000 participants. Prognostic importance of anthropometric measurements and total-cholesterol was evaluated using adjusted Cox proportional-hazards regression, logistic regression, area under the receiver-operating-characteristic curve (AUCROC), and net reclassification improvement (NRI). The primary endpoint was MACE, a composite of stroke, myocardial infarction, or death from coronary heart disease. Age interacted significantly with anthropometric measures and total-cholesterol on MACE (P ≤ 0.003), and therefore age-stratified analyses (

Multidrug-resistant pathogens constitute a serious global issue and, therefore, novel antimicrobials with new modes of action are urgently needed. Here, we investigated the effect of a phenothiazine derivative (JBC 1847) with high antimicrobial activity on Staphylococcus aureus, using a wide range of in vitro assays, flow cytometry, and RNA transcriptomics. The flow cytometry results showed that JBC 1847 rapidly caused depolarization of the cell membrane, while the macromolecule synthesis inhibition assay showed that the synthesis rates of DNA, RNA, cell wall, and proteins, respectively, were strongly decreased. Transcriptome analysis of S. aureus exposed to sub-inhibitory concentrations of JBC 1847 identified a total of 78 downregulated genes, whereas not a single gene was found to be significantly upregulated. Most importantly, there was downregulation of genes involved in adenosintrifosfat (ATP)-dependent pathways, including histidine biosynthesis, which is likely to correlate with the observed lower level of intracellular ATP in JBC 1847–treated cells. Furthermore, we showed that JBC 1847 is bactericidal against both exponentially growing cells and cells in a stationary growth phase. In conclusion, our results showed that the antimicrobial properties of JBC 1847 were primarily caused by depolarization of the cell membrane resulting in dissipation of the proton motive force (PMF), whereby many essential bacterial processes are affected. JBC 1847 resulted in lowered intracellular levels of ATP followed by decreased macromolecule synthesis rate and downregulation of genes essential for the amino acid metabolism in S. aureus. Bacterial compensatory mechanisms for this proposed multi-target activity of JBC 1847 seem to be limited based on the observed very low frequency of resistance toward the compound.

Respiratory syncytial virus (RSV) is a highly contagious human pathogen that poses a significant threat to children under the age of two, and there is a current need for new small molecule treatments. The Antarctic sponge Suberites sp. is a known source of sesterterpenes, and following an NMR-guided fractionation procedure, it was found to produce several previously unreported metabolites. Neosuberitenone (1), with a new carbon scaffold herein termed the ‘neosuberitane’ backbone, six suberitenone derivatives (2–7), an ansellane-type terpenoid (8), and a highly degraded sesterterpene (9), as well as previously reported suberitenones A (10) and B (11), were characterized. The structures of all of the isolated metabolites including absolute configurations are proposed on the basis of NMR, HRESIMS, optical rotation, and XRD data. The biological activities of the metabolites were evaluated in a range of infectious disease assays. Suberitenones A, B, and F (3) were found to be active against RSV, though, along with other Suberites sp. metabolites, they were inactive in bacterial and fungal screens. None of the metabolites were cytotoxic for J774 macrophages or A549 adenocarcinoma cells. The selectivity of suberitenones A, B, and F for RSV among other infectious agents is noteworthy.

North American waterfowl conservation, management, and harvest regulation are delegated across administrative flyways and primarily guided by breeding population estimates. The Ring-necked Duck (Aythya collaris) is a late-nesting migratory species that winters and breeds across all of the United States Fish and Wildlife Service administrative flyways. We used satellite telemetry to characterize the spring migration and breeding distribution of 25 female Ring-necked Ducks marked in the southern Atlantic Flyway, USA in the winters of 2017-2018 and 2018-2019. Mean migratory initiation date was 17 March (range: 24 Feb - 5 April) and mean migratory completion date (i.e., arrival to a suspected breeding site) was 16 May (range: 17 April - 27 June), with migratory duration averaging 61.1 days (95% CI: 53.6 - 68.6 days). Total migratory distance averaged 3,409.6 km (95% CI: 2,956.7 - 3,862.6 km). Individuals took, on average, 3.3 stopovers (95% CI: 2.7 - 4.0 stopovers) that lasted an average of 13.5 days (95% CI: 13.3 - 13.8 days). The majority of individuals migrated northwestward and primarily traveled within the Mississippi Flyway prior to reaching Canada. Ten of 25 marked birds migrated through but did not settle in the Prairie Pothole Region (PPR) during the time when the Waterfowl Breeding Population and Habitat Survey (WBPHS) was conducted. Total indicated bird population estimates could be inflated if individuals are counted in multiple WBPHS strata. We also note that 24 of 25 marked birds bred outside of strata comprising the WBPHS eastern survey area, which suggests that more Ring-necked Ducks wintering in the Atlantic Flyway breed outside of the WBPHS eastern survey area than is currently assumed by a scaling parameter incorporated in Atlantic Flyway models used to estimate population size. Individuals from a single wintering site in the southern Atlantic Flyway dispersed widely across two states (USA), five provinces, and one territory (CAN) during the breeding season. Our results support concerns over the efficacy of the WBPHS for Ring-necked Ducks and other late-nesting waterfowl and suggest that the bounds of the scaling parameter incorporated in the Atlantic Flyway multi-stock population model may need to be widened to more accurately account for individuals breeding outside of the Flyway.

Objective To explore living with heritable retinoblastoma, specifically survivors’ perceived role of regular follow-up at a retinoblastoma survivorship clinic.Methods and analysis Adult survivors of heritable retinoblastoma were recruited from the Retinoblastoma Survivorship Clinic, Aarhus University Hospital. Ten survivors participated in individual explorative, semistructured interviews. Thematic data analysis was conducted.Results Five key themes relating to vision, social life, family, second cancer risk and the healthcare system were identified. Subthemes relating to the Retinoblastoma Survivorship Clinic included the retinoblastoma coordinator, cancer risk, psychosocial support and genetic knowledge. The retinoblastoma-related physical and psychosocial issues influenced survivors’ everyday living; however, the opportunity to live a normal life varied considerably, with the majority experiencing no major limitations. The need for specialised management and a coordinator was emphasised to be the main value of the Retinoblastoma Survivorship Clinic.Conclusion Despite reporting an overall normal life and no major limitations in daily living activities, our data confirm that heritable retinoblastoma impacts several aspects of daily living. Uniquely, this study demonstrates that the main value of the Retinoblastoma Survivorship Clinic was a specialised contact person and coordinator in the healthcare system, providing continuous and necessary management and guidance after retinoblastoma treatment, and for all aspects of health related to heritable retinoblastoma. The needs of heritable retinoblastoma survivors are complex and extensive, and the specific role of the healthcare system to support survivorship should be prioritised, specialised and multidisciplinary.

Objective: Environmental factors can influence obesity by epigenetic mechanisms. The aim of this study was to investigate obesity-related epigenetic changes and the potential for reversal of these changes in the liver of Göttingen minipigs subjected to diet interventions.Methods: High-throughput liquid hybridization capture-based bisulfite sequencing (LHC-BS) was used to quantify the methylation status of gene promotor regions in liver tissue in three groups of male castrated Göttingen minipigs: a standard chow group (SD, N = 7); a group fed high fat/fructose/cholesterol diet (FFC, N = 10) and a group fed high fat/fructose/cholesterol diet during 7 months and reversed to standard diet for 6 months (FFC/SD, N = 12). Expression profiling by qPCR of selected metabolically relevant genes was performed in liver tissue from all pigs.Results: The pigs in the FFC diet group became morbidly obese. The FFC/SD diet did not result in a complete reversal of the body weight to the same weight as in the SD group, but it resulted in reversal of all lipid related metabolic parameters. Here we identified widespread differences in the patterning of cytosine methylation of promoters between the different feeding groups. By combining detection of differentially methylated genes with a rank-based hypergeometric overlap algorithm, we identified 160 genes showing differential methylation in corresponding promoter regions in the FFC diet group when comparing with both the SD and FFC/SD groups. As expected, this differential methylation under FFC diet intervention induced de-regulation of several metabolically-related genes involved in lipid/cholesterol metabolism, inflammatory response and fibrosis generation. Moreover, five genes, of which one is a fibrosis-related gene (MMP9), were still perturbed after diet reversion.Conclusion: Our findings highlight the potential of exploring diet-epigenome interactions for treatment of obesity.