Quality of life during olaparib maintenance therapy in platinum-sensitive relapsed serous ovarian cancer

Maintenance monotherapy with the poly(ADP-ribose) polymerase inhibitor olaparib significantly prolongs progression-free survival over placebo in patients with platinum-sensitive relapsed serous ovarian cancer, with greatest benefit seen in patients with a BRCA1/2 mutation (BRCAm). Preservation of health-related quality of life (HRQoL) is important during maintenance therapy; we evaluated the effect of olaparib on HRQoL in this Phase II trial (NCT00753545, Study 19).status: publishe

Towards real-time cardiovascular magnetic resonance guided transarterial CoreValve implantation: in vivo evaluation in swine

<p>Abstract</p> <p>Background</p> <p>Real-time cardiovascular magnetic resonance (rtCMR) is considered attractive for guiding TAVI. Owing to an unlimited scan plane orientation and an unsurpassed soft-tissue contrast with simultaneous device visualization, rtCMR is presumed to allow safe device navigation and to offer optimal orientation for precise axial positioning. We sought to evaluate the preclinical feasibility of rtCMR-guided transarterial aortic valve implatation (TAVI) using the nitinol-based Medtronic CoreValve bioprosthesis.</p> <p>Methods</p> <p>rtCMR-guided transfemoral (n = 2) and transsubclavian (n = 6) TAVI was performed in 8 swine using the original CoreValve prosthesis and a modified, CMR-compatible delivery catheter without ferromagnetic components.</p> <p>Results</p> <p>rtCMR using TrueFISP sequences provided reliable imaging guidance during TAVI, which was successful in 6 swine. One transfemoral attempt failed due to unsuccessful aortic arch passage and one pericardial tamponade with subsequent death occurred as a result of ventricular perforation by the device tip due to an operating error, this complication being detected without delay by rtCMR. rtCMR allowed for a detailed, simultaneous visualization of the delivery system with the mounted stent-valve and the surrounding anatomy, resulting in improved visualization during navigation through the vasculature, passage of the aortic valve, and during placement and deployment of the stent-valve. Post-interventional success could be confirmed using ECG-triggered time-resolved cine-TrueFISP and flow-sensitive phase-contrast sequences. Intended valve position was confirmed by ex-vivo histology.</p> <p>Conclusions</p> <p>Our study shows that rtCMR-guided TAVI using the commercial CoreValve prosthesis in conjunction with a modified delivery system is feasible in swine, allowing improved procedural guidance including immediate detection of complications and direct functional assessment with reduction of radiation and omission of contrast media.</p

Comparative Dynamics of Retrograde Actin Flow and Focal Adhesions: Formation of Nascent Adhesions Triggers Transition from Fast to Slow Flow

Dynamic actin network at the leading edge of the cell is linked to the extracellular matrix through focal adhesions (FAs), and at the same time it undergoes retrograde flow with different dynamics in two distinct zones: the lamellipodium (peripheral zone of fast flow), and the lamellum (zone of slow flow located between the lamellipodium and the cell body). Cell migration involves expansion of both the lamellipodium and the lamellum, as well as formation of new FAs, but it is largely unknown how the position of the boundary between the two flow zones is defined, and how FAs and actin flow mutually influence each other. We investigated dynamic relationship between focal adhesions and the boundary between the two flow zones in spreading cells. Nascent FAs first appeared in the lamellipodium. Within seconds after the formation of new FAs, the rate of actin flow decreased locally, and the lamellipodium/lamellum boundary advanced towards the new FAs. Blocking fast actin flow with cytochalasin D resulted in rapid dissolution of nascent FAs. In the absence of FAs (spreading on poly-L-lysine-coated surfaces) retrograde flow was uniform and the velocity transition was not observed. We conclude that formation of FAs depends on actin dynamics, and in its turn, affects the dynamics of actin flow by triggering transition from fast to slow flow. Extension of the cell edge thus proceeds through a cycle of lamellipodium protrusion, formation of new FAs, advance of the lamellum, and protrusion of the lamellipodium from the new base

Substrate protein folds while it is bound to the ATP-independent chaperone Spy

Chaperones assist the folding of many proteins in the cell. While the most well studied chaperones use cycles of ATP binding and hydrolysis to assist protein folding, a number of chaperones have been identified that promote protein folding in the absence of highenergy cofactors. Precisely how ATP-independent chaperones accomplish this feat is unclear. Here we have characterized the kinetic mechanism of substrate folding by the small, ATP-independent chaperone, Spy. Spy rapidly associates with its substrate, Immunity protein 7 (Im7), eliminating its potential for aggregation. Remarkably, Spy then allows Im7 to fully fold into its native state while remaining bound to the surface of the chaperone. These results establish a potentially widespread mechanism whereby ATP-independent chaperones can assist in protein refolding. They also provide compelling evidence that substrate proteins can fold while continuously bound to a chaperone

Effect of hypoxia and Beraprost sodium on human pulmonary arterial smooth muscle cell proliferation: the role of p27kip1

<p>Abstract</p> <p>Background</p> <p>Hypoxia induces the proliferation of pulmonary arterial smooth muscle cell (PASMC) <it>in vivo </it>and <it>in vitro</it>, and prostacyclin analogues are thought to inhibit the growth of PASMC. Previous studies suggest that p27^kip1, a kind of cyclin-dependent kinase inhibitor, play an important role in the smooth muscle cell proliferation. However, the mechanism of hypoxia and the subcellular interactions between p27^kip1and prostacyclin analogues in human pulmonary arterial smooth muscle cell (HPASMC) are not fully understood.</p> <p>Methods</p> <p>We investigated the role of p27^kip1in the ability of Beraprost sodium (BPS; a stable prostacyclin analogue) to inhibit the proliferation of HPASMC during hypoxia. To clarify the biological effects of hypoxic air exposure and BPS on HPASMC, the cells were cultured in a hypoxic chamber under various oxygen concentrations (0.1–21%). Thereafter, DNA synthesis was measured as bromodeoxyuridine (BrdU) incorporation, the cell cycle was analyzed by flow cytometry with propidium iodide staining. The p27^kip1mRNA and protein expression and it's stability was measured by real-time RT-PCR and Western blotting. Further, we assessed the role of p27^kip1in HPASMC proliferation using p27^kip1gene knockdown using small interfering RNA (siRNA) transfection.</p> <p>Results</p> <p>Although severe hypoxia (0.1% oxygen) suppressed the proliferation of serum-stimulated HPASMC, moderate hypoxia (2% oxygen) enhanced proliferation in accordance with enhanced p27^kip1protein degradation, whereas BPS suppressed HPASMC proliferation under both hypoxic and normoxic conditions by suppressing p27^kip1degradation with intracellular cAMP-elevation. The 8-bromo-cyclic adenosine monophosphate (8-Br-cAMP), a cAMP analogue, had similar action as BPS in the regulation of p27^kip1. Moderate hypoxia did not affect the stability of p27^kip1protein expression, but PDGF, known as major hypoxia-induced growth factors, significantly decreased p27^kip1protein stability. We also demonstrated that BPS and 8-Br-cAMP suppressed HPASMC proliferation under both hypoxic and normoxic conditions by blocking p27^kip1mRNA degradation. Furthermore, p27^kip1gene silencing partially attenuated the effects of BPS and partially restored hypoxia-induced proliferation.</p> <p>Conclusion</p> <p>Our study suggests that moderate hypoxia induces HPASMC proliferation, which is partially dependent of p27^kip1down-regulation probably <it>via </it>the induction of growth factors such as PDGF, and BPS inhibits both the cell proliferation and p27^kip1mRNA degradation through cAMP pathway.</p

International challenges without borders: a descriptive study of family physicians' educational needs in the field of diabetes

<p>Abstract</p> <p>Background</p> <p>The optimal care of persons with diabetes by general practitioners and family physicians (GP/FP) is complex and requires multiple competencies. This is a fairly unrecognized key challenge in the healthcare systems. In some cases, local and national Continuous Professional Development (CPD) initiatives target these challenges; however there have been few international initiatives, possibly because challenges emerging from different studies have not been linked across national boundaries. In this context, the authors have compiled data about gaps and/or barriers inherent to GP/FP care of persons with type 2 diabetes from Austria, Canada, Germany and the United Kingdom.</p> <p>Methods</p> <p>Secondary analyzes of pre-existing studies were conducted to identify challenges in the care of patients with type 2 diabetes as faced by GPs/FPs. Two sources of data were reviewed: unpublished research data from collaborating organizations and articles from a literature search (in English and German). Articles retrieved were scanned by the research team for relevance to the study objectives and to extract existing gaps and barriers. The identified challenges were then categorized along three major axes: (1) phase of the continuum of care {from screening to management}; (2) learning domain {knowledge, skills, attitudes, behavior, context}; and (3) by country/region. Compilation and categorization were performed by qualitative researchers and discrepancies were resolved through discussion until concordance was achieved.</p> <p>Results and discussion</p> <p>Thirteen challenges faced by GPs/FPs in the care for patients with type 2 diabetes were common in at least 3 of the 4 targeted countries/regions. These issues were found across the entire continuum of care and included: pathophysiology of diabetes, diagnostic criteria, treatment targets assessment, drugs' modes of action, decision-making in therapies, treatment guidelines, insulin therapy, adherence, management of complications, lifestyle changes, team integration, bureaucracy and third-party payers. The issues reported were not restricted to the physicians' knowledge, but also related to their skills, attitudes, behaviours and context.</p> <p>Conclusions</p> <p>This study revealed challenges faced by GPs/FPs when caring for patients with diabetes, which were similar across international and health system borders. Common issues might be addressed more efficiently through international educational designs, adapted to each country's healthcare system, helping develop and maintain physicians' competencies.</p

No-go trials can modulate switch cost by interfering with effects of task preparation

It has recently been shown that the cost associated with switching tasks is eliminated following ‘no-go’ trials, in which response selection is not completed, suggesting that the switch cost depends on response selection. However, no-go trials may also affect switch costs by interfering with the effects of task preparation that precede response selection. To test this hypothesis we evaluated switch costs following standard go trials with those following two types of non-response trials: no-go trials, for which a stimulus is presented that indicates no response should be made (Experiment 1); and cue-only trials in which no stimulus is presented following the task cue (Experiment 2). We hypothesized that eliminating no-go stimuli would reveal effects of task preparation on the switch cost in cue-only trials. We found no switch cost following no-go trials (Experiment 1), but a reliable switch cost in cue-only trials (i.e., when no-go stimuli were removed; Experiment 2). We conclude that no-go trials can modulate the switch cost, independent of their effect on response selection, by interfering with task preparation, and that the effects of task preparation on switch cost are more directly assessed by cue-only trials

Raising AWaRe-ness of antimicrobial stewardship challenges in pediatric emergency care: results from the PERFORM study assessing consistency and appropriateness of antibiotic prescribing across Europe.

OBJECTIVES Optimization of antimicrobial stewardship (AMS) is key to tackling antimicrobial resistance (AMR), which is exacerbated by over-prescription of antibiotics in pediatric Emergency Departments (EDs). We described patterns of empiric antibiotic use in European EDs, and characterized appropriateness and consistency of prescribing. METHODS Between August 2016 and December 2019 febrile children attending the ED in nine European countries with suspected infection were recruited into the PERFORM (Personalised Risk assessment in Febrile illness to Optimise Real-life Management) study. Empiric systemic antibiotic use was determined in view of assigned final 'bacterial' or 'viral' phenotype. Antibiotics were classified according to WHO AWaRe. RESULTS Of 2130 febrile episodes (excluding children with non-bacterial/non-viral phenotypes), 1549 (72.7%) were assigned a 'bacterial' and 581 (27.3%) a 'viral' phenotype. A total of 1318/1549 (85.1%) episodes with a 'bacterial' and 269/581 (46.3%) with a 'viral' phenotype received empiric systemic antibiotics (first two days of admission). Of those, the majority (87.8% in 'bacterial' and 87.0% in 'viral' group) received parenteral antibiotics. The top three antibiotics prescribed were third-generation cephalosporins, penicillins and penicillin/beta-lactamase inhibitor combinations. Of those treated with empiric systemic antibiotics in the 'viral' group 216/269 (80.3%) received ≥ one Watch antibiotic. CONCLUSIONS Differentiating bacterial from viral etiology in febrile illness on initial ED presentation remains challenging, resulting in a substantial over-prescription of antibiotics. A significant proportion of patients with a 'viral' phenotype received systemic antibiotics, predominantly classified as WHO Watch. Rapid and accurate point-of-care tests in the ED differentiating between bacterial and viral etiology, could significantly improve AMS

Acoustic Oddball during NREM Sleep: A Combined EEG/fMRI Study

Background: A condition vital for the consolidation and maintenance of sleep is generally reduced responsiveness to external stimuli. Despite this, the sleeper maintains a level of stimulus processing that allows to respond to potentially dangerous environmental signals. The mechanisms that subserve these contradictory functions are only incompletely understood. Methodology/Principal Findings: Using combined EEG/fMRI we investigated the neural substrate of sleep protection by applying an acoustic oddball paradigm during light NREM sleep. Further, we studied the role of evoked K-complexes (KCs), an electroencephalographic hallmark of NREM sleep with a still unknown role for sleep protection. Our main results were: (1) Other than in wakefulness, rare tones did not induce a blood oxygenation level dependent (BOLD) signal increase in the auditory pathway but a strong negative BOLD response in motor areas and the amygdala. (2) Stratification of rare tones by the presence of evoked KCs detected activation of the auditory cortex, hippocampus, superior and middle frontal gyri and posterior cingulate only for rare tones followed by a KC. (3) The typical high frontocentral EEG deflections of KCs were not paralleled by a BOLD equivalent. Conclusions/Significance: We observed that rare tones lead to transient disengagement of motor and amygdala responses during light NREM sleep. We interpret this as a sleep protective mechanism to delimit motor responses and to reduce the sensitivity of the amygdala towards further incoming stimuli. Evoked KCs are suggested to originate from a brain state wit