Renal transplant recipient and deceased-donor risk profiles at Wits Donald Gordon Medical Centre, Johannesburg, South Africa: A 9-year review.

BACKGROUND: Renal transplantation is the gold-standard therapy for end-stage renal disease. Decision-making around the acceptance of deceased-donor organs is complex and time sensitive. Risk scoring systems for both donors and recipients attempt to simplify the allocation of renal grafts to the most appropriate recipient. OBJECTIVES: To investigate the role of these transplant risk scores in the South African (SA) setting. METHODS: A total of 188 adult deceased-donor organ referrals over the 9-year period 1 January 2013 - 31 December 2021 were included. The Kidney Donor Risk Index (KDRI) and the UK KDRI were calculated for each donor. Recipients who were allocated these grafts were characterised, and the Hennepin Transplant Risk Score and the Kidney Transplant Morbidity Index (KTMI) were calculated. RESULTS: The median (interquartile range) KDRI was 1.2 (0.9 - 1.6), confirming that low- to average-risk donors were being utilised. Similarly, the median UK KDRI was 0.9 (0.8 - 1.2). Both these scores performed poorly in predicting graft and patient survival, with a C-statistic of 0.5. Renal recipient risk scores also demonstrated low- to average-risk patients being transplanted, with a median Hennepin score of 2 - 4 points and a KTMI of 2 points. These recipient scores predict increased recipient mortality at high scores, albeit with low sensitivity, and were not significantly associated with graft survival. CONCLUSION: Deceased-donor and renal recipient risk scores commonly used internationally performed poorly in predicting graft survival in our cohort, and should be used with caution in the SA setting. A conservative approach to organ donor referral and utilisation as well as renal transplant recipient listing was noted.

South African surgical trainees Master of Medicine dissertation survey.

BACKGROUND: Since 2011, South African specialist registration requires a research component in the form of a Master of Medicine (MMed) degree. The aim of the study was to assess opinion regarding research and the progression and obstacles toward the completion of the research component of the MMed amongst South African surgical registrars. METHODS: One hundred and sixty-eight (24%) from 708 nationally registered surgical registrars participated. The participants completed an electronic survey that focused on research progression timeline, registrar research perspectives, factors affecting research success and obstacles, and interest in future research. RESULTS: There was an expected progression of research with increasing seniority. Forty-two (25%) started their research 6-12 months into their training time. One hundred and ten (66%) were confident their research would be completed timeously. Obstacles to timeous completion included clinical responsibilities with lack of protected research time in 130 (75%) and lack of funding in 46 (28%). From the registrars' perspective, their confidence to complete their research timeously was increased when they had attended a structured research course and had prior research experience. CONCLUSION: Completion of the MMed research component was considered to be hampered by a lack of dedicated time and funding and aided by prior research experience and a structured research training course.

GeoHealth Perspectives on Integrated, Coordinated, Open, Networked (ICON) Science.

GeoHealth research both characterizes and predicts problems at the nexus of earth and human systems like climate change, pollution, and natural hazards. While GeoHealth excels in the area of integrated science, there is a need to improve coordinated and networked efforts to produce open science to enable environmental justice. There is a need to resource and empower frontline populations that are disproportionately marginalized by environmental injustice (i.e., the unequal protection from environmental harms and lack of access and meaningful engagement in decision making for a healthy environment; EPA, 2022, https://www.epa.gov/environmentaljustice). GeoHealth practice has the opportunity to advance environmental justice or the "fair treatment and meaningful involvement of all people regardless of race, color, national origin, or income" with respect to how research and collaboration of GeoHealth professionals supports the "development, implementation, and enforcement of environmental laws, regulations, and policies" that produce equal protection from environmental and health hazards and access to the decision making for a health environment (EPA, 2022, https://www.epa.gov/environmentaljustice). Here we highlight barriers and opportunities to apply an equity-centered ICON framework to the field of GeoHealth to advance environmental justice and health equity.

Biogeosciences Perspectives on Integrated, Coordinated, Open, Networked (ICON) Science.

This article is composed of three independent commentaries about the state of Integrated, Coordinated, Open, Networked (ICON) principles in the American Geophysical Union Biogeosciences section, and discussion on the opportunities and challenges of adopting them. Each commentary focuses on a different topic: (a) Global collaboration, technology transfer, and application (Section 2), (b) Community engagement, community science, education, and stakeholder involvement (Section 3), and (c) Field, experimental, remote sensing, and real-time data research and application (Section 4). We discuss needs and strategies for implementing ICON and outline short- and long-term goals. The inclusion of global data and international community engagement are key to tackling grand challenges in biogeosciences. Although recent technological advances and growing open-access information across the world have enabled global collaborations to some extent, several barriers, ranging from technical to organizational to cultural, have remained in advancing interoperability and tangible scientific progress in biogeosciences. Overcoming these hurdles is necessary to address pressing large-scale research questions and applications in the biogeosciences, where ICON principles are essential. Here, we list several opportunities for ICON, including coordinated experimentation and field observations across global sites, that are ripe for implementation in biogeosciences as a means to scientific advancements and social progress.

Revealing x-ray and gamma ray temporal and spectral similarities in the GRB 190829A afterglow.

Gamma-ray bursts (GRBs), which are bright flashes of gamma rays from extragalactic sources followed by fading afterglow emission, are associated with stellar core collapse events. We report the detection of very-high-energy (VHE) gamma rays from the afterglow of GRB 190829A, between 4 and 56 hours after the trigger, using the High Energy Stereoscopic System (H.E.S.S.). The low luminosity and redshift of GRB 190829A reduce both internal and external absorption, allowing determination of its intrinsic energy spectrum. Between energies of 0.18 and 3.3 tera-electron volts, this spectrum is described by a power law with photon index of 2.07 ± 0.09, similar to the x-ray spectrum. The x-ray and VHE gamma-ray light curves also show similar decay profiles. These similar characteristics in the x-ray and gamma-ray bands challenge GRB afterglow emission scenarios.

A Comparison Between Selected Noncommunicable Disease Mortality Rates Between 2010 and 2016 Among Selected Southern African Countries.

Researchers have identified cancer, diabetes mellitus, cardiovascular, and respiratory diseases as being the principal pathologies of increased aged standardized death rates (ASDRs) among noncommunicable diseases (NCDs). The objective of this study was to compare the change in the ASDR of these principal NCDs between the years 2010 and 2016 in Botswana, Mozambique, Namibia, South Africa, and Zimbabwe. ASDR data were collected from the 2016 Global Health Estimate. Among the selected Southern African countries for both 2010 and 2016, the order of prevalence of NCDs linked to increased ASDR was cardiovascular diseases (both cardiac and stroke), cancer, diabetes mellitus, and chronic respiratory diseases. The percentage of the total number of NCDs linked to increased ASDR in relation to total deaths increased from 43.8% (in 2010) to 51.0% (in 2016) from (p < .0001). The percentage of principal NCDs in relation to total ASDR increased from 33.0% (in 2010) to 38.2% (in 2016; p < .0001).

A very-high-energy component deep in the γ-ray burst afterglow.

Gamma-ray bursts (GRBs) are brief flashes of γ-rays and are considered to be the most energetic explosive phenomena in the Universe1. The emission from GRBs comprises a short (typically tens of seconds) and bright prompt emission, followed by a much longer afterglow phase. During the afterglow phase, the shocked outflow-produced by the interaction between the ejected matter and the circumburst medium-slows down, and a gradual decrease in brightness is observed2. GRBs typically emit most of their energy via γ-rays with energies in the kiloelectronvolt-to-megaelectronvolt range, but a few photons with energies of tens of gigaelectronvolts have been detected by space-based instruments3. However, the origins of such high-energy (above one gigaelectronvolt) photons and the presence of very-high-energy (more than 100 gigaelectronvolts) emission have remained elusive4. Here we report observations of very-high-energy emission in the bright GRB 180720B deep in the GRB afterglow-ten hours after the end of the prompt emission phase, when the X-ray flux had already decayed by four orders of magnitude. Two possible explanations exist for the observed radiation: inverse Compton emission and synchrotron emission of ultrarelativistic electrons. Our observations show that the energy fluxes in the X-ray and γ-ray range and their photon indices remain comparable to each other throughout the afterglow. This discovery places distinct constraints on the GRB environment for both emission mechanisms, with the inverse Compton explanation alleviating the particle energy requirements for the emission observed at late times. The late timing of this detection has consequences for the future observations of GRBs at the highest energies.

Search for γ-Ray Line Signals from Dark Matter Annihilations in the Inner Galactic Halo from 10 Years of Observations with H.E.S.S.

Spectral lines are among the most powerful signatures for dark matter (DM) annihilation searches in very-high-energy γ rays. The central region of the Milky Way halo is one of the most promising targets given its large amount of DM and proximity to Earth. We report on a search for a monoenergetic spectral line from self-annihilations of DM particles in the energy range from 300 GeV to 70 TeV using a two-dimensional maximum likelihood method taking advantage of both the spectral and spatial features of the signal versus background. The analysis makes use of Galactic center observations accumulated over ten years (2004-2014) with the H.E.S.S. array of ground-based Cherenkov telescopes. No significant γ-ray excess above the background is found. We derive upper limits on the annihilation cross section ⟨σv⟩ for monoenergetic DM lines at the level of 4×10^{-28} cm^{3} s^{-1} at 1 TeV, assuming an Einasto DM profile for the Milky Way halo. For a DM mass of 1 TeV, they improve over the previous ones by a factor of 6. The present constraints are the strongest obtained so far for DM particles in the mass range 300 GeV-70 TeV. Ground-based γ-ray observations have reached sufficient sensitivity to explore relevant velocity-averaged cross sections for DM annihilation into two γ-ray photons at the level expected from the thermal relic density for TeV DM particles.

H.E.S.S. Limits on Linelike Dark Matter Signatures in the 100 GeV to 2 TeV Energy Range Close to the Galactic Center.

A search for dark matter linelike signals iss performed in the vicinity of the Galactic Center by the H.E.S.S. experiment on observational data taken in 2014. An unbinned likelihood analysis iss developed to improve the sensitivity to linelike signals. The upgraded analysis along with newer data extend the energy coverage of the previous measurement down to 100 GeV. The 18 h of data collected with the H.E.S.S. array allow one to rule out at 95% C.L. the presence of a 130 GeV line (at l=-1.5°, b=0° and for a dark matter profile centered at this location) previously reported in Fermi-LAT data. This new analysis overlaps significantly in energy with previous Fermi-LAT and H.E.S.S. RESULTS: No significant excess associated with dark matter annihilations was found in the energy range of 100 GeV to 2 TeV and upper limits on the gamma-ray flux and the velocity weighted annihilation cross section are derived adopting an Einasto dark matter halo profile. Expected limits for present and future large statistics H.E.S.S. observations are also given.

Search for Dark Matter Annihilations towards the Inner Galactic Halo from 10 Years of Observations with H.E.S.S.

The inner region of the Milky Way halo harbors a large amount of dark matter (DM). Given its proximity, it is one of the most promising targets to look for DM. We report on a search for the annihilations of DM particles using γ-ray observations towards the inner 300 pc of the Milky Way, with the H.E.S.S. array of ground-based Cherenkov telescopes. The analysis is based on a 2D maximum likelihood method using Galactic Center (GC) data accumulated by H.E.S.S. over the last 10 years (2004-2014), and does not show any significant γ-ray signal above background. Assuming Einasto and Navarro-Frenk-White DM density profiles at the GC, we derive upper limits on the annihilation cross section ⟨σv⟩. These constraints are the strongest obtained so far in the TeV DM mass range and improve upon previous limits by a factor 5. For the Einasto profile, the constraints reach ⟨σv⟩ values of 6×10^{-26} cm^{3} s^{-1} in the W^{+}W^{-} channel for a DM particle mass of 1.5 TeV, and 2×10^{-26} cm^{3} s^{-1} in the τ^{+}τ^{-} channel for a 1 TeV mass. For the first time, ground-based γ-ray observations have reached sufficient sensitivity to probe ⟨σv⟩ values expected from the thermal relic density for TeV DM particles.

The effect of an offset polar cap dipolar magnetic field on the modeling of the Vela pulsar's γ-ray light curves.

We performed geometric pulsar light curve modeling using static, retarded vacuum, and offset polar cap (PC) dipole B-fields (the latter is characterized by a parameter ε), in conjunction with standard two-pole caustic (TPC) and outer gap (OG) emission geometries. The offset-PC dipole B-field mimics deviations from the static dipole (which corresponds to ε = 0). In addition to constant-emissivity geometric models, we also considered a slot gap (SG) E-field associated with the offset-PC dipole B-field and found that its inclusion leads to qualitatively different light curves. Solving the particle transport equation shows that the particle energy only becomes large enough to yield significant curvature radiation at large altitudes above the stellar surface, given this relatively low E-field. Therefore, particles do not always attain the radiation-reaction limit. Our overall optimal light curve fit is for the retarded vacuum dipole field and OG model, at an inclination angle [Formula: see text] and observer angle [Formula: see text]. For this B-field, the TPC model is statistically disfavored compared to the OG model. For the static dipole field, neither model is significantly preferred. We found that smaller values of ε are favored for the offset-PC dipole field when assuming constant emissivity, and larger ε values favored for variable emissivity, but not significantly so. When multiplying the SG E-field by a factor of 100, we found improved light curve fits, with α and ζ being closer to best fits from independent studies, as well as curvature radiation reaction at lower altitudes.

Are anxiety and fear separable emotions in driving? A laboratory study of behavioural and physiological responses to different driving environments.

Research into anxiety and driving has indicated that those higher in anxiety are potentially more dangerous on the roads. However, simulator findings suggest that conclusions are mixed at best. It is possible that anxiety is becoming confused with fear, which has a focus on more clearly defined sources of threat from the environment, as opposed to the internal, thought-related process associated with anxiety. This research aimed to measure feelings of fear, as well as physiological and attentional reactions to increasing levels of accident risk. Trait anxiety was also measured to see if it interacted with levels of risk or its associated reactions. Participants watched videos of driving scenarios with varying levels of accident risk and had to rate how much fear they would feel if they were the driver of the car, whilst skin conductance, heart rate, and eye movements were recorded. Analysis of the data suggested that perceptions of fear increased with increasing levels of accident risk, and skin conductance reflected this pattern. Eye movements, when considered alongside reaction times, indicated different patterns of performance according to different dangerous situations. These effects were independent of trait anxiety, which was only associated with higher rates of disliking driving and use of maladaptive coping mechanisms on questionnaires. It is concluded that these results could provide useful evidence in support for training-based programmes; it may also be beneficial to study trait anxiety within a more immersive driving environment and on a larger scale.

Do immature platelet levels in chest pain patients presenting to the emergency department aid in the diagnosis of acute coronary syndrome?

INTRODUCTION: Early and accurate identification of acute coronary syndrome (ACS) vs. noncardiac chest pain in patients presenting to the emergency department (ED) is problematic and new diagnostic markers are needed. Previous studies reported that elevated mean platelet volume (MPV) is associated with ACS and predictive of cardiovascular risk. MPV is closely related to the immature platelet fraction (IPF), and recent studies have suggested that IPF may be a more sensitive marker of ACS than MPV. The objective of the present study was to determine whether the measurement of IPF assists in the diagnosis of ACS in patients presenting to the ED with chest pain. METHODS: In this single-center, prospective, cross-sectional study, adult patients presenting to the ED with chest pain and/or suspected ACS were considered for enrollment. Blood samples from 236 ACS-negative and 44 ACS-positive patients were analyzed in a Sysmex XE-2100 for platelet count, MPV, IPF, and the absolute count of immature platelets (IPC). RESULTS: Total platelet counts, MPV, IPF, and IPC were not statistically different between ACS-negative and ACS-positive patients. The IPF was 4.6 ± 2.7% and 5.0 ± 2.8% (mean ± SD, P = 0.24), and the IPC was 10.0 ± 4.6 and 11.5 ± 7.5 × 10(3) /µL (P = 0.27) for ACS-negative and ACS-positive patients, respectively. CONCLUSION: In 280 patients presenting to the ED with chest pain and/or suspected ACS, no differences in IPF, IPC or MPV were observed in ACS-negative vs. ACS-positive patients, suggesting that these parameters do not assist in the diagnosis of ACS.

Tuberculosis in the pituitary fossa: a common pathology in an uncommon site.

UNLABELLED: Tuberculosis (TB) is an important cause of mortality and morbidity across the world. In 2-5% of all cases of systemic TB, the C is affected, with lesions reported in the meninges, cortex and ventricles. Intrasellar tuberculomas, however, are extremely rare. We report the interesting case of a young female patient who presented with secondary hypothyroidism and hyperprolactinaemia. She was treated successfully for pituitary TB. We also highlight and discuss some interesting (and hitherto unreported) endocrine issues. Radiological and histological features and treatment of pituitary TB are discussed using this case as an example. LEARNING POINTS: Intrasellar TB continues to be a rare presentation, but incidence and prevalence are expected to grow with increasing numbers of multidrug-resistant TB and shrinking geographical boundaries across the world.Pituitary TB can present with features of a typical adenoma, but has certain radiological and histological features that help to differentiate from an adenoma.Patients can present with a variety of endocrine abnormalities at different times.The presence of an intrasellar mass in individuals at a high risk of developing TB, or with a previous history of systemic TB, should prompt the diagnosis of pituitary TB. In such individuals, it may be worth considering a trial of anti-tuberculous therapy, before considering surgery.

Modified diadenosine tetraphosphates with dual specificity for P2Y1 and P2Y12 are potent antagonists of ADP-induced platelet activation.

BACKGROUND: Diadenosine 5',5'''-P(1),P(4)-tetraphosphate (Ap(4)A), a natural compound stored in platelet dense granules, inhibits ADP-induced platelet aggregation. Ap(4)A inhibits the platelet ADP receptors P2Y(1) and P2Y(12), is a partial agonist of P2Y(12), and is a full agonist of the platelet ATP-gated ion channel P2X1. Modification of the Ap(4)A tetraphosphate backbone enhances inhibition of ADP-induced platelet aggregation. However, the effects of these Ap(4)A analogs on human platelet P2Y(1), P2Y(12) and P2X1 are unclear. OBJECTIVE: To determine the agonist and antagonist activities of diadenosine tetraphosphate analogs towards P2Y(1), P2Y(12), and P2X1. METHODS: We synthesized the following Ap(4)A analogs: P(1),P(4)-dithiotetraphosphate; P(2),P(3)-chloromethylenetetraphosphate; P(1)-thio-P(2),P(3)-chloromethylenetetraphosphate; and P(1),P(4)-dithio-P(2),P(3)-chloromethylenetetraphosphate. We then measured the effects of these analogs on: (i) ADP-induced platelet aggregation; (ii) P2Y(1)-mediated changes in cytosolic Ca(2+); (iii) P2Y(12)-mediated changes in vasodilator-stimulated phosphoprotein phosphorylation; and (iv) P2X1-mediated entry of extracellular Ca(2+). RESULTS: Ap(4)A analogs with modifications in the phosphate backbone inhibited both P2Y(1) and P2Y(12), and showed no agonist activity towards these receptors. The dithio modification increased inhibition of P2Y(1), P2Y(12), and platelet aggregation, whereas the chloromethylene modification increased inhibition of P2Y(12) and platelet aggregation, but decreased P2Y(1) inhibition. Combining the dithio and chloromethylene modifications increased P2Y(1) and P2Y(12) inhibition. As compared with Ap(4)A, each modification decreased agonist activity towards P2X1, and the dual modification completely eliminated P2X1 agonist activity. CONCLUSIONS: As compared with Ap(4)A, tetraphosphate backbone analogs of Ap(4)A have diminished activity towards P2X1 but inhibit both P2Y(1) and P2Y(12) and, with greater potency, inhibit ADP-induced platelet aggregation. Thus, diadenosine tetraphosphate analogs with dual receptor selectivity may have potential as antiplatelet drugs.

The diagnostic performance of the GenoType MTBDRplus version 2 line probe assay is equivalent to that of the Xpert MTB/RIF assay.

Molecular diagnostics for Mycobacterium tuberculosis have recently been endorsed by the World Health Organization. The Xpert MTB/RIF assay was endorsed for use on patient material, regardless of smear gradation, while the GenoType MTBDRplus (version 1) has been limited for use on smear-positive patient material. In this study, we evaluated the diagnostic performance of the Xpert MTB/RIF and GenoType MTBDRplus (version 2) assays on smear-positive and smear-negative patient specimens submitted to a high-throughput diagnostic laboratory. A total of 282 consecutive specimens were subjected to the two new molecular assays, and their performance characteristics were assessed relative to the routine diagnostic standard. Both assays showed similar diagnostic performance characteristics. The sensitivities of the GenoType MTBDRplus (v2.0) and Xpert MTB/RIF assays for the detection of culture-positive M. tuberculosis were 73.1% and 71.2%, respectively, while the specificities of both assays were 100%. Both assays were able to diagnose the presence of M. tuberculosis in 57 to 58% of smear-negative cases, suggesting that the performance characteristics were dependent on bacillary load. The detection of M. tuberculosis in culture-negative specimens confirmed that molecular assays should not be used for treatment monitoring. The sensitivity and specificity for rifampin resistance detection were 100% in both assays; however, the GenoType MTBDRplus (v2.0) assay provided additional information on isoniazid susceptibility. The GenoType MTBDRplus (v2.0) assay will complement the Xpert MTB/RIF screening assay by validating rifampin susceptibility and providing information on isoniazid susceptibility. In addition, the GenoType MTBDRplus (v2.0) assay will provide pharmacogenetic information that may be critical in guiding appropriate treatment.

Differences in platelet function in patients with acute myeloid leukemia and myelodysplasia compared to equally thrombocytopenic patients with immune thrombocytopenia.

BACKGROUND: Severe thrombocytopenia is a major risk factor for hemorrhage, but platelet function and bleeding risk at low platelet counts are poorly understood, because of the limitations of platelet function testing at very low platelet counts. OBJECTIVES: To examine and compare platelet function in severely thrombocytopenic patients with acute myeloid leukemia (AML) or myelodysplasia (MDS) with that in patients with immune thrombocytopenia (ITP). METHODS: Whole blood flow cytometric measurement of platelet activation and platelet reactivity to agonists was correlated with the immature platelet fraction (IPF) and bleeding symptoms. RESULTS: Patients with AML/MDS had smaller platelets, lower IPF and substantially lower platelet surface expression of activated glycoprotein (GP)IIb-IIIa and GPIb, both with and without addition of ex vivo ADP or thrombin receptor-activating peptide, than patients with ITP. In both ITP and AML/MDS patients, increased platelet surface GPIb on circulating platelets and expression of activated GPIIb-IIIa and GPIb on ex vivo activated platelets correlated with a higher IPF. Whereas platelet reactivity was higher for AML/MDS patients with bleeding than for those with no bleeding, platelet reactivity was lower for ITP patients with bleeding than for those with no bleeding. CONCLUSIONS: AML/MDS patients have lower in vivo platelet activation and ex vivo platelet reactivity than patients with ITP. The proportion of newly produced platelets correlates with the expression of platelet surface markers of activation. These differences might contribute to differences in bleeding tendency between AML/MDS and ITP patients. This study is the first to define differences in platelet function between AML/MDS patients and ITP patients with equivalent degrees of thrombocytopenia.

Agonist and antagonist effects of diadenosine tetraphosphate, a platelet dense granule constituent, on platelet P2Y1, P2Y12 and P2X1 receptors.

INTRODUCTION: Diadenosine 5',5'''-P(1),P(4)- tetraphosphate (Ap(4)A) is stored in platelet dense granules, but its effects on platelet function are not well understood. METHODS AND RESULTS: We examined the effects of Ap(4)A on platelet purinergic receptors P2Y(1), P2Y(12) and P2X(1). Flow cytometry was used to measure the effects of Ap(4)A in the presence or absence of ADP on: a) P2Y(12)-mediated decrease in intraplatelet phosphorylated vasodilator stimulated phosphoprotein (VASP), b) P2Y(1)-mediated increase in platelet cytosolic Ca(2+), and c) P2X(1)-mediated intraplatelet entry of extracellular Ca(2+). ADP-stimulated platelet shape change (P2Y(1)-mediated) and aggregation (P2Y(1)- and P2Y(12)-mediated) were measured optically. Ap(4)A inhibited 3 microM ADP-induced: a) platelet aggregation (IC(50) 9.8+/-2.8 microM), b) P2Y(1)-mediated shape change, c) P2Y(1)-mediated increase in platelet cytosolic Ca(2+) (IC(50) 40.8+/-12.3 microM), and d) P2Y(12)-mediated decrease in VASP phosphorylation (IC(50)>250 microM). In the absence of added ADP, Ap(4)A had agonist effects on platelet P2X(1) and P2Y(12), but not P2Y(1), receptors. CONCLUSION: Ap(4)A, a constituent of platelet dense granules, is a) an antagonist of platelet P2Y(1) and P2Y(12) receptors, where it inhibits the effects of ADP, and b) an agonist of platelet P2X(1) and P2Y(12) receptors.

Targeted inhibition of the serotonin 5HT2A receptor improves coronary patency in an in vivo model of recurrent thrombosis.

BACKGROUND: Release of serotonin and activation of serotonin 5HT2A receptors on platelet surfaces is a potent augmentative stimulus for platelet aggregation. However, earlier-generation serotonin receptor antagonists were not successfully exploited as antiplatelet agents, possibly owing to their lack of specificity for the 5HT2A receptor subtype. OBJECTIVE: To assess whether targeted inhibition of the serotonin 5HT2A receptor attenuates recurrent thrombosis and improves coronary patency in an in vivo canine model mimicking unstable angina. METHODS: In protocol 1, anesthetized dogs were pretreated with a novel, selective inverse agonist of the 5HT2A receptor (APD791) or saline. Recurrent coronary thrombosis was then initiated by coronary artery injury+stenosis, and coronary patency was monitored for 3 h. Protocol 2 was similar, except that: (i) treatment with APD791 or saline was begun 1 h after the onset of recurrent thrombosis; (ii) template bleeding time was measured; and (iii) blood samples were obtained for in vitro flow cytometric assessment of platelet responsiveness to serotonin. RESULTS: APD791 attenuated recurrent thrombosis, irrespective of the time of treatment: in both protocols, flow-time area (index of coronary patency; normalized to baseline coronary flow) averaged 58-59% (P<0.01) following administration of APD791 vs. 21-28% in saline controls. Moreover, the in vivo antithrombotic effect of APD791 was not accompanied by increased bleeding, but was associated with significant and selective inhibition of serotonin-mediated platelet activation. CONCLUSION: 5HT2A receptor inhibition with APD791, even when initiated after the onset of recurrent thrombosis, improves coronary patency in the in vivo canine model.

Randomized controlled trial to assess the impact of continuous glucose monitoring on HbA(1c) in insulin-treated diabetes (MITRE Study).

AIMS: To determine whether continuous glucose information provided through use of either the GlucoWatch G2 Biographer or the MiniMed continuous glucose monitoring system (CGMS) results in improved glycated haemoglobin (HbA(1c)) for insulin-treated adults with diabetes mellitus, relative to an attention control and standard care group. METHODS: Four hundred and four adults taking at least two daily insulin injections and with two consecutive HbA(1c) values > or = 7.5% were recruited to this randomized controlled trial (RCT). All were trained at baseline to use the same monitor for traditional capillary glucose testing throughout the 18-month study. The CGMS group were asked to wear the device three times during the first 3 months of the trial and on another three occasions thereafter. The GlucoWatch group wore the device a minimum of four times per month and a maximum of four times per week during the first 3 months and as desired for the remainder of the trial. Trained diabetes research nurses used downloaded data to guide therapy adjustments. Proportional reduction in HbA(1c) from baseline to 18 months was the primary outcome measure. RESULTS: Neither an intention-to-treat nor per-protocol analysis showed improvement in HbA(1c) in the device groups compared with standard care. For the intention-to-treat analysis, when the standard care group was compared with each of the other groups, this equated to differences in mean relative HbA(1c) reduction (95% confidence interval) from baseline to 18 months of 3.5% (-1.3 to 8.3; GlucoWatch), 0.7% (-4.1 to 5.5; CGMS), and -0.1% (-4.6 to 4.3; attention control). CONCLUSIONS: The additional information provided by these devices did not result in improvements in HbA(1c) in this population.