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Introduction Diabetic retinopathy (DR), diabetic kidney disease (DKD) and distal symmetric polyneuropathy (DSPN) share common pathophysiology and pose an additive risk of early mortality.Research design and methods In adults with type 1 diabetes, 49 metabolites previously associated with either DR or DKD were assessed in relation to presence of DSPN. Metabolites overlapping in significance with presence of all three complications were assessed in relation to microvascular burden severity (additive number of complications—ie, presence of DKD±DR±DSPN) using linear regression models. Subsequently, the same metabolites were assessed with progression to endpoints: soft microvascular events (progression in albuminuria grade, ≥30% estimated glomerular filtration rate (eGFR) decline, or any progression in DR grade), hard microvascular events (progression to proliferative DR, chronic kidney failure, or ≥40% eGFR decline), and hard microvascular or macrovascular events (hard microvascular events, cardiovascular events (myocardial infarction, stroke, or arterial interventions), or cardiovascular mortality), using Cox models. All models were adjusted for sex, baseline age, diabetes duration, systolic blood pressure, HbA1c, body mass index, total cholesterol, smoking, and statin treatment.Results The full cohort investigated consisted of 487 participants. Mean (SD) follow-up was 4.8 (2.9, 5.7) years. Baseline biothesiometry was available in 202 participants, comprising the cross-sectional cohort. Eight metabolites were significantly associated with presence of DR, DKD, and DSPN, and six with additive microvascular burden severity. In the full cohort longitudinal analysis, higher levels of 3,4-dihydroxybutanoic acid (DHBA), 2,4-DHBA, ribonic acid, glycine, and ribitol were associated with development of events in both crude and adjusted models. Adding 3,4-DHBA, ribonic acid, and glycine to a traditional risk factor model improved the discrimination of hard microvascular events.Conclusions While prospective studies directly assessing the predictive ability of these markers are needed, our results strengthen the role of clinical metabolomics in relation to risk assessment of diabetic complications in chronic type 1 diabetes.

Abstract Background Diabetic cardiovascular autonomic neuropathy (CAN) and distal symmetrical polyneuropathy (DSPN) are severe diabetic complications. Collagen type VI (COL6) and III (COL3) have been associated with nerve function. We investigated if markers of COL6 formation (PRO-C6) and COL3 degradation (C3M) were associated with neuropathy in people with type 1 diabetes (T1D). Methods In a cross-sectional study including 300 people with T1D, serum and urine PRO-C6 and C3M were obtained. CAN was assessed by cardiovascular reflex tests: heart rate response to deep breathing (E/I ratio), to standing (30/15 ratio) and to the Valsalva maneuver (VM). Two or three pathological CARTs constituted CAN. DSPN was assessed by biothesiometry. Symmetrical vibration sensation threshold above 25 V constituted DSPN. Results Participants were (mean (SD)) 55.7 (9.3) years, 51% were males, diabetes duration was 40.0 (8.9) years, HbA1c was 63 (11 mmol/mol, (median (IQR)) serum PRO-C6 was 7.8 (6.2;11.0) ng/ml and C3M 8.3 (7.1;10.0) ng/ml. CAN and DSPN were diagnosed in 34% and 43% of participants, respectively. In models adjusted for relevant confounders a doubling of serum PRO-C6, was significantly associated with odds ratio > 2 for CAN and > 1 for DSPN, respectively. Significance was retained after additional adjustments for eGFR only for CAN. Higher serum C3M was associated with presence of CAN, but not after adjustment for eGFR. C3M was not associated with DSPN. Urine PRO-C6 analyses indicated similar associations. Conclusions Results show previously undescribed associations between markers of collagen turnover and risk of CAN and to a lesser degree DSPN in T1D.

Abstract Background Idiopathic non-clonal cytopenia (ICUS) and clonal cytopenia (CCUS) are common in the elderly population. While these entities have similar clinical presentations with peripheral blood cytopenia and less than 10% bone marrow dysplasia, their malignant potential is different and the biological relationship between these disorders and myeloid neoplasms such as myelodysplastic syndrome (MDS) is not fully understood. Aberrant DNA methylation has previously been described to play a vital role in MDS and acute myeloid leukemia (AML) pathogenesis. In addition, obesity confers a poorer prognosis in MDS with inferior overall survival and a higher rate of AML transformation. In this study, we measured DNA methylation of the promoter for the obesity-regulated gene LEP, encoding leptin, in hematopoietic cells from ICUS, CCUS and MDS patients and healthy controls. We investigated whether LEP promoter methylation is an early event in the development of myeloid neoplasms and whether it is associated with clinical outcome. Results We found that blood cells of patients with ICUS, CCUS and MDS all have a significantly hypermethylated LEP promoter compared to healthy controls and that LEP hypermethylation is associated with anemia, increased bone marrow blast percentage, and lower plasma leptin levels. MDS patients with a high LEP promoter methylation have a higher risk of progression, shorter progression-free survival, and inferior overall survival. Furthermore, LEP promoter methylation was an independent risk factor for the progression of MDS in a multivariate Cox regression analysis. Conclusion In conclusion, hypermethylation of the LEP promoter is an early and frequent event in myeloid neoplasms and is associated with a worse prognosis.

Abstract Background Species- and genetic diversity can change in parallel, resulting in a species-genetic diversity correlation (SGDC) and raising the question if the same drivers influence both biological levels of diversity. The SGDC can be either positive or negative, depending on whether the species diversity and the genetic diversity of the measured species respond in the same or opposite way to drivers. Using a traditional species diversity approach together with ultra-conserved elements and high throughput sequencing, we evaluated the SGDCs in benthic macrofauna communities in the Baltic Sea, a geologically young brackish water sea characterised by its steep salinity gradient and low species richness. Assessing SGDCs from six focal marine invertebrate species from different taxonomic groups and with differing life histories and ecological functions on both a spatial and temporal scale gives a more comprehensive insight into the community dynamics of this young ecosystem and the extrinsic factors that might drive the SGDCs. Results No significant correlations between species diversity and genetic diversity were found for any of the focal species. However, both negative and positive trends of SGDCs for the individual focal species were observed. When examining the environmental drivers, no common trends between the species were found, even when restricting the analysis to specific taxonomic classes. Additionally, there were no common environmental factors driving the diversity relationships for species sharing the same SGDC trend (positive or negative). Local population dynamics, together with the invasion history of the individual species and their unique adaptation to the distinctive environment of the Baltic Sea, are expected to be of major influence on the outcome of the SGDCs. Conclusions The present results highlight the importance of assessing SGDCs using multiple species, not just a single indicator species. This emphasises a need to pay attention to the ecology and life history of the focal species. This study also provides insight into the large differences in both patterns and drivers of genetic diversity, which is important when including genetic biodiversity in conservation plans. We conclude that the effects of environmental and biological factors and processes that affects diversity patterns at both the community and genetic levels are likely species dependent, even in an environment such as the Baltic Sea with strong environmental gradients.

In humans, methionine derived from dietary proteins is necessary for cellular homeostasis and regeneration of sulfur containing pathways, which produce inorganic sulfur species (ISS) along with essential organic sulfur compounds (OSC). In recent years, inorganic sulfur species have gained attention as key players in the crosstalk of human health and the gut microbiome. Endogenously, ISS includes hydrogen sulfide (H2S), sulfite (SO32−), thiosulfate (S2O32−), and sulfate (SO42−), which are produced by enzymes in the transsulfuration and sulfur oxidation pathways. Additionally, sulfate-reducing bacteria (SRB) in the gut lumen are notable H2S producers which can contribute to the ISS pools of the human host. In this review, we will focus on the systemic effects of sulfur in biological pathways, describe the contrasting mechanisms of sulfurylation versus phosphorylation on the hydroxyl of serine/threonine and tyrosine residues of proteins in post-translational modifications, and the role of the gut microbiome in human sulfur metabolism.

Abstract Background Cardiovascular disease remains the leading cause of mortality in individuals with diabetes and improved understanding of its pathophysiology is needed. We investigated the association of a large panel of metabolites and molecular lipid species with future cardiovascular events in type 1 diabetes. Methods The study included 669 individuals with type 1 diabetes. Non-targeted serum metabolomics and lipidomics analyses were performed using mass spectrometry. Data on cardiovascular events (cardiovascular mortality, coronary artery disease, stroke, and peripheral arterial interventions) were obtained from Danish Health registries and analyzed by Cox hazards models. Metabolites and molecular lipid species were analyzed in univariate models adjusted for false discovery rate (FDR). Metabolites and molecular lipid species fulfilling a pFDR

Abstract This work employs the spectral reconstruction approach of ref. [1] to determine an inclusive rate in the 1 + 1 dimensional O(3) non-linear σ-model, analogous to the QCD part of e + e − → hadrons. The Euclidean two-point correlation function of the conserved current j is computed using Monte Carlo lattice field theory simulations for a variety of spacetime volumes and lattice spacings. The spectral density of this correlator is related to the inclusive rate for j → X in which all final states produced by the external current are summed. The ill-posed inverse problem of determining the spectral density from the correlation function is made tractable through the determination of smeared spectral densities in which the desired density is convolved with a set of known smearing kernels of finite width ϵ. The smooth energy dependence of the underlying spectral density enables a controlled ϵ → 0 extrapolation in the inelastic region, yielding the real-time inclusive rate without reference to individual finite-volume energies or matrix elements. Systematic uncertainties due to cutoff effects and residual finite-volume effects are estimated and taken into account in the final error budget. After taking the continuum limit, the results are consistent with the known analytic rate to within the combined statistical and systematic errors. Above energies where 20-particle states contribute, the overall precision is sufficient to discern the four-particle contribution to the spectral density.

Background Coronary microvascular disease (CMD) may be part of a systemic small vessel disease that also manifests as neurological impairment and kidney disease. However, clinical evidence supporting a potential link is scarce. We assessed whether CMD is associated with an increased risk of small vessel disease in the kidney and brain. Methods and Results A retrospective multicenter (n=3) study of patients clinically referred to 82‐rubidium positron emission tomography myocardial perfusion imaging was conducted between January 2018 and August 2020. Exclusion criterion was reversible perfusion defects >5%. CMD was defined as myocardial flow reserve (MFR) ≤2. The primary outcome, microvascular event, was defined by hospital contact for chronic kidney disease, stroke, or dementia. Among 5122 patients, 51.7% were men, median age 69.0 [interquartile range, 60.0–75.0] years, 11.0% had left ventricular ejection fraction ≤40%, and 32.4% had MFR ≤2. MFR was associated with baseline estimated glomerular filtration rate after multivariable adjustment (β=0.04 [95% CI, 0.03–0.05]; P2 (11.6% versus 5.5%, P

BackgroundDiabetic kidney disease is a major cause of morbidity and mortality. Dysregulated turnover of collagen type III is associated with development of kidney fibrosis. We investigated whether a degradation product of collagen type III (C3M) was a risk marker for progression of chronic kidney disease (CKD), occurrence of cardiovascular disease (CVD), and mortality during follow up in people with type 2 diabetes (T2D) and microalbuminuria. Moreover, we investigated whether C3M was correlated with markers of inflammation and endothelial dysfunction at baseline.MethodsC3M was measured in serum (sC3M) and urine (uC3M) in 200 participants with T2D and microalbuminuria included in an observational, prospective study at Steno Diabetes Center Copenhagen in Denmark from 2007-2008. Baseline measurements included 12 markers of inflammation and endothelial dysfunction. The endpoints were CVD, mortality, and CKD progression (>30% decline in eGFR).ResultsMean (SD) age was 59 (9) years, eGFR 90 (17) ml/min/1.73m2 and median (IQR) urine albumin excretion rate 102 (39-229) mg/24-h. At baseline all markers for inflammation were positively correlated with sC3M (p≤0.034). Some, but not all, markers for endothelial dysfunction were correlated with C3M. Median follow-up ranged from 4.9 to 6.3 years. Higher sC3M was associated with CKD progression (with mortality as competing risk) with a hazard ratio (per doubling) of 2.98 (95% CI: 1.41-6.26; p = 0.004) adjusted for traditional risk factors. uC3M was not associated with CKD progression. Neither sC3M or uC3M were associated with risk of CVD or mortality.ConclusionsHigher sC3M was a risk factor for chronic kidney disease progression and was correlated with markers of inflammation.

Background Hypertension and diabetes cause chronic kidney disease (CKD) and diastolic left ventricular dysfunction (DVD) as forerunners of disability and death. Home blood pressure telemonitoring (HTM) and urinary peptidomic profiling (UPP) are technologies enabling prevention. Methods UPRIGHT-HTM (Urinary Proteomics Combined with Home Blood Pressure Telemonitoring for Health Care Reform [NCT04299529]) is an investigator-initiated 5-year clinical trial with patient-centred design, which will randomise 1148 patients to be recruited in Europe, sub-Saharan Africa and South America. During the whole study, HTM data will be collected and freely accessible for patients and caregivers. The UPP, measured at enrolment only, will be communicated early during follow-up to 50% of patients and their caregivers (intervention), but only at trial closure in 50% (control). The hypothesis is that early knowledge of the UPP risk profile will lead to more rigorous risk factor management and result in benefit. Eligible patients, aged 55–75 years old, are asymptomatic, but have ≥5 CKD- or DVD-related risk factors, preferably including hypertension, type-2 diabetes, or both. The primary endpoint is a composite of new-onset intermediate and hard cardiovascular and renal outcomes. Demonstrating that combining UPP with HTM is feasible in a multicultural context and defining the molecular signatures of early CKD and DVD are secondary endpoints. Expected outcomes The expected outcome is that application of UPP on top of HTM will be superior to HTM alone in the prevention of CKD and DVD and associated complications and that UPP allows shifting emphasis from treating to preventing disease, thereby empowering patients.

Abstract Anti-inflammatory effects of glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatment in T2D may contribute to the cardiovascular benefits observed with GLP-1 RAs in outcome studies. We investigated if the GLP-1 RA liraglutide exerts anti-inflammatory effects through modulation of inflammatory gene expression in peripheral blood mononuclear cells (PBMCs). From 54 participants of a double-blinded trial where individuals with type 2 diabetes (T2D) were randomized to liraglutide (1.8 mg/day) or placebo for 26 weeks, a sub-study was performed in which PBMCs were extracted from fresh blood at study start and at end-of-treatment. The expression of selected inflammatory genes in PBMCs were measured by quantitative real-time polymerase chain reaction (PCR). Moreover, the expression of the GLP-1 receptor (GLP1R) was examined in a subset (n = 40) of the PBMC samples. The human monocytic cell line THP-1 was used for in vitro GLP-1 exposure experiments. The expression of tumor necrosis factor-α (TNFA) (p = 0.004) and interleukin-1β (IL1B) was downregulated (p = 0.046) in the liraglutide-treated group (n = 31), and unchanged in the placebo group (n = 21, p ≥ 0.11), with no significant differences between the two groups (p ≥ 0.67). The expression of interferon-γ (IFNG) and cluster of differentiation 163 (CD163) were upregulated in both groups (p ≤ 0.006) with no differences between groups (p ≥ 0.47). C–C Motif Chemokine Ligand 5 (CCL5) was upregulated in the liraglutide-treated group (p = 0.002) and unchanged in the placebo group (p = 0.14), with no significant difference between groups (p = 0.36). Intercellular adhesion molecule 1 (ICAM1) was unchanged in both groups (p ≥ 0.43). GLP1R expression in the PBMCs was undetectable. In vitro experiments showed no effect of GLP-1 treatment on inflammatory gene expression in THP-1 cells. GLP1R expression in THP-1 cells was not detectable. In summary, we observed a discrete modulatory effect of liraglutide on the expression of inflammatory genes in PBMCs. The lack of evidence for GLP1R expression in PBMCs and THP-1 cells suggests that possible effects of liraglutide on the PBMCs’ gene expression are most likely indirect. Further investigations are needed to establish the anti-inflammatory potential of GLP-1 RAs.

Climate services are playing an increasing role in efforts to build the resilience of African agriculture to a variable and changing climate. Efforts to improve the contribution of climate services to agriculture must contend with substantial differences in national agricultural climate services landscapes. Context-specific factors influence the effectiveness, scalability and sustainability of agricultural climate service, but in ways that are challenging to anticipate. In the context of six countries (Ethiopia, Ghana, Kenya, Mali, Senegal, Zambia), this paper addresses the need to consider differing national contexts when developing strategies to make agricultural climate services in sub-Saharan Africa more effective, scalable and sustainable. Based on authors' collective firsthand knowledge and a review of information from secondary sources, we identify key strengths and weaknesses of climate services relative to agriculture sector needs in the focus countries; and assess factors that have contributed to those differences. Focus countries differ substantially in areas such as the degree of public support, alignment of services with agricultural needs, service delivery channels, degree of decentralization, and public—private-sector balance. These differences have been driven largely by differing national policies, delivery capacity and external actors, but not by responsiveness to agricultural sector demands. Building on the analyses of country differences and their drivers, we then discuss four key opportunities to further strengthen the contribution of climate services to agriculture: (a) leveraging farmer demand to drive scaling and sustainability; (b) exploiting digital innovation within a diverse delivery strategy; (c) balancing public and private sector comparative advantage; and (d) embedding climate services in agricultural extension. For each of these opportunities, we consider how different country contexts can impact the potential effectiveness, scalability and sustainability of services; and how efforts to strengthen those services can account for context-specific drivers to manage the tradeoffs among effectiveness, scalability and sustainability.

We describe an innovative forecast presentation that aims to overcome obstacles to using seasonal climate forecasts for decision making, trace factors that influenced how seasonal forecast conventions have evolved, and describe a workshop process for training and supporting farmers in sub-Saharan Africa to use probabilistic seasonal forecasts. Mainstreaming seasonal climate forecasts through Regional Climate Outlook Forums (RCOFs) was an important milestone in the development of climate services. Most RCOFs and National Meteorological Services (NMS) adopted a subjective process to arrive at a consensus among different sources of prediction, and express the forecast as probabilities that rainfall in the upcoming season will fall in “below-normal,” “normal” or “above-normal” historical tercile categories. The Flexible Forecast is an online presentation that rectifies the main criticisms of the tercile convention by presenting downscaled forecasts as full probability distributions in probability-of-exceedance format along with the historical climate distribution. A map view provides seasonal forecast quantities, anomalies, or probabilities of experiencing above or below a user-selected threshold in amount or percentile, at the spatial resolution of the underlying gridded data (typically 4 to 5 km). We discuss factors that contributed to the persistence of the tercile convention, and milestones that paved the way to adopting seasonal forecast methods and formats that better align with user needs. The experience of adopting the new flexible forecast presentation regionally and at a national level in Eastern Africa illustrates the challenges and how they can be overcome. We also describe a seasonal forecast training and planning workshop process that has been piloted with smallholder farmers in several African countries. Beginning with participants' collective memory of past seasonal climate variations, the process leads them incrementally to understand the forecast presented in probability-of-exceedance format, and apply it to their seasonal planning decisions.

Considerable progress has been made in establishing climate service capabilities over the last few decades, but the gap between the resulting services and national needs remains large. Using climate services for agriculture in Bangladesh as a case study example, we highlight mismatches between local needs on the one hand, and international initiatives that have focused largely on prediction on the other, and we make suggestions for addressing such mismatches in similar settings. To achieve greater benefit at the national level, there should be a stronger focus on addressing important preliminaries for building services. These preliminaries include the identification of priorities, the definition of responsibilities and expectations, the development of climate services skills, and the construction of a high-quality and easily usable national climate record. Once appropriate institutional, human resources and data infrastructure are in place, the implementation of a climate monitoring and watch system would form a more logical basis for initial climate service implementation than attempting to promote sub-seasonal to seasonal climate forecasting, especially when and where the inherent predictability is limited at best. When and where forecasting at these scales is viable, efforts should focus on defining and predicting high-impact events important for decision making, rather than on simple seasonal aggregates that often correlate poorly with outcomes. Some such forecasts may be more skillful than the 3- to 4-month seasonal aggregates that have become the internationally adopted standard. By establishing a firm foundation for climate services within National Meteorological Services, there is a greater chance that individual climate service development initiatives will be sustainable after their respective project lifetimes.

Abstract Glucagon-like peptide 1 receptor agonists have shown cardioprotective effects which have been suggested to be mediated through inhibition of oxidative stress. We investigated the effect of treatment with a glucagon-like peptide 1 receptor agonist (liraglutide) on oxidative stress measured as urinary nucleic acid oxidation in persons with type 2 diabetes. Post-hoc analysis of two independent, randomised, placebo-controlled and double-blinded clinical trials. In a cross-over study where persons with type 2 diabetes and microalbuminuria (LIRALBU, n = 32) received liraglutide (1.8 mg/day) or placebo for 12 weeks in random order, separated by 4 weeks of wash-out. In a parallel-grouped study where obese persons with type 2 diabetes (SAFEGUARD, n = 56) received liraglutide (1.8 mg/day), sitagliptin (100 mg/day) or placebo for 12 weeks. Endpoints were changes in the urinary markers of DNA oxidation (8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG)) and RNA oxidation [8-oxo-7,8-dihydroguanosine (8-oxoGuo)]. In LIRALBU, we observed no significant differences between treatment periods in urinary excretion of 8-oxodG [0.028 (standard error (SE): 0.17] nmol/mmol creatinine, p = 0.87) or of 8-oxoGuo [0.12 (0.12) nmol/mmol creatinine, p = 0.31]. In SAFEGUARD, excretion of 8-oxodG was not changed in the liraglutide group [2.8 (− 8.51; 15.49) %, p = 0.62] but a significant decline was demonstrated in the placebo group [12.6 (− 21.3; 3.1) %, p = 0.02], resulting in a relative increase in the liraglutide group compared to placebo (0.16 nmol/mmol creatinine, SE 0.07, p = 0.02). Treatment with sitagliptin compared to placebo demonstrated no significant difference (0.07 (0.07) nmol/mmol creatinine, p = 0.34). Nor were any significant differences for urinary excretion of 8-oxoGuo liraglutide vs placebo [0.09 (SE: 0.07) nmol/mmol creatinine, p = 0.19] or sitagliptin vs placebo [0.07 (SE: 0.07) nmol/mmol creatinine, p = 0.35] observed. This post-hoc analysis could not demonstrate a beneficial effect of 12 weeks of treatment with liraglutide or sitagliptin on oxidatively generated modifications of nucleic acid in persons with type 2 diabetes.

IntroductionDiabetic cardiovascular autonomic neuropathy (CAN) is associated with increased mortality and morbidity. To explore metabolic mechanisms associated with CAN we investigated associations between serum metabolites and CAN in persons with type 1 diabetes (T1D).Materials and MethodsCardiovascular reflex tests (CARTs) (heart rate response to: deep breathing; lying-to-standing test; and the Valsalva maneuver) were used to diagnose CAN in 302 persons with T1D. More than one pathological CARTs defined the CAN diagnosis. Serum metabolomics and lipidomic profiles were analyzed with two complementary non-targeted mass-spectrometry methods. Cross-sectional associations between metabolites and CAN were assessed by linear regression models adjusted for relevant confounders.ResultsParticipants were median (IQR) aged 55(49, 63) years, 48% males with diabetes duration 39(32, 47) years, HbA1c 63(55,69) mmol/mol and 34% had CAN. A total of 75 metabolites and 106 lipids were analyzed. In crude models, the CAN diagnosis was associated with higher levels of hydroxy fatty acids (2,4- and 3,4-dihydroxybutanoic acids, 4−deoxytetronic acid), creatinine, sugar derivates (ribitol, ribonic acid, myo-inositol), citric acid, glycerol, phenols, phosphatidylcholines and lower levels of free fatty acids and the amino acid methionine (p

Background: Elevated soluble urokinase plasminogen activator receptor (suPAR) is highly associated with increased risk of diabetic complications. Dapagliflozin is a drug inhibiting the sodium-glucose co-transporter 2 in the kidney to decrease blood glucose, while also decreasing risk of kidney disease, heart failure, and death. Therefore, we have investigated suPAR as a monitor for treatment effect with dapagliflozin in diabetes.Methods: suPAR was measured in two double-blinded randomized clinical cross-over trials. The first trial investigated the effect of a single dose dapagliflozin 50 mg or placebo 12 h after intake, in individuals with type 1 diabetes and albuminuria. The second trial investigated the effect of a daily dose dapagliflozin 10 mg or placebo for 12 weeks, in individuals with type 2 diabetes and albuminuria. suPAR was measured in serum samples taken, in the acute trial, after treatment with dapagliflozin and placebo, and in the long-term trial, before and after treatment with dapagliflozin and placebo. Effect of dapagliflozin on suPAR levels were assessed using paired t-test.Results: 15 participants completed the acute trial and 35 completed the long-term trial. Mean difference in suPAR between dapagliflozin and placebo in the acute trial after 12 h was 0.70 ng/ml (95% CI: 0.66; 1.33, p = 0.49). In the long-term trial the mean difference was 0.06 ng/ml (95% CI -0.15; 0.27, p = 0.57).Conclusion: Based on our findings we conclude that suPAR is not a feasible marker to monitor the effect of treatment with dapagliflozin. Thus, a further search of suitable markers must continue.

Abstract Background Mid-regional pro-atrial natriuretic peptide (MR-proANP) is a useful biomarker in outpatients with type 2 diabetes (T2D) to diagnose heart failure (HF). Elevated B-type natriuretic peptides are included in the definition of HF with preserved ejection fraction (HFpEF) but little is known about the prognostic value of including A-type natriuretic peptides (MR-proANP) in the evaluation of patients with T2D. Methods We prospectively evaluated the risk of incident cardiovascular (CV) events in outpatients with T2D (n = 806, mean ± standard deviation age 64 ± 10 years, 65% male, median [interquartile range] duration of diabetes 12 [6–17] years, 17.5% with symptomatic HFpEF) according to MR-proANP levels and stratified according to HF-status including further stratification according to a prespecified cut-off level of MR-proANP. Results A total of 126 CV events occurred (median follow-up 4.8 [4.1–5.3] years). An elevated MR-proANP, with a cut-off of 60 pmol/l or as a continuous variable, was associated with incident CV events (p

A new Sentinel-1 image-based sea ice classification algorithm using a machine-learning-based model trained in a semi-automated manner is proposed to support daily ice charting. Previous studies mostly rely on manual work in selecting training and validation data. We show that the readily available ice charts from the operational ice services can reduce the amount of manual work in preparation of large amounts of training/testing data. Furthermore, they can feed highly reliable data to the trainer by indirectly exploiting the best ability of the sea ice experts working at the operational ice services. The proposed scheme has two phases: training and operational. Both phases start from the removal of thermal, scalloping, and textural noise from Sentinel-1 data and calculation of grey level co-occurrence matrix and Haralick texture features in a sliding window. In the training phase, the weekly ice charts are reprojected into the SAR image geometry. A random forest classifier is trained with the texture features on input and labels from the rasterized ice charts on output. Then, the trained classifier is directly applied to the texture features from Sentinel-1 images operationally. Test results from the two datasets spanning winter (January–March) and summer (June–August) seasons acquired over the Fram Strait and the Barents Sea showed that the classifier is capable of retrieving three generalized cover types (open water, mixed first-year ice, old ice) with overall accuracies of 87 % and 67 % in winter and summer seasons, respectively. For the summer season, the classifier failed in distinguishing mixed first-year ice from old ice with accuracy of only 12 %; however, it performed rather like an ice–water discriminator with high accuracy of 98 % as the misclassification between the mixed first-year ice and old ice was between them. The accuracy for five cover types (open water, new ice, young ice, first-year ice, old ice) in the winter season was 60 %. The errors are attributed both to incorrect manual classification on the ice charts and to the semi-automated algorithm. Finally, we demonstrate the potential for near-real-time service of the ice map using daily mosaicked Sentinel-1 images.

Abstract Background Cardiac adipose tissue may have local paracrine effects on epicardial arteries and the underlying myocardium, promoting calcification and affecting myocardial microcirculation. We explored whether the total amount of cardiac adipose tissue was associated with coronary artery calcium score (CAC) and myocardial flow reserve in persons with type 1 or type 2 diabetes and healthy controls. Methods We studied three groups: (1) 30 controls, (2) 60 persons with type 1 diabetes and (3) 60 persons with type 2 diabetes. The three groups were matched for sex and age. The three groups derived from retrospective analysis of two clinical studies. All underwent cardiac 82Rb positron emission tomography/computed tomography (PET/CT) scanning. Cardiac adipose tissue volume (the sum of epicardial and pericardial fat), CAC, and myocardial flow reserve (ratio of pharmacological stress flow and rest flow) were evaluated using semiautomatic software. We applied linear regression to assess the association between cardiac adipose tissue, CAC and myocardial flow reserve. Results Mean (SD) cardiac adipose tissue volume was 99 (61) mL in the control group, 106 (78) mL in the type 1 diabetes group and 228 (97) mL in the type 2 diabetes group. Cardiac adipose tissue was positively associated with body mass index in all three groups (p ≤ 0.02). In the controls, cardiac adipose tissue was positively associated with CAC score (p = 0.008) and negatively associated with myocardial flow reserve (p = 0.005). However, cardiac adipose tissue was not associated with CAC or myocardial flow reserve in the groups including persons with type 1 or type 2 diabetes (p ≥ 0.50). Conclusions In contrast to what was found in healthy controls, we could not establish a relation between cardiac adipose tissue and coronary calcification or myocardial microvascular function in person with type 1 or type 2 diabetes. The role of cardiac adipose tissue in cardiovascular disease in diabetes remains unclear.

Despite recent and mostly global efforts to promote climate services in developing countries, Africa still faces significant limitations in its institutional infrastructure and capacity to develop, access, and use decision-relevant climate data and information products at multiple levels of governance. The Enhancing National Climate Services (ENACTS) initiative, led by Columbia University's International Research Institute for Climate and Society (IRI), strives to overcome these challenges by co-developing tailored, actionable, and decision-relevant climate information with and for a wide variety of users at the local, regional, and national levels. This is accomplished through an approach emphasizing direct engagement with the National Meteorological and Hydrological Services (NMHS) and users of their products, and investments in both technological and human capacities for improving the availability, access, and use of quality climate data and information products at decision-relevant spatial and temporal scales. In doing so, the ENACTS approach has been shown to be an effective means of transforming decision-making surrounding vulnerabilities and risks at multiple scales, through implementation in over a dozen countries at national level as well as at the regional levels in both East and West Africa. Through the ENACTS approach, challenges to availability of climate data are alleviated by combining quality-controlled station observations with global proxies to generate spatially and temporally complete climate datasets. Access to climate information is enhanced by developing an online mapping service that provides a user-friendly interface for analyzing and visualizing climate information products. Use of the generated climate data and the derived information products is promoted through raising awareness in relevant communities, training users, and co-production processes.

BackgroundThe mechanisms linking cardiovascular autonomic neuropathy, diabetic kidney disease and cardiovascular mortality in type 2 diabetes are widely unknown. We investigated the relationship between baseline cardiovascular autonomic function and changes in kidney and myocardial function over six years in patients with type 2 diabetes and healthy controls.MethodsPost-hoc analysis of a cohort study in 24 patients with type 2 diabetes and 18 healthy controls. Baseline determinants were cardiovascular autonomic reflex tests (heart rate response to: standing (30:15); deep breathing (E:I); and the Valsalva test) and time- and frequency-domain heart rate variability indices. Outcomes were changes in estimated glomerular filtration rate (eGFR), albuminuria, myocardial flow reserve (MFR) measured by cardiac 82Rb Positron emission tomography computed tomography (PET/CT), and coronary artery calcium score (CACS).ResultsMean age at inclusion was 61 ± 10 years and 36% were female. Mean follow up time was 6 ± 0 years. A lower response in heart rate to the Valsalva test (corresponding to weaker autonomic function) was associated with a larger decline in eGFR (p=0.04), but not significantly after adjustment for sex, baseline age, smoking status, systolic blood pressure, heart rate, HbA1c, body mass index and baseline eGFR (p=0.12). A higher baseline response in heart rate to standing (30:15) was associated with a larger decline in myocardial flow reserve in the unadjusted analysis (p=0.02) and after adjustment (p=0.02). A higher response in heart rate to the Valsalva maneuver was associated with a larger increase in CACS (p = 0.02), but the association became insignificant after adjustment (p = 0.16).ConclusionA lower response in heart rate to the Valsalva test was associated with a larger decline in kidney function, indicating that autonomic dysfunction may predict future loss of kidney function. However, we did not find any association between lower values in cardiovascular autonomic function at baseline and a worsening in albuminuria, myocardial function, or atherosclerotic burden.

BackgroundQuantification of coronary artery inflammation and atherosclerosis remains a challenge in high-risk individuals. In this study we sought to investigate if the glucagon like peptide-1 receptor agonist liraglutide has a direct anti-inflammatory effect in the coronary arteries using positron emission tomography (PET) with a radioactive tracer targeting activated macrophages in the vessel-wall.MethodsThirty randomly selected participants with type 2 diabetes from the placebo-controlled trial LIRAFLAME were enrolled in this sub-study. Participants were, prior to enrollment in this sub-study, randomized to either treatment with daily liraglutide (n=15) or placebo (n=15). Both groups underwent a combined [64Cu]Cu-DOTATATE positron emission tomography and computed tomography scan of the heart at baseline and after 26 weeks of treatment. Coronary artery uptake of [64Cu]Cu-DOTATATE were measured as maximum standardized uptake values (SUVmax); and means of the maximum values (mSUVmax), both values were calculated at the level of each participant and each individual coronary-segment.ResultsSUVmax and mSUVmax values decreased significantly in the liraglutide group both at the participant level (SUVmax: p=0.013; mSUVmax: p=0.004) and at the coronary-segment level (SUVmax: p=0.001; mSUVmax: p

Summary: Xia-Gibbs syndrome (XGS; MIM: 615829) is a phenotypically heterogeneous neurodevelopmental disorder (NDD) caused by newly arising mutations in the AT-Hook DNA-Binding Motif-Containing 1 (AHDC1) gene that are predicted to lead to truncated AHDC1 protein synthesis. More than 270 individuals have been diagnosed with XGS worldwide. Despite the absence of an independent assay for AHDC1 protein function to corroborate potential functional consequences of rare variant genetic findings, there are also reports of individuals with XGS-like trait manifestations who have de novo missense AHDC1 mutations and who have been provided a molecular diagnosis of the disorder. To investigate a potential contribution of missense mutations to XGS, we mapped the missense mutations from 10 such individuals to the AHDC1 conserved protein domain structure and detailed the observed phenotypes. Five newly identified individuals were ascertained from a local XGS Registry, and an additional five were taken from external reports or databases, including one publication. Where clinical data were available, individuals with missense mutations all displayed phenotypes consistent with those observed in individuals with AHDC1 truncating mutations, including delayed motor milestones, intellectual disability (ID), hypotonia, and speech delay. A subset of the 10 reported missense mutations cluster in two regions of the AHDC1 protein with known conserved domains, likely representing functional motifs. Variants outside the clustered regions score lower for computational prediction of their likely damaging effects. Overall, de novo missense variants in AHDC1 are likely diagnostic of XGS when in silico analysis of their position relative to conserved regions is considered together with disease trait manifestations.

Breast cancer (BC), the most common malignancy in women, results from significant alterations in genetic and epigenetic mechanisms that alter multiple signaling pathways in growth and malignant progression, leading to limited long-term survival. Current studies with numerous drug therapies have shown that BC is a complex disease with tumor heterogeneity, rapidity, and dynamics of the tumor microenvironment that result in resistance to existing therapy. Targeting a single cell-signaling pathway is unlikely to treat or prevent BC. Curcumin (a natural yellow pigment), the principal ingredient in the spice turmeric, is well-documented for its diverse pharmacological properties including anti-cancer activity. However, its clinical application has been limited because of its low solubility, stability, and bioavailability. To overcome the limitation of curcumin, several modified curcumin conjugates and curcumin mimics were developed and studied for their anti-cancer properties. In this review, we have focused on the application of curcumin mimics and their conjugates for breast cancer.

The management of heart failure patients via the implantation of cardiac pacemakers has become a well-known therapy. However, the complications associated with traditional cardiac pacemakers are usually related to finite-battery life, transvenous pacing leads, and subcutaneous device pocket. In this paper, we propose a wearable RF-powered leadless pacing system, which can be implanted directly inside the heart and powered via RF energy, without any batteries or pacing leads. More specifically, we have realized a prototype rectenna-based leadless pacemaker (LP), the implant, which consists of an implantable rectenna, charging and pacing circuits, as well as the pacing electrodes. In addition, a wearable transmit-antenna array was designed, developed, and fabricated for RF energy transmission into the body. In an acute animal study, using ovine models, the proposed LP was implanted at the left ventricular apex by thoracotomy. Using the prototype wearable transmit-antenna array, the prototype LP was powered wirelessly and as a result, leadless pacing was successfully demonstrated in the in vivo ECG results. Besides measuring the efficiency of the rectenna, the computations of specific absorption rate (SAR) are presented and found to be under the IEEE recommended limits. We conclude that a wearable RF-powered leadless pacing system is realizable with the SAR under the safe levels. Thus, the proposed leadless pacing method has the potential to be significantly safer as it completely eliminates the battery, leads, and device pocket and all the associated complications.

Objectives To investigate if inflammation detected by MRI or ultrasound at rheumatoid arthritis (RA) onset is predictive of erosive progression or poor response to methotrexate monotherapy, and to investigate if subclinical inflammation in remission is predictive of future treatment escalation or erosive progression.Methods In a 2-year study, 218 patients with disease-modifying antirheumatic drug-naïve early RA were treated by a tight-control treat-to-target strategy corresponding to current recommendations. MRI and ultrasound were performed at regular intervals. Baseline imaging-based inflammation measures were analysed as predictors for early methotrexate failure and erosive progression using univariate and multivariate regression adjusted for clinical, laboratory and radiographic measures. In patients in remission after 1 year, imaging measures were analysed as predictors of treatment escalation and erosive progression during the second year. The added value of imaging in prediction models was assessed using receiver operating characteristic analyses.Results Baseline MRI inflammation was associated with MRI erosive progression and ultrasound with radiographic erosive progression. No imaging inflammation measure was associated with early methotrexate failure. Imaging inflammation was present in a majority of patients in clinical remission. Tenosynovitis was associated with treatment escalation, and synovitis and tenosynovitis with MRI/radiographic erosive progression during the second year. Imaging information did not improve prediction models for any of the outcomes.Conclusions Imaging-detected inflammation, both at diagnosis and in remission, is associated with elements of future disease development. However, the lack of a significant effect on prediction models indicates limited value of systematic MRI and ultrasound in management of early RA.

Introduction We investigated the association between cardiovascular autonomic neuropathy (CAN) and decline in kidney function in type 1 diabetes.Research design and methods We included 329 persons with type 1 diabetes. CAN was assessed by cardiovascular reflex tests (CARTs): heart rate response to deep breathing (E/I ratio), to standing (30/15 ratio) and to the Valsalva maneuvre. Two or more pathological CARTs defined CAN diagnosis. Outcomes were yearly change in albuminuria or yearly change in estimated glomerular filtration rate (eGFR). An endpoint of eGFR decline >30%, development of end-stage kidney disease (ESKD) or death was examined.Associations were assessed by linear and Cox regression.Results Participants were aged 55.2 (9.4) years, 52% were male, with a diabetes duration of 40.1 (8.9) years, HbA1c of 7.9% (62.5 mmol/mol), eGFR 77.9 (27.7) mL/min/1.73 m2, urinary albumin excretion rate of 14.5 (7–58) mg/24 hours, and 31% were diagnosed with CAN.CAN was associated with a 7.8% higher albuminuria increase per year (95% CI: 0.50% to 15.63%, p=0.036) versus no CAN. The endpoint of ESKD, all-cause mortality and ≥30% decline in eGFR was associated with CAN (HR=2.497, p=0.0254).Conclusion CAN and sympathetic dysfunction were associated with increase in albuminuria in individuals with type 1 diabetes suggesting its role as a potential marker of diabetic kidney disease progression.

Summary: De novo germline variation in POLR2A was recently reported to associate with a neurodevelopmental disorder. We report twelve individuals harboring putatively pathogenic de novo or inherited variants in POLR2A, detail their phenotypes, and map all known variants to the domain structure of POLR2A and crystal structure of RNA polymerase II. Affected individuals were ascertained from a local data lake, pediatric genetics clinic, and an online community of families of affected individuals. These include six affected by de novo missense variants (including one previously reported individual), four clinical laboratory samples affected by missense variation with unknown inheritance—with yeast functional assays further supporting altered function—one affected by a de novo in-frame deletion, and one affected by a C-terminal frameshift variant inherited from a largely asymptomatic mother. Recurrently observed phenotypes include ataxia, joint hypermobility, short stature, skin abnormalities, congenital cardiac abnormalities, immune system abnormalities, hip dysplasia, and short Achilles tendons. We report a significantly higher occurrence of epilepsy (8/12, 66.7%) than previously reported (3/15, 20%) (p value = 0.014196; chi-square test) and a lower occurrence of hypotonia (8/12, 66.7%) than previously reported (14/15, 93.3%) (p value = 0.076309). POLR2A-related developmental disorders likely represent a spectrum of related, multi-systemic developmental disorders, driven by distinct mechanisms, converging at a single locus.

Introduction Workplace social capital (WSC) has been shown to affect employees’ well-being and health, yet it is not clear how public managers can create WSC and which forms of WSC are most important. This study is the first prospective cohort study to examine the relationship between management behaviour, WSC, well-being and sickness absence. It uses a validated and detailed scale on WSC, which can distinguish between bonding, bridging, linking and organisational WSC over time. The study thereby provides rich data giving a much-needed detailed image of how WSC impacts on public employees’ well-being and health. Additionally, the study pays special attention to the fact that these relationships can be different for different types of employees and therefore tests a set of relevant employee and context-related variables.Methods and analysis Project preparations in terms of agreements and data preparation of existing data started in 2019. This prospective cohort study considers and collects organisational data from 2016 to 2025. Annual employee surveys of more than 8000 employees (in a large Danish municipality) will be combined with register data in all years. This generates a unique cohort of public employees in different professions that are traceable over several years. The annual surveys include information on the management behaviour, WSC and employee outcomes. Fine-grained information on sickness absences will be matched for all employees and years under study. Moreover, confounders and the nested nature of the data will be considered.Ethics and dissemination Approval has been obtained from The Regional Committee on Health Research Ethics from Southern Denmark and from the University of Southern Denmark. The results will be presented at conferences and published in international peer-reviewed journals and in a practice-oriented monography targeted at public managers. The result will furthermore be disseminated to the involved employees through seminars and workshops in the participating organisations.

Sensing of signals from biological processes, such as action potential propagation in nerves, are essential for clinical diagnosis and basic understanding of physiology. Sensing can be performed electrically by placing sensor probes near or inside a living specimen or dissected tissue using well-established electrophysiology techniques. However, these electrical probe techniques have poor spatial resolution and cannot easily access tissue deep within a living subject, in particular within the brain. An alternative approach is to detect the magnetic field induced by the passage of the electrical signal, giving the equivalent readout without direct electrical contact. Such measurements are performed today using bulky and expensive superconducting sensors with poor spatial resolution. An alternative is to use nitrogen vacancy (NV) centers in diamond that promise biocompatibilty and high sensitivity without cryogenic cooling. In this work we present advances in biomagnetometry using NV centers, demonstrating magnetic field sensitivity of ~100 pT/Hz in the DC/low frequency range using a setup designed for biological measurements. Biocompatibility of the setup with a living sample (mouse brain slice) is studied and optimized, and we show work toward sensitivity improvements using a pulsed magnetometry scheme. In addition to the bulk magnetometry study, systematic artifacts in NV-ensemble widefield fluorescence imaging are investigated.

Background The southern California biodiversity hotspot has had a complex geological history, with both plate tectonic forces and sea level changes repeatedly reconfiguring the region, and likely driving both lineage splittings and extinctions. Here we investigate patterns of genetic divergence in two species of slender salamanders (Plethodontidae: Batrachoseps) in this region. The complex geological history in combination with several organismal traits led us to predict that these species harbor multiple ancient mitochondrial lineages endemic to southern California. These species belong to a clade characterized by fine-scale mitochondrial structure, which has been shown to track ancient splits. Both focal species, Batrachoseps major and B. nigriventris, are relatively widely distributed in southern California, and estimated to have persisted there across millions of years. Recently several extralimital populations of Batrachoseps were found in the San Joaquin Valley of California, a former desert area that has been extensively modified for agriculture. The origins of these populations are unknown, but based on morphology, they are hypothesized to result from human-mediated introductions of B. major. Methods We sequenced the mitochondrial gene cytochrome b from a geographically comprehensive sampling of the mitochondrial lineages of B. major and B. nigriventris that are endemic to southern California. We used phylogenetic analyses to characterize phylogeographic structure and identify mitochondrial contact zones. We also included the San Joaquin Valley samples to test whether they resulted from introductions. We used a bootstrap resampling approach to compare the strength of isolation-by-distance in both Batrachoseps species and four other salamander species with which they co-occur in southern California. Results The northern lineage of B. major harbors at least eight deeply differentiated, geographically cohesive mitochondrial subclades. We identify geographic contact between many of these mtDNA lineages and some biogeographic features that are concordant with lineage boundaries. Batrachoseps nigriventris also has multiple deeply differentiated clades within the region. Comparative analyses highlight the smaller spatial scales over which mitochondrial divergence accumulates in Batrachoseps relative to most other salamander species in southern California. The extralimital populations of Batrachoseps from the San Joaquin Valley are assigned to B. major and are shown to result from at least two independent introductions from different source populations. We also suggest that B. major on Catalina Island, where it is considered native, may be the result of an introduction. Some of the same traits that facilitate the build-up of deep phylogeographic structure in Batrachoseps likely also contribute to its propensity for introductions, and we anticipate that additional introduced populations will be discovered.

Background: Guidelines on the required number of ambulatory blood pressure (ABP) readings focus on individual patients. Clinical researchers often face the dilemma of applying recommendations and discarding potentially valuable information or accepting fewer readings. Methods: Starting from ABP recordings with ≥30/≥10 awake/asleep readings in 4277 participants enrolled in eight population studies in the International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcomes (IDACO), we randomly selected a certain number of readings (from 30 to 1 awake and 10 to 1 asleep readings) at a time over 1000 bootstraps at each step. We evaluated: (i) concordance of the ABP level; (ii) consistency of the cross-classification based on office blood pressure and ABP; and (iii) accuracy in predicting cardiovascular complications. For each criterion, we fitted a regression line joining data points relating outcome to the number of readings covering the ranges of 30-20/10-7 for awake/asleep readings. Results: Reducing readings widened the SD of the systolic/diastolic differences between full (reference) and selected recordings from 1.7/1.2 (30 readings) to 14.3/10.3 mm Hg (single reading) during wakefulness, and from 1.9/1.4 to 10.3/7.7 mm Hg during sleep; lowered the κ statistic from 0.94 to 0.63, and decreased the hazard ratio associated with 10/5 mm Hg increments in systolic/diastolic ABP from 1.21/1.14 to 1.06/1.04 during wakefulness and from 1.26/1.17 to 1.14/1.08 during sleep. The first data points falling off these regression lines during wakefulness/sleep corresponded to 8/3 and 8/4 readings for criteria (i) and (iii) and to 5 awake readings for criterion (ii). Conclusions: 24-h ambulatory recordings with ≥8/≥4 awake/asleep readings yielded ABP levels similar to recordings including the guideline-recommended ≥20/≥7 readings. These criteria save valuable data in a research setting, but are not applicable to clinical practice.