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Background Empiric antifungal therapy is considered the standard of care for high-risk neutropenic patients with persistent fever. The impact of a preemptive, diagnostic-driven approach based on galactomannan screening and chest computed tomography scan on demand on survival and on the risk of invasive fungal disease (IFD) during the first weeks of high-risk neutropenia is unknown. Methods Patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) and allogeneic hematopoietic cell transplant recipients were randomly assigned to receive caspofungin empirically (arm A) or preemptively (arm B), while receiving fluconazole 400 mg daily prophylactically. The primary end point of this noninferiority study was overall survival (OS) 42 days after randomization. Results Of 556 patients recruited, 549 were eligible: 275 in arm A and 274 in arm B. Eighty percent of the patients had AML or MDS requiring high-dose chemotherapy, and 93% of them were in the first induction phase. At day 42, the OS was not inferior in arm B (96.7%; 95% confidence interval [CI], 93.8%–98.3%) when compared with arm A (93.1%; 95% CI, 89.3%–95.5%). The rates of IFDs at day 84 were not significantly different, 7.7% (95% CI, 4.5%–10.8%) in arm B vs 6.6% (95% CI, 3.6%–9.5%) in arm A. The rate of patients who received caspofungin was significantly lower in arm B (27%) than in arm A (63%; P < .001). Conclusions The preemptive antifungal strategy was safe for high-risk neutropenic patients given fluconazole as prophylaxis, halving the number of patients receiving antifungals without excess mortality or IFDs. Clinical Trials Registration. NCT01288378; EudraCT 2010-020814-27.

Background The performance of the galactomannan enzyme immunoassay (GM-EIA) is impaired in patients receiving mould-active antifungal therapy. The impact of mould-active antifungal therapy on Aspergillus PCR testing needs to be determined. Objectives To determine the influence of anti-mould prophylaxis (AMP) on the performance of PCR blood testing to aid the diagnosis of proven/probable invasive aspergillosis (IA). Methods As part of the systematic review and meta-analysis of 22 cohort studies investigating Aspergillus PCR blood testing in 2912 patients at risk of IA, subgroup analysis was performed to determine the impact of AMP on the accuracy of Aspergillus PCR. The incidence of IA was calculated in patients receiving and not receiving AMP. The impact of two different positivity thresholds (requiring either a single PCR positive test result or ≥2 consecutive PCR positive test results) on accuracy was evaluated. Meta-analytical pooling of sensitivity and specificity was performed by logistic mixed-model regression. Results In total, 1661 (57%) patients received prophylaxis. The incidence of IA was 14.2%, significantly lower in the prophylaxis group (11%–12%) compared with the non-prophylaxis group (18%–19%) (P Conclusions Contrary to its influence on GM-EIA, AMP significantly decreases Aspergillus PCR specificity, without affecting sensitivity, possibly as a consequence of AMP limiting the clinical progression of IA and/or leading to false-negative GM-EIA results, preventing the classification of probable IA using the EORTC/MSGERC definitions.

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BACKGROUND: Few studies have explored the cerebral venous compartment or the correlation between venous and arterial cerebral blood flows. We aimed to correlate cerebral blood flow velocities in the arterial (middle cerebral artery) and venous (straight sinus) compartments in healthy volunteers and traumatic brain injury (TBI) patients. In addition, we determined the normative range of these parameters.; MATERIALS AND METHODS: A total of 122 healthy volunteers and 95 severe TBI patients of both sexes were included and stratified into 3 age groups as follows: group 1 (aged, 18 to 44y); group 2 (aged, 45 to 64y); group 3 (older than 65y). Transcranial Doppler systolic cerebral blood flow velocity, diastolic cerebral blood flow velocity, and mean cerebral blood flow velocity (FVs, FVd, FVm, respectively) were measured in the middle cerebral artery and peak cerebral venous blood flow velocity (FVVs) was measured in the straight sinus. The arteriovenous correlation was assessed on the basis of a positive relationship between FVs and FVVs.; RESULTS: There was an arteriovenous correlation (FVs vs. FVVs) in healthy volunteers (R=0.39, P

International audience; Interlaboratory evaluations of Mucorales qPCR assays were developed to assess the reproducibility and performance of methods currently used. The participants comprised 12 laboratories from French university hospitals (nine of them participating in the Modimucor study) and 11 laboratories participating in the Fungal PCR Initiative. For panel 1, three sera were each spiked with DNA from three different species (Rhizomucor pusillus, Lichtheimia corymbifera, Rhizopus oryzae). For panel 2, six sera with three concentrations of R. pusillus and L. corymbifera (1, 10, and 100 genomes/ml) were prepared. Each panel included a blind negative-control serum. A form was distributed with each panel to collect results and required technical information, including DNA extraction method, sample volume used, DNA elution volume, qPCR method, qPCR template input volume, qPCR total reaction volume, qPCR platform, and qPCR reagents used. For panel 1, assessing 18 different protocols, qualitative results (positive or negative) were correct in 97% of cases (70/72). A very low interlaboratory variability in Cq values (SD = 1.89 cycles) were observed. For panel 2 assessing 26 different protocols, the detection rates were high (77-100%) for 5/6 of spiked serum. There was a significant association between the qPCR platform and performance. However, certain technical steps and optimal combinations of factors may also impact performance. The good reproducibility and performance demonstrated in this study support the use of Mucorales qPCR as part of the diagnostic strategy for mucormycosis.

ispartof: CLINICAL INFECTIOUS DISEASES vol:71 issue:12 pages:3266-3266 ispartof: location:United States status: published

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Invasive fungal diseases (IFDs) remain important causes of morbidity and mortality. The consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group have been of immense value to researchers who conduct clinical trials of antifungals, assess diagnostic tests, and undertake epidemiologic studies. However, their utility has not extended beyond patients with cancer or recipients of stem cell or solid organ transplants. With newer diagnostic techniques available, it was clear that an update of these definitions was essential. To achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups' findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved. There is no change in the classifications of "proven," "probable," and "possible" IFD, although the definition of "probable" has been expanded and the scope of the category "possible" has been diminished. The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable and possible categories are proposed for immunocompromised patients only, except for endemic mycoses. These updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk.

Objective To evaluate whether a structured exercise programme improved functional and health related quality of life outcomes compared with usual care for women at high risk of upper limb disability after breast cancer surgery. Design Multicentre, pragmatic, superiority, randomised controlled trial with economic evaluation. Setting 17 UK National Health Service cancer centres. Participants 392 women undergoing breast cancer surgery, at risk of postoperative upper limb morbidity, randomised (1:1) to usual care with structured exercise (n=196) or usual care alone (n=196). Interventions Usual care (information leaflets) only or usual care plus a physiotherapy led exercise programme, incorporating stretching, strengthening, physical activity, and behavioural change techniques to support adherence to exercise, introduced at 7-10 days postoperatively, with two further appointments at one and three months. Main outcome measures Disability of Arm, Hand and Shoulder (DASH) questionnaire at 12 months, analysed by intention to treat. Secondary outcomes included DASH subscales, pain, complications, health related quality of life, and resource use, from a health and personal social services perspective. Results Between 26 January 2016 and 31 July 2017, 951 patients were screened and 392 (mean age 58.1 years) were randomly allocated, with 382 (97%) eligible for intention to treat analysis. 181 (95%) of 191 participants allocated to exercise attended at least one appointment. Upper limb function improved after exercise compared with usual care (mean DASH 16.3 (SD 17.6) for exercise (n=132); 23.7 (22.9) usual care (n=138); adjusted mean difference 7.81, 95% confidence interval 3.17 to 12.44; P=0.001). Secondary outcomes favoured exercise over usual care, with lower pain intensity at 12 months (adjusted mean difference on numerical rating scale −0.68, −1.23 to −0.12; P=0.02) and fewer arm disability symptoms at 12 months (adjusted mean difference on Functional Assessment of Cancer Therapy-Breast+4 (FACT-B+4) −2.02, −3.11 to −0.93; P=0.001). No increase in complications, lymphoedema, or adverse events was noted in participants allocated to exercise. Exercise accrued lower costs per patient (on average −£387 (€457; $533) (95% confidence interval −£2491 to £1718; 2015 pricing) and was cost effective compared with usual care. Conclusions The PROSPER exercise programme was clinically effective and cost effective and reduced upper limb disability one year after breast cancer treatment in patients at risk of treatment related postoperative complications. Trial registration ISRCTN Registry ISRCTN35358984 .

Quantitative real-time PCR (qPCR) is increasingly used to detect Pneumocystis jirovecii for the diagnosis of Pneumocystis pneumonia (PCP), but there are differences in the nucleic acids targeted, DNA only versus whole nucleic acid (WNA), and also the target genes for amplification. Through the Fungal qPCR Initiative, a working group of the International Society for Human and Animal Mycology, a multicentre and monocentre evaluation of PCP qPCR assays was performed. For the multicentre study, 16 reference laboratories from eight different countries, performing 20 assays analysed a panel consisting of two negative and three PCP positive samples. Aliquots were prepared by pooling residual material from 20 negative or positive- P. jirovecii bronchoalveolar lavage fluids (BALFs). The positive pool was diluted to obtain three concentrations (pure 1:1; 1:100; and 1:1000 to mimic high, medium, and low fungal loads respectively). The monocentre study compared five in-house and five commercial qPCR assays testing 19 individual BALFs on the same amplification platform. Across both evaluations and for all fungal loads, targeting WNA and the mitochondrial small sub-unit (mtSSU) provided the earliest Cq values, compared to only targeting DNA and the mitochondrial large subunit, the major surface glycoprotein or the beta-tubulin genes. Thus, Reverse Transcriptase-qPCR targeting the mtSSU gene could serve as a basis for standardizing the P. jirovecii load, which is essential if qPCR is to be incorporated into clinical care pathways as the reference method, accepting that additional parameters such as amplification platforms still need evaluation

Cerebral autoregulatory dysfunction after traumatic brain injury (TBI) is strongly linked to poor global outcome in patients at 6 months after injury. However, our understanding of what drives this dysfunction is limited. Genetic variation among individuals within a population gives rise to single nucleotide polymorphisms (SNPs) that have the potential to influence a given patient’s cerebrovascular response to an injury. Associations have been reported between a variety of genetic polymorphisms and global outcome in patients with TBI, but few studies have explored the association between genetics and cerebrovascular function after injury. In this Review, we explore polymorphisms that might play an important part in cerebral autoregulatory capacity after TBI. We outline a variety of SNPs, their biological substrates and their potential role in mediating cerebrovascular reactivity. A number of candidate polymorphisms exist in genes that are involved in myogenic, endothelial, metabolic and neurogenic vascular responses to injury. Furthermore, polymorphisms in genes involved in inflammation, the central autonomic response and spreading cortical depression might drive cerebrovascular reactivity. Identification of candidate genes involved in cerebral autoregulation after TBI provides a platform and rationale for further prospective investigation of the link between genetic polymorphisms and autoregulatory function.

The mission of EnABLES is to open up key research infrastructure in the Internet of Things (IoT) to all European researchers, from both academia and industry. Six research Institutes together with 5 knowledge hubs are providing access to researchers to enable them to create ‘self-sustaining’ energy solutions to ‘power the internet of things’ based on energy harvesting, storage, micro-power management and system integration activities. This paper provides an overview of the reasons why EnABLES is needed, particularly for enabling researchers address key challenges such as extending battery life of wireless IoT edge devices, and, where possible, eliminating the need for battery replacement. The ultimate goal of EnABLES is to create a ‘starting community’ to foster collaborations to address these challenges and opportunities & accelerate technology development. The 2 primary approaches used in EnABLES are outlined:- (i) A transnational access (TA) and virtual access (VA) program open to all external stakeholders to do free-of-charge feasibility studies leveraging from the facilities and expertise of EnABLES partners. (ii) Joint Research Activities (JRAs) between partners. (Some examples of JRA activities are outlined at high level). Simulations and data libraries are retained in an open access repository with an emphasis on creating standardized and interoperable parts and understanding their system level behaviour. EnABLES also fosters internal collaboration between partners (JRAs) guided by needs and opportunities. A key goal of the project is to create standardised and interoperable libraries of parts & simulation tools for optimising system level performance.

"L'intenzione del libro è sempre stata chiara per noi: offrire una presentazione comprensibile e concisa dei principi basilari del marketing. Ciò è per noi una sfida continua che ci spinge a concentrarci su quello che gli studenti hanno realmente bisogno di conoscere e, allo stesso tempo, a trattare i concetti chiave in modo sufficientemente approfondito da garantire una comprensione esaustiva della materia. Per raggiungere questo scopo, da un lato, è necessario accrescere la qualità dei contenuti e dall'altro essere chiari e sintetici."

Contains fulltext : 171209.pdf (Publisher’s version ) (Closed access) Pneumocystis jirovecii can cause life-threatening pneumonia following treatment for haematological malignancies or after HSCT. The mortality rate of P. jirovecii pneumonia (PCP) in these patients is 30%-60%, especially after HSCT. The clinical presentation of PCP in haematology differs from that associated with HIV infection, with the disease being acute and more often severe, having a lower fungal burden and being more frequently linked to treatment with corticosteroids. Most cases occur in patients not receiving adequate prophylaxis. The development of new therapies, including targeted treatments and monoclonal antibodies in various haematological diseases, justifies constant vigilance in order to identify new at-risk populations and give prophylaxis accordingly. The fifth and sixth European Conferences on Infections in Leukaemia (ECIL-5 and ECIL-6) aimed to review risk factors for PCP in haematology patients and to establish evidence-based recommendations for PCP diagnosis, prophylaxis and treatment. This article focuses on the magnitude of the problem, the main differences in clinical presentation between haematology patients and other immunocompromised populations, especially HIV-infected patients, and the main risk factors.

Objective: Monitoring cerebral autoregulation (CA) is important for TBI patients, 1 as impaired CA correlates with poor outcome. 2 3 Today, automated algorithms allow to assess CPP for which autoregulation is best preserved (CPPopt) continuously and present it at the bedside 5 6 . Individualising CPP treatment using CPPopt is attractive and this has been recognised in published guidelines. However there are no specifications for its use clinically and it has therefore never been prospectively evaluated 1 . Numerous logistic, technical, feasibility and safety questions remain before the idea of selecting individual CPP treatment targets based on the state of CA 4 can be incorporated into clinical practice. How far are we from strict guidelines on the incorporation of this methodology into TBI protocols? Design: Literature review Subjects: Methods: Systematic review Results: The feasibility of CPPot-guided therapy has only been evaluated retrospectively and in non-clinical ways, whereas no studies exist on its safety. A prospective investigation of CPPopt-guided therapy has been initiated with ‘CppOpt Guided Therapy: Assessment of Target Effectiveness’ (COGiTATE), a multicenter randomized trial assessing feasibility and safety of a continuous CA monitoring-based therapy in adult TBI patients. Conclusions: COGiTATE seems to be the first step to define the physiological effect of targeting CPPopt and should pave the way toward establishing the exact protocol of CPPopt-oriented therapy and the phase III study. References: 1. Carney N, Totten AM, OʼReilly C, et al. Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery. 2016;80(1):1. doi:10.1227/NEU.0000000000001432. 2. Hlatky R, Furuya Y, Valadka AB, et al. Dynamic autoregulatory response after severe head injury. J Neurosurg. 2002;97(5):1054-1061. doi:10.3171/jns.2002.97.5.1054. 3. Czosnyka M, Czosnyka Z, Smielewski P. Pressure reactivity index: journey through the past 20 years. doi:10.1007/s00701-017-3310-1. 4. Steiner LA, Czosnyka M, Piechnik SK, et al. Continuous monitoring of cerebrovascular pressure reactivity allows determination of optimal cerebral perfusion pressure in patients with traumatic brain injury. Crit Care Med. 2002;30(4):733-738. http://www.ncbi.nlm.nih.gov/pubmed/11940737. Accessed December 28, 2017. 5. Aries MJH, Czosnyka M, Budohoski KP, et al. Continuous determination of optimal cerebral perfusion pressure in traumatic brain injury*. Crit Care Med. 2012. doi:10.1097/CCM.0b013e3182514eb6. 6. Liu X, Maurits NM, Aries MJH, et al. Monitoring of Optimal Cerebral Perfusion Pressure in Traumatic Brain Injured Patients Using a Multi-Window Weighting Algorithm. J Neurotrauma. 2017;34(22):3081-3088. doi:10.1089/neu.2017.5003. 7. Depreitere B, Güiza F, Berghe G Van Den, et al. Pressure autoregulation monitoring and cerebral perfusion pressure target recommendation in patients with severe traumatic brain injury based on minute-by-minute monitoring data. J Neurosurg. 2014;120(120):1451-1457. doi:10.3171/2014.3.JNS131500. 8. Güiza F, Meyfroidt G, Piper I, et al. Cerebral Perfusion Pressure Insults and Associations with Outcome in Adult Traumatic Brain Injury. doi:10.1089/neu.2016.4807. 9. Oshorov A V, Savin IA, Goriachev AS, Popugaev KA, Potapov AA, Gavrilov AG. [The first experience in monitoring the cerebral vascular autoregulation in the acute period of severe brain injury]. Anesteziol Reanimatol. (2):61-64. http://www.ncbi.nlm.nih.gov/pubmed/18540464. Accessed January 1, 2018. 10. Donnelly J, Czosnyka M, Adams H, et al. Individualizing Thresholds of Cerebral Perfusion Pressure Using Estimated Limits of Autoregulation. Crit Care Med. 2017;45(9):1464-1471. doi:10.1097/CCM.0000000000002575. 11. Dias C, Silva MJ, Pereira E, et al. Optimal Cerebral Perfusion Pressure Management at Bedside: A Single-Center Pilot Study. Neurocrit Care. 2015;23(1):92-102. doi:10.1007/s12028-014-0103-8. 12. Jaeger M, Dengl M, Jü, Schuhmann MU. Effects of cerebrovascular pressure reactivity-guided optimization of cerebral perfusion pressure on brain tissue oxygenation after traumatic brain injury*. Crit Care Med. 2010;38(5):1343-1347. doi:10.1097/ccm.0b013e3181d45530.

BACKGROUND: Optimal cerebral perfusion pressure (CPPopt) targeting in traumatic brain injury (TBI) patients constitutes an active and controversial area of research. It has been suggested that an autoregulation guided CPP therapy may improve TBI outcome. Prerequisites of a CPPopt intervention study would be objective criteria for the CPPopt detection.. This study compared the agreement between automated and visual CPPopt detection. METHODS: Twenty-five clinicians from 18 centres worldwide, familiar with brain monitoring and using dedicated software, reviewed ten 4-hour CPPopt screenshots at 48 hrs after ictus in selected TBI patients. Each screenshot displayed the trends of cerebral perfusion pressure (CPP), intracranial pressure (ICP), cerebrovascular pressure reactivity (PRx) as well as the ‘CPP-optimal’ curve and its associated value (automated CPPopt). The main objective was to evaluate the agreement between expert clinicians as well as the agreement between the clinicians and automated CPPopt. RESULTS: Twenty-two clinicians responded to our call (88%). Three screenshots were judged as ‘CPPopt not determinable’ by > 45% of the clinicians. For the whole group, the consensus between automated CPPopt and clinicians’ visual CPPopt was high. Three clinicians were identified as outliers. All clinicians recommended to modify CPP when patients differed > ± 5 mmHg from their CPPopt. The inter-observer consensus was highest in cases with current CPP below the optimal value. CONCLUSIONS: The overall agreement between automated CPPopt and visual CPPopt identified by autoregulation experts was high, except for those cases when the curve was deemed by the clinicians not reliable enough to yield a trustworthy CPPopt.

Cerebral autoregulation is conceptualized as a vascular self-regulatory mechanism within the brain. Controlled by elusive relationships between various biophysical processes, it functions to protect the brain against potential damages caused by sudden changes in cerebral perfusion pressures and flow. Following events such as traumatic brain injuries (TBI), autoregulation may be compromised, potentially leading to an unfavorable outcome. In spite of its complexity, autoregulation has been able to be quantified non-invasively within the neuro-critical care setting with the aid of transcranial Doppler. This information is interpreted particularly through calculated derived indices based on commonly-monitored input signals such as arterial blood pressure and intracranial pressure (i.e. Pressure reactivity index (PRx), mean flow index (Mx), etc.). For example, PRx values that trend towards positive numbers are correlated with unfavorable outcome. These predictors are primarily surrogate markers of cerebral hemodynamic activity, although suggesting robust correlations between these indices and patient outcome. This review of the literature seeks to explain the methodology behind the calculations of various measures of autoregulation in adult patients suffering from traumatic brain injuries, and how they can interact with one another to both create larger effects on patient outcome and general outcome prediction models. Insight into the driving forces behind cerebral autoregulation is imperative for guiding both clinical decision-making and global treatment protocols for neuro-critically ill patients. The evidence that autoregulation-oriented therapy may improve outcome after TBI is still oscillating around Level III.

To perform systematically a scoping review of the literature on commonly described continuous autoregulation measurement techniques in adult TBI. The goal was to provide an overview of methodology and comprehensive reference library of the available literature for each technique. Five separate small systematic reviews were conducted for each of the continuous techniques: pressure reactivity index (PRx), laser Doppler flowmetry (LDF), near infrared spectroscopy (NIRS) techniques, brain tissue oxygen tension (PbtO2), and thermal diffusion (TD) techniques. Articles from MEDLINE, BIOSIS, EMBASE, Global Health, Scopus, Cochrane Library (inception to December 2016) and reference lists of relevant articles were searched. A two-tier filter of references was conducted. The literature base identified from the individual searches was limited, except for PRx. The total number of articles utilizing each of the 5 searched techniques for continuous autoregulation in adult TBI were: PRx (28), LDF (4), NIRS (9), PbtO2 (10), and TD (8). All continuous techniques described in adult TBI are based on moving correlation coefficients. The premise behind the calculation of these moving correlation coefficients focuses on the impact of slow fluctuations in either MAP or CPP on some indirect measure of CBF, such as: intracranial pressure (ICP), LDF, NIRS signals, PbtO2 or TD CBF. The thought is the correlation between a hemodynamic driving factor, such as MAP or CPP, and a surrogate for CBF or cerebral perfusion sheds insight on the state of cerebral autoregulation. Both PRx and NIRS indices were validated experimentally against ‘golden standard’ static autoregulatory curve (Lassen curve) at least around lower threshold of autoregulation. PRx has the largest literature base supporting the association with patient outcome. Various methods of continuous autoregulation assessment are described within the adult TBI literature. Many studies exist on these various indices, suggesting an association between their values and patient morbidity/mortality.

NEW FINDINGS: What is the central question of this study? Does passive heat stress of +2°C oesophageal temperature change concentrations of circulating arterial endothelial- and platelet-derived microparticles in healthy adults? What is the main finding and its importance? Concentrations of circulating endothelial- and platelet-derived microparticles were markedly decreased in heat stress. Reductions in circulating microparticles might indicate favourable vascular changes associated with non-pathological hyperthermia. Interest in circulating endothelial- and platelet-derived microparticles (EMPs and PMPs, respectively) has increased because of their potential pathogenic role in vascular disease and as biomarkers for vascular health. Hyperthermia is commonly associated with a pro-inflammatory stress but might also provide vascular protection when the temperature elevation is non-pathological. Circulating microparticles might contribute to the cellular adjustments and resultant vascular impacts of hyperthermia. Here, we determined whether circulating concentrations of arterial EMPs and PMPs are altered by passive heat stress (+2°C oesophageal temperature). Ten healthy young men (age 23 ± 3 years) completed the study. Hyperthermia was achieved by circulating ∼49°C water through a water-perfused suit that covered the entire body except the hands, feet and head. Arterial (radial) blood samples were obtained immediately before heating (normothermia) and in hyperthermia. The mean ± SD oesophageal temperature in normothermia was 37.2 ± 0.1°C and in hyperthermia 39.1 ± 0.1°C. Concentrations of circulating EMPs and PMPs were markedly decreased in hyperthermia. Activation-derived EMPs were reduced by ∼30% (mean ± SD; from 61 ± 8 to 43 ± 7 microparticles μl-1 ; P < 0.05) and apoptosis-derived EMPs by ∼45% (from 46 ± 7 to 23 ± 3 microparticles μl-1 ; P < 0.05). Likewise, circulating PMPs were reduced by ∼75% in response to hyperthermia (from 256 ± 43 to 62 ± 14 microparticles μl-1 ). These beneficial reductions in circulating EMPs and PMPs in response to a 2°C increase in core temperature might partly underlie the reported vascular improvements following therapeutic bouts of physiological hyperthermia.

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Contains fulltext : 169784.pdf (Publisher’s version ) (Closed access)

[Objectives] To prevent invasive fungal disease (IFD) in adult patients undergoing remission-induction chemotherapy for newly diagnosed acute lymphoblastic leukaemia (ALL)., [Patients and methods] In a double-blind multicentre Phase 3 study, patients received prophylactic liposomal amphotericin B (L-AMB) at 5 mg/kg intravenously or placebo twice weekly in a 2:1 random allocation during remission-induction treatment. The primary endpoint was the development of proven or probable IFD. Secondary endpoints included those focused on the safety and tolerability of prophylactic L-AMB., [Results] Three hundred and fifty-five patients from 86 centres in Europe and South America received at least one dose of L-AMB (n = 237) or placebo (n = 118). Rates of proven and probable IFD assessed independently were 7.9% (18/228) in the L-AMB group and 11.7% (13/111) in the placebo group (P = 0.24). Rates of possible IFD were 4.8% (11/228) in the L-AMB and 5.4% (6/111) in the placebo group (P = 0.82). The remission-induction phase was a median of 22 days for both groups. Overall mortality was similar between the groups: 7.2% (17/237) for L-AMB and 6.8% (8/118) for placebo (P = 1.00). Hypokalaemia and creatinine increase were significantly more frequent with L-AMB., [Conclusions] The IFD rate among adult patients undergoing remission-induction chemotherapy for newly diagnosed ALL was 11.7% in the placebo group, and was not significantly different in patients receiving L-AMB, suggesting that the L-AMB regimen studied is not effective as prophylaxis against IFD. The IFD rate appears higher than previously reported, warranting further investigation. Tolerability of L-AMB was what might be expected. Further studies are needed to determine the optimal antifungal strategy during remission-induction chemotherapy of ALL., This study was funded by Gilead Sciences, Inc. M. B., W. G. and M. J. H. are employees of Gilead Sciences. All other authors or their institutions have received compensation for study participation from Gilead Sciences International Ltd.

As the mortality associated with invasive Candida infections remains high, it is important to make optimal use of available diagnostic tools to initiate antifungal therapy as early as possible and to select the most appropriate antifungal drug. A panel of experts of the European Fungal Infection Study Group (EFISG) of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) undertook a data review and compiled guidelines for the clinical utility and accuracy of different diagnostic tests and procedures for detection of Candida infections. Recommendations about the microbiological investigation and detection of candidaemia, invasive candidiasis, chronic disseminated candidiasis, and oropharyngeal, oesophageal, and vaginal candidiasis were included. In addition, remarks about antifungal susceptibility testing and therapeutic drug monitoring were made.

Contains fulltext : 172373.pdf (Publisher’s version ) (Closed access) The 5th European Conference on Infections in Leukaemia (ECIL-5) meeting aimed to establish evidence-based recommendations for the prophylaxis of Pneumocystis jirovecii pneumonia (PCP) in non-HIV-infected patients with an underlying haematological condition, including allogeneic HSCT recipients. Recommendations were based on the grading system of the IDSA. Trimethoprim/sulfamethoxazole given 2-3 times weekly is the drug of choice for the primary prophylaxis of PCP in adults ( A-II: ) and children ( A-I: ) and should be given during the entire period at risk. Recent data indicate that children may benefit equally from a once-weekly regimen ( B-II: ). All other drugs, including pentamidine, atovaquone and dapsone, are considered second-line alternatives when trimethoprim/sulfamethoxazole is poorly tolerated or contraindicated. The main indications of PCP prophylaxis are ALL, allogeneic HSCT, treatment with alemtuzumab, fludarabine/cyclophosphamide/rituximab combinations, >4 weeks of treatment with corticosteroids and well-defined primary immune deficiencies in children. Additional indications are proposed depending on the treatment regimen.

It is shown that when the moving finite elements are used on a number of parabolic problems there are steady-state, stationary, similarity, or travelling-wave solutions that can be found numerically.

When M.F.E. is applied to the viscous Burgers' equation the discrete equations have an exact, linearly stable, travelling wave solution whose error is first order.

Entropy is presented as a concave function relating two sets of quantities called densities and field. It allows a simple classification of the standard relations of classical thermodynamics and yields a simple derivation of the conditions for concavity of the entropy function. It also allows a formal derivation of the equations of fluid motion. Dissipation, mixtures, and phase changes may also be included in the theory in a natural manner.

Item does not contain fulltext The Fifth European Conference on Infections in Leukaemia (ECIL-5) convened a meeting to establish evidence-based recommendations for using tests to diagnose Pneumocystis jirovecii pneumonia (PCP) in adult patients with haematological malignancies. Immunofluorescence assays are recommended as the most sensitive microscopic method (recommendation A-II: ). Real-time PCR is recommended for the routine diagnosis of PCP ( A-II: ). Bronchoalveolar lavage (BAL) fluid is recommended as the best specimen as it yields good negative predictive value ( A-II: ). Non-invasive specimens can be suitable alternatives ( B-II: ), acknowledging that PCP cannot be ruled out in case of a negative PCR result ( A-II: ). Detecting beta-d-glucan in serum can contribute to the diagnosis but not the follow-up of PCP ( A-II: ). A negative serum beta-d-glucan result can exclude PCP in a patient at risk ( A-II: ), whereas a positive test result may indicate other fungal infections. Genotyping using multilocus sequence markers can be used to investigate suspected outbreaks ( A-II: ). The routine detection of dihydropteroate synthase mutations in cases of treatment failure is not recommended ( B-II: ) since these mutations do not affect response to high-dose co-trimoxazole. The clinical utility of these diagnostic tests for the early management of PCP should be further assessed in prospective, randomized interventional studies.

Objective: Slow vasogenic intracranial pressure (ICP) waves are spontaneous ICP oscillations with a low frequency bandwidth of 0.3-4 cycles/min (B-waves). B-waves reflect dynamic oscillations in cerebral blood volume associated with autoregulatory cerebral vasodilation and vasoconstriction. This study quantifies the effects of general anaesthesia (GA) on the magnitude of B-waves compared to natural sleep and conscious state. Materials and methods: The magnitude of B-waves was assessed in 4 groups of 30 patients each with clinical indications for ICP monitoring. Normal pressure hydrocephalus patients undergoing Cerebrospinal Fluid (CSF) infusion studies in the conscious state (GROUP A) and under GA (GROUP B), and hydrocephalus patients undergoing overnight ICP monitoring during physiological sleep (GROUP C) were compared to deeply sedated traumatic brain injury (TBI) patients with well-controlled ICP during the first night of Intensive Care Unit (ICU) stay (GROUP D). Results: A total of 120 patients were included. During CSF infusion studies, the magnitude of slow waves was higher in conscious patients (GROUP A: 0.23+/−0.10 mm Hg) when compared to anaesthetised patients (GROUP B: 0.15+/−0.10 mm Hg; p = 0.011). Overnight magnitude of slow waves was higher in patients during natural sleep (GROUP C: 0.20+/−0.13 mm Hg) when compared to TBI patients under deep sedation (GROUP D: 0.11+/− 0.09 mm Hg; p = 0.002). Conclusion: GA and deep sedation are associated with a reduced magnitude of B-waves. ICP monitoring carried out under GA is affected by iatrogenic suppression of slow vasogenic waves of ICP. Accounting for the effects of anaesthesia on vasogenic waves may prevent the misidentification of potential shunt-responders as non-responders. © 2016 Informa UK Limited, trading as Taylor & Francis Group.

The European Aspergillus PCR Initiative (EAPCRI) has provided recommendations for the PCR testing of whole blood (WB) and serum/plasma. It is important to test these recommended protocols on nonsimulated “ in vivo ” specimens before full clinical evaluation. The testing of an animal model of invasive aspergillosis (IA) overcomes the low incidence of disease and provides experimental design and control that is not possible in the clinical setting. Inadequate performance of the recommended protocols at this stage would require reassessment of methods before clinical trials are performed and utility assessed. The manuscript describes the performance of EAPCRI protocols in an animal model of invasive aspergillosis. Blood samples taken from a guinea pig model of IA were used for WB and serum PCR. Galactomannan and β- d -glucan detection were evaluated, with particular focus on the timing of positivity and on the interpretation of combination testing. The overall sensitivities for WB PCR, serum PCR, galactomannan, and β- d -glucan were 73%, 65%, 68%, and 46%, respectively. The corresponding specificities were 92%, 79%, 80%, and 100%, respectively. PCR provided the earliest indicator of IA, and increasing galactomannan and β- d -glucan values were indicators of disease progression. The combination of WB PCR with galactomannan and β- d -glucan proved optimal (area under the curve [AUC], 0.95), and IA was confidently diagnosed or excluded. The EAPRCI-recommended PCR protocols provide performance comparable to commercial antigen tests, and clinical trials are warranted. By combining multiple tests, IA can be excluded or confirmed, highlighting the need for a combined diagnostic strategy. However, this approach must be balanced against the practicality and cost of using multiple tests.

Ecological selection forces for weedy and domesticated traits have influenced the evolution of seed shape in Setaria resulting in similarity in seed shape that reflects similarity in ecological function rather than reflecting phylogenetic relatedness. Seeds from two diploid subspecies of Setaria viridis, consisting of one weedy subspecies and two races of the domesticated subspecies, and four other polyploidy weedy species of Setaria. We quantified seed shape from the silhouettes of the seeds in two separate views. Differences in shape were compared to ecological role (weed vs. crop) and the evolutionary trajectory of shape change by phylogenetic grouping from a single reference species was calculated. Idealized three-dimensional models were created to examine the differences in shape relative to surface area and volume. All populations were significantly different in shape, with crops easily distinguished from weeds, regardless of relatedness between the taxa. Trajectory of shape change varied by view, but separated crops from weeds and phylogenetic groupings. Three-dimensional models gave further evidence of differences in shape reflecting adaptation for environmental exploitation. The selective forces for weedy and domesticated traits have exceeded phylogenetic constraints, resulting in seed shape similarity due to ecological role rather than phylogenetic relatedness. Seed shape and surface-to-volume ratio likely reflect the importance of the water film that accumulates on the seed surface when in contact with soil particles. Seed shape may also be a mechanism of niche separation between taxa., 21 pages, 6 figures, 2 tables

The development of hospital-acquired pressure ulcers on the heel is a growing problem. The best way of preventing this is to ensure the heel is completely free from pressure.

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Clin Microbiol Infect 2012; 18 (Suppl. 7): 3852 Abstract Invasive candidiasis (IC) is a relatively common syndrome in neonates and children and is associated with significant morbidity and mortality. These guidelines provide recommendations for the prevention and treatment of IC in neonates and children. Appropriate agents for the prevention of IC in neonates at high risk include fluconazole (A-I), nystatin (B-II) or lactoferrin +/- Lactobacillus (B-II). The treatment of IC in neonates is complicated by the high likelihood of disseminated disease, including the possibility of infection within the central nervous system. Amphotericin B deoxycholate (B-II), liposomal amphotericin B (B-II), amphotericin B lipid complex (ABLC) (C-II), fluconazole (B-II), micafungin (B-II) and caspofungin (C-II) can all be potentially used. Recommendations for the prevention of IC in children are largely extrapolated from studies performed in adults with concomitant pharmacokinetic data and models in children. For allogeneic HSCT recipients, fluconazole (A-I), voriconazole (A-I), micafungin (A-I), itraconazole (B-II) and posaconazole (B-II) can all be used. Similar recommendations are made for the prevention of IC in children in other risk groups. With several exceptions, recommendations for the treatment of IC in children are extrapolated from adult studies, with concomitant pharmacokinetic studies. Amphotericin B deoxycholate (C-I), liposomal amphotericin B (A-I), ABLC (B-II), micafungin (A-I), caspofungin (A-I), anidulafungin (B-II), fluconazole (B-I) and voriconazole (B-I) can all be used.

Clin Microbiol Infect 2012; 18 (Suppl. 7): 1937 Abstract This part of the EFISG guidelines focuses on non-neutropenic adult patients. Only a few of the numerous recommendations can be summarized in the abstract. Prophylactic usage of fluconazole is supported in patients with recent abdominal surgery and recurrent gastrointestinal perforations or anastomotic leakages. Candida isolation from respiratory secretions alone should never prompt treatment. For the targeted initial treatment of candidaemia, echinocandins are strongly recommended while liposomal amphotericin B and voriconazole are supported with moderate, and fluconazole with marginal strength. Treatment duration for candidaemia should be a minimum of 14 days after the end of candidaemia, which can be determined by one blood culture per day until negativity. Switching to oral treatment after 10 days of intravenous therapy has been safe in stable patients with susceptible Candida species. In candidaemia, removal of indwelling catheters is strongly recommended. If catheters cannot be removed, lipid-based amphotericin B or echinocandins should be preferred over azoles. Transoesophageal echocardiography and fundoscopy should be performed to detect organ involvement. Native valve endocarditis requires surgery within a week, while in prosthetic valve endocarditis, earlier surgery may be beneficial. The antifungal regimen of choice is liposomal amphotericin B +/- flucytosine. In ocular candidiasis, liposomal amphotericin B +/- flucytosine is recommended when the susceptibility of the isolate is unknown, and in susceptible isolates, fluconazole and voriconazole are alternatives. Amphotericin B deoxycholate is not recommended for any indication due to severe side effects.

Clin Microbiol Infect 2012; 18 (Suppl. 7): 5367 Abstract Fungal diseases still play a major role in morbidity and mortality in patients with haematological malignancies, including those undergoing haematopoietic stem cell transplantation. Although Aspergillus and other filamentous fungal diseases remain a major concern, Candida infections are still a major cause of mortality. This part of the ESCMID guidelines focuses on this patient population and reviews pertaining to prophylaxis, empirical/pre-emptive and targeted therapy of Candida diseases. Anti-Candida prophylaxis is only recommended for patients receiving allogeneic stem cell transplantation. The authors recognize that the recommendations would have most likely been different if the purpose would have been prevention of all fungal infections (e.g. aspergillosis). In targeted treatment of candidaemia, recommendations for treatment are available for all echinocandins, that is anidulafungin (AI), caspofungin (AI) and micafungin (AI), although a warning for resistance is expressed. Liposomal amphotericin B received a BI recommendation due to higher number of reported adverse events in the trials. Amphotericin B deoxycholate should not be used (DII); and fluconazole was rated CI because of a change in epidemiology in some areas in Europe. Removal of central venous catheters is recommended during candidaemia but if catheter retention is a clinical necessity, treatment with an echinocandin is an option (CIIt). In chronic disseminated candidiasis therapy, recommendations are liposomal amphotericin B for 8 weeks (AIII), fluconazole for >3 months or other azoles (BIII). Granulocyte transfusions are only an option in desperate cases of patients with Candida disease and neutropenia (CIII).

AIM: To determine if there is a relationship between maternal methadone dose in pregnancy and the diagnosis or medical treatment of neonatal abstinence syndrome (NAS). METHODS: PubMed, EMBASE, the Cochrane Library and PsychINFO were searched for studies reporting on methadone use in pregnancy and NAS (1966-2009). The relative risk (RR) of NAS was compared for methadone doses above versus below a range of cut-off points. Summary RRs and 95% confidence intervals (CI) were estimated using random effects meta-analysis. Sensitivity analyses explored the impact of limiting meta-analyses to prospective studies or studies using an objective scoring system to diagnose NAS. RESULTS: A total of 67 studies met inclusion criteria for the systematic review; 29 were included in the meta-analysis. Any differences in the incidence of NAS in infants of women on higher compared with lower doses were statistically non-significant in analyses restricted to prospective studies or to those using an objective scoring system to diagnose NAS. CONCLUSIONS: Severity of the neonatal abstinence syndrome does not appear to differ according to whether mothers are on high- or low-dose methadone maintenance therapy.

High-quality cross sections for the reaction gamma+d->pi^0+d have been measured using the CLAS at Jefferson Lab over a wide energy range near and above the eta-meson photoproduction threshold. At backward c.m. angles for the outgoing pions, we observe a resonance-like structure near E_gamma=700 MeV. Our model analysis shows that it can be explained by eta excitation in the intermediate state. The effect is the result of the contribution of the N(1535)S_11 resonance to the amplitudes of the subprocesses occurring between the two nucleons and of a two-step process in which the excitation of an intermediate eta meson dominates., Comment: slightly modified title, additional paragraph and a table (Table 2) added on p. 5; to be submitted to EPJA, 6 pages, 3 figures