Nervous System Regionalization Entails Axial Allocation before Neural Differentiation.

Neural induction in vertebrates generates a CNS that extends the rostral-caudal length of the body. The prevailing view is that neural cells are initially induced with anterior (forebrain) identity; caudalizing signals then convert a proportion to posterior fates (spinal cord). To test this model, we used chromatin accessibility to define how cells adopt region-specific neural fates. Together with genetic and biochemical perturbations, this identified a developmental time window in which genome-wide chromatin-remodeling events preconfigure epiblast cells for neural induction. Contrary to the established model, this revealed that cells commit to a regional identity before acquiring neural identity. This "primary regionalization" allocates cells to anterior or posterior regions of the nervous system, explaining how cranial and spinal neurons are generated at appropriate axial positions. These findings prompt a revision to models of neural induction and support the proposed dual evolutionary origin of the vertebrate CNS.

Probing single electrons across 300-mm spin qubit wafers.

Building a fault-tolerant quantum computer will require vast numbers of physical qubits. For qubit technologies based on solid-state electronic devices1-3, integrating millions of qubits in a single processor will require device fabrication to reach a scale comparable to that of the modern complementary metal-oxide-semiconductor (CMOS) industry. Equally important, the scale of cryogenic device testing must keep pace to enable efficient device screening and to improve statistical metrics such as qubit yield and voltage variation. Spin qubits1,4,5 based on electrons in Si have shown impressive control fidelities6-9 but have historically been challenged by yield and process variation10-12. Here we present a testing process using a cryogenic 300-mm wafer prober13 to collect high-volume data on the performance of hundreds of industry-manufactured spin qubit devices at 1.6 K. This testing method provides fast feedback to enable optimization of the CMOS-compatible fabrication process, leading to high yield and low process variation. Using this system, we automate measurements of the operating point of spin qubits and investigate the transitions of single electrons across full wafers. We analyse the random variation in single-electron operating voltages and find that the optimized fabrication process leads to low levels of disorder at the 300-mm scale. Together, these results demonstrate the advances that can be achieved through the application of CMOS-industry techniques to the fabrication and measurement of spin qubit devices.

A shared transcriptional code orchestrates temporal patterning of the central nervous system.

The molecular mechanisms that produce the full array of neuronal subtypes in the vertebrate nervous system are incompletely understood. Here, we provide evidence of a global temporal patterning program comprising sets of transcription factors that stratifies neurons based on the developmental time at which they are generated. This transcriptional code acts throughout the central nervous system, in parallel to spatial patterning, thereby increasing the diversity of neurons generated along the neuraxis. We further demonstrate that this temporal program operates in stem cell-derived neurons and is under the control of the TGFß signaling pathway. Targeted perturbation of components of the temporal program, Nfia and Nfib, reveals their functional requirement for the generation of late-born neuronal subtypes. Together, our results provide evidence for the existence of a previously unappreciated global temporal transcriptional program of neuronal subtype identity and suggest that the integration of spatial and temporal patterning mechanisms diversifies and organizes neuronal subtypes in the vertebrate nervous system.

Comparing Robotic, Thoracoscopic, and Open Segmentectomy: A National Cancer Database Analysis.

INTRODUCTION: Minimally invasive approaches to lung resection have become widely acceptable and more recently, segmentectomy has demonstrated equivalent oncologic outcomes when compared to lobectomy for early-stage non-small cell lung cancer (NSCLC). However, studies comparing outcomes following segmentectomy by different surgical approaches are lacking. Our objective was to investigate the outcomes of patients undergoing robotic, video-assisted thoracoscopic surgery (VATS), or open segmentectomy for NSCLC using the National Cancer Database. METHODS: NSCLC patients with clinical stage I who underwent segmentectomy from 2010 to 2016 were identified. After propensity-score matching (1:4:1), multivariate logistic regression analyses were performed to determine predictors of 30-d readmissions, 90-d mortality, and overall survival. RESULTS: 22,792 patients met study inclusion. After matching, approaches included robotic (n = 2493; 17%), VATS (n = 9972; 66%), and open (n = 2493; 17%). An open approach was associated with higher 30-d readmissions (7% open versus 5.5% VATS versus 5.6% robot, P = 0.033) and 90-d mortality (4.4% open versus 2.2% VATS versus 2.5% robot, P < 0.001). A robotic approach was associated with improved 5-y survival (50% open versus 58% VATS versus 63% robot, P < 0.001). CONCLUSIONS: For patients with clinical stage I NSCLC undergoing segmentectomy, compared to the open approach, a VATS approach was associated with lower 30-d readmission and 90-d mortality. A robotic approach was associated with improved 5-y survival compared to open and VATS approaches when matched. Additional studies are necessary to determine if unrecognized covariates contribute to these differences.

Delta Oscillations Coordinate Intracerebellar and Cerebello-Hippocampal Network Dynamics during Sleep.

During sleep, the widespread coordination of neuronal oscillations across both cortical and subcortical brain regions is thought to support various physiological functions. However, how sleep-related activity within the brain's largest sensorimotor structure, the cerebellum, is multiplexed with well-described sleep-related mechanisms in regions such as the hippocampus remains unknown. We therefore simultaneously recorded from the dorsal hippocampus and three distinct regions of the cerebellum (Crus I, lobule VI, and lobules II/III) in male mice during natural sleep. Local field potential (LFP) oscillations were found to be coordinated between these structures in a sleep stage-specific manner. During non-REM sleep, prominent δ frequency coherence was observed between lobule VI and hippocampus, whereas non-REM-associated hippocampal sharp-wave ripple activity evoked discrete LFP modulation in all recorded cerebellar regions, with the shortest latency effects in lobule VI. We also describe discrete phasic sharp potentials (PSPs), which synchronize across cerebellar regions and trigger sharp-wave ripple suppression. During REM, cerebellar δ phase significantly modulated hippocampal theta frequency, and this effect was greatest when PSPs were abundant. PSPs were phase-locked to cerebellar δ oscillation peak and hippocampal theta oscillation trough, respectively. Within all three cerebellar regions, prominent LFP oscillations were observed at both low (δ, <4 Hz) and very high frequencies (∼250 Hz) during non-REM and REM sleep. Intracerebellar cross-frequency analysis revealed that δ oscillations modulate those in the very high-frequency range. Together, these results reveal multiple candidate physiological mechanisms to support "offline," bidirectional interaction within distributed cerebello-hippocampal networks.SIGNIFICANCE STATEMENT Sleep is associated with widespread coordination of activity across a range of brain regions. However, little is known about how activity within the largest sensorimotor region of the brain, the cerebellum, is both intrinsically organized and links with higher-order structures, such as the hippocampus, during sleep. By making multisite local field potential recordings in naturally sleeping mice, we reveal and characterize multiple sleep stage-specific physiological mechanisms linking three distinct cerebellar regions with the hippocampus. Central to these physiological mechanisms is a prominent δ (<4 Hz) oscillation, which temporally coordinates both intracerebellar and cerebello-hippocampal network dynamics. Understanding this distributed network activity is important for gaining insight into cerebellar contributions to sleep-dependent processes, such as memory consolidation.

Medial septal GABAergic neurons reduce seizure duration upon optogenetic closed-loop stimulation.

Seizures can emerge from multiple or large foci in temporal lobe epilepsy, complicating focally targeted strategies such as surgical resection or the modulation of the activity of specific hippocampal neuronal populations through genetic or optogenetic techniques. Here, we evaluate a strategy in which optogenetic activation of medial septal GABAergic neurons, which provide extensive projections throughout the hippocampus, is used to control seizures. We utilized the chronic intrahippocampal kainate mouse model of temporal lobe epilepsy, which results in spontaneous seizures and as is often the case in human patients, presents with hippocampal sclerosis. Medial septal GABAergic neuron populations were immunohistochemically labelled and were not reduced in epileptic conditions. Genetic labelling with mRuby of medial septal GABAergic neuron synaptic puncta and imaging across the rostral to caudal extent of the hippocampus, also indicated an unchanged number of putative synapses in epilepsy. Furthermore, optogenetic stimulation of medial septal GABAergic neurons consistently modulated oscillations across multiple hippocampal locations in control and epileptic conditions. Finally, wireless optogenetic stimulation of medial septal GABAergic neurons, upon electrographic detection of spontaneous hippocampal seizures, resulted in reduced seizure durations. We propose medial septal GABAergic neurons as a novel target for optogenetic control of seizures in temporal lobe epilepsy.

The importance of the online storage of patient data in Indian COVID-19 scenario: A narrative review.

Generation Z has seen drastic changes in the medical sector with the health-care industry constantly updating itself with newer tools to provide quality treatment. The COVID-19 pandemic has greatly tested the services in every aspect of life and has led to an unprecedented increase in the online storage of patient data. Electronic health records (EHRs) are real-time records that make health information of any patient available securely to authorized users. EHRs in the Indian scenario are still in their budding stages, described as "islands of excellence in an ocean of inadequacy." The central institutes and corporate hospitals have implemented it, but the state medical colleges and peripheral health centers have miles to go. These patient data records become an essential tool in physician's decision-making, expertise, and management. One can review the data which is just a click away even after the patients have been discharged, especially in the follow-up period. The current scenario is such that health-care workers and nonhealth-care workers alike share the data of the patients in respect to their records, radiographs, and laboratory data using social media such as WhatsApp, Facebook, and Telegram. In the absence of adequate regulations, the reliability of the EHRs is questionable and doubt creates a preference for the traditional medical services among the health-care workers. To conclude, a clear and precise guideline that can enlighten the patient and health-care workers is the need of the hour. The concerns of online storage of data need to be alleviated and privacy regulations need to be addressed.

Surgical and endoscopic management options for patients with GERD based on proton pump inhibitor symptom response: recommendations from an expert U.S. panel.

BACKGROUND AND AIMS: The objective of this study was to examine expert opinion and agreement on the treatment of distinct GERD profiles from surgical and therapeutic endoscopy perspectives. METHODS: We used the RAND/University of California, Los Angeles Appropriateness Method over 6 months (July 2018 to January 2019) to assess the appropriateness of antireflux interventions among foregut surgeons and therapeutic gastroenterologists. Patients with primary atypical or extraesophageal symptoms were not considered. Patient scenarios were grouped according to their symptom response to proton pump inhibitor (PPI) therapy. The primary outcome was appropriateness of an intervention. RESULTS: Antireflux surgery with laparoscopic fundoplication (LF) and magnetic sphincter augmentation (MSA) were ranked as appropriate for all complete and partial PPI responder scenarios. Transoral incisionless fundoplication was ranked as appropriate in complete and partial PPI responders without a hiatal hernia. Radiofrequency energy was not ranked as appropriate for complete or partial responders. There was lack of agreement between surgery and interventional gastroenterology groups on the appropriateness of LF and MSA for PPI nonresponders. Rankings for PPI nonresponders were similar when results from impedance-pH testing on PPI therapy were available, except that LF and MSA were not ranked as appropriate for PPI nonresponders if the impedance-pH study was negative. CONCLUSIONS: This work highlights areas of agreement for invasive therapeutic approaches for GERD and provides impetus for further interdisciplinary collaboration and trials to compare and generate novel and effective treatment approaches and care pathways, including the role of impedance-pH testing in PPI nonresponders.

Diesel Soot and Amine-Containing Organic Sulfate Aerosols in an Arctic Oil Field.

The rapid decrease in Arctic sea ice is motivating development and increasing oil and gas extraction activities. However, few observations of these local Arctic emissions exist, limiting the understanding of impacts on atmospheric composition and climate. To address this knowledge gap, the chemical composition of atmospheric aerosols was measured within the North Slope of Alaska oil fields during August and September 2016 using an aerosol time-of-flight mass spectrometer (ATOFMS) and a time-of-flight aerosol chemical speciation monitor (ToF-ACSM). Plumes from oil and gas extraction activities were characterized by soot internally mixed with sulfate (matching diesel soot) and organic carbon particles containing aminium sulfate salts. Sea spray aerosol at the coastal site was frequently internally mixed with sulfate and nitrate, from multiphase chemical processing from elevated NOx and SO2 within the oil field. Background (nonplume) air masses were characterized by aged combustion aerosol. No periods of "clean" (nonpolluted) Arctic air were observed. The composition of the nonrefractory aerosol measured with the ACSM was similar during plume and background periods and was consistent with the mass concentrations of nonrefractory particles measured by ATOFMS. Two ultrafine aerosol growth events were observed during oil field background periods and were correlated with fine mode amine-containing particles.

Metagenomic Next-Generation Sequencing for Identification and Quantitation of Transplant-Related DNA Viruses.

Infections with DNA viruses are frequent causes of morbidity and mortality in transplant recipients. This study describes the analytical and clinical performance characteristics of the Arc Bio Galileo Pathogen Solution, an all-inclusive metagenomic next-generation sequencing (mNGS) reagent and bioinformatics pipeline that allows the simultaneous quantitation of 10 transplant-related double-stranded DNA (dsDNA) viruses (adenovirus [ADV], BK virus [BKV], cytomegalovirus [CMV], Epstein-Barr virus [EBV], human herpesvirus 6A [HHV-6A], HHV-6B, herpes simplex virus 1 [HSV-1], HSV-2, JC virus [JCV], and varicella-zoster virus [VZV]). The mNGS 95% limit of detection ranged from 14 copies/ml (HHV-6) to 191 copies/ml (BKV), and the lower limit of quantitation ranged from 442 international units (IU)/ml (EBV) to 661 copies/ml (VZV). An evaluation of 50 residual plasma samples with at least one DNA virus detected in prior clinical testing showed a total percent agreement of mNGS and quantitative PCR (qPCR) of 89.2% (306/343), with a κ statistic of 0.725. The positive percent agreement was 84.9% (73/86), and the negative percent agreement was 90.7% (233/257). Furthermore, mNGS detected seven subsequently confirmed coinfections that were not initially requested by qPCR. Passing-Bablok regression revealed a regression line of y = 0.953x + 0.075 (95% confidence interval [CI] of the slope, 0.883 to 1.011; intercept, -0.100 to 0.299), and Bland-Altman analysis (mNGS - qPCR) showed a slight positive bias (0.28 log10 concentration; 95% limits of agreement, -0.62 to 1.18). In conclusion, the mNGS-based Galileo pipeline demonstrates analytical and clinical performance comparable to that of qPCR for transplant-related DNA viruses.

Isoprene photochemistry over the Amazon rainforest.

Isoprene photooxidation is a major driver of atmospheric chemistry over forested regions. Isoprene reacts with hydroxyl radicals (OH) and molecular oxygen to produce isoprene peroxy radicals (ISOPOO). These radicals can react with hydroperoxyl radicals (HO2) to dominantly produce hydroxyhydroperoxides (ISOPOOH). They can also react with nitric oxide (NO) to largely produce methyl vinyl ketone (MVK) and methacrolein (MACR). Unimolecular isomerization and bimolecular reactions with organic peroxy radicals are also possible. There is uncertainty about the relative importance of each of these pathways in the atmosphere and possible changes because of anthropogenic pollution. Herein, measurements of ISOPOOH and MVK + MACR concentrations are reported over the central region of the Amazon basin during the wet season. The research site, downwind of an urban region, intercepted both background and polluted air masses during the GoAmazon2014/5 Experiment. Under background conditions, the confidence interval for the ratio of the ISOPOOH concentration to that of MVK + MACR spanned 0.4-0.6. This result implies a ratio of the reaction rate of ISOPOO with HO2 to that with NO of approximately unity. A value of unity is significantly smaller than simulated at present by global chemical transport models for this important, nominally low-NO, forested region of Earth. Under polluted conditions, when the concentrations of reactive nitrogen compounds were high (>1 ppb), ISOPOOH concentrations dropped below the instrumental detection limit (<60 ppt). This abrupt shift in isoprene photooxidation, sparked by human activities, speaks to ongoing and possible future changes in the photochemistry active over the Amazon rainforest.

Scalable deep text comprehension for Cancer surveillance on high-performance computing.

BACKGROUND: Deep Learning (DL) has advanced the state-of-the-art capabilities in bioinformatics applications which has resulted in trends of increasingly sophisticated and computationally demanding models trained by larger and larger data sets. This vastly increased computational demand challenges the feasibility of conducting cutting-edge research. One solution is to distribute the vast computational workload across multiple computing cluster nodes with data parallelism algorithms. In this study, we used a High-Performance Computing environment and implemented the Downpour Stochastic Gradient Descent algorithm for data parallelism to train a Convolutional Neural Network (CNN) for the natural language processing task of information extraction from a massive dataset of cancer pathology reports. We evaluated the scalability improvements using data parallelism training and the Titan supercomputer at Oak Ridge Leadership Computing Facility. To evaluate scalability, we used different numbers of worker nodes and performed a set of experiments comparing the effects of different training batch sizes and optimizer functions. RESULTS: We found that Adadelta would consistently converge at a lower validation loss, though requiring over twice as many training epochs as the fastest converging optimizer, RMSProp. The Adam optimizer consistently achieved a close 2nd place minimum validation loss significantly faster; using a batch size of 16 and 32 allowed the network to converge in only 4.5 training epochs. CONCLUSIONS: We demonstrated that the networked training process is scalable across multiple compute nodes communicating with message passing interface while achieving higher classification accuracy compared to a traditional machine learning algorithm.

Neural Correlates of Fear in the Periaqueductal Gray.

The dorsal and ventral periaqueductal gray (dPAG and vPAG, respectively) are embedded in distinct survival networks that coordinate, respectively, innate and conditioned fear-evoked freezing. However, the information encoded by the PAG during these survival behaviors is poorly understood. Recordings in the dPAG and vPAG in rats revealed differences in neuronal activity associated with the two behaviors. During innate fear, neuronal responses were significantly greater in the dPAG compared with the vPAG. After associative fear conditioning and during early extinction (EE), when freezing was maximal, a field potential was evoked in the PAG by the auditory fear conditioned stimulus (CS). With repeated presentations of the unreinforced CS, animals displayed progressively less freezing accompanied by a reduction in event-related field potential amplitude. During EE, the majority of dPAG and vPAG units increased their firing frequency, but spike-triggered averaging showed that only ventral activity during the presentation of the CS was significantly coupled to EMG-related freezing behavior. This PAG-EMG coupling was only present for the onset of freezing activity during the CS in EE. During late extinction, a subpopulation of units in the dPAG and vPAG continued to show CS-evoked responses; that is, they were extinction resistant. Overall, these findings support roles for the dPAG in innate and conditioned fear and for the vPAG in initiating but not maintaining the drive to muscles to generate conditioned freezing. The existence of extinction-susceptible and extinction-resistant cells also suggests that the PAG plays a role in encoding fear memories. SIGNIFICANCE STATEMENT: The periaqueductal gray (PAG) orchestrates survival behaviors, with the dorsal (dPAG) and ventral (vPAG) PAG concerned respectively with innate and learnt fear responses. We recorded neural activity from dPAG and vPAG in rats during the expression of innate fear and extinction of learned freezing. Cells in dPAG responded more robustly during innate fear, but dPAG and vPAG both encoded the time of the conditioned stimulus during early extinction and displayed extinction sensitive and resistant characteristics. Only vPAG discharge was correlated with muscle activity, but this was limited to the onset of conditioned freezing. The data suggest that the roles of dPAG and vPAG in fear behavior are more complex than previously thought, including a potential role in fear memory.

Transmission of Predictable Sensory Signals to the Cerebellum via Climbing Fiber Pathways Is Gated during Exploratory Behavior.

UNLABELLED: Pathways arising from the periphery that target the inferior olive [spino-olivocerebellar pathways (SOCPs)] are a vital source of information to the cerebellum and are modulated (gated) during active movements. This limits their ability to forward signals to climbing fibers in the cerebellar cortex. We tested the hypothesis that the temporal pattern of gating is related to the predictability of a sensory signal. Low-intensity electrical stimulation of the ipsilateral hindlimb in awake rats evoked field potentials in the C1 zone in the copula pyramidis of the cerebellar cortex. Responses had an onset latency of 12.5 ± 0.3 ms and were either short or long duration (8.7 ± 0.1 vs 31.2 ± 0.3 ms, respectively). Both types of response were shown to be mainly climbing fiber in origin and therefore evoked by transmission in hindlimb SOCPs. Changes in response size (area of field, millivolts per millisecond) were used to monitor differences in transmission during rest and three phases of rearing: phase 1, rearing up; phase 2, upright; and phase 3, rearing down. Responses evoked during phase 2 were similar in size to rest but were smaller during phases 1 and 3, i.e., transmission was reduced during active movement when self-generated (predictable) sensory signals from the hindlimbs are likely to occur. To test whether the pattern of gating was related to the predictability of the sensory signal, some animals received the hindlimb stimulation only during phase 2. Over ∼10 d, the responses became progressively smaller in size, consistent with gating-out transmission of predictable sensory signals relayed via SOCPs. SIGNIFICANCE STATEMENT: A major route for peripheral information to gain access to the cerebellum is via ascending climbing fiber pathways. During active movements, gating of transmission in these pathways controls when climbing fiber signals can modify cerebellar activity. We investigated this phenomenon in rats during their exploratory behavior of rearing. During rearing up and down, transmission was reduced at a time when self-generated, behaviorally irrelevant (predictable) signals occur. However, during the upright phase of rearing, transmission was increased when behaviorally relevant (unpredictable) signals may occur. When the peripheral stimulation was delivered only during the upright phase, so its occurrence became predictable over time, transmission was reduced. Therefore, the results indicate that the gating is related to the level of predictability of a sensory signal.

Esophageal Cancer: Associations With (pN+) Lymph Node Metastases.

OBJECTIVES: To identify the associations of lymph node metastases (pN+), number of positive nodes, and pN subclassification with cancer, treatment, patient, geographic, and institutional variables, and to recommend extent of lymphadenectomy needed to accurately detect pN+ for esophageal cancer. SUMMARY BACKGROUND DATA: Limited data and traditional analytic techniques have precluded identifying intricate associations of pN+ with other cancer, treatment, and patient characteristics. METHODS: Data on 5806 esophagectomy patients from the Worldwide Esophageal Cancer Collaboration were analyzed by Random Forest machine learning techniques. RESULTS: pN+, number of positive nodes, and pN subclassification were associated with increasing depth of cancer invasion (pT), increasing cancer length, decreasing cancer differentiation (G), and more regional lymph nodes resected. Lymphadenectomy necessary to accurately detect pN+ is 60 for shorter, well-differentiated cancers (<2.5 cm) and 20 for longer, poorly differentiated ones. CONCLUSIONS: In esophageal cancer, pN+, increasing number of positive nodes, and increasing pN classification are associated with deeper invading, longer, and poorly differentiated cancers. Consequently, if the goal of lymphadenectomy is to accurately define pN+ status of such cancers, few nodes need to be removed. Conversely, superficial, shorter, and well-differentiated cancers require a more extensive lymphadenectomy to accurately define pN+ status.

The Periaqueductal Gray Orchestrates Sensory and Motor Circuits at Multiple Levels of the Neuraxis.

The periaqueductal gray (PAG) coordinates behaviors essential to survival, including striking changes in movement and posture (e.g., escape behaviors in response to noxious stimuli vs freezing in response to fear-evoking stimuli). However, the neural circuits underlying the expression of these behaviors remain poorly understood. We demonstrate in vivo in rats that activation of the ventrolateral PAG (vlPAG) affects motor systems at multiple levels of the neuraxis through the following: (1) differential control of spinal neurons that forward sensory information to the cerebellum via spino-olivo-cerebellar pathways (nociceptive signals are reduced while proprioceptive signals are enhanced); (2) alterations in cerebellar nuclear output as revealed by changes in expression of Fos-like immunoreactivity; and (3) regulation of spinal reflex circuits, as shown by an increase in α-motoneuron excitability. The capacity to coordinate sensory and motor functions is demonstrated in awake, behaving rats, in which natural activation of the vlPAG in fear-conditioned animals reduced transmission in spino-olivo-cerebellar pathways during periods of freezing that were associated with increased muscle tone and thus motor outflow. The increase in spinal motor reflex excitability and reduction in transmission of ascending sensory signals via spino-olivo-cerebellar pathways occurred simultaneously. We suggest that the interactions revealed in the present study between the vlPAG and sensorimotor circuits could form the neural substrate for survival behaviors associated with vlPAG activation. SIGNIFICANCE STATEMENT: Neural circuits that coordinate survival behaviors remain poorly understood. We demonstrate in rats that the periaqueductal gray (PAG) affects motor systems at the following multiple levels of the neuraxis: (1) through altering transmission in spino-olivary pathways that forward sensory signals to the cerebellum, reducing and enhancing transmission of nociceptive and proprioceptive information, respectively; (2) by alterations in cerebellar output; and (3) through enhancement of spinal motor reflex pathways. The sensory and motor effects occurred at the same time and were present in both anesthetized animals and behavioral experiments in which fear conditioning naturally activated the PAG. The results provide insights into the neural circuits that enable an animal to be ready and able to react to danger, thus assisting in survival.

Long-term Outcomes of Patients Receiving a Magnetic Sphincter Augmentation Device for Gastroesophageal Reflux.

BACKGROUND & AIMS: Based on results from year 2 of a 5-year trial, in 2012 the US Food and Drug Administration approved the use of a magnetic device to augment lower esophageal sphincter function in patients with gastroesophageal reflux disease (GERD). We report the final results of 5 years of follow-up evaluation of patients who received this device. METHODS: We performed a prospective study of the safety and efficacy of a magnetic device in 100 adults with GERD for 6 months or more, who were partially responsive to daily proton pump inhibitors (PPIs) and had evidence of pathologic esophageal acid exposure, at 14 centers in the United States and The Netherlands. The magnetic device was placed using standard laparoscopic tools and techniques. Eighty-five subjects were followed up for 5 years to evaluate quality of life, reflux control, use of PPIs, and side effects. The GERD-health-related quality of life (GERD-HRQL) questionnaire was administered at baseline to patients on and off PPIs, and after placement of the device; patients served as their own controls. A partial response to PPIs was defined as a GERD-HRQL score of 10 or less on PPIs and a score of 15 or higher off PPIs, or a 6-point or more improvement when scores on vs off PPI were compared. RESULTS: Over the follow-up period, no device erosions, migrations, or malfunctions occurred. At baseline, the median GERD-HRQL scores were 27 in patients not taking PPIs and 11 in patients on PPIs; 5 years after device placement this score decreased to 4. All patients used PPIs at baseline; this value decreased to 15.3% at 5 years. Moderate or severe regurgitation occurred in 57% of subjects at baseline, but only 1.2% at 5 years. All patients reported the ability to belch and vomit if needed. Bothersome dysphagia was present in 5% at baseline and in 6% at 5 years. Bothersome gas-bloat was present in 52% at baseline and decreased to 8.3% at 5 years. CONCLUSIONS: Augmentation of the lower esophageal sphincter with a magnetic device provides significant and sustained control of reflux, with minimal side effects or complications. No new safety risks emerged over a 5-year follow-up period. These findings validate the long-term safety and efficacy of the magnetic sphincter augmentation device for patients with GERD. ClinicalTrials.gov no: NCT00776997.

Translational neurophysiology in sheep: measuring sleep and neurological dysfunction in CLN5 Batten disease affected sheep.

Creating valid mouse models of slowly progressing human neurological diseases is challenging, not least because the short lifespan of rodents confounds realistic modelling of disease time course. With their large brains and long lives, sheep offer significant advantages for translational studies of human disease. Here we used normal and CLN5 Batten disease affected sheep to demonstrate the use of the species for studying neurological function in a model of human disease. We show that electroencephalography can be used in sheep, and that longitudinal recordings spanning many months are possible. This is the first time such an electroencephalography study has been performed in sheep. We characterized sleep in sheep, quantifying characteristic vigilance states and neurophysiological hallmarks such as sleep spindles. Mild sleep abnormalities and abnormal epileptiform waveforms were found in the electroencephalographies of Batten disease affected sheep. These abnormalities resemble the epileptiform activity seen in children with Batten disease and demonstrate the translational relevance of both the technique and the model. Given that both spontaneous and engineered sheep models of human neurodegenerative diseases already exist, sheep constitute a powerful species in which longitudinal in vivo studies can be conducted. This will advance our understanding of normal brain function and improve our capacity for translational research into neurological disorders.

Gas phase RDX decomposition pathways using coupled cluster theory.

Electronic and free energy barriers for a series of gas-phase RDX decomposition mechanisms have been obtain using coupled cluster singles, doubles, and perturbative triples with complete basis set (CCSD(T)/CBS) electronic energies for MBPT(2)/cc-pVTZ structures. Importantly, we have located a well-defined transition state for NN homolysis, in the initial RDX decomposition step, thereby obtaining a true barrier for this reaction. These calculations support the view that HONO elimination is preferred at STP over other proposed mechanisms, including NN homolysis, "triple whammy" and NONO isomerization. Indeed, our calculated values of Arrhenius parameters are in agreement with experimental findings for gas phase RDX decomposition. We also investigate a number of new pathways leading to breakdown of the intermediate formed by the initial HONO elimination, and find that NN homolysis in this intermediate has an activation energy barrier comparable with that computed for HONO elimination.

Optoactivation of locus ceruleus neurons evokes bidirectional changes in thermal nociception in rats.

Pontospinal noradrenergic neurons are thought to form part of a descending endogenous analgesic system that exerts inhibitory influences on spinal nociception. Using optogenetic targeting, we tested the hypothesis that excitation of the locus ceruleus (LC) is antinociceptive. We transduced rat LC neurons by direct injection of a lentiviral vector expressing channelrhodopsin2 under the control of the PRS promoter. Subsequent optoactivation of the LC evoked repeatable, robust, antinociceptive (+4.7°C ± 1.0, p < 0.0001) or pronociceptive (-4.4°C ± 0.7, p < 0.0001) changes in hindpaw thermal withdrawal thresholds. Post hoc anatomical characterization of the distribution of transduced somata referenced against the position of the optical fiber and subsequent further functional analysis showed that antinociceptive actions were evoked from a distinct, ventral subpopulation of LC neurons. Therefore, the LC is capable of exerting potent, discrete, bidirectional influences on thermal nociception that are produced by specific subpopulations of noradrenergic neurons. This reflects an underlying functional heterogeneity of the influence of the LC on the processing of nociceptive information.