Early processed electroencephalography for the monitoring of deeply sedated mechanically ventilated critically ill patients.

Deep sedation may be indicated in the intensive care unit (ICU) for the management of acute organ failure, but leads to sedative-induced delirium. Whether processed electroencephalography (p-EEG) is useful in this setting is unclear. We conducted a single-centre observational study of non-neurological ICU patients sedated according to a standardized guideline of deep sedation (Richmond Agitation Sedation Scale [RASS] between -5 and -4) during the acute phase of respiratory and/or cardio-circulatory failure. The SedLine (Masimo Incorporated, Irvine, California) was used to monitor the Patient State Index (PSI) (ranging from 0 to 100, <25 = very deep sedation and >50 = light sedation to full awareness) during the first 72 h of care. Delirium was assessed with the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). The median duration of PSI monitoring was 43 h. Patients spent 49% in median of the total PSI monitoring duration with a PSI <25. Patients with delirium (n = 41/97, 42%) spent a higher percentage of total monitored time with PSI <25 (median 67% [19-91] vs. 47% [12.2-78.9]) in non-delirious patients (p .047). After adjusting for the cumulative dose of analgesia and sedation, increased time spent with PSI <25 was associated with higher delirium (odds ratio 1.014; 95% CI 1.001-1.027, p = .036). A clinical protocol of deep sedation targeted to RASS at the acute ICU phase may be associated with prolonged EEG suppression and increased delirium. Whether PSI-targeted sedation may help reducing sedative dose and delirium deserves further clinical investigation. Patients requiring deep sedation are at high risk of being over-sedated and developing delirium despite the application of an evidence-based sedation guideline. Development of early objective measures are essential to improve sedation management in these critically ill patients

Lock-in detection using a cryogenic low noise looped current preamplifier for the readout of resistive bolometers

We implemented a low noise current preamplifier for the readout of resistive bolometers. We tested the apparatus on thermometer resistances ranging from 10 Ohm to 500 Mohm. The use of current preamplifier overcomes constraints introduced by the readout time constant due to the thermometer resistance and the input capacitance. Using cold JFETs, this preamplifier board is shown to have very low noise: the Johnson noise of the source resistor (1 fA/Hz1/2) dominated in our noise measurements. We also implemented a lock-in chain using this preamplifier. Because of fast risetime, compensation of the phase shift may be unnecessary. If implemented, no tuning is necessary when the sensor impedance changes. Transients are very short, and thus low-passing or sampling of the signal is simplified. In case of spurious noise, the modulation frequency can be chosen in a much wider frequency range, without requiring a new calibration of the apparatus.Comment: 18 pages, 7 figures, Accepted in NIM

Regulation of plasma volume in male lowlanders during 4 days of exposure to hypobaric hypoxia equivalent to 3500 m altitude.

Acclimatization to hypoxia leads to a reduction in plasma volume (PV) that restores arterial O <sub>2</sub> content. Findings from studies investigating the mechanisms underlying this PV contraction have been controversial, possibly as experimental conditions were inadequately controlled. We examined the mechanisms underlying the PV contraction evoked by 4 days of exposure to hypobaric hypoxia (HH) in 11 healthy lowlanders, while strictly controlling water intake, diet, temperature and physical activity. Exposure to HH-induced an ∼10% PV contraction that was accompanied by a reduction in total circulating protein mass, whereas diuretic fluid loss and total body water remained unchanged. Our data support an oncotically driven fluid redistribution from the intra- to the extravascular space, rather than fluid loss, as the mechanism underlying HH-induced PV contraction. Extended hypoxic exposure reduces plasma volume (PV). The mechanisms underlying this effect are controversial, possibly as previous studies have been confounded by inconsistent experimental conditions. Here, we investigated the effect of hypobaric hypoxia (HH) on PV in a cross-over study that strictly controlled for diet, water intake, physical activity and temperature. Eleven males completed two 4-day sojourns in a hypobaric chamber, one in normoxia (NX) and one in HH equivalent to 3500 m altitude. PV, urine output, volume-regulating hormones and plasma protein concentration were determined daily. Total body water (TBW) was determined at the end of both sojourns by deuterium dilution. Although PV was 8.1 ± 5.8% lower in HH than in NX after 24 h and remained ∼10% lower thereafter (all P < 0.002), no differences were detected in TBW (P = 0.17) or in 24 h urine volumes (all P > 0.23). Plasma renin activity and circulating aldosterone were suppressed in HH during the first half of the sojourn (all P < 0.05) but thereafter similar to NX, whereas no differences were detected for copeptin between sojourns (all P > 0.05). Markers for atrial natriuretic peptide were higher in HH than NX after 30 min (P = 0.001) but lower during the last 2 days (P < 0.001). While plasma protein concentration was similar between sojourns, total circulating protein mass (TCP) was reduced in HH at the same time points as PV (all P < 0.03). Despite transient hormonal changes favouring increased diuresis, HH did not enhance urine output. Instead, the maintained TBW and reduced TCP support an oncotically driven fluid redistribution into the extravascular compartment as the mechanism underlying PV contraction

Vaccination of stage III/IV melanoma patients with long NY-ESO-1 peptide and CpG-B elicits robust CD8(+) and CD4(+) T-cell responses with multiple specificities including a novel DR7-restricted epitope.

Long synthetic peptides and CpG-containing oligodeoxynucleotides are promising components for cancer vaccines. In this phase I trial, 19 patients received a mean of 8 (range 1-12) monthly vaccines s.c. composed of the long synthetic NY-ESO-179-108 peptide and CpG-B (PF-3512676), emulsified in Montanide ISA-51. In 18/18 evaluable patients, vaccination induced antigen-specific CD8(+) and CD4(+) T-cell and antibody responses, starting early after initiation of immunotherapy and lasting at least one year. The T-cells responded antigen-specifically, with strong secretion of IFNγ and TNFα, irrespective of patients' HLAs. The most immunogenic regions of the vaccine peptide were NY-ESO-189-102 for CD8(+) and NY-ESO-183-99 for CD4(+) T-cells. We discovered a novel and highly immunogenic epitope (HLA-DR7/NY-ESO-187-99); 7/7 HLA-DR7(+) patients generated strong CD4(+) T-cell responses, as detected directly ex vivo with fluorescent multimers. Thus, vaccination with the long synthetic NY-ESO-179-108 peptide combined with the strong immune adjuvant CpG-B induced integrated, robust and functional CD8(+) and CD4(+) T-cell responses in melanoma patients, supporting the further development of this immunotherapeutic approach

Moduli Stabilisation versus Chirality for MSSM like Type IIB Orientifolds

We investigate the general question of implementing a chiral MSSM like D-brane sector in Type IIB orientifold models with complete moduli stabilisation via F-terms induced by fluxes and space-time instantons, respectively gaugino condensates. The prototype examples are the KKLT and the so-called large volume compactifications. We show that the ansatz of first stabilising all moduli via F-terms and then introducing the Standard Model module is misleading, as a chiral sector notoriously influences the structure of non-perturbative effects and induces a D-term potential. Focusing for concreteness on the large volume scenario, we work out the geometry of the swiss-cheese type Calabi-Yau manifold P_[1,3,3,3,5][15]_(3,75) and analyse whether controllable and phenomenologically acceptable Kaehler moduli stabilisation can occur by the combination of F- and D-terms.Comment: 43 pages, 4 figures, v2: refs. adde

Scattering of Stark-decelerated OH radicals with rare-gas atoms

We present a combined experimental and theoretical study on the rotationally inelastic scattering of OH (X\,^2\Pi_{3/2}, J=3/2, f) radicals with the collision partners He, Ne, Ar, Kr, Xe, and D$_2$ as a function of the collision energy between $\sim 70$ cm$^{-1}$ and 400~cm$^{-1}$. The OH radicals are state selected and velocity tuned prior to the collision using a Stark decelerator, and field-free parity-resolved state-to-state inelastic relative scattering cross sections are measured in a crossed molecular beam configuration. For all OH-rare gas atom systems excellent agreement is obtained with the cross sections predicted by close-coupling scattering calculations based on accurate \emph{ab initio} potential energy surfaces. This series of experiments complements recent studies on the scattering of OH radicals with Xe [Gilijamse \emph{et al.}, Science {\bf 313}, 1617 (2006)], Ar [Scharfenberg \emph{et al.}, Phys. Chem. Chem. Phys. {\bf 12}, 10660 (2010)], He, and D$_2$ [Kirste \emph{et al.}, Phys. Rev. A {\bf 82}, 042717 (2010)]. A comparison of the relative scattering cross sections for this set of collision partners reveals interesting trends in the scattering behavior.Comment: 10 pages, 5 figure

Stellar dynamics in young clusters: the formation of massive runaways and very massive runaway mergers

In the present paper we combine an N-body code that simulates the dynamics of young dense stellar systems with a massive star evolution handler that accounts in a realistic way for the effects of stellar wind mass loss. We discuss two topics: 1. The formation and the evolution of very massive stars (with a mass >120 Mo) is followed in detail. These very massive stars are formed in the cluster core as a consequence of the successive (physical) collison of 10-20 most massive stars of the cluster (the process is known as runaway merging). The further evolution is governed by stellar wind mass loss during core hydrogen burning and during core helium burning (the WR phase of very massive stars). Our simulations reveal that as a consequence of runaway merging in clusters with solar and supersolar values, massive black holes can be formed but with a maximum mass of 70 Mo. In small metallicity clusters however, it cannot be excluded that the runaway merging process is responsible for pair instability supernovae or for the formation of intermediate mass black holes with a mass of several 100 Mo. 2. Massive runaways can be formed via the supernova explosion of one of the components in a binary (the Blaauw scenario) or via dynamical interaction of a single star and a binary or between two binaries in a star cluster. We explore the possibility that the most massive runaways (e.g., zeta Pup, lambda Cep, BD+433654) are the product of the collision and merger of 2 or 3 massive stars.Comment: Updated and final versio

Antiretroviral-naive and -treated HIV-1 patients can harbour more resistant viruses in CSF than in plasma

Objectives The neurological disorders in HIV-1-infected patients remain prevalent. The HIV-1 resistance in plasma and CSF was compared in patients with neurological disorders in a multicentre study. Methods Blood and CSF samples were collected at time of neurological disorders for 244 patients. The viral loads were >50 copies/mL in both compartments and bulk genotypic tests were realized. Results On 244 patients, 89 and 155 were antiretroviral (ARV) naive and ARV treated, respectively. In ARV-naive patients, detection of mutations in CSF and not in plasma were reported for the reverse transcriptase (RT) gene in 2/89 patients (2.2%) and for the protease gene in 1/89 patients (1.1%). In ARV-treated patients, 19/152 (12.5%) patients had HIV-1 mutations only in the CSF for the RT gene and 30/151 (19.8%) for the protease gene. Two mutations appeared statistically more prevalent in the CSF than in plasma: M41L (P = 0.0455) and T215Y (P = 0.0455). Conclusions In most cases, resistance mutations were present and similar in both studied compartments. However, in 3.4% of ARV-naive and 8.8% of ARV-treated patients, the virus was more resistant in CSF than in plasma. These results support the need for genotypic resistance testing when lumbar puncture is performe

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele