Acute thalamic connectivity precedes chronic post-concussive symptoms in mild traumatic brain injury.

Chronic post-concussive symptoms are common after mild traumatic brain injury (mTBI) and are difficult to predict or treat. Thalamic functional integrity is particularly vulnerable in mTBI and may be related to long-term outcomes but requires further investigation. We compared structural MRI and resting state functional MRI in 108 patients with a Glasgow Coma Scale (GCS) of 13-15 and normal CT, and 76 controls. We examined whether acute changes in thalamic functional connectivity were early markers for persistent symptoms and explored neurochemical associations of our findings using PET data. Of the mTBI cohort, 47% showed incomplete recovery 6 months post-injury. Despite the absence of structural changes, we found acute thalamic hyperconnectivity in mTBI, with specific vulnerabilities of individual thalamic nuclei. Acute fMRI markers differentiated those with chronic post-concussive symptoms, with time- and outcome-dependent relationships in a sub-cohort followed longitudinally. Moreover, emotional and cognitive symptoms were associated with changes in thalamic functional connectivity to known serotonergic and noradrenergic targets, respectively. Our findings suggest that chronic symptoms can have a basis in early thalamic pathophysiology. This may aid identification of patients at risk of chronic post-concussive symptoms following mTBI, provide a basis for development of new therapies and facilitate precision medicine application of these therapies.

Triggered electromyography (tEMG) in the lumbar spine It́s reliable? Correlation of tEMG with postoperative CT images in lumbar instrumentation. / Electromiografía evocada (tEMG) en la columna lumbar. ¿Es confiable? Correlación de tEMG con imágenes de TC posoperatorias en la instrumentación lumbar.

INTRODUCTION: Instrumentation with pedicle screws (PS) can compromise the adjacent neural structures. Triggered electromyography (tEMG) is a modality of intraoperative neuromonitoring, used to assist in the placement of these. The objective of the present study is to evaluate the reliability of this tool. METHOD: Retrospective review of patients underwent posterior lumbar fusions from January 2017 to December 2019, correlating postoperative CT images (postop CT) with tEMG results for each PS with a threshold of 10mA, establishing sensitivity and specificity of this tool. Diagnostic test and receiver operating characteristic curve were performed to evaluate the area under the curve. RESULT: A total of 275 PS were evaluated between L1 to S1; 5 PS showed concordance for an inadequate trajectory, while 10PS, with tEMG <10mA, were correctly positioned. The postoperative CT identified 17 pedicle gaps not noticed by the tEMG. Sensitivity and specificity were 23% (95% CI: 8-45) and 96% (95% CI: 93-98), respectively, with a PPV of 33.3% and a NPV of 93.6%. The area under the curve was 0.74 (95% CI: 0.62-0.86) with a cut-off point of 24mA, showing a sensitivity of 77% (95% CI: 0.55-0.92) and specificity of 69% (95% CI: 0.63-0.75). CONCLUSION: Given its low sensitivity, we do not recommend tEMG as the sole test in the verification of PS. We recommend using a cut-off point ≤8mA as it demonstrated the highest levels of sensitivity and specificity. We do not recommend using high thresholds to increase sensitivity.

Trapping Alkaline Earth Rydberg Atoms Optical Tweezer Arrays.

Neutral atom qubits with Rydberg-mediated interactions are a leading platform for developing large-scale coherent quantum systems. In the majority of experiments to date, the Rydberg states are not trapped by the same potential that confines ground state atoms, resulting in atom loss and constraints on the achievable interaction time. In this Letter, we demonstrate that the Rydberg states of an alkaline earth atom, ytterbium, can be stably trapped by the same red-detuned optical tweezer that also confines the ground state, by leveraging the polarizability of the Yb^{+} ion core. Using the previously unobserved ^{3}S_{1} series, we demonstrate trapped Rydberg atom lifetimes exceeding 100 µs, and observe no evidence of auto- or photoionization from the trap light for these states. We measure a coherence time of T_{2}=59 µs between two Rydberg levels, exceeding the 28 µs lifetime of untrapped Rydberg atoms under the same conditions. These results are promising for extending the interaction time of Rydberg atom arrays for quantum simulation and computing, and are vital to capitalize on the extended Rydberg lifetimes in circular states or cryogenic environments.

Drinking water quality in the glacial aquifer system, northern USA.

Groundwater supplies 50% of drinking water worldwide, but compromised water quality from anthropogenic and geogenic contaminants can limit usage of groundwater as a drinking water source. Groundwater quality in the glacial aquifer system, USA (GLAC), is presented in the context of a hydrogeologic framework that divides the study area into 17 hydrogeologic terranes. Results are reported at aquifer-system scale and regional (terrane) scale. This paper presents a quantitative assessment of groundwater quality in the GLAC using data from numerous sources for samples collected 2005-2013, compared to health-based and aesthetic (non-health) benchmarks, and evaluated with areal and population metrics. Concentrations above a benchmark are considered high. Trace elements are widespread across the study area, with an estimated 5.7 million people relying on groundwater with high concentrations of one or more trace elements; manganese and arsenic are most often at high concentration. Nitrate is found at high concentration in 4.0% of the study area, serving about 740 thousand people. Organic compounds including pesticides and volatile organic compounds are high in 2.0% of the assessed study area, with about 870 thousand people relying on groundwater with high concentrations of an organic compound. High arsenic and manganese concentrations occur primarily in the terranes with thick, stratigraphically complex, fine-grained glacial sediment, coincident with groundwater under reducing conditions (indicated by iron concentrations >100 µg/L); high nitrate is uncommon in those same terranes. When nitrate is high in thick, fine-grained, complex terranes, though, it is much more commonly associated with groundwater under more oxidizing conditions. Common geogenic trace elements occur at high concentration due to characteristic geologic and geochemical conditions. Conversely, anthropogenic nitrate and organic compounds are introduced at or near the land surface. High concentrations of nitrate or organic compounds are generally limited to areas in proximity where people live and use the chemicals.

Narrow-Line Cooling and Imaging of Ytterbium Atoms in an Optical Tweezer Array.

Engineering controllable, strongly interacting many-body quantum systems is at the frontier of quantum simulation and quantum information processing. Arrays of laser-cooled neutral atoms in optical tweezers have emerged as a promising platform because of their flexibility and the potential for strong interactions via Rydberg states. Existing neutral atom array experiments utilize alkali atoms, but alkaline-earth atoms offer many advantages in terms of coherence and control, and also open the door to new applications in precision measurement and time keeping. In this Letter, we present a technique to trap individual alkaline-earth-like ytterbium (Yb) atoms in optical tweezer arrays. The narrow ^{1}S_{0}-^{3}P_{1} intercombination line is used for both cooling and imaging in a magic-wavelength optical tweezer at 532 nm. The low Doppler temperature allows for imaging near the saturation intensity, resulting in a very high atom detection fidelity. We demonstrate the imaging fidelity concretely by observing rare (<1 in 10^{4} images) spontaneous quantum jumps into and out of a metastable state. We also demonstrate stochastic loading of atoms into a two-dimensional, 144-site tweezer array. This platform will enable advances in quantum information processing, quantum simulation, and precision measurement. The demonstrated narrow-line Doppler imaging may also be applied in tweezer arrays or quantum gas microscopes using other atoms with similar transitions, such as erbium and dysprosium.

Dynamic intracellular delivery of antibiotics via pH-responsive polymersomes.

Reversible addition-fragmentation chain transfer (RAFT) polymerization was employed to prepare a series of copolymers consisting of 2-hdroxyethyl methacrylate (HEMA) and poly(ethylene glycol) methyl ether methacrylate (FWavg ~ 950 Da) (O950) with variable comonomer compositions and molecular weights for use as polymeric scaffolds. Reactivity ratios for the monomer pair were determined to be 1.37 and 0.290 respectively. To these scaffolds trithiocarbonate-based RAFT chain transfer agents (CTAs) were grafted using carbodiimide chemistry. The resultant graft chain transfer agents (gCTA) were subsequently employed to polymerize dimethylaminoethyl methacrylate (DMAEMA) and (HPMA) between degrees of polymerization (DP) of 25 and 200. Kinetic analysis for the polymerization of DMAEMA targeting a DP of 100 from a 34 arm graft gCTA show linear Mn conversion and pseudo first order rate plots with narrow molecular weight distributions that move toward lower elution volumes with monomer conversion. D values for these polymerizations remain low at around 1.20 at monomer conversions as high as 70 %. pH-responsive endosomalytic brushes capable of spontaneously self-assembling into polymersomes were synthesized and a combination of dynamic light scattering (DLS), cryoTEM, and red blood cell hemolysis were employed to evaluate the aqueous solution properties of the polymeric brush as a function of pH. Successful encapsulation of ceftazidime and pH-dependent drug release properties were confirmed by HPLC. Intracellular antibiotic activity of the drug-loaded polymersomes was confirmed in a macrophage coculture model of infection with B. thailandensis and RAW 264.7 cells.

Lessons from traumatic head injury for assessing functional status after brain tumour.

Assessment of global functional status plays a central role in describing outcome after traumatic head injury, but has played a relatively minor role as an endpoint in brain tumour studies. Advantages of functional status as an outcome include simplicity, objectivity, and interpretability, and it is particularly useful in conditions where cognitive impairment is common. Work in the field of traumatic brain injury, specifically on the Glasgow Outcome Scale (GOS), provides lessons in how the validity and reliability of global outcome assessment can be improved. Functional status is conceptually and empirically distinct from cognition and health-related quality of life, and neither of these can adequately substitute for it as an outcome. The strongest candidate for a global outcome measure in brain tumour work is the Karnofsky Performance Status (KPS). Many of the lessons from the GOS could be applied to improvement of KPS assessment. However, the KPS has additional limitations, particularly that it is not brain injury specific. Global functional status is potentially a useful outcome for brain tumour studies, but there is a gap in the tools currently available.

Thrombomodulin improves early outcomes after intraportal islet transplantation.

Primary islet nonfunction due to an instant blood mediated inflammatory reaction (IBMIR) leads to an increase in donor islet mass required to achieve euglycemia. In the presence of thrombin, thrombomodulin generates activated protein C (APC), which limits procoagulant and proinflammatory responses. In this study, we postulated that liposomal formulations of thrombomodulin (lipo-TM), due to its propensity for preferential uptake in the liver, would enhance intraportal engraftment of allogeneic islets by inhibiting the IBMIR. Diabetic C57BL/6J mice underwent intraportal transplantation with B10.BR murine islets. In the absence of treatment, conversion to euglycemia was observed among 29% of mice receiving 250 allo-islets. In contrast, a single infusion of lipo-TM led to euglycemia in 83% of recipients (p = 0.0019). Fibrin deposition (p < 0.0001), neutrophil infiltration (p < 0.0001), as well as expression TNF-alpha and IL-beta (p < 0.03) were significantly reduced. Significantly, thrombotic responses mediated by human islets in contact with human blood were also reduced by this approach. Lipo-TM improves the engraftment of allogeneic islets through a reduction in local thrombotic and inflammatory processes. As an enzyme-based pharmacotherapeutic, this strategy offers the potential for local generation of APC at the site of islet infusion, during the initial period of elevated thrombin production.

Observer variation in the assessment of outcome in traumatic brain injury: experience from a multicenter, international randomized clinical trial.

OBJECTIVE: Accurate and consistent outcome assessment is essential to randomized clinical trials. We aimed to explore observer variation in the assessment of outcome in a recently completed trial of dexanabinol in head injury and to consider steps to reduce such variation. METHODS: Eight hundred sixty-one patients with severe traumatic brain injury who were admitted to 86 centers were included in a multicenter, placebo-controlled, Phase III trial. Outcome was assessed at 3 and 6 months postinjury using the extended Glasgow Outcome Scale; standardized assessment was facilitated by the use of a structured interview. Before initiation of trial centers, outcome ratings were obtained for sample cases to establish initial levels of agreement. Training sessions in outcome assessment were held, and problems in assigning outcome were investigated. During the trial, a process of central review was established to monitor performance. Interobserver variation was analyzed using the kappa statistic. RESULTS: Substantial observer variation was found in the rating of sample cases (weighted kappa, 0.72; confidence interval, 0.68-0.75) and in assigning outcome based on completed structured interviews (weighted kappa, 0.61; confidence interval, 0.57-0.64). In the early stages of the trial, a relatively large number of discrepancies (29-37%) were identified on central review. This number declined as the trial progressed and coincided with investigator training and feedback from central review. Centers with higher enrollment rates showed better performance. CONCLUSION: Observer variation in outcome assessment is a significant problem for head injury trials. Consistency can be improved by standardizing procedures, training assessors, and monitoring the quality of assessments and providing feedback to interviewers.

Ontogeny of dextromethorphan O- and N-demethylation in the first year of life.

The exponential increase in the number of drugs used to treat infant and childhood illnesses necessitates an understanding of the ontogeny of drug biotransformation for the development of safe and effective therapies. Healthy infants received an oral dose (0.3 mg/kg) of dextromethorphan (DM) at 0.5, 1, 2, 4, 6, and 12 months of age. DM and its major metabolites were measured in urine. CYP2D6 genotype was determined by polymerase chain reaction-restriction fragment length polymorphism. Genotyping data indicated a strong correlation between CYP2D6 genotype and DM O-demethylation (beta=-0.638; 95% CI: -0.745, -0.532; P<0.001). CYP2D6 activity was detectable and concordant with genotype by 2 weeks of age, showed no relationship with gestational age, and did not change with post natal age up to 1 year. In contrast, DM N-demethylation developed significantly more slowly over the first year of life. Genotype and the temporal acquisition of drug biotransformation are critical determinants of a drug response in infants.

Premorbid intelligence and brain injury.

OBJECTIVES: To determine whether NART scores are associated with severity of brain injury and therefore presumably affected by brain injury. In addition, to compare the Cambridge Contextual Reading Test (CCRT) with injury severity in head-injured individuals. DESIGN AND METHODS: Participants were 55 survivors of traumatic head injury, who completed the NART and the CCRT. The scores on these premorbid measures were then compared with indices of injury severity from their initial neurosurgical admission. RESULTS: The NART was significantly correlated with Glasgow coma scale, with greater severity of injury associated with poorer performance. Poorer NART performance was also significantly more likely amongst those whose injury resulted in coma. The CCRT was preferred by patients, though it was also significantly associated with Glasgow coma scale and presence of coma. CONCLUSIONS: The data suggest that performance on both the NART and the CCRT are affected by brain injury severity and thus may underestimate true premorbid ability in these individuals. Similar findings would be likely with the conceptually identical WTAR measure. These measures should be used with appropriate caution and may be usefully supplemented by predictions based on demographic information.

Is there impairment of a specific frontal lobe circuit in head injury?

There has been considerable interest in the role of anterior cingulate and lateral frontal cortex in normal cognition, and particularly its role in cognitive control. It has also been suggested that dysfunction of this frontal brain circuit is responsible for many of the cognitive deficits observed after head injury. Several recent PET and SPECT studies of head injury have lent support to this idea, and suggest that the hypothesis is worth further examination. The paper presents a selective overview of evidence that this specific frontal lobe circuit is impaired after head injury.

Reliability of the modified Rankin Scale across multiple raters: benefits of a structured interview.

BACKGROUND AND PURPOSE: The modified Rankin Scale (mRS) is widely used to assess global outcome after stroke. The aim of the study was to examine rater variability in assessing functional outcomes using the conventional mRS, and to investigate whether use of a structured interview (mRS-SI) reduced this variability. METHODS: Inter-rater agreement was studied among raters from 3 stroke centers. Fifteen raters were recruited who were experienced in stroke care but came from a variety of professional backgrounds. Patients at least 6 months after stroke were first assessed using conventional mRS definitions. After completion of initial mRS assessments, raters underwent training in the use of a structured interview, and patients were re-assessed. In a separate component of the study, intrarater variability was studied using 2 raters who performed repeat assessments using the mRS and the mRS-SI. The design of the latter part of the study also allowed investigation of possible improvement in rater agreement caused by repetition of the assessments. Agreement was measured using the kappa statistic (unweighted and weighted using quadratic weights). RESULTS: Inter-rater reliability: Pairs of raters assessed a total of 113 patients on the mRS and mRS-SI. For the mRS, overall agreement between raters was 43% (kappa=0.25, kappa(w)=0.71), and for the structured interview overall agreement was 81% (kappa=0.74, kappa(w)=0.91). Agreement between raters was significantly greater on the mRS-SI than the mRS (P<0.001). Intrarater reliability: Repeatability of both the mRS and mRS-SI was excellent (kappa=0.81, kappa(w) > or =0.94). CONCLUSIONS: Although individual raters are consistent in their use of the mRS, inter-rater variability is nonetheless substantial. Rater variability on the mRS is thus particularly problematic for studies involving multiple raters. There was no evidence that improvement in inter-rater agreement occurred simply with repetition of the assessment. Use of a structured interview improves agreement between raters in the assessment of global outcome after stroke.

Differential responses in three thalamic nuclei in moderately disabled, severely disabled and vegetative patients after blunt head injury.

In vivo imaging techniques have indicated for many years that there is loss of white matter after human traumatic brain injury (TBI) and that the loss is inversely related to cognitive outcome. However, correlated, quantitative evidence for loss of neurons from either the cerebral cortex or the diencephalon is largely lacking. There is some evidence in models of TBI that neuronal loss occurs within the thalamus, but no systematic studies of such loss have been undertaken in the thalamus of humans after blunt head injury. We have undertaken a stereological analysis of changes in numbers of neurons within the dorsomedial, ventral posterior and lateral posterior thalamic nuclei in patients assessed by the Glasgow Outcome Scale as moderately disabled (n = 9), severely disabled (n = 12) and vegetative (n = 10) head-injured patients who survived between 6 h and 3 years, and controls (n = 9). In histological sections at the level of the lateral geniculate body, the cross-sectional area of each nucleus and the number and the mean size of neurons within each nucleus was quantified. A statistically significant loss of cross-sectional area and number of neurons occurred in the dorsomedial nucleus in moderately disabled, and both the dorsomedial and ventral posterior thalamic nuclei in severely disabled and vegetative head-injured patients. However, there was no change in neuronal cell size. In the lateral posterior nucleus, despite a reduction in mean cell size, there was not a significant change in either nuclear area or number of neurons in cases of moderately disabled, severely disabled or vegetative patients. We posit, although detailed neuropsychological outcome for the patients included within this study was not available, that neuronal loss in the dorsomedial thalamus in moderately and severely disabled and vegetative patients may be the structural basis for the clinical assessment in the Glasgow Outcome Scale. In severely disabled and vegetative patients, loss of neurons from the ventral posterior thalamic nucleus may also reflect loss of response to afferent stimuli.

Apolipoprotein E polymorphism and neuropsychological outcome following subarachnoid haemorrhage.

OBJECTIVES: To investigate the association between APOE genotype and cognitive and emotional outcome following spontaneous subarachnoid haemorrhage (SAH). MATERIALS AND METHODS: Neuropsychological assessments were conducted with 70 SAH survivors derived from a consecutive series of neurosurgical admissions. Outcomes, including cognitive tests, health questionnaires and Glasgow Outcome Scale at a mean of 16 months after SAH, were compared with presence or absence of the epsilon4 allele. RESULTS: There was no evidence that SAH survivors possessing the epsilon4 allele had poorer outcome. The only suggestion of an association between the epsilon4 allele and outcome was in a subgroup of patients with a Fisher grade 4 haemorrhage, although this trend did not reach statistical significance. CONCLUSIONS: Overall, possession of the APOE epsilon4 allele is not significantly associated with neuropsychological outcome following SAH. However, there may be an effect amongst those with a Fisher grade 4 haemorrhage.

Anxiety and depression after spontaneous subarachnoid hemorrhage.

OBJECTIVE: Relatively little attention has been paid to emotional outcome after subarachnoid hemorrhage (SAH). This study assessed levels of anxiety and depression among SAH survivors and related these to clinical indices. METHODS: Seventy SAH patients from a consecutive series of neurosurgical admissions participated in semistructured assessments of functional outcome; 52 of the patients also returned standardized measures of emotional outcome. These data were compared with clinical indices collected during the initial hospital admission. RESULTS: Moderate to severe levels of anxiety were present in approximately 40% of patients 16 months after hemorrhage, with approximately 20% experiencing moderate to severe levels of depression. Although anxiety was more likely to be reported at interview by those with an SAH of Fisher Grade 4, the standardized measures of anxiety and depression were not associated with severity of hemorrhage or any other clinical variables. Both anxiety and depression were significantly associated with outcome indices such as return to work and engagement in social activities. CONCLUSION: Anxiety is a significant and lasting problem for approximately 40% of survivors of SAH. It is suggested that measures taken to prevent or treat such anxiety among survivors of SAH may serve to significantly improve functional outcome.

Role of the research-subject locator (RSL) in the performance of a pediatric drug trial.

This article examines the feasibility, effectiveness, and ethical constraints relevant to appropriate financial compensation of the pediatric house officer who functions as a research-subject locator (RSL). When carefully trained and supervised, the RSL can facilitate timely enrollment of research subjects in pediatric drug trials, augment the house officer training experience, and advocate for children to increase therapeutic options available for pediatric care. When monitored within the clinical trial schema, the RSL has no direct link to the study outcome and thus performs within ethical standards for subject enrollment and study participation.