Cerebral autoregulation-based mean arterial pressure targets and delirium in critically ill adults without brain injury: a retrospective cohort study.

PURPOSE: Cerebral autoregulation (CA) is a mechanism that acts to maintain consistent cerebral perfusion across a range of blood pressures, and impaired CA is associated with delirium. Individualized CA-derived blood pressure targets are poorly characterized in critically ill patients and the association with intensive care unit (ICU) delirium is unknown. Our objectives were to characterize optimal mean arterial pressure (MAPopt) ranges in critically ill adults without brain injury and determine whether deviations from these targets contribute to ICU delirium. METHODS: We performed a retrospective cohort analysis of patients with shock of any etiology and/or respiratory failure requiring invasive mechanical ventilation, without a neurologic admitting diagnosis. Patients were screened daily for delirium. Cerebral oximetry and mean arterial pressure data were captured for the first 24 hr from enrolment. RESULTS: Forty-two patients with invasive blood pressure monitoring data were analyzed. Optimal mean arterial pressure targets ranged from 55 to 100 mm Hg. Optimal mean arterial pressure values were not significantly different based on history of hypertension or delirium status, and delirium was not associated with deviations from MAPopt. Nevertheless, the majority (69%) of blood pressure targets exceeded the current 65 mm Hg Surviving Sepsis guidelines. CONCLUSION: We observed that MAPopt targets across patients were highly variable, but did not observe an association with the incidence of delirium. Studies designed to evaluate the impact on neurologic outcomes are needed to understand the association with individualized mean arterial pressure targets in the ICU. STUDY REGISTRATION: ClinicalTrials.gov (NCT02344043); first submitted 22 January 2015.

RéSUMé: OBJECTIF: L'autorégulation cérébrale (AC) est un mécanisme qui agit pour maintenir une perfusion cérébrale constante pour une gamme de tensions artérielles, et une altération de l'AC est associée au delirium. Les cibles de tension artérielle individualisées dérivées de l'AC sont mal caractérisées chez les patient·es gravement malades et l'association avec le delirium à l'unité de soins intensifs (USI) est inconnue. Nos objectifs étaient de caractériser la tension artérielle moyenne optimale (TAMopt) chez les adultes gravement malades sans lésion cérébrale et de déterminer si les écarts par rapport à ces cibles contribuaient au delirium à l'USI. MéTHODE: Nous avons réalisé une analyse de cohorte rétrospective de patient·es présentant un choc de toute étiologie et/ou une insuffisance respiratoire nécessitant une ventilation mécanique invasive, et n'ayant pas reçu de diagnostic d'atteinte neurologique à l'admission. Les patients ont été dépistés quotidiennement pour le delirium. Les données d'oxymétrie cérébrale et de tension artérielle moyenne ont été saisies pendant les 24 premières heures suivant le recrutement. RéSULTATS: Quarante-deux patient·es pour qui des données de monitorage invasif de la tension artérielle étaient disponibles ont été analysé·es. Les cibles optimales de tension artérielle moyenne variaient de 55 à 100 mm Hg. Les valeurs optimales de tension artérielle moyenne n'étaient pas significativement différentes en fonction des antécédents d'hypertension ou de delirium, et le delirium n'était pas associé à des écarts par rapport à la TAMopt. Néanmoins, la majorité (69 %) des cibles de tension artérielle dépassaient celle de 65 mm Hg préconisée par les lignes directrices Surviving Sepsis. CONCLUSION: Nous avons observé que les cibles de TAMopt étaient très variables chez les patient·es, mais nous n'avons pas observé d'association avec l'incidence de delirium. Des études conçues pour évaluer l'impact sur les issues neurologiques sont nécessaires pour comprendre l'association avec les cibles de tension artérielle moyenne individualisées à l'USI. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT02344043); soumis pour la première fois le 22 janvier 2015.

Compact Yb fiber few-cycle pulse source based on precision pulse compression and shaping with an adaptive fiber Bragg grating.

We generate bandwidth limited 10 µJ pulses of 92 fs pulse width using an adaptive fiber Bragg grating stretcher (FBG) in conjunction with a Lyot filter. The temperature controlled FBG is used to optimize the group delay, whereas the Lyot filter counteracts gain narrowing in the amplifier chain. Soliton compression in a hollow core fiber (HCF) allows for access to the few-cycle pulse regime. Adaptive control further enables the generation of nontrivial pulse shapes.

Coherent supercontinuum shaping for multiple wavelength optimization over an octave.

We shape the spectrum of an octave spanning supercontinuum from an erbium fiber laser. The group delay dispersion is controlled through the temperature profile of a chirped fiber Bragg grating. We demonstrate control of spectral broadening, switching in spectral windows, and optimizing power at six wavelengths corresponding to Yb, Ca, and Sr clock transitions, an f-2f pair, and a C-band reference for frequency transfer applications. We verify locking of the shaped f-2f beat note, and the coherence of the shaped supercontinuum by interference with an unshaped supercontinuum branch with relative frequency deviation of 10-17 at 1 s averaging time.

Threshold photodissociation dynamics of NO2 studied by time-resolved cold target recoil ion momentum spectroscopy.

We study the near-threshold photodissociation dynamics of NO2 by a kinematically complete femtosecond pump-probe scheme using a cold target recoil ion momentum spectrometer. We excite NO2 to the optically bright Ã2B2 state with a 400 nm pulse and probe the ensuing dynamics via strong field single and double ionization with a 25 fs, 800 nm pulse. The pump spectrum spans the NO(X2Π) + O(3P) dissociation channel threshold, and therefore, following internal conversion, excited NO2 is energetically prepared both "above threshold" (dissociating) and "below threshold" (nondissociating). Experimentally, we can clearly discriminate a weak two-photon pump channel from the dominant single-photon data. In the single ionization channel, we observe NO+ fragments with nonzero momentum at 200 fs delay and an increasing yield of NO+ fragments with near-zero momentum at 3.0 ps delay. For double ionization events, we observe a time-varying Coulombic kinetic energy release between the NO+ and O+ fragments impulsively created from the evolving "hot" neutral ground state. Supported by classical trajectory calculations, we assign the decreasing Coulombic kinetic energy release at longer time delays to the increasing average NO-O distances in the ground electronic state during its large amplitude phase space evolution toward free products. The time-resolved kinetic energy release in the double ionization channel probes the large amplitude ground state evolution from a strongly coupled "inner region" to a loosely coupled "outer region" where one O atom is on average much further away from the NO. Both the time evolution of the kinetic energy release and the NO+ angular distributions support our assignments.

Midinfrared frequency comb by difference frequency of erbium and thulium fiber lasers in orientation-patterned gallium phosphide.

We generate over 60 mW of pulses with wavelengths from 6 to 11 micrometers by difference frequency mixing between erbium and thulium fiber amplifiers in orientation-patterned GaP with a photon conversion efficiency of 0.2. By stabilizing the repetition rate of the shared oscillator and adding a frequency shifter to one arm, the output becomes a frequency comb with tunable carrier envelope offset.

Harmonic generation in solids with direct fiber laser pumping.

High harmonic generation in solids presents the possibility for bringing attosecond techniques to semiconductors and a simple source for frequency comb spectroscopy in the vacuum ultraviolet. We generate up to the seventh harmonic of a Tm fiber laser by focusing in silicon or zinc oxide. The harmonics are strong and stable, with no indication of material damage. Calculations show the potential for generating nineteenth harmonic photons at 12 eV photons of energy.

Self-referenced, accurate and sensitive optical frequency comb spectroscopy with a virtually imaged phased array spectrometer.

We present a cavity-enhanced direct optical frequency comb spectroscopy system with a virtually imaged phased array (VIPA) spectrometer and either a dither or a Pound-Drever-Hall (PDH) locking scheme used for stable transmission of the comb through the cavity. A self-referenced scheme for frequency axis calibration is shown along with an analysis of its accuracy. A careful comparison between both locking schemes is performed based on near-IR measurements of the carbon monoxide ν=3←0 band P branch transitions in a gas sample with known composition. The noise-equivalent absorptions (NEA) for the PDH and dither schemes are 9.9×10(-10) cm(-1) and 5.3×10(-9) cm(-1), respectively.

Fourier transform and Vernier spectroscopy using an optical frequency comb at 3-5.4 µm.

We present a versatile mid-infrared frequency comb spectroscopy system based on a doubly resonant optical parametric oscillator tunable in the 3-5.4 µm range and two detection methods: a Fourier transform spectrometer (FTS) and a continuous-filtering Vernier spectrometer (CF-VS). Using the FTS with a multipass cell, we measure high precision broadband absorption spectra of CH4 at 3.3 µm and NO at 5.25 µm, the latter for the first time with comb spectroscopy, and we detect atmospheric species (CH4, CO, CO2, and H2O) in air in the signal and idler ranges. Multiline fitting yields minimum detectable concentrations of 10-20 ppb Hz-1/2 for CH4, NO, and CO. For the first time in the mid-infrared, we perform CF-VS using an enhancement cavity, a grating, and a single detector, and we measure the absorption spectrum of CH4 and H2O in ambient air at ∼3.3 µm, reaching a 40 ppb concentration detection limit for CH4 in 2 ms.

Three-photon absorption in optical parametric oscillators based on OP-GaAs.

We report on, to the best of our knowledge, the first singly resonant (SR), synchronously pumped optical parametric oscillator (OPO) based on orientation-patterned gallium arsenide (OP-GaAs). Together with a doubly resonant (DR) degenerate OPO based on the same OP-GaAs material, the output spectra cover 3 to 6 µm within ∼3 dB of relative power. The DR-OPO has the highest output power reported to date from a femtosecond, synchronously pumped OPO based on OP-GaAs. We observed strong three-photon absorption with a coefficient of 0.35±0.08 cm3/GW2 for our OP-GaAs sample, which limits the output power of these OPOs as mid-IR light sources. We present a detailed study of the three-photon loss on the performance of both the SR- and DR-OPOs, and compare them to those without this loss mechanism.

Midinfrared frequency comb from self-stable degenerate GaAs optical parametric oscillator.

We pump a degenerate frequency-divide-by-two optical parametric oscillator (OPO) based on orientation-patterned GaAs with a stable Tm frequency comb at 2 micrometer wavelength and measure the OPO comb offset frequency and linewidth. We show frequency division by two with sub-Hz relative linewidth of the comb teeth. The OPO thermally self-stabilizes and oscillates for nearly an hour without any active control.

Differential subcellular targeting of glutamate receptor subtypes during homeostatic synaptic plasticity.

Homeostatic processes are believed to contribute to the stability of neuronal networks that are perpetually influenced by Hebbian forms of synaptic plasticity. Whereas the rules governing the targeting and trafficking of AMPA and NMDA subtypes of glutamate receptors during rapid Hebbian LTP have been extensively studied, those that are operant during homeostatic forms of synaptic strengthening are less well understood. Here, we used biochemical, biophysical, and pharmacological approaches to investigate glutamate receptor regulation during homeostatic synaptic plasticity. We show in rat organotypic hippocampal slices that prolonged network silencing induced a robust surface upregulation of GluA2-lacking AMPARs, not only at synapses, but also at extrasynaptic dendritic and somatic regions of CA1 pyramidal neurons. We also detected a shift in NMDAR subunit composition that, in contrast to the cell-wide surface delivery of GluA2-lacking AMPARs, occurred exclusively at synapses. The subunit composition and subcellular distribution of AMPARs and NMDARs are therefore distinctly regulated during homeostatic synaptic plasticity. Thus, because subunit composition dictates key channel properties, such as agonist affinity, gating kinetics, and calcium permeability, the homeostatic synaptic process transcends the simple modulation of synaptic strength by also regulating the signaling and integrative properties of central synapses.

Midinfrared frequency combs from coherent supercontinuum in chalcogenide and optical parametric oscillation.

We observe the coherence of the supercontinuum generated in a nanospike chalcogenide-silica hybrid waveguide pumped at 2 µm. The supercontinuum is shown to be coherent with the pump by interfering it with a doubly resonant optical parametric oscillator (OPO) that is itself coherent with the shared pump laser. This enables coherent locking of the OPO to the optically referenced pump frequency comb, resulting in a composite frequency comb with wavelengths from 1 to 6 µm.

The legacy of immigration policies and employment exclusion: Assessing the relationship between employment exclusions and immigrant health.

Restrictive federal and state immigration policies create conditions of employment exclusion that may negatively influence the health of immigrants. In particular, these policy effects are reflected in labor market and workplace experiences that determine the types of work and employment opportunities that immigrants are able to access and pursue. This study examines the relationship between both cumulative and individual measures of employment exclusion and self-rated health and psychological distress among Asian and Latino immigrants in California, and whether this relationship is modified by legal status. We used data from the Research on Immigrant Health and State Policy (RIGHTS) study (n = 2010). We used both multivariable logistic regression and linear regression models for our analyses. For cumulative models, labor market exclusion was associated with poor health (OR = 1.21, 95% CI: 1.01, 1.46). Workplace exclusion was also associated with poor self-rated health (OR = 1.45, 95% CI: 1.15, 1.82) and increased psychological distress (ß = 0.69, 95% CI: 0.31, 1.07). For individual measures of employment exclusion, settling for a job - a labor market exclusion - and working in a dangerous job and experiencing wage theft - workplace exclusions - were associated with poor health and increased psychological distress. There was no evidence that the association between employment exclusions and health varied by legal status. These findings demonstrate that the combined effect of employment exclusions is detrimental to immigrant health. To improve population health, public health researchers should continue to interrogate the policy conditions at the federal, state, and local level that exclude immigrants from employment opportunities and workplace protections.

LIM domain only 4 (LMO4) regulates calcium-induced calcium release and synaptic plasticity in the hippocampus.

The LIM domain only 4 (LMO4) transcription cofactor activates gene expression in neurons and regulates key aspects of network formation, but the mechanisms are poorly understood. Here, we show that LMO4 positively regulates ryanodine receptor type 2 (RyR2) expression, thereby suggesting that LMO4 regulates calcium-induced calcium release (CICR) in central neurons. We found that CICR modulation of the afterhyperpolarization in CA3 neurons from mice carrying a forebrain-specific deletion of LMO4 (LMO4 KO) was severely compromised but could be restored by single-cell overexpression of LMO4. In line with these findings, two-photon calcium imaging experiments showed that the potentiation of RyR-mediated calcium release from internal stores by caffeine was absent in LMO4 KO neurons. The overall facilitatory effect of CICR on glutamate release induced during trains of action potentials was likewise defective in LMO4 KO, confirming that CICR machinery is severely compromised in these neurons. Moreover, the magnitude of CA3-CA1 long-term potentiation was reduced in LMO4 KO mice, a defect that appears to be secondary to an overall reduced glutamate release probability. These cellular phenotypes in LMO4 KO mice were accompanied with deficits in hippocampus-dependent spatial learning as determined by the Morris water maze test. Thus, our results establish LMO4 as a key regulator of CICR in central neurons, providing a mechanism for LMO4 to modulate a wide range of neuronal functions and behavior.

Calcium influx through N-type channels and activation of SK and TRP-like channels regulates tonic firing of neurons in rat paraventricular thalamus.

The thalamus is a major relay and integration station in the central nervous system. While there is a large body of information on the firing and network properties of neurons contained within sensory thalamic nuclei, less is known about the neurons located in midline thalamic nuclei, which are thought to modulate arousal and homeostasis. One midline nucleus that has been implicated in mediating stress responses is the paraventricular nucleus of the thalamus (PVT). Like other thalamic neurons, these neurons display two distinct firing modes, burst and tonic. In contrast to burst firing, little is known about the ionic mechanisms modulating tonic firing in these cells. Here we performed a series of whole cell recordings to characterize tonic firing in PVT neurons in acute rat brain slices. We found that PVT neurons are able to fire sustained, low-frequency, weakly accommodating trains of action potentials in response to a depolarizing stimulus. Unexpectedly, PVT neurons displayed a very high propensity to enter depolarization block, occurring at stimulus intensities that would elicit tonic firing in other thalamic neurons. The tonic firing behavior of these cells is modulated by a functional interplay between N-type Ca(2+) channels and downstream activation of small-conductance Ca(2+)-dependent K(+) (SK) channels and a transient receptor potential (TRP)-like conductance. Thus these ionic conductances endow PVT neurons with a narrow dynamic range, which may have fundamental implications for the integrative properties of this nucleus.

Carrier envelope offset frequency of a doubly resonant, nondegenerate, mid-infrared GaAs optical parametric oscillator.

We measure the carrier envelope offset (CEO) frequency of the mid-infrared frequency comb (wavelength tunable between 3 and 6 µm) from a doubly resonant nondegenerate synchronously pumped optical parametric oscillator (SPOPO) as a function of the CEO frequency of the Tm-fiber pump laser. We show that the CEO frequency of the SPOPO signal wave is a linear function of the CEO frequency of the pump laser, with a slope determined by the signal to pump center-frequency ratio.

Examining form and function of dendritic spines.

The majority of fast excitatory synaptic transmission in the central nervous system takes place at protrusions along dendrites called spines. Dendritic spines are highly heterogeneous, both morphologically and functionally. Not surprisingly, there has been much speculation and debate on the relationship between spine structure and function. The advent of multi-photon laser-scanning microscopy has greatly improved our ability to investigate the dynamic interplay between spine form and function. Regulated structural changes occur at spines undergoing plasticity, offering a mechanism to account for the well-described correlation between spine size and synapse strength. In turn, spine structure can influence the degree of biochemical and perhaps electrical compartmentalization at individual synapses. Here, we review the relationship between dendritic spine morphology, features of spine compartmentalization and synaptic plasticity. We highlight emerging molecular mechanisms that link structural and functional changes in spines during plasticity, and also consider circumstances that underscore some divergence from a tight structure-function coupling. Because of the intricate influence of spine structure on biochemical and electrical signalling, activity-dependent changes in spine morphology alone may thus contribute to the metaplastic potential of synapses. This possibility asserts a role for structural dynamics in neuronal information storage and aligns well with current computational models.

Strong ligand-protein interactions revealed by ultrafast infrared spectroscopy of CO in the heme pocket of the oxygen sensor FixL.

In heme-based sensor proteins, ligand binding to heme in a sensor domain induces conformational changes that eventually lead to changes in enzymatic activity of an associated catalytic domain. The bacterial oxygen sensor FixL is the best-studied example of these proteins and displays marked differences in dynamic behavior with respect to model globin proteins. We report a mid-IR study of the configuration and ultrafast dynamics of CO in the distal heme pocket site of the sensor PAS domain FixLH, employing a recently developed method that provides a unique combination of high spectral resolution and range and high sensitivity. Anisotropy measurements indicate that CO rotates toward the heme plane upon dissociation, as is the case in globins. Remarkably, CO bound to the heme iron is tilted by ~30° with respect to the heme normal, which contrasts to the situation in myoglobin and in present FixLH-CO X-ray crystal structure models. This implies protein-environment-induced strain on the ligand, which is possibly at the origin of a very rapid docking-site population in a single conformation. Our observations likely explain the unusually low affinity of FixL for CO that is at the origin of the weak ligand discrimination between CO and O(2). Moreover, we observe orders of magnitude faster vibrational relaxation of dissociated CO in FixL than in globins, implying strong interactions of the ligand with the distal heme pocket environment. Finally, in the R220H FixLH mutant protein, where CO is H-bonded to a distal histidine, we demonstrate that the H-bond is maintained during photolysis. Comparison with extensively studied globin proteins unveils a surprisingly rich variety in both structural and dynamic properties of the interaction of a diatomic ligand with the ubiquitous b-type heme-proximal histidine system in different distal pockets.

Delirium, Cerebral Perfusion, and High-Frequency Vital-Sign Monitoring in the Critically Ill. The CONFOCAL-2 Feasibility Study.

Rationale: Studies suggest that reduced cerebral perfusion may contribute to delirium development in the intensive care unit (ICU). However, evidence is limited because of factors including small sample size and limited inclusion of covariates.Objectives: To assess the feasibility of a multicenter prospective observational study using a multimodal data collection platform. Feasibility was assessed by enrollment, data-capture, and follow-up rates. The full study will aim to assess the association between noninvasively derived surrogate markers of cerebral perfusion, delirium development, and long-term cognitive outcomes in critically ill patients.Methods: Adult patients in the ICU were enrolled if they had shock and/or respiratory failure requiring invasive mechanical ventilation for >24 hours. For the first 72 hours, a near-infrared spectroscopic sensor was placed on the forehead to continuously monitor regional cerebral oxygenation (rSo2) and high-frequency (1 Hz) vital signs were concurrently captured via an arterial line. Cerebral perfusion was estimated using three variables, including mean rSo2, duration of disturbed autoregulation, and time/magnitude away from optimal mean arterial pressure (MAP). Patients were screened for delirium in the ICU and ward daily for up to 30 days. Cognitive function was assessed 3 and 12 months after ICU admission to identify cognitive impairment.Results: Fifty-nine patients were enrolled across four sites in 1 year. Data-capture rates varied across modalities but exceeded 80% for rSo2, blood gas, and delirium data capture. Vital-sign capture and 3-month follow-up rates were lower at 53% and 55%, respectively. Eighty-three percent (49 of 59) of patients experienced delirium, with a median severity of 0.56 in the ICU. Mean physiological (±standard deviation) values were: rSo2 (70.4% ± 7.0%), heart rate (83.9 ± 16.45 beats/min), MAP (76.4 ± 12.8 mm Hg), peripheral oxygenation saturation (96.5% ± 2.1%), proportion of recording time spent with disturbed autoregulation (10.1% ± 7.3%) and proportion of area under the curve outside optimal MAP (39.6% ± 22.4%). Thirty-two (54%) individuals had cerebral autoregulation curves where a targeted optimal MAP was identified. Barriers to data collection included missing vital-sign data and low follow-up rates.Conclusions: Given our current protocol, a multicenter study examining the association between cerebral oxygenation, delirium, and long-term cognitive impairment is not feasible. However, by performing an early assessment of feasibility, we identified strategies to increase capture rates to ensure success as the study begins the next phase of study recruitment.Clinical trial registered with clinicaltrials.gov (NCT03141619).