Development and validation of a cryogenic far-infrared diffraction grating spectrometer used to post-disperse the output from a Fourier transform spectrometer.

Recent advances in far-infrared detector technology have led to increases in raw sensitivity of more than an order of magnitude over previous state-of-the-art detectors. With such sensitivity, photon noise becomes the dominant noise component, even when using cryogenically cooled optics, unless a method of restricting the spectral bandpass is employed. The leading instrument concept features reflecting diffraction gratings, which post-disperse the light that has been modulated by a polarizing Fourier transform spectrometer (FTS) onto a detector array, thereby reducing the photon noise on each detector. This paper discusses the development of a cryogenic (4 K) diffraction grating spectrometer that operates over the wavelength range of 285 to 500 µm and was used to post-disperse the output from a room-temperature polarizing FTS. Measurements of the grating spectral response and diffraction efficiency are presented as a function of both wavelength and polarization to characterize the instrumental performance.

In the fast lane: Receptor trafficking during status epilepticus.

Status epilepticus (SE) remains a significant cause of morbidity and mortality and often is refractory to standard first-line treatments. A rapid loss of synaptic inhibition and development of pharmacoresistance to benzodiazepines (BZDs) occurs early during SE, while NMDA and AMPA receptor antagonists remain effective treatments after BZDs have failed. Multimodal and subunit-selective receptor trafficking within minutes to an hour of SE involves GABA-A, NMDA, and AMPA receptors and contributes to shifts in the number and subunit composition of surface receptors with differential impacts on the physiology, pharmacology, and strength of GABAergic and glutamatergic currents at synaptic and extrasynaptic sites. During the first hour of SE, synaptic GABA-A receptors containing γ2 subunits move to the cell interior while extrasynaptic GABA-A receptors with δ subunits are preserved. Conversely, NMDA receptors containing N2B subunits are increased at synaptic and extrasynaptic sites, and homomeric GluA1 ("GluA2-lacking") calcium permeant AMPA receptor surface expression also is increased. Molecular mechanisms, largely driven by NMDA receptor or calcium permeant AMPA receptor activation early during circuit hyperactivity, regulate subunit-specific interactions with proteins involved with synaptic scaffolding, adaptin-AP2/clathrin-dependent endocytosis, endoplasmic reticulum (ER) retention, and endosomal recycling. Reviewed here is how SE-induced shifts in receptor subunit composition and surface representation increase the excitatory to inhibitory imbalance that sustains seizures and fuels excitotoxicity contributing to chronic sequela such as "spontaneous recurrent seizures" (SRS). A role for early multimodal therapy is suggested both for treatment of SE and for prevention of long-term comorbidities.

Virtual Adaptation of Resident I-PASS Training Session During COVID-19.

Introduction: Effective communication during the patient handoff process is critical for ensuring patient safety. At our academic medical center, first-year interns complete hand-off training before starting clinical rotations. The purpose of this study was to evaluate a virtual handoff training for residents as an alternative to in-person sessions due to limitations imposed by COVID-19. Methods: Fifty residents were administered pre/post surveys to gauge the helpfulness of the training for clinical practice, familiarity and confidence in providing a hand-off, and whether they would recommend the virtual format for incoming interns. Additionally, faculty rated the virtual form of the hand-off activity, made comparisons to in-person sessions, and assessed the helpfulness of the session for residents in clinical practice. Results: Forty-four residents (88%) and 11 faculty (85%) completed surveys. After the training session, residents who received instruction and feedback reported significant improvements in familiarity with the hand-off tool and confidence in their hand-off abilities (both p < 0.001). Both residents and faculty were satisfied with the virtual format of hand-off training. Most faculty felt the virtual platform was comparable to in-person sessions and would recommend ongoing use of the virtual platform when in-person sessions were not possible. Conclusions: Teaching hospitals mandate resident training to include strategies for a uniform hand-off method to avoid medical errors. Adaptation to a virtual platform can be a successful instruction strategy, allowing for didactic and interactive sessions with direct faculty observation and feedback.

Blood Pressure Changes While Hiking at Moderate Altitudes: A Prospective Cohort Study.

Recreational hiking in the mountains is a common activity, whether for a single day or for several days in a row. We sought to measure blood pressure (BP) response during a 10-day trek at moderate-altitude elevation (6500-13,000 feet) and observe for uncontrolled hypertension and/or adverse cardiovascular outcomes. A total of 1279 adult participants completed an observational study of resting BP during a 10-day trek in the Sangre de Cristo mountains. Following initial recruitment, participants were issued a trail data card to record BP measurements at day 0 (basecamp), day 3, day 6 and day 9. BP was measured using a sphygmomanometer and auscultation. Demographic data, height, weight, home altitude, daily water and sports drink intake, existence of pre-arrival hypertension and BP medication class were also recorded. We observed a rise in mean blood pressure for the cohort during all exposures to moderate altitudes. The increases were greatest for individuals with pre-existing hypertension and/or obesity. There were no observed life-threatening cardiovascular events for participants. We conclude that for individuals with a modestly controlled blood pressure of 160/95 mmHg, hiking at a moderate altitude is a safe activity.

An angle-scanned cryogenic Fabry-Pérot interferometer for far-infrared astronomy.

The sensitivity of state-of-the-art superconducting far-infrared detectors used in conjunction with cryogenically cooled space telescopes and instrumentation is such that spectroscopic observations are generally limited by photon noise from the astronomical source or by galactic foreground or zodiacal emission within the field-of-view. Therefore, an instrument design that restricts the spectral bandpass viewed by the detector must be employed. One method of achieving background limited, high resolution spectroscopy is to combine a high resolution component such as a Fabry-Pérot interferometer (FPI) with a lower resolution, post-dispersing system, such as a grating spectrometer, the latter serving to restrict the spectral bandpass. The resonant wavelength of an FPI is most often tuned by changing the spacing or medium between the parallel reflecting plates of the etalon. In this paper, we present a novel design for an FPI in which the wavelength is tuned by scanning the angle of incidence on a high refractive index etalon. This concept simplifies the cryomechanical design, actuation, and metrology. The first results from the realized instrument are presented and compared with theory. The effects on the spectral response as a function of the incident angle have been simulated and shown to agree well with the observation.

Rational polytherapy in the treatment of cholinergic seizures.

The initiation and maintenance phases of cholinergic status epilepticus (SE) are associated with maladaptive trafficking of synaptic GABAA and glutamate receptors. The resulting pharmacoresistance reflects a decrease in synaptic GABAA receptors and increase in NMDA and AMPA receptors, which tilt the balance between inhibition and excitation in favor of the latter. If these changes are important to the pathophysiology of SE, both should be treated, and blocking their consequences should have therapeutic potential. We used a model of benzodiazepine-refractory SE (RSE) (Tetz et al., 2006) and a model of soman-induced SE to test this hypothesis. Treatment of RSE with combinations of the GABAAR agonists midazolam or diazepam and the NMDAR antagonists MK-801 or ketamine terminated RSE unresponsive to high-dose monotherapy with benzodiazepines, ketamine or other antiepileptic drugs (AEDs). It also reduced RSE-associated neuronal injury, spatial memory deficits and the occurrence of spontaneous recurrent seizures (SRS), tested several weeks after SE. Treatment of sc soman-induced SE similarly showed much greater reduction of EEG power by a combination of midazolam with ketamine, compared to midazolam monotherapy. When treating late (40 min after seizure onset), there may not be enough synaptic GABAAR left to be able to restore inhibition with maximal GABAAR stimulation, and further benefit is derived from the addition of an AED which increases inhibition or reduces excitation by a non-GABAergic mechanism. The midazolam-ketamine-valproate combination is effective in terminating RSE. 3-D isobolograms demonstrate positive cooperativity between midazolam, ketamine and valproate, without any interaction between the toxicity of these drugs, so that the therapeutic index is increased by combination therapy between GABAAR agonist, NMDAR antagonist and selective AEDs. We compared this drug combination based on the receptor trafficking hypothesis to treatments based on clinical practice. The midazolam-ketamine-valproate combination is far more effective in stopping RSE than the midazolam-fosphenytoin-valproate combination inspired from clinical guidelines. Furthermore, sequential administration of midazolam, ketamine and valproate is far less effective than simultaneous treatment with the same drugs at the same dose. These data suggest that we should re-evaluate our traditional treatment of RSE, and that treatment should be based on pathophysiology. The search for a better drug has to deal with the fact that most monotherapy leaves half the problem untreated. The search for a better benzodiazepine should acknowledge the main cause of pharmacoresistance, which is loss of synaptic GABAAR. Future clinical trials should consider treating both the failure of inhibition and the runaway excitation which characterize RSE, and should include an early polytherapy arm.

Early polytherapy for benzodiazepine-refractory status epilepticus.

The transition from single seizures to status epilepticus (SE) is associated with malaptive trafficking of synaptic gamma-aminobutyric acid (GABAA) and glutamate receptors. The receptor trafficking hypothesis proposes that these changes are key events in the development of pharmacoresistance to antiepileptic drugs (AEDs) during SE, and that blocking their expression will help control drug-refractory SE (RSE). We tested this hypothesis in a model of SE induced by very high-dose lithium and pilocarpine (RSE), and in a model of SE induced by sc soman. Both models are refractory to benzodiazepines when treated 40 min after seizure onset. Our treatments aimed to correct the loss of inhibition because of SE-associated internalization of synaptic GABAA receptors (GABAAR), using an allosteric GABAAR modulator, sometimes supplemented by an AED acting at a nonbenzodiazepine site. At the same time, we reduced excitation because of increased synaptic localization of NMDA and AMPA (?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate) receptors (NMDAR, AMPAR (?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, N-methyl-D-aspartate receptors)) with an NMDAR channel blocker, since AMPAR changes are NMDAR-dependent. Treatment of RSE with combinations of the GABAAR allosteric modulators midazolam or diazepam and the NMDAR antagonists dizocilpine or ketamine terminated RSE unresponsive to high-dose monotherapy. It also reduced RSE-associated neuronal injury, spatial memory deficits, and the occurrence of spontaneous recurrent seizures (SRS), tested several weeks after SE. Treatment of soman-induced SE also reduced seizures, behavioral deficits, and epileptogenesis. Addition of an AED further improved seizure outcome in both models. Three-dimensional isobolograms demonstrated positive cooperativity between midazolam, ketamine, and valproate, without any interaction between the toxicity of these drugs, so that the therapeutic index was increased by combination therapy. The midazolam-ketamine-valproate combination based on the receptor trafficking hypothesis was far more effective in stopping RSE than the midazolam-fosphenytoin-valproate combination inspired from clinical guidelines for the treatment of SE. Furthermore, sequential administration of midazolam, ketamine, and valproate was far less effective than simultaneous treatment with the same drugs at the same dose. These data suggest that treatment of RSE should be based at least in part on its pathophysiology. The search for a better treatment should focus on the cause of pharmacoresistance, which is loss of synaptic GABAAR and gain of synaptic glutamate receptors. Both need to be treated. Monotherapy addresses only half the problem. Improved pharmacokinetics will not help pharmacoresistance because of loss of receptors. Waiting for one drug to fail before giving the second drugs gives pharmacoresistance time to develop. Future clinical trials should consider treating both the failure of inhibition and the runaway excitation which characterize RSE, and should include an early polytherapy arm. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".

α7-Nicotinic acetylcholine receptor inhibition by indinavir: implications for cognitive dysfunction in treated HIV disease.

OBJECTIVE: The study set out to determine if the HIV protease inhibitor, indinavir, alters responsiveness of α7-nicotinic acetylcholine receptors to acetylcholine. DESIGN: Treatment with HAART has dramatically reduced development of HIV-associated dementia and more severe forms of cognitive impairment. However, many individuals continue to experience cognitive decline of uncertain cause. Previous studies have failed to demonstrate significant alterations of functional brain connectivity, structural brain changes, or changes in cerebral blood flow sufficient to explain cognitive decline in virally suppressed individuals. This suggests that the mechanisms underlying development and progression of cognitive problems likely occurs at a micro rather than macro level, such as disruptions in neurotransmitter system signaling. MATERIALS AND METHODS: Indinavir's effects on α7-nicotinic acetylcholine receptor activity was tested using a ScreenPatch IonWorks Barracuda-based assay in a mammalian cell model. RESULTS: At low concentrations (0.0003-10 µmol/l) indinavir acts as a positive allosteric modulator (EC50 = 0.021 µmol/l), whereas at concentrations greater than 10 µmol/l (30-100 µmol/l) indinavir acts as an inhibitor of the α7-nicotinic acetylcholine receptor. CONCLUSION: At concentrations greater than 10 µmol/l indinavir reduces synaptic transmission in the acetylcholine neurotransmitter system, which could possibly contribute to cognitive dysfunction. These results suggest that further experiments should be considered to assess whether patients might benefit from treatment with cholinesterase inhibitors that counteract the effects of indinavir.

Benzodiazepine-refractory status epilepticus: pathophysiology and principles of treatment.

Cholinergic status epilepticus (CSE) quickly becomes self-sustaining, independent of its initial trigger, and resistant to benzodiazepines and other antiepileptic drugs. We review a few of the many physiological changes associated with CSE, with an emphasis on receptor trafficking. Time-dependent internalization of synaptic γ-aminobutyric acid (GABA)A receptors explains, in part, the loss of inhibition and the loss of response to benzodiazepines in the early stages of CSE. The increase in N-methyl-d-aspartate receptors may contribute to the runaway excitation and excitotoxicity of CSE. These changes have therapeutic implications. The time-dependent increase in maladaptive changes points to the importance of early treatment. The involvement of both inhibitory and excitatory systems challenges current therapeutic guidelines, which recommend treating only one system, and questions the rationale for monotherapy. It suggests that polytherapy may be needed, especially when treatment is delayed, so that drugs can only reach a much reduced number of GABAA receptors. Finally, it raises the possibility that the current practice of waiting for one treatment to fail before starting the next drug may need to be reevaluated.

Safety of laronidase delivered into the spinal canal for treatment of cervical stenosis in mucopolysaccharidosis I.

Enzyme replacement therapy with laronidase (recombinant human alpha-l-iduronidase) is successfully used to treat patients with mucopolysaccharidosis type I (MPS I). However, the intravenously-administered enzyme is not expected to treat or prevent neurological deterioration. As MPS I patients suffer from spinal cord compression due in part to thickened spinal meninges, we undertook a phase I clinical trial of lumbar intrathecal laronidase in MPS I subjects age 8 years and older with symptomatic (primarily cervical) spinal cord compression. The study faced significant challenges, including a heterogeneous patient population, difficulty recruiting subjects despite an international collaborative effort, and an inability to include a placebo-controlled design due to ethical concerns. Nine serious adverse events occurred in the subjects. All subjects reported improvement in symptomatology and showed improved neurological examinations, but objective outcome measures did not demonstrate change. Despite limitations, we demonstrated the safety of this approach to treating neurological disease due to MPS I.

Profesionales de la salud para el nuevo siglo: transformando la educación para fortalecer los sistemas de salud en un mundo interdependiente / Health professionals for a new century: transforming education to strengthen health systems in an interdependent world

Hace 100 años, diversos estudios sobre la educación de los profesionales de la salud dieron lugar a reformas innovadoras. Los nuevos retos del siglo xxiobligan a rediseñar nuevamente la educación profesional en salud. La Comisión sobre la Educación de los Profesionales de la Salud para el Siglo XXI se reunió para desarrollar una visión compartida y una estrategia común para la educación en medicina, enfermería y salud pública. Esta comisión ofrece una visión que llama a una nueva era de la educación profesional que promueva un aprendizaje transformativo y domine el poder que genera la interdependencia en la educación. Así como las reformas de principios del Siglo XX se apoyaron en la teoría microbiana de la enfermedad y las ciencias médicas modernas, esta comisión cree que el futuro será moldeado por la adaptación de competencias a contextos específicos basándose en el poder de los flujos globales de información y conocimiento. Materializar esta visión requerirá de reformas en la instrucción y el desarrollo institucional, guiadas por los dos resultados que se persiguen: el aprendizaje transformativo y la interdependencia en la educación. Sobre la base de estas nociones esenciales, la comisión ofrece diez recomendaciones específicas. La puesta en práctica de estas reformas requerirá de acciones que faciliten su implantación, entre las que destacan la movilización del liderazgo, la expansión de la inversión en educación profesional en salud, el alineamiento de los procesos de acreditación y el fortalecimiento del aprendizaje global. La implantación de estas recomendaciones deberá contar asimismo con el impulso de un movimiento global que involucre a todos los actores como parte de un esfuerzo concertado para fortalecer los sistemas de salud

100 years ago, a series of studies about the education of health professionals sparked groundbreaking reforms. The challenges of the 21st century demand a new redesign of professional health education. The Commission on Education of Health Professionals for the 21st Century came together to develop a shared vision and a common strategy for postsecondary education in medicine, nursing, and public health. The Commission provides a vision that calls for a new era of professional education that advances transformative learning and harnesses the power of interdependence in education. Just as reforms in the early 20th century were advanced by the germ theory and the establishment of the modern medical sciences, so too the Commission believes that the future will be shaped by adaptation of competencies to specific contexts drawing on the power of global flows of information and knowledge. Undertaking of this vision requires a series of instructional and institutional reforms, which are guided by the two expected outcomes, transformative learning and interdependence in education. On the basis of these core notions, the Commission offers 10 specific recommendations. The implementation of these recommendations require a series of enabling actions, including the mobilization of leadership, the enhancement of investments in health education, the alignment of the accreditation processes, and the strengthening of global learning. These recommendations also demand the support of a global movement engaging all stakeholders as part of a concerted effort to strengthen health systems

Treating acute seizures with benzodiazepines: does seizure duration matter?

Several clinical trials have shown improved seizure control and outcome by early initiation of treatment with benzodiazepines, before arrival in the emergency department and before intravenous access can be established. Here, evidence is provided and reviewed for rapid treatment of acute seizures in order to avoid the development of benzodiazepine pharmacoresistance and the emergence of self-sustaining status epilepticus. Alterations in the physiology, pharmacology, and postsynaptic level of GABA-A receptors can develop within minutes to an hour and hinder the ability of synaptic inhibition to stop seizures while also impairing the efficacy of GABAergic agents, such as benzodiazepines, to boost impaired inhibition. In addition, heightened excitatory transmission further exacerbates the inhibitory/excitatory balance and makes seizure control even more resistant to treatment. The acute increase in the surface expression of NMDA receptors during prolonged seizures also may cause excitotoxic injury, cell death, and other pathological expressions and re-arrangements of receptor subunits that all contribute to long-term sequelae such as cognitive impairment and chronic epilepsy. In conclusion, a short window of opportunity exists when seizures are maximally controlled by first-line benzodiazepine treatment. After that, multiple pathological mechanisms quickly become engaged that make seizures increasingly more difficult to control with high risk for long-term harm.

Trafficking of NMDA receptors during status epilepticus: therapeutic implications.

We used two models of status epilepticus (SE) to study trafficking of N-methyl-d-aspartate (NMDA) receptors. SE is associated with increased surface expression of NR1 subunits of NMDA receptors, and with an increase of NMDA synaptic and extrasynaptic currents suggesting an increase in number of functional NMDA receptors on dentate granule cells. The therapeutic implications of these results are discussed.

Immune response to intrathecal enzyme replacement therapy in mucopolysaccharidosis I patients.

BACKGROUND: Intrathecal (IT) enzyme replacement therapy with recombinant human α-L-iduronidase (rhIDU) has been studied to treat glycosaminoglycan storage in the central nervous system of mucopolysaccharidosis (MPS) I dogs and is currently being studied in MPS I patients. METHODS: We studied the immune response to IT rhIDU in MPS I subjects with spinal cord compression who had been previously treated with intravenous rhIDU. We measured the concentrations of specific antibodies and cytokines in serum and cerebrospinal fluid (CSF) collected before monthly IT rhIDU infusions and compared the serologic findings with clinical adverse event (AE) reports to establish temporal correlations with clinical symptoms. RESULTS: Five MPS I subjects participating in IT rhIDU trials were studied. One subject with symptomatic spinal cord compression had evidence of an inflammatory response with CSF leukocytosis, elevated interleukin-5, and elevated immunoglobulin G. This subject also complained of lower back pain and buttock paresthesias temporally correlated with serologic abnormalities. Clinical symptoms were managed with oral medication, and serologic abnormalities were resolved, although this subject withdrew from the trial to have spinal decompressive surgery. CONCLUSION: IT rhIDU was generally well tolerated in the subjects studied, although one subject had moderate to severe clinical symptoms and serologic abnormalities consistent with an immune response.

Beam profile for the Herschel-SPIRE Fourier transform spectrometer.

One of the instruments on board the Herschel Space Observatory is the Spectral and Photometric Imaging Receiver (SPIRE). SPIRE employs a Fourier transform spectrometer with feed-horn-coupled bolometers to provide imaging spectroscopy. To interpret the resultant spectral images requires knowledge of the wavelength-dependent beam, which in the case of SPIRE is complicated by the use of multimoded feed horns. In this paper we describe a series of observations and the analysis conducted to determine the wavelength dependence of the SPIRE spectrometer beam profile.

Rapid surface accumulation of NMDA receptors increases glutamatergic excitation during status epilepticus.

After 1h of lithium-pilocarpine status epilepticus (SE), immunocytochemical labeling of NMDA receptor NR1 subunits reveals relocation of subunits from the interior to the cell surface of dentate gyrus granule cells and CA3 pyramidal cells. Simultaneously, an increase in NMDA-miniature excitatory postsynaptic currents (mEPSC) as well as an increase in NMDA receptor-mediated tonic currents is observed in hippocampal slices after SE. Mean-variance analysis of NMDA-mEPSCs estimates that the number of functional postsynaptic NMDA receptors per synapse increases 38% during SE, and antagonism by ifenprodil suggests that an increase in the surface representation of NR2B-containing NMDA receptors is responsible for the augmentation of both the phasic and tonic excitatory currents with SE. These results provide a potential mechanism for an enhancement of glutamatergic excitation that maintains SE and may contribute to excitotoxic injury during SE. Therapies that directly antagonize NMDA receptors may be a useful therapeutic strategy during refractory SE.

Using sensor networks to study the effect of peripatetic healthcare workers on the spread of hospital-associated infections.

BACKGROUND: Super-spreading events, in which an individual with measurably high connectivity is responsible for infecting a large number of people, have been observed. Our goal is to determine the impact of hand hygiene noncompliance among peripatetic (eg, highly mobile or highly connected) healthcare workers compared with less-connected workers. METHODS: We used a mote-based sensor network to record contacts among healthcare workers and patients in a 20-bed intensive care unit. The data collected from this network form the basis for an agent-based simulation to model the spread of nosocomial pathogens with various transmission probabilities. We identified the most- and least-connected healthcare workers. We then compared the effects of hand hygiene noncompliance as a function of connectedness. RESULTS: The data confirm the presence of peripatetic healthcare workers. Also, agent-based simulations using our real contact network data confirm that the average number of infected patients was significantly higher when the most connected healthcare worker did not practice hand hygiene and significantly lower when the least connected healthcare workers were noncompliant. CONCLUSIONS: Heterogeneity in healthcare worker contact patterns dramatically affects disease diffusion. Our findings should inform future infection control interventions and encourage the application of social network analysis to study disease transmission in healthcare settings.

Rational polytherapy in the treatment of acute seizures and status epilepticus.

We used a model of severe cholinergic status epilepticus (SE) to study polytherapy aimed at reversing the effects of seizure-induced loss of synaptic GABA(A) receptors and seizure-induced gain of synaptic NMDA receptors. Combinations of a benzodiazepine with ketamine and valproate, or with ketamine and brivaracetam, were more effective and less toxic than benzodiazepine monotherapy in this model of SE.