Economic appraisal of dabigatran as first-line therapy for stroke prevention in atrial fibrillation

Background. Dabigatran is an oral anticoagulant direct thrombin inhibitor recently registered in South Africa (SA) to reduce the risk of stroke and systemic embolism in patients with atrial fibrillation (AF). Owing to the price disparity between warfarin (the current gold standard for treatment of patients with AF) and dabigatran, we conducted an economic appraisal of the use of dabigatran compared with warfarin from a payer perspective in the South African private healthcare setting.Objectives. To estimate the cost-effectiveness (CE) and budget impact of dabigatran compared with warfarin for the prevention of strokein AF patients.Methods. A previously published Markov model was populated with SA cost and mortality data to estimate the CE and budget impact analysis of dabigatran over a lifetime horizon. The model population consisted of a cohort of patients of whom those aged younger than 80 years used dabigatran 150 mg twice daily and those older than 80 years 110 mg twice daily. Modelled outcomes included total cost, qualityadjusted life years (QALYs) and incremental CE ratio (ICER), with the effectiveness measured by QALYs gained.Results. Dabigatran compared with warfarin as first-line treatment was estimated to have an ICER of R93 290 and an average incrementalcost per beneficiary per month of R0.39 over a 5-year period. Conservative assumptions were made regarding the number of international normalised ratio monitoring tests for patients on warfarin, and the ICER is estimated to decrease by as much as 15.7% under less stringent assumptions. A robust sensitivity analysis was also performed.Conclusion. Dabigatran as first-line treatment compared with warfarin for the use of stroke prevention in patients with AF is deemed costeffectivewhen used in accordance with its registered indication in the SA private sector

Innovation in sport medicine and science: a global social network analysis of stakeholder collaboration in rugby union

Objectives To investigate the network of stakeholders involved in rugby union research across the globe. Methods Using author affiliations listed on scientific publications, we identified the organisations that contributed to rugby union research from 1977 to 2022 and examine collaboration through coauthorship indicators. We determined the locations and sectors of identified organisations and constructed a collaboration network. Network metrics, including degree centrality and betweenness centrality, are computed to identify influential organisations and measure intersector collaboration. Results There is an increase in scientific knowledge creation and collaboration between organisations for rugby union research over time. Among the sectors, the university, professional sports team and sports governing body sectors exhibit the highest intersectoral and intrasectoral density. Predominantly, influential actors are located in England, Australia, France, New Zealand, Ireland and South Africa. Australian Catholic University, Leeds Beckett University, Stellenbosch University, Swansea University, University College London and the University of Cape Town emerge as influential actors between 2016 and 2022. Conclusions Our study underscores the ongoing growth of scientific knowledge generation in rugby union, primarily led by organisations in tier 1 rugby-playing nations within the university sector. Intersectoral collaboration with sports governing bodies plays a crucial role, acting as a broker between sectors. However, the overall collaboration landscape between and within sectors is low. These results highlight an opportunity for improved collaboration opportunities, as the organisations driving knowledge creation have been identified

Revival of the magnetar PSR J1622-4950: observations with MeerKAT, Parkes, XMM-Newton, Swift, Chandra, and NuSTAR

New radio (MeerKAT and Parkes) and X-ray (XMM-Newton, Swift, Chandra, and NuSTAR) observations of PSR J1622-4950 indicate that the magnetar, in a quiescent state since at least early 2015, reactivated between 2017 March 19 and April 5. The radio flux density, while variable, is approximately 100x larger than during its dormant state. The X-ray flux one month after reactivation was at least 800x larger than during quiescence, and has been decaying exponentially on a 111+/-19 day timescale. This high-flux state, together with a radio-derived rotational ephemeris, enabled for the first time the detection of X-ray pulsations for this magnetar. At 5%, the 0.3-6 keV pulsed fraction is comparable to the smallest observed for magnetars. The overall pulsar geometry inferred from polarized radio emission appears to be broadly consistent with that determined 6-8 years earlier. However, rotating vector model fits suggest that we are now seeing radio emission from a different location in the magnetosphere than previously. This indicates a novel way in which radio emission from magnetars can differ from that of ordinary pulsars. The torque on the neutron star is varying rapidly and unsteadily, as is common for magnetars following outburst, having changed by a factor of 7 within six months of reactivation.Comment: Published in ApJ (2018 April 5); 13 pages, 4 figure

Antibacterial and dermal toxicological profiles of ethyl acetate extract from Crassocephalum bauchiense (Hutch.) Milne-Redh (Asteraceae)

<p>Abstract</p> <p>Background</p> <p>The emergence in recent years of numerous resistant strains of pathogenic bacteria to a range of formerly efficient antibiotics constitutes a serious threat to public health. <it>Crassocephalum bauchiense</it>, a medicinal herb found in the West Region of Cameroon is used to treat gastrointestinal infections as well as liver disorders. The ethyl acetate extract from the leaves of <it>C. bauchiense </it>was evaluated for its antibacterial activity as well as acute and sub-acute toxicities.</p> <p>Methods</p> <p>The plant extract was prepared by maceration in ethyl acetate. Its phytochemical screening was done by standard methods. The broth microdilution method was used to evaluate the <it>in vitro </it>antibacterial activity. The <it>in vivo </it>antibacterial activity of a gel formulation (0.05, 1 and 2% w/v) of this extract was evaluated using a <it>Staphylococcus aureus</it>-induced dermatitis in a murine model. Selected haematological and biochemical parameters were used to evaluate the dermal sub-acute toxicity of the extract in rats.</p> <p>Results</p> <p>Phytochemical screening of the <it>C. bauchiense </it>extract revealed the presence of alkaloids, phenols, tannins and sterols. <it>In vitro </it>antibacterial activities were observed against all the tested microorganisms (MIC = 0.04-6.25 mg/ml). Formulated extract-gel (2% w/v) and gentamycin (reference drug) eradicated the microbial infection after five days of treatment. A single dermal dose of this extract up to 32 g/kg body weight (bw) did not produce any visible sign of toxicity. Also, daily dermal application of the <it>C. bauchiense </it>extract gel formulation for 28 days did not show any negative effect, instead some biochemical parameters such as alanine aminotransferase (ALT and AST), low density lipoprotein (LDL), high density lipoprotein (HDL) and triglycerides were significantly (p < 0.05) affected positively.</p> <p>Conclusion</p> <p>These results indicate that the <it>C. bauchiense </it>ethyl acetate extract can be used safely for the treatment of some bacterial infections.</p

Growth hormone secretion is correlated with neuromuscular innervation rather than motor neuron number in early-symptomatic male amyotrophic lateral sclerosis mice

GH deficiency is thought to be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, therapy with GH and/or IGF-I has not shown benefit. To gain a better understanding of the role of GH secretion in ALS pathogenesis, we assessed endogenous GH secretion in wild-type and hSOD1(G93A) mice throughout the course of ALS disease. Male wild-type and hSOD1(G93A) mice were studied at the presymptomatic, onset, and end stages of disease. To assess the pathological features of disease, we measured motor neuron number and neuromuscular innervation. We report that GH secretion profile varies at different stages of disease progression in hSOD1(G93A) mice; compared with age-matched controls, GH secretion is unchanged prior to the onset of disease symptoms, elevated at the onset of disease symptoms, and reduced at the end stage of disease. In hSOD1(G93A) mice at the onset of disease, GH secretion is positively correlated with the percentage of neuromuscular innervation but not with motor neuron number. Moreover, this occurs in parallel with an elevation in the expression of muscle IGF-I relative to controls. Our data imply that increased GH secretion at symptom onset may be an endogenous endocrine response to increase the local production of muscle IGF-I to stimulate reinnervation of muscle, but that in the latter stages of disease this response no longer occurs

Target Gene Analysis by Microarrays and Chromatin Immunoprecipitation Identifies HEY Proteins as Highly Redundant bHLH Repressors

HEY bHLH transcription factors have been shown to regulate multiple key steps in cardiovascular development. They can be induced by activated NOTCH receptors, but other upstream stimuli mediated by TGFß and BMP receptors may elicit a similar response. While the basic and helix-loop-helix domains exhibit strong similarity, large parts of the proteins are still unique and may serve divergent functions. The striking overlap of cardiac defects in HEY2 and combined HEY1/HEYL knockout mice suggested that all three HEY genes fulfill overlapping function in target cells. We therefore sought to identify target genes for HEY proteins by microarray expression and ChIPseq analyses in HEK293 cells, cardiomyocytes, and murine hearts. HEY proteins were found to modulate expression of their target gene to a rather limited extent, but with striking functional interchangeability between HEY factors. Chromatin immunoprecipitation revealed a much greater number of potential binding sites that again largely overlap between HEY factors. Binding sites are clustered in the proximal promoter region especially of transcriptional regulators or developmental control genes. Multiple lines of evidence suggest that HEY proteins primarily act as direct transcriptional repressors, while gene activation seems to be due to secondary or indirect effects. Mutagenesis of putative DNA binding residues supports the notion of direct DNA binding. While class B E-box sequences (CACGYG) clearly represent preferred target sequences, there must be additional and more loosely defined modes of DNA binding since many of the target promoters that are efficiently bound by HEY proteins do not contain an E-box motif. These data clearly establish the three HEY bHLH factors as highly redundant transcriptional repressors in vitro and in vivo, which explains the combinatorial action observed in different tissues with overlapping expression

The MeerKAT telescope as a pulsar facility: System verification and early science results from MeerTime

We describe system verification tests and early science results from the pulsar processor (PTUSE) developed for the newly commissioned 64-dish SARAO MeerKAT radio telescope in South Africa. MeerKAT is a high-gain ( ) low-system temperature ( ) radio array that currently operates at 580–1 670 MHz and can produce tied-array beams suitable for pulsar observations. This paper presents results from the MeerTime Large Survey Project and commissioning tests with PTUSE. Highlights include observations of the double pulsar , pulse profiles from 34 millisecond pulsars (MSPs) from a single 2.5-h observation of the Globular cluster Terzan 5, the rotation measure of Ter5O, a 420-sigma giant pulse from the Large Magellanic Cloud pulsar PSR , and nulling identified in the slow pulsar PSR J0633–2015. One of the key design specifications for MeerKAT was absolute timing errors of less than 5 ns using their novel precise time system. Our timing of two bright MSPs confirm that MeerKAT delivers exceptional timing. PSR exhibits a jitter limit of whilst timing of PSR over almost 11 months yields an rms residual of 66 ns with only 4 min integrations. Our results confirm that the MeerKAT is an exceptional pulsar telescope. The array can be split into four separate sub-arrays to time over 1 000 pulsars per day and the future deployment of S-band (1 750–3 500 MHz) receivers will further enhance its capabilities

Acute hyperglycemia abolishes cardioprotection by remote ischemic perconditioning

BACKGROUND: Remote ischemic perconditioning (RIPerC) has a promising therapeutic insight to improve the prognosis of acute myocardial infarction. Chronic comorbidities such as diabetes are known to interfere with conditioning interventions by modulating cardioprotective signaling pathways, such as e.g., mTOR pathway and autophagy. However, the effect of acute hyperglycemia on RIPerC has not been studied so far. Therefore, here we investigated the effect of acute hyperglycemia on cardioprotection by RIPerC. METHODS: Wistar rats were divided into normoglycemic (NG) and acute hyperglycemic (AHG) groups. Acute hyperglycemia was induced by glucose infusion to maintain a serum glucose concentration of 15-20 mM throughout the experimental protocol. NG rats received mannitol infusion of an equal osmolarity. Both groups were subdivided into an ischemic (Isch) and a RIPerC group. Each group underwent reversible occlusion of the left anterior descending coronary artery (LAD) for 40 min in the presence or absence of acute hyperglycemia. After the 10-min LAD occlusion, RIPerC was induced by 3 cycles of 5-min unilateral femoral artery and vein occlusion and 5-min reperfusion. After 120 min of reperfusion, infarct size was measured by triphenyltetrazolium chloride staining. To study underlying signaling mechanisms, hearts were harvested for immunoblotting after 35 min in both the NG and AHG groups. RESULTS: Infarct size was significantly reduced by RIPerC in NG, but not in the AHG group (NG + Isch: 46.27 +/- 5.31 % vs. NG + RIPerC: 24.65 +/- 7.45 %, p < 0.05; AHG + Isch: 54.19 +/- 4.07 % vs. 52.76 +/- 3.80 %). Acute hyperglycemia per se did not influence infarct size, but significantly increased the incidence and duration of arrhythmias. Acute hyperglycemia activated mechanistic target of rapamycine (mTOR) pathway, as it significantly increased the phosphorylation of mTOR and S6 proteins and the phosphorylation of AKT. In spite of a decreased LC3II/LC3I ratio, other markers of autophagy, such as ATG7, ULK1 phopsphorylation, Beclin 1 and SQSTM1/p62, were not modulated by acute hyperglycemia. Furthermore, acute hyperglycemia significantly elevated nitrative stress in the heart (0.87 +/- 0.01 vs. 0.50 +/- 0.04 microg 3-nitrotyrosine/mg protein, p < 0.05). CONCLUSIONS: This is the first demonstration that acute hypreglycemia deteriorates cardioprotection by RIPerC. The mechanism of this phenomenon may involve an acute hyperglycemia-induced increase in nitrative stress and activation of the mTOR pathway