Reduced dose direct oral anticoagulants compared with warfarin with high time in therapeutic range in nonvalvular atrial fibrillation.

Direct oral anticoagulants (DOACs) used in nonvalvular atrial fibrillation (NVAF) are dose-reduced in elderly and patients with impaired renal function. Only reduced dose dabigatran is concluded as having similar stroke risk reduction and lower risk of major bleeding than warfarin in the pivotal studies. In clinical practice, reduced dose is prescribed more often than expected making this an important issue. The objective of this study was to compare effectiveness and safety between reduced dose DOACs and high TTR warfarin treatment (TTR ≥ 70%) in NVAF. A Swedish anticoagulation registry was used in identifying eligible patients from July 2011 to December 2017. The study cohort consisted of 40,564 patients with newly initiated DOAC (apixaban, dabigatran, or rivaroxaban) (11,083 patients) or warfarin treatment (29,481 patients) after exclusion of 374,135 patients due to not being warfarin or DOAC naïve, not being prescribed reduced dose, having previous mechanical heart valve (MHV), or being under 18 years old. The median durations of follow up were 365, 419, 432 and 473 days for apixaban, dabigatran, rivaroxaban and warfarin, respectively. Warfarin TTR identified from Auricula was 70.0%. Endpoints (stroke and major bleeding) and baseline characteristics were collected from hospital administrative registers using ICD-10 codes. Cohorts were compared using weighted adjusted Cox regression after full optimal matching based on propensity scores. DOACs are associated with lower risk of major bleeding (HR with 95% CI) 0.85 (0.78-0.93), intracranial bleeding HR 0.64 (0.51-0.80), hemorrhagic stroke HR 0.68 (0.50-0.92), gastrointestinal bleeding HR 0.81 (0.69-0.96) and all-cause stroke HR 0.87 (0.76-0.99), than warfarin. Apixaban and dabigatran are associated with lower risk of major bleeding, HR 0.70 (0.63-0.78) and HR 0.80 (0.69-0.94), and rivaroxaban is associated with lower risk of ischemic stroke, HR 0.73 (0.59-0.96), with higher major bleeding risk, HR 1.31 (1.15-1.48), compared to warfarin. Apixaban is associated with higher all-cause mortality compared to warfarin, HR 1.12 (1.03-1.21). DOACs are associated with lower risk of major bleeding and all-cause stroke, than high quality warfarin treatment, with exception of rivaroxaban that carried higher risk of major bleeding and lower risk of stroke or systemic embolism. In this large observational registry-based NVAF cohort, DOACs are preferred treatment in patients with indication for DOAC dose reduction, even in a high TTR setting.

A high-content, in vitro cardiac fibrosis assay for high-throughput, phenotypic identification of compounds with anti-fibrotic activity.

A key feature in the pathogenesis of heart failure is cardiac fibrosis, but effective treatments that specifically target cardiac fibrosis are currently not available. A major impediment to progress has been the lack of reliable in vitro models with sufficient throughput to screen for activity against cardiac fibrosis. Here, we established cell culture conditions in micro-well format that support extracellular deposition of mature collagen from primary human cardiac fibroblasts - a hallmark of cardiac fibrosis. Based on robust biochemical characterization we developed a high-content phenotypic screening platform, that allows for high-throughput identification of compounds with activity against cardiac fibrosis. Our platform correctly identifies compounds acting on known cardiac fibrosis pathways. Moreover, it can detect anti-fibrotic activity for compounds acting on targets that have not previously been reported in in vitro cardiac fibrosis assays. Taken together, our experimental approach provides a powerful platform for high-throughput screening of anti-fibrotic compounds as well as discovery of novel targets to develop new therapeutic strategies for heart failure.

Effects of Bi incorporation on recombination processes in wurtzite GaBiAs nanowires.

The effects of Bi incorporation on the recombination process in wurtzite (WZ) GaBiAs nanowires are studied by employing micro-photoluminescence (µ-PL) and time-resolved PL spectroscopies. It is shown that at low temperatures (T < 75 K) Bi-induced localization effects cause trapping of excitons within band-tail states, which prolongs their lifetime and suppresses surface nonradiative recombination (SNR). With increasing temperature, the trapped excitons become delocalized and their lifetime rapidly shortens due to facilitated SNR. Furthermore, Bi incorporation in the GaBiAs NW is found to have a minor influence on the surface states responsible for SNR.

Effects of growth temperature and thermal annealing on optical quality of GaNAs nanowires emitting in the near-infrared spectral range.

We report on optimization of growth conditions of GaAs/GaNAs/GaAs core/shell/shell nanowire (NW) structures emitting at ∼1 µm, aiming to increase their light emitting efficiency. A slight change in growth temperature is found to critically affect optical quality of the active GaNAs shell and is shown to result from suppressed formation of non-radiative recombination (NRR) centers under the optimum growth temperature. By employing the optically detected magnetic resonance spectroscopy, we identify gallium vacancies and gallium interstitials as being among the dominant NRR defects. The radiative efficiency of the NWs can be further improved by post-growth annealing at 680 °C, which removes the gallium interstitials.

Is low-level HIV-1 viraemia associated with elevated levels of markers of immune activation, coagulation and cardiovascular disease?

OBJECTIVES: The clinical significance of low-level viraemia (LLV) during antiretroviral therapy (ART) is debated. We retrospectively investigated longitudinal levels of plasma markers associated with inflammation, altered coagulation and cardiovascular disease in Swedish HIV-positive adults in relation to LLV or permanent virological suppression during long-term ART. METHODS: Plasma levels of C-reactive protein (CRP), D-dimer, vascular cell adhesion molecule 1 (VCAM-1), suppression of tumorigenicity 2 (ST2), growth differentiation factor 15 (GDF-15), soluble CD14 (sCD14), soluble CD163 (sCD163), interferon-γ-induced protein 10 (IP-10) and ß-2-microglobulin were measured in 34 individuals with LLV (viral load 50-999 HIV-1 RNA copies/mL) and in matched controls with persistent virological suppression. Biomarker levels were analysed in samples obtained during episodes of LLV and follow-up samples obtained 1 year later (with similar timing for controls). All biomarkers were analysed using an independent sample t-test and analysis of covariance (ANCOVA) after logarithmic transformation. Log-rank analysis was applied for markers with concentration values out of range. RESULTS: Compared with controls, patients with LLV had significantly higher levels of GDF-15 [geometric mean 3416 (95% confidence interval (CI) 804-14 516) pg/mL versus 2002 (95% CI 355-11 295) pg/mL in controls; P = 0.026] and D-dimer [mean 1114 (95% CI 125-9917) ng/mL versus 756 (95% CI 157-3626) ng/mL; P = 0.038] after adjustment for age, CD4 count nadir and type of ART. In the unadjusted t-test, only GDF-15 was significantly higher and in the log-rank test, both GDF-15 and D-dimer were significantly elevated. No significant differences were observed for the other biomarkers analysed. CONCLUSIONS: Although levels of inflammation markers were similar in ART recipients with and without LLV, persons with LLV had significantly higher levels of GDF-15 and D-dimer. These findings suggest a potential link between LLV and cardiovascular outcomes.

Molecular beam epitaxial growth of dilute nitride GaNAs and GaInNAs nanowires.

We report the growth of dilute nitride GaNAs and GaInNAs core-multishell nanowires (NWs) using molecular beam epitaxy assisted by a plasma source. Using the self-catalyst vapor-liquid-solid growth mode, these NWs were grown on Si(111) and silicon on insulator substrates. The GaNAs and GaInNAs shells contain nitrogen up to 3%. Axial cross-sectional scanning transmission electron microscopy measurements and energy-dispersive x-ray spectrometry confirm the formation of the core-multishell NW structure. We obtained high-quality GaNAs NWs with nitrogen compositions up to 2%. On the other hand, GaNAs containing 3% nitrogen, and GaInNAs NWs, show distorted structures; moreover, the optical emissions seem to be related to defects. Further optimisations of the growth conditions will improve these properties, promising future applications in nanoscale optoelectronics.

Trends in cutaneous malignant melanoma in Sweden 1997-2011: thinner tumours and improved survival among men.

BACKGROUND: Both patient survival and the proportion of patients diagnosed with thin cutaneous malignant melanoma (CMM) have been steadily rising in Sweden as in most Western countries, although the rate of improvement in survival appears to have declined in Sweden at the end of the last millennium. OBJECTIVES: To analyse the most recent trends in the distribution of tumour thickness (T category) as well as CMM-specific survival in Swedish patients diagnosed during 1997-2011. METHODS: This nationwide population-based study included 30,590 patients registered in the Swedish Melanoma Register (SMR) and diagnosed with a first primary invasive CMM during 1997-2011. The patients were followed through 2012 in the national Cause of Death Register. RESULTS: Logistic and Cox regression analyses adjusting for age at diagnosis, tumour site and healthcare region were carried out. The odds ratio for being diagnosed with thicker tumours was significantly reduced (P < 0·001) and the CMM-specific survival significantly improved in men diagnosed during 2007-2011 compared with men diagnosed during 1997-2001 (hazard ratio = 0·81; 95% confidence interval 0·72-0·91; P < 0·001), while the corresponding differences for women were not significant. Women were diagnosed with significantly thicker tumours during 2002-2006 and a tendency towards decreased survival was observed compared with those diagnosed earlier (during 1997-2001) and later (during 2007-2011). CONCLUSIONS: In Sweden, the CMMs of men are detected earlier over time and this seems to be followed by an improved CMM-specific survival for men. Women are still diagnosed with considerably thinner tumours and they experience a better survival than men.

Recent breeding history of dog breeds in Sweden: modest rates of inbreeding, extensive loss of genetic diversity and lack of correlation between inbreeding and health.

One problem in modern dogs is a high occurrence of physical diseases, defects and disorders. Many breeds exhibit physical problems that affect individual dogs throughout life. A potential cause of these problems is inbreeding that is known to reduce the viability of individuals. We investigated the possible correlation between recent inbreeding and health problems in dogs and used studbook data from 26 breeds provided by the Swedish Kennel Club for this purpose. The pedigrees date back to the mid-20th century and comprise 5-10 generations and 1 000-50 000 individuals per pedigree over our study period of 1980-2010. We compared levels of inbreeding and loss of genetic variation measured in relation to the number of founding animals during this period in the investigated dog breeds that we classified as 'healthy' (11 breeds) or 'unhealthy' (15) based on statistics on the extent of veterinary care obtained from Sweden's four largest insurance companies for pets. We found extensive loss of genetic variation and moderate levels of recent inbreeding in all breeds examined, but no strong indication of a difference in these parameters between healthy versus unhealthy breeds over this period. Thus, recent breeding history with respect to rate of inbreeding does not appear to be a main cause of poor health in the investigated dog breeds in Sweden. We identified both strengths and weaknesses of the dog pedigree data important to consider in future work of monitoring and conserving genetic diversity of dog breeds.

Lattice dynamics and carrier recombination in GaAs/GaAsBi nanowires.

GaAsBi nanowires represent a novel and promising material platform for future nano-photonics. However, the growth of high-quality GaAsBi nanowires and GaAsBi alloy is still a challenge due to a large miscibility gap between GaAs and GaBi. In this work we investigate effects of Bi incorporation on lattice dynamics and carrier recombination processes in GaAs/GaAsBi core/shell nanowires grown by molecular-beam epitaxy. By employing photoluminescence (PL), PL excitation, and Raman scattering spectroscopies complemented by scanning electron microscopy, we show that increasing Bi-beam equivalent pressure (BEP) during the growth does not necessarily result in a higher alloy composition but largely affects the carrier localization in GaAsBi. Specifically, it is found that under high BEP, bismuth tends either to be expelled from a nanowire shell towards its surface or to form larger clusters within the GaAsBi shell. Due to these two processes the bandgap of the Bi-containing shell remains practically independent of the Bi BEP, while the emission spectra of the NWs experience a significant red shift under increased Bi supply as a result of the localization effect.

Intrahost evolution of the HIV-2 capsid correlates with progression to AIDS.

HIV-2 infection will progress to AIDS in most patients without treatment, albeit at approximately half the rate of HIV-1 infection. HIV-2 capsid (p26) amino acid polymorphisms are associated with lower viral loads and enhanced processing of T cell epitopes, which may lead to protective Gag-specific T cell responses common in slower progressors. Lower virus evolutionary rates, and positive selection on conserved residues in HIV-2 env have been associated with slower progression to AIDS. In this study we analysed 369 heterochronous HIV-2 p26 sequences from 12 participants with a median age of 30 years at enrolment. CD4% change over time was used to stratify participants into relative faster and slower progressor groups. We analysed p26 sequence diversity evolution, measured site-specific selection pressures and evolutionary rates, and determined if these evolutionary parameters were associated with progression status. Faster progressors had lower CD4% and faster CD4% decline rates. Median pairwise sequence diversity was higher in faster progressors (5.7x10-3 versus 1.4x10-3 base substitutions per site, P<0.001). p26 evolved under negative selection in both groups (dN/dS=0.12). Median virus evolutionary rates were higher in faster than slower progressors - synonymous rates: 4.6x10-3 vs. 2.3x10-3; and nonsynonymous rates: 6.9x10-4 vs. 2.7x10-4 substitutions/site/year, respectively. Virus evolutionary rates correlated negatively with CD4% change rates (ρ = -0.8, P=0.02), but not CD4% level. The signature amino acid at p26 positions 6, 12 and 119 differed between faster (6A, 12I, 119A) and slower (6G, 12V, 119P) progressors. These amino acid positions clustered near to the TRIM5α/p26 hexamer interface surface. p26 evolutionary rates were associated with progression to AIDS and were mostly driven by synonymous substitutions. Nonsynonymous evolutionary rates were an order of magnitude lower than synonymous rates, with limited amino acid sequence evolution over time within hosts. These results indicate HIV-2 p26 may be an attractive therapeutic target.

Clinical impact of chromosomal aberrations in multiple myeloma.

Chromosomal aberrations are frequently found in multiple myeloma cells and play a major role in patient outcome and management of the disease. The most important chromosomal aberrations associated with poor outcome are del(17p), t(4;14), t(14;16) and t(14;20). Others that may be associated with adverse prognosis include amp(1)(q21), del(1p32), del(13), del(8p21) and hypodiploidy. Many chromosomal aberrations have no or uncertain impact; for example, t(11;14), t(8;14) and hyperdiploidy. Attempts have been made to overcome the negative prognostic impact of chromosomal aberrations using autologous or allogeneic transplantation or new immunomodulatory drugs such as thalidomide, lenalidomide and the proteasome inhibitor bortezomib, but the results are controversial. Data suggest that allogeneic transplantation and treatment with bortezomib or lenalidomide may help to overcome the negative effect of del(13) on prognosis, whereas bortezomib may have some influence on reducing the impact of del(17p), t(4;14) and t(14;16). Chromosome analysis should always be performed at diagnosis of multiple myeloma to improve the prediction of outcome and to aid treatment decision-making.

Human immunodeficiency virus type 1 biological variation and coreceptor use: from concept to clinical significance.

There is ample evidence for intra-patient evolution of the human immunodeficiency virus type 1 (HIV-1) biological phenotype during the pathogenic process. Evolution often involves switch of coreceptor use from CCR5 to CXCR4, but change to more flexible use of CCR5 occurs over time even in patients with maintained CCR5 use. The increasing use of entry inhibitors in the clinic, often specific for one or the other HIV-1 coreceptor or with different binding properties to CCR5, calls for virus testing in patients prior to treatment initiation. Cell lines expressing CCR5/CXCR4 chimeric receptors are tools for testing viruses for mode of CCR5 use. It is conceivable that small-molecule entry inhibitors that differentially bind to CCR5 can be matched for best effect against HIV-1 with different modes of CCR5 use, thereby allowing an individualized drug choice specifically tailored for each patient.

Lake secondary production fueled by rapid transfer of low molecular weight organic carbon from terrestrial sources to aquatic consumers.

Carbon of terrestrial origin often makes up a significant share of consumer biomass in unproductive lake ecosystems. However, the mechanisms for terrestrial support of lake secondary production are largely unclear. By using a modelling approach, we show that terrestrial export of dissolved labile low molecular weight carbon (LMWC) compounds supported 80% (34-95%), 54% (19-90%) and 23% (7-45%) of the secondary production by bacteria, protozoa and metazoa, respectively, in a 7-km(2) boreal lake (conservative to liberal estimates in brackets). Bacterial growth on LMWC was of similar magnitude as that of primary production (PP), and grazing on bacteria effectively channelled the LMWC carbon to higher trophic levels. We suggest that rapid turnover of forest LMWC pools enables continuous export of fresh photosynthates and other labile metabolites to aquatic systems, and that substantial transfer of LMWC from terrestrial sources to lake consumers can occur within a few days. Sequestration of LMWC of terrestrial origin, thus, helps explain high shares of terrestrial carbon in lake organisms and implies that lake food webs can be closely dependent on recent terrestrial PP.

Direct comparisons of effectiveness and safety of treatment with Apixaban, Dabigatran and Rivaroxaban in atrial fibrillation.

INTRODUCTION: Direct oral anticoagulants (DOACs) have been proven non-inferior or superior to warfarin in preventing stroke and systemic embolism, with a lower risk of major hemorrhage, in patients with non-valvular atrial fibrillation (NVAF). We sought to investigate whether effectiveness and safety differs among apixaban, rivaroxaban and dabigatran. MATERIALS AND METHODS: Patients with newly initiated DOAC treatment were identified from the Swedish anticoagulation quality registry, ranging from January 1, 2013 to December 31, 2015. Patients were assigned to apixaban, dabigatran or rivaroxaban cohorts based on initiated DOAC and dose (standard or reduced). Baseline characteristics and endpoints were retrieved from validated Swedish quality registers and the National Patient Registry. Cohorts were matched using full optimal matching and directly compared. RESULTS: A total of 25,843 NVAF patients were included. Patients treated with standard dose apixaban or dabigatran had lower risk of major bleeding than patients treated with rivaroxaban, HR 0.69 (95% CI 0.54-0.88) and HR 0.64 (95% CI 0.48-0.87). Regarding reduced dose, patients treated with apixaban had lower risk of major bleeding than those treated with dabigatran or rivaroxaban, HR 0.62 (95% CI 0.44-0.88) and HR 0.45 (95% CI 0.33-0.61). In reduced dose, patients treated with dabigatran had the lowest all-cause mortality. No differences in effectiveness were found. CONCLUSIONS: In this large real-world NVAF cohort, direct comparisons show a favorable bleeding risk profile for dabigatran and apixaban in standard dose, and for apixaban in reduced dose. No differences in effectiveness were found. This study confirms previous indirect DOAC comparisons. Further studies are needed.

Phosphatases in lake water: characterization of enzymes from phytoplankton and zooplankton by gel filtration.

Sephadex gel filtration was used to characterize phosphomonoesterases in two small takes in northern Sweden. Two fractions, here termed phosphatase A and phosphatase B, were found both as free enzymes and associated with seston. The activity of phosphatase A was correlated with the presence of algal biomass. Phosphatase B, on the other hand, was derived from zooplankton. Phosphate served as an effective inhibitor of phosphatase A but had no such effect on phosphatase B. Both fractions had pH optima between 6.5 and 7.0.

Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity.

Cell-mediated (type-1) immunity is necessary for immune protection against most intracellular pathogens and, when excessive, can mediate organ-specific autoimmune destruction. Mice deficient in Eta-1 (also called osteopontin) gene expression have severely impaired type-1 immunity to viral infection [herpes simplex virus-type 1 (KOS strain)] and bacterial infection (Listeria monocytogenes) and do not develop sarcoid-type granulomas. Interleukin-12 (IL-12) and interferon-gamma production is diminished, and IL-10 production is increased. A phosphorylation-dependent interaction between the amino-terminal portion of Eta-1 and its integrin receptor stimulated IL-12 expression, whereas a phosphorylation-independent interaction with CD44 inhibited IL-10 expression. These findings identify Eta-1 as a key cytokine that sets the stage for efficient type-1 immune responses through differential regulation of macrophage IL-12 and IL-10 cytokine expression.

Endometrial endothelial cells are derived from donor stem cells in a bone marrow transplant recipient.

BACKGROUND: The endometrium is a dynamic, cyclically regenerating tissue: a unique model of physiological angiogenesis in adults. However, the source of new endothelial cells (ECs) for vessel regrowth is obscure. We studied if male EC could be detected in the endometrial blood vessels of female human or mouse recipients of haematological stem cells from male donors. METHODS: Endometrial biopsies, obtained from one patient after non-myeloablative allogeneic bone marrow transplantation and two controls, were analysed by immunohistochemistry of CD34 and VEGFR2 antibodies for the immunophenotyping of EC, and FISH probes for the detection of donor cells. Chimerism was analysed using real-time PCR. The same experiment was also applied on the animal model. RESULTS: At the time of a Caesarean section in a female bone marrow transplanted patient, an average 14% of her endometrial EC were donor-derived. One year later, that figure was 10%. In contrast, none of two non-transplanted females demonstrated a mismatch in endometria at Caesarean section. In samples from female mice, harvested 40 days after a haematological stem cell transplant, a 6% average of donor-derived EC was detected. CONCLUSIONS: Bone marrow-derived endothelial progenitors contribute to the formation of new blood vessels in the endometrium.

The effect of administration order of BU and CY on engraftment and toxicity in HSCT mouse model.

Conditioning regimens are an important issue determining the outcome of hematopoietic stem cell transplantation (HSCT). Less toxicity, early engraftment and no relapse are the aims of efficient conditioning. Our objective was to investigate the long-term effects of BU-CY and their administration order on the toxicity and chimerism in a mouse model of HSCT. Female BALB/c mice were treated with either BU (15 mg/kg/day x 4)-CY (100 mg/kg/day x 2) or CY-BU. Treated mice were transplanted with Sca-1+ cells from male BALB/c mice. Until 90 days after HSCT, the animals were monitored for body weight and analyzed for cellular phenotype of the thymus, spleen and BM, total chimerism, the spleen chimerism of DCs and T regulatory (Treg) cells, and hepatotoxicity. BU-CY and CY-BU treatments exerted comparable myeloablative and immunosuppressive effects. The long-term engraftment of donor cells in the BM and thymus regeneration showed the same features in both groups. However, the two regimens differed; in general, hepatotoxicity and chimerism of DC and Treg cells. In the long term, BU-CY, but not CY-BU caused a marked decrease in body weight and a significant increase in the activities of the liver enzymes, particularly aspartate amino transferase (AST). We conclude that the alteration of the administration order of BU-CY to CY-BU not only gives the same level of engraftment but also reduces the toxicity of the conditioning regimen that might be valuable specially in young patients who are undergoing HSCT.

Leptin secretion from adipose tissue in women. Relationship to plasma levels and gene expression.

The role of expression and secretion of the ob gene product, leptin, for the regulation of plasma leptin levels has been investigated in vitro using abdominal subcutaneous adipose tissue of 20 obese, otherwise healthy, and 11 nonobese women. Body mass index (BMI, mean+/-SEM; kg/m2) in the two groups was 41+/-2 and 23+/-1, respectively. Fat cell volume was 815+/-55 pl in the obese and 320+/-46 pl in the nonobese group. In the obese group, plasma leptin concentrations and adipose leptin mRNA (relative to gamma actin) were increased five and two times, respectively. Moreover, adipose tissue secretion rates per gram lipid weight or per fat cell number were also increased two and seven times, respectively, in the obese group. There were strong linear correlations (r = 0.6-0.8) between plasma leptin, leptin secretion, and leptin mRNA. All of these leptin measurements correlated strongly with BMI and fat cell volume (r = 0.7- 0.9). About 60% of the variation in plasma leptin could be attributed to variations in leptin secretion rate, BMI, or fat cell volume. We conclude that elevated circulating levels of leptin in obese women above all result from accelerated secretion rates of the peptide from adipose tissue because of increased ob gene expression. However, leptin mRNA, leptin secretion, and circulating leptin levels are all more closely related to the stored amount of lipids in the fat cells of adipose tissue than they are to an arbitrary division into obese versus nonobese.

The Lighthouse Alarm and Locator trial - a pilot study.

An important factor for health is the possibility to be active and mobile. To make this possible various kinds of support are needed. Integrating geographical information systems technology and user experiences is important in the development of more user-friendly positioning devices. The Lighthouse Alarm and Locator trial aimed to test a new mobile alarm system with additional functionality such as positioning and monitoring of vital signs which can be used regardless of location (in hospital, at home). The system was tested by elderly persons from a pensioner organisation and home care personnel answered up on the alarms. After the tests qualitative interviews were performed with the two groups. The results showed that their experiences of the new mobile alarm system could be described in three main categories: to be supervised, to feel safe and to be mobile. These categories formed a theme: Positioning - an ethical dilemma. The clients' mobility was perceived to increase. The personnel did not think that positioning was ethical but the clients (elderly) did.