One-Year Safety Analysis of the COMPARE-AMI Trial: Comparison of Intracoronary Injection of CD133+ Bone Marrow Stem Cells to Placebo in Patients after Acute Myocardial Infarction and Left Ventricular Dysfunction

Bone marrow stem cell therapy has emerged as a promising approach to improve healing of the infarcted myocardium. Despite initial excitement, recent clinical trials using non-homogenous stem cells preparations showed variable and mixed results. Selected CD133+ hematopoietic stem cells are candidate cells with high potential. Herein, we report the one-year safety analysis on the initial 20 patients enrolled in the COMPARE-AMI trial, the first double-blind randomized controlled trial comparing the safety, efficacy, and functional effect of intracoronary injection of selected CD133+ cells to placebo following acute myocardial infarction with persistent left ventricular dysfunction. At one year, there is no protocol-related complication to report such as death, myocardial infarction, stroke, or sustained ventricular arrhythmia. In addition, the left ventricular ejection fraction significantly improved at four months as compared to baseline and remained significantly higher at one year. These data indicate that in the setting of the COMPARE-AMI trial, the intracoronary injection of selected CD133+ stem cells is secure and feasible in patients with left ventricle dysfunction following acute myocardial infarction

Islands of linkage in an ocean of pervasive recombination reveals two-speed evolution of human cytomegalovirus genomes

Human cytomegalovirus (HCMV) infects most of the population worldwide, persisting throughout the host's life in a latent state with periodic episodes of reactivation. While typically asymptomatic, HCMV can cause fatal disease among congenitally infected infants and immunocompromised patients. These clinical issues are compounded by the emergence of antiviral resistance and the absence of an effective vaccine, the development of which is likely complicated by the numerous immune evasins encoded by HCMV to counter the host's adaptive immune responses, a feature that facilitates frequent super-infections. Understanding the evolutionary dynamics of HCMV is essential for the development of effective new drugs and vaccines. By comparing viral genomes from uncultivated or low-passaged clinical samples of diverse origins, we observe evidence of frequent homologous recombination events, both recent and ancient, and no structure of HCMV genetic diversity at the whole-genome scale. Analysis of individual gene-scale loci reveals a striking dichotomy: while most of the genome is highly conserved, recombines essentially freely and has evolved under purifying selection, 21 genes display extreme diversity, structured into distinct genotypes that do not recombine with each other. Most of these hyper-variable genes encode glycoproteins involved in cell entry or escape of host immunity. Evidence that half of them have diverged through episodes of intense positive selection suggests that rapid evolution of hyper-variable loci is likely driven by interactions with host immunity. It appears that this process is enabled by recombination unlinking hyper-variable loci from strongly constrained neighboring sites. It is conceivable that viral mechanisms facilitating super-infection have evolved to promote recombination between diverged genotypes, allowing the virus to continuously diversify at key loci to escape immune detection, while maintaining a genome optimally adapted to its asymptomatic infectious lifecycle

Occurrence of an unusual extensive ice-free feature within the pack ice of the central Weddell Sea, Antarctica

We investigate an unusual extensive ice-free feature (EIF) within the pack ice that developed in the central Weddell Sea in December 1980 on the edge of the multi-year sea ice off the east coast of the Antarctic Peninsula. The EIF was first apparent on satellite imagery on 8 December 1980 and expanded until it reached its largest areal extent of ~5.4 × 105 km2 on 26 December. The combined influences of near-record strength ( ~ 15 ms−1) cold winds from the Antarctic continent (transporting sea ice northward and creating an area of thin ice), increased shortwave radiation and net heat flux into the ocean, passage of deep polar storms, and the upwelling of high saline warm water led to the opening of this unique EIF. It is still the largest ice-free feature within the pack ice resembling a polynya observed in the central Weddell Sea during the satellite era, contributing significantly to the 1981 Weddell Sea sea ice extent minimum of 0.793 × 106 km2, the lowest on record. The development mechanism of this EIF was different from the 1970’s Weddell open ocean polynya which occurred within the winter sea ice cover through enhanced ocean convection

Record low Antarctic sea ice cover in February 2022

On 25 February 2022 Antarctic sea ice extent (SIE) dropped to a satellite-era record low level of 1.92 × 106 km2, 0.92 × 106 km2 below the long-term mean. The area of sea ice was also at a record low level of 1.24 × 106 km2. Although no individual sector was at a record low, at the minimum there were negative sea ice anomalies in all sectors of the Southern Ocean, with the largest in the Ross (contributing 46%) and Weddell Seas (26%). The Amundsen Sea Low had a record low depth in October/November 2021, with a series of very deep depressions giving strong offshore winds. These accelerated ice loss during the melt season, creating a 1.00 × 106 km2 coastal polynya in the Ross Sea. In the northern Weddell Sea, westerly winds of record strength led to ice export from the region

Problem formulation by medical students: an observation study

<p>Abstract</p> <p>Background</p> <p>Medical problems are often complex and ill-structured. In formulating the problem, one has to discriminate pertinent elements from irrelevant information in order to effectively find a solution. In this observation study, we describe how medical students formulate the problem of a complex case.</p> <p>Methods</p> <p>32 third year medical students were presented with a complex case of endocarditis. They were asked to synthesize the case and give the best formulation of the problem. They were then asked to provide a diagnosis. A subsequent group of 25 students were presented with the problem already formulated and were also asked for the diagnosis. We analyzed the student's problem formulations using the presence or absence of essential elements of the case, the use of higher-order concepts and the use of relations between concepts.</p> <p>Results</p> <p>12/32 students presented with the case made the correct diagnosis. Diagnostic accuracy was significantly associated with the use of higher-order concepts and relations between concepts. Establishing explicit relations was particularly important. Almost all students who missed the diagnosis could not elicit any relations between concepts but only reported factual observations. When presented with an already formulated problem, 19/25 students made the correct diagnosis. (p < 0.05)</p> <p>Conclusion</p> <p>When faced with a complex new case, students may not have the structured knowledge to recognize the nature of the problem. They have to build new schema or problem representation. Our observations suggest that this process involves using higher-order concepts and establishing new relations between concepts. The fact that students could recognize the disease when presented with a formulated problem but had more difficulty when presented with the original complex case indicates that knowledge of the clinical features may be necessary but not sufficient for problem formulation. Our hypothesis is that problem formulation represents a distinct ability.</p

No iron fertilization in the equatorial Pacific Ocean during the last ice age

The equatorial Pacific Ocean is one of the major high-nutrient, low-chlorophyll regions in the global ocean. In such regions, the consumption of the available macro-nutrients such as nitrate and phosphate is thought to be limited in part by the low abundance of the critical micro-nutrient iron1. Greater atmospheric dust deposition2 could have fertilized the equatorial Pacific with iron during the last ice age—the Last Glacial Period (LGP) but the effect of increased ice-age dust fluxes on primary productivity in the equatorial Pacific remains uncertain. Here we present meridional transects of dust (derived from the 232Th proxy), phytoplankton productivity (using opal, 231Pa/230Th and excess Ba), and the degree of nitrate consumption (using foraminifera-bound δ15N) from six cores in the central equatorial Pacific for the Holocene (0–10,000 years ago) and the LGP (17,000–27,000 years ago). We find that, although dust deposition in the central equatorial Pacific was two to three times greater in the LGP than in the Holocene, productivity was the same or lower, and the degree of nitrate consumption was the same. These biogeochemical findings suggest that the relatively greater ice-age dust fluxes were not large enough to provide substantial iron fertilization to the central equatorial Pacific. This may have been because the absolute rate of dust deposition in the LGP (although greater than the Holocene rate) was very low. The lower productivity coupled with unchanged nitrate consumption suggests that the subsurface major nutrient concentrations were lower in the central equatorial Pacific during the LGP. As these nutrients are today dominantly sourced from the Subantarctic Zone of the Southern Ocean, we propose that the central equatorial Pacific data are consistent with more nutrient consumption in the Subantarctic Zone, possibly owing to iron fertilization as a result of higher absolute dust fluxes in this region7,8. Thus, ice-age iron fertilization in the Subantarctic Zone would have ultimately worked to lower, not raise, equatorial Pacific productivity

Exercise and the Prevention of Oesophageal Cancer (EPOC) study protocol: a randomized controlled trial of exercise versus stretching in males with Barrett's oesophagus

<p>Abstract</p> <p>Background</p> <p>Chronic gastro-oesophageal reflux disease and excessive body fat are considered principal causes of Barrett's oesophagus (a metaplastic change in the cells lining the oesophagus) and its neoplastic progression, oesophageal adenocarcinoma. Metabolic disturbances including altered levels of obesity-related cytokines, chronic inflammation and insulin resistance have also been associated with oesophageal cancer development, especially in males. Physical activity may have the potential to abrogate metabolic disturbances in males with Barrett's oesophagus and elicit beneficial reductions in body fat and gastro-oesophageal reflux symptoms. Thus, exercise may be an effective intervention in reducing oesophageal adenocarcinoma risk. However, to date this hypothesis remains untested.</p> <p>The 'Exercise and the Prevention of Oesophageal Cancer Study' will determine whether 24 weeks of exercise training will lead to alterations in risk factors or biomarkers for oesophageal adenocarcinoma in males with Barrett's oesophagus. Our primary outcomes are serum concentrations of leptin, adiponectin, tumour necrosis factor-alpha, C-reactive protein and interleukin-6 as well as insulin resistance. Body composition, gastro-oesophageal reflux disease symptoms, cardiovascular fitness and muscular strength will also be assessed as secondary outcomes.</p> <p>Methods/Design</p> <p>A randomized controlled trial of 80 overweight or obese, inactive males with Barrett's oesophagus will be conducted in Brisbane, Australia. Participants will be randomized to an intervention arm (60 minutes of moderate-intensity aerobic and resistance training, five days per week) or a control arm (45 minutes of stretching, five days per week) for 24 weeks. Primary and secondary endpoints will be measured at baseline (week 0), midpoint (week 12) and at the end of the intervention (week 24).</p> <p>Discussion</p> <p>Due to the increasing incidence and very high mortality associated with oesophageal adenocarcinoma, interventions effective in preventing the progression of Barrett's oesophagus are urgently needed. We propose that exercise may be successful in reducing oesophageal adenocarcinoma risk. This primary prevention trial will also provide information on whether the protective association between physical activity and cancer is causal.</p> <p>Trial Registration</p> <p>ACTRN12609000401257</p

Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically-characterised cohort

n/

Multivariate analysis of FcR-mediated NK cell functions identifies unique clustering among humans and rhesus macaques

Rhesus macaques (RMs) are a common pre-clinical model used to test HIV vaccine efficacy and passive immunization strategies. Yet, it remains unclear to what extent the Fc-Fc receptor (FcR) interactions impacting antiviral activities of antibodies in RMs recapitulate those in humans. Here, we evaluated the FcR-related functionality of natural killer cells (NKs) from peripheral blood of uninfected humans and RMs to identify intra- and inter-species variation. NKs were screened for FcγRIIIa (human) and FcγRIII (RM) genotypes (FcγRIII(a)), receptor signaling, and antibody-dependent cellular cytotoxicity (ADCC), the latter mediated by a cocktail of monoclonal IgG1 antibodies with human or RM Fc. FcγRIII(a) genetic polymorphisms alone did not explain differences in NK effector functionality in either species cohort. Using the same parameters, hierarchical clustering separated each species into two clusters. Importantly, in principal components analyses, ADCC magnitude, NK contribution to ADCC, FcγRIII(a) cell-surface expression, and frequency of phosphorylated CD3ζ NK cells all contributed similarly to the first principal component within each species, demonstrating the importance of measuring multiple facets of NK cell function. Although ADCC potency was similar between species, we detected significant differences in frequencies of NK cells and pCD3ζ+ cells, level of cell-surface FcγRIII(a) expression, and NK-mediated ADCC (P&lt;0.001), indicating that a combination of Fc-FcR parameters contribute to overall inter-species functional differences. These data strongly support the importance of multi-parameter analyses of Fc-FcR NK-mediated functions when evaluating efficacy of passive and active immunizations in pre- and clinical trials and identifying correlates of protection. The results also suggest that pre-screening animals for multiple FcR-mediated NK function would ensure even distribution of animals among treatment groups in future preclinical trials