Targeting the post-synaptic proteome has therapeutic potential for psychosis in Alzheimer Disease.

Individuals with Alzheimer Disease who develop psychotic symptoms (AD + P) experience more rapid cognitive decline and have reduced indices of synaptic integrity relative to those without psychosis (AD-P). We sought to determine whether the postsynaptic density (PSD) proteome is altered in AD + P relative to AD-P, analyzing PSDs from dorsolateral prefrontal cortex of AD + P, AD-P, and a reference group of cognitively normal elderly subjects. The PSD proteome of AD + P showed a global shift towards lower levels of all proteins relative to AD-P, enriched for kinases, proteins regulating Rho GTPases, and other regulators of the actin cytoskeleton. We computationally identified potential novel therapies predicted to reverse the PSD protein signature of AD + P. Five days of administration of one of these drugs, the C-C Motif Chemokine Receptor 5 inhibitor, maraviroc, led to a net reversal of the PSD protein signature in adult mice, nominating it as a novel potential treatment for AD + P.

Combining ALS and UAV to derive the height of \textit{Araucaria angustifolia.

Quantitative data obtained from native forests is costly and time-consuming. Thus, alternative measurement methods need to be developed to provide reliable information, especially in Atlantic Rain Forests. In this study we evaluated the hypothesis that the combination of an Airborne Laser Scanner (ALS) and an Unmanned Aerial Vehicle (UAV) can provide accurate quantitative information on tree height, volume, and aboveground biomass of the Araucaria angustifolia species. The study was carried out in Atlantic Rain forest fragments in southern Brazil. We tested and evaluated 3 digital canopy height model (CHM) scenarios: 1) CHM derived from ALS models; 2) CHM derived from UAV models; and 3) CHM from a combined ALS digital terrain model and UAV digital surface model. The height value at each tree coordinate was extracted from the pixel in the three evaluated scenarios and compared with the field measured values. ALS and UAV+ALS obtained RMSE% of 6.38 and 12.82 for height estimates, while UAV was 49.91%. Volume and aboveground biomass predictions are more accurate by ALS and UAV+ALS, while the UAV produced biased estimates. Since the ALS is currently used, periodic monitoring can be carried out by a combination of active (ALS) and passive (UAV) sensors.

Radiological positioning of a proximal interphalangeal joint resurfacing implant: Reliability and functional outcomes correlation.

OBJECTIVES: The aims of this study were to define radiological measurements for quantifying the position of a surface replacing implant (CapFlex-PIP) in the proximal interphalangeal (PIP) joint, to test the reliability of these measurements, and to explore whether implant position influences patient-reported and clinical outcomes one year after surgery. MATERIAL AND METHODS: We developed 7 radiographic measurements to quantify the position of the proximal and distal implant components. Two independent surgeons analyzed the 1-year postoperative radiographs of 63 fingers documented in our registry. Inter-rater reliability of these measurements was calculated with the intraclass correlation coefficient (ICC). Correlations between the radiographic measurements and PIP range of motion (ROM), the brief Michigan Hand Outcomes Questionnaire (MHQ), and pain were determined using Spearman's correlation coefficient. Radiographic measurements of patients with the worst and best postoperative ROM were compared using the Mann-Whitney-U test. RESULTS: Inter-rater reliability was only good for 1 measurement (ICC = 0.89), but poor to moderate for the other measurements (ICC ranging from 0.34 to 0.69). These measurements neither correlated with ROM, brief MHQ nor pain based on correlation coefficients ranging from 0.00 to 0.31. There were no relevant differences in the radiographic measurements between patients with the worst and best ROM. CONCLUSION: The position of the CapFlex-PIP implant could not be reliably quantified on plain radiographs. The lack of correlations between implant position and postoperative outcomes can be attributed either to the unreliable measurements or the actual lack of influence of the implant position on pain and function.

Genetic dissection of seed characteristics in field pennycress via genome-wide association mapping studies.

Field pennycress (Thlaspi arvense L.) is a new winter annual cash cover crop with high oil content and seed yield, excellent winter hardiness, early maturation, and resistance to most pests and diseases. It provides living cover on fallow croplands between summer seasons, and in doing so reduces nutrient leaching into water sources, mitigates soil erosion, and suppresses weed growth. The first ever genome-wide association study (GWAS) was conducted on a pennycress diversity panel to identify marker trait associations with important seed size and composition related traits. The entire population was phenotyped in three total environments over 2 yr, and seed area, length, width, thousand grain weight, total oil, and total protein were measured post-harvest with specialized high-throughput imaging and near-infrared spectroscopy. Basic unbiased linear prediction values were calculated for each trait. Seed size traits tended to have higher entry mean reliabilities (0.76-0.79) compared with oil content (0.51) and protein content (0.37). Genotyping-by-sequencing identified 33,606 high quality genome-wide single nucleotide polymorphism (SNPs) that were coupled with phenotypic data to perform GWAS for seed area, length, width, thousand grain weight, total oil, and total protein content. Fifty-nine total marker-trait associations were identified revealing genomic regions controlling each trait. The significant SNPs explained 0.06-0.18% of the total variance for that trait in our population. A list of candidate genes was identified based on their functional annotations and characterization in other species. Our results confirm that GWAS is an efficient strategy to identify significant marker-trait associations that can be incorporated into marker-assisted selection pipelines to accelerate pennycress breeding progress.

Field pennycress is an excellent winter annual oilseed that can serve as a cash cover crop. Genotyping-by-sequencing is an effective strategy to genotype pennycress affordably for high-quality genome-wide single nucleotide polymorphisms. First-ever mapping study in a field pennycress association mapping population was conducted. GWAS identified 59 significant marker-trait associations for important quantitative traits. Seed size traits had a higher reliability estimate compared with seed composition traits.

Chromosome-level Thlaspi arvense genome provides new tools for translational research and for a newly domesticated cash cover crop of the cooler climates.

Thlaspi arvense (field pennycress) is being domesticated as a winter annual oilseed crop capable of improving ecosystems and intensifying agricultural productivity without increasing land use. It is a selfing diploid with a short life cycle and is amenable to genetic manipulations, making it an accessible field-based model species for genetics and epigenetics. The availability of a high-quality reference genome is vital for understanding pennycress physiology and for clarifying its evolutionary history within the Brassicaceae. Here, we present a chromosome-level genome assembly of var. MN106-Ref with improved gene annotation and use it to investigate gene structure differences between two accessions (MN108 and Spring32-10) that are highly amenable to genetic transformation. We describe non-coding RNAs, pseudogenes and transposable elements, and highlight tissue-specific expression and methylation patterns. Resequencing of forty wild accessions provided insights into genome-wide genetic variation, and QTL regions were identified for a seedling colour phenotype. Altogether, these data will serve as a tool for pennycress improvement in general and for translational research across the Brassicaceae.

Thumb Interphalangeal Joint Arthroplasty With a Surface Replacing Implant: Two-Year Results.

PURPOSE: The aim of this study was to evaluate the 2-year clinical and patient-reported outcomes of thumb interphalangeal (IP) joint arthroplasty. METHODS: In this prospective pilot study, we included patients who received a surface replacing implant at the thumb IP joint. Patients rated their pain at rest on a numeric rating scale (0-10) and completed the brief Michigan Hand Outcomes Questionnaire. The range of motion of the IP joint was also measured. If the patient acceptable symptom state was inadequate (i.e., pain at rest ≤ 1.5), the reasons for the remaining symptoms were descriptively presented. RESULTS: Of the 13 patients who underwent arthroplasty, 1 withdrew participation and 1 was considered for arthrodesis because of a dislocated implant. Therefore, the study included 11 patients with a median age of 67 years. The median pain at rest decreased from 6 preoperatively to 0 at 2 years, and the preoperative brief Michigan Hand Outcomes Questionnaire score increased from 38 to 58 at follow-up. The total range of motion of the IP joint was 45° at 2 years. Patient acceptable symptom state was not achieved in 4 patients including a heavy manual worker and a patient with severe systemic lupus erythematosus. CONCLUSIONS: Based on the inconsistency of the results, we conclude that thumb IP joint arthroplasty with a surface replacing implant is rarely indicated; it could be an alternative in patients who place great importance on precision tasks. For patients who either have high demands for a powerful pinch grip, the high physical demands of a manual job, or rheumatoid disease, IP joint arthrodesis should be preferred. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Technologies enabling rapid crop improvements for sustainable agriculture: example pennycress (Thlaspi arvense L.).

Growing concerns over food insecurity and ecosystems health related to population growth and climate change have challenged scientists to develop new crops, employing revolutionary technologies in combination with traditional methods. In this review, we discuss the domestication of the oilseed-producing cover crop pennycress, which along with the development of other new crops and improvements to farming practices can provide sustainable solutions to address malnutrition and environmental impacts of production agriculture. We highlight some of the new technologies such as bioinformatics-enabled next-generation sequencing and CRISPR genome editing in combination with traditional mutation breeding that has accelerated pennycress development as a new crop and a potential model system. Furthermore, we provide a brief overview of the technologies that can be integrated for improving pennycress and other crops and the status of pennycress development using these technologies.

Tissue at Risk and Ischemic Core Estimation Using Deep Learning in Acute Stroke.

BACKGROUND AND PURPOSE: In acute stroke patients with large vessel occlusions, it would be helpful to be able to predict the difference in the size and location of the final infarct based on the outcome of reperfusion therapy. Our aim was to demonstrate the value of deep learning-based tissue at risk and ischemic core estimation. We trained deep learning models using a baseline MR image in 3 multicenter trials. MATERIALS AND METHODS: Patients with acute ischemic stroke from 3 multicenter trials were identified and grouped into minimal (≤20%), partial (20%-80%), and major (≥80%) reperfusion status based on 4- to 24-hour follow-up MR imaging if available or into unknown status if not. Attention-gated convolutional neural networks were trained with admission imaging as input and the final infarct as ground truth. We explored 3 approaches: 1) separate: train 2 independent models with patients with minimal and major reperfusion; 2) pretraining: develop a single model using patients with partial and unknown reperfusion, then fine-tune it to create 2 separate models for minimal and major reperfusion; and 3) thresholding: use the current clinical method relying on apparent diffusion coefficient and time-to-maximum of the residue function maps. Models were evaluated using area under the curve, the Dice score coefficient, and lesion volume difference. RESULTS: Two hundred thirty-seven patients were included (minimal, major, partial, and unknown reperfusion: n = 52, 80, 57, and 48, respectively). The pretraining approach achieved the highest median Dice score coefficient (tissue at risk = 0.60, interquartile range, 0.43-0.70; core = 0.57, interquartile range, 0.30-0.69). This was higher than the separate approach (tissue at risk = 0.55; interquartile range, 0.41-0.69; P = .01; core = 0.49; interquartile range, 0.35-0.66; P = .04) or thresholding (tissue at risk = 0.56; interquartile range, 0.42-0.65; P = .008; core = 0.46; interquartile range, 0.16-0.54; P < .001). CONCLUSIONS: Deep learning models with fine-tuning lead to better performance for predicting tissue at risk and ischemic core, outperforming conventional thresholding methods.

Development and internal validation of a diagnostic prediction model for COVID-19 at time of admission to hospital.

BACKGROUND: Early coronavirus disease 2019 (COVID-19) diagnosis prior to laboratory testing results is crucial for infection control in hospitals. Models exist predicting COVID-19 diagnosis, but significant concerns exist regarding methodology and generalizability. AIM: To generate the first COVID-19 diagnosis risk score for use at the time of hospital admission using the TRIPOD (transparent reporting of a multivariable prediction model for individual prognosis or diagnosis) checklist. DESIGN: A multivariable diagnostic prediction model for COVID-19 using the TRIPOD checklist applied to a large single-centre retrospective observational study of patients with suspected COVID-19. METHODS: 581 individuals were admitted with suspected COVID-19; the majority had laboratory-confirmed COVID-19 (420/581, 72.2%). Retrospective collection was performed of electronic clinical records and pathology data. RESULTS: The final multivariable model demonstrated AUC 0.8535 (95% confidence interval 0.8121-0.8950). The final model used six clinical variables that are routinely available in most low and high-resource settings. Using a cut-off of 2, the derived risk score has a sensitivity of 78.1% and specificity of 86.8%. At COVID-19 prevalence of 10% the model has a negative predictive value (NPV) of 96.5%. CONCLUSIONS: Our risk score is intended for diagnosis of COVID-19 in individuals admitted to hospital with suspected COVID-19. The score is the first developed for COVID-19 diagnosis using the TRIPOD checklist. It may be effective as a tool to rule out COVID-19 and function at different pandemic phases of variable COVID-19 prevalence. The simple score could be used by any healthcare worker to support hospital infection control prior to laboratory testing results.

Determinants of long-term satisfaction after silicone MCP arthroplasty in patients with inflammatory diseases.

The aim was to identify determinants of satisfaction in patients with inflammatory diseases who underwent hand reconstruction using silicone metacarpophalangeal (MCP) arthroplasty. We hypothesized that patients taking biologic drugs would be more satisfied with the outcome. Patients who underwent silicone arthroplasty and had a minimum follow-up of 1 year were included. Patients rated their satisfaction with the treatment result and hand appearance on a 5-point Likert scale with a score of 5 indicating "very satisfied" and 1 indicating "very dissatisfied" and completed the brief Michigan Hand Outcomes questionnaire (MHQ). MCP range of motion (ROM), ulnar drift and grip strength were measured. Ordered logistic regression modelling and the Mann-Whitney U test were used. Forty-one patients with 118 operated fingers were available for follow-up at an average of 5.6 years after surgery. Patients were satisfied with the overall treatment result (score 4.4; SD 0.8), but only somewhat satisfied (score 3.3; SD 1.5) with their hand's appearance. Total MCP ROM was 61° (SD 21) with an ulnar deviation of 10° (SD 14). Appearance and ulnar deviation were significant determinants of satisfaction (R2=0.35). There was no difference in outcomes between patients using biologics and those who were not. Our hypothesis that patients taking biologics are more satisfied after surgery could not be proven. Hand appearance and ulnar drift are the most important determinants of satisfaction after reconstruction of MCP deformity.

Measurement properties of the German Unité Rhumatologique des Affections de la Main (URAM) scale in patients treated for Dupuytren's disease.

We sought to investigate the reliability, validity, responsiveness, and interpretability of the German version of the Unité Rhumatologique des Affections de la Main (URAM) scale in patients with Dupuytren's disease. Patients with Dupuytren's disease were evaluated before receiving an injection of collagenase Clostridium histolyticum or undergoing surgical treatment and again 1 year later. Patients completed the URAM, the brief Michigan Hand Outcomes Questionnaire (brief MHQ), and the 5-level EuroQol version (EQ-5D-5L). Flexion contracture was measured. Internal consistency (Cronbach's alpha), construct validity (Spearman's correlation coefficient, r), responsiveness (effect size), and the minimally important change (MIC) and minimally important difference (MID) were determined. Confirmatory factor analysis was used to test the structural validity of the questionnaire. We included 231 patients (273 cases) with a mean age of 67 (SD, 9) years. Cronbach's alpha was 0.91. Correlations between the URAM and the brief MHQ, EQ-5D-5L and flexion contracture were r=-0.76, r=-0.46 and r=0.53, respectively. The URAM effect size was 0.96 and the MIC and MID were 6 and 7 points, respectively. The factor analysis revealed unidimensionality but indicated that one item (pick up small objects) could be removed. The German URAM has high reliability, good construct validity and excellent responsiveness. However, the questionnaire could be shortened by one item to increase its structural validity. We recommend using the URAM as a specific tool for evaluating the treatment effect in patients with Dupuytren's disease in daily practice and for research purposes.

A novel cohorting and isolation strategy for suspected COVID-19 cases during a pandemic.

BACKGROUND: The COVID-19 pandemic presents a significant infection prevention and control challenge. The admission of large numbers of patients with suspected COVID-19 disease risks overwhelming the capacity to protect other patients from exposure. The delay between clinical suspicion and confirmatory testing adds to the complexity of the problem. METHODS: We implemented a triage tool aimed at minimizing hospital-acquired COVID-19 particularly in patients at risk of severe disease. Patients were allocated to triage categories defined by likelihood of COVID-19 and risk of a poor outcome. Category A (low-likelihood; high-risk), B (high-likelihood; high-risk), C (high-likelihood; low-risk) and D (low-likelihood; low-risk). This determined the order of priority for isolation in single-occupancy rooms with Category A the highest. Patients in other groups were cohorted when isolation capacity was limited with additional interventions to reduce transmission. RESULTS: Ninety-three patients were evaluated with 79 (85%) receiving a COVID-19 diagnosis during their admission. Of those without a COVID-19 diagnosis: 10 were initially triaged to Category A; 0 to B; 1 to C and 4 to D. All high-risk patients requiring isolation were, therefore, admitted to single-occupancy rooms and protected from exposure. Twenty-eight (30%) suspected COVID-19 patients were evaluated to be low risk (groups C and D) and eligible for cohorting. No symptomatic hospital-acquired infections were detected in the cohorted patients. DISCUSSION: Application of a clinical triage tool to guide isolation and cohorting decisions may reduce the risk of hospital-acquired transmission of COVID-19 especially to individuals at the greatest of risk of severe disease.

Lateral stability in healthy proximal interphalangeal joints versus surface replacement and silicone arthroplasty: Results of a three-dimensional motion analysis study.

The objective of this study was to quantify the lateral stability of healthy proximal interphalangeal (PIP) joints using a three-dimensional motion capture system and compare it to affected joints after surface replacement or silicone arthroplasty. Three study groups comprised healthy participants, patients with PIP joint osteoarthritis treated with a surface replacing implant (CapFlex-PIP) and those with a silicone arthroplasty. All participants were matched on gender and finger, and the two patient groups were also matched on length of follow-up. An optical tracking system was used to measure lateral stability. Radial and ulnar stability of the PIP joint was measured as the maximal lateral deviation angle of the middle phalanx under loads of 40 g, 90 g and 170g at 0°, 20° and 45° PIP joint flexion. Measurement reliability was evaluated with a test-retest trial [intraclass correlation coefficient (ICC)]. A total of 30 joints were assessed with 5 index and 5 middle fingers per test group. Lateral deviation increased proportionally with applied weight. Silicone arthroplasty joints had a higher median lateral deviation angle of 5.1° (range 0.7-7.9) than healthy [3.0° (0.5-11.0)] and surface replacement joints [3.3° (0.3-7.4)] at 45° flexion and under 170g load. Test-retest reliability was high with an ICC of 0.93. Lateral PIP joint stability is highly variable in both healthy participants and patients after PIP joint arthroplasty. PIP joint surface replacement arthroplasty tends to achieve better anatomical stability compared to flexible silicone implants.

The importance of proper and prompt treatment of ocular syphilis: a lesson from permanent vision loss in 52 eyes.

BACKGROUND: Ocular involvement can occur at any stage of syphilis. Prompt diagnosis and proper treatment of ocular syphilis are vital to avoid long-term consequences. OBJECTIVES: To describe the risk factors for ocular syphilis and clinical features of blindness caused by syphilis. METHODS: We report risk factors for ocular syphilis amongst patients seen at the Shanghai Skin Disease Hospital between October 2009 and October 2017. We identify patients with ocular syphilis resulting in blindness and report the clinical characteristics, laboratory findings and treatment outcomes of these patients. RESULTS: A total of 8310 new cases of syphilis were seen, of which 213 patients had ocular disease and 50 patients had blindness due to syphilis. Increasing age and higher RPR titres were associated with ocular involvement but there was no association with HIV status. Blindness in syphilis was restricted predominantly to patients with optic nerve involvement and not patients with isolated uveitis. Fifty patients (and a total of 67 eyes) met the WHO definition of blindness prior to treatment for syphilis. At the end of follow-up, vision had improved in 24 of 67 eyes (35.8%) after treatment. Successful treatment of uveitis was associated with the best improvement in visual acuity, whilst patient with underlying optic atrophy prior to treatment had the worst visual outcome. CONCLUSIONS: Ocular involvement is an important manifestation of syphilis which may result in blindness. Our data demonstrate outcomes for ocular syphilis are poor if detected late; early recognition and diagnosis is therefore vital to avoid permanent visual loss.

Hypoperfusion intensity ratio correlates with angiographic collaterals in acute ischaemic stroke with M1 occlusion.

BACKGROUND AND PURPOSE: Among patients with an acute ischaemic stroke secondary to large-vessel occlusion, the hypoperfusion intensity ratio (HIR) [time to maximum (TMax) > 10 volume/TMax > 6 volume] is a strong predictor of infarct growth. We studied the correlation between HIR and collaterals assessed with digital subtraction angiography (DSA) before thrombectomy. METHODS: Between January 2014 and March 2018, consecutive patients with an acute ischaemic stroke and an M1 middle cerebral artery (MCA) occlusion who underwent perfusion imaging and endovascular treatment at our center were screened. Ischaemic core (mL), HIR and perfusion mismatch (TMax > 6 s minus core volume) were assessed through magnetic resonance imaging or computed tomography perfusion. Collaterals were assessed on pre-intervention DSA using the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) scale. Baseline clinical and perfusion characteristics were compared between patients with good (ASITN/SIR score 3-4) and those with poor (ASITN/SIR score 0-2) DSA collaterals. Correlation between HIR and ASITN/SIR scores was evaluated using Pearson's correlation. Receiver operating characteristic analysis was performed to determine the optimal HIR threshold for the prediction of good DSA collaterals. RESULTS: A total of 98 patients were included; 49% (48/98) had good DSA collaterals and these patients had significantly smaller hypoperfusion volumes (TMax > 6 s, 89 vs. 125 mL; P = 0.007) and perfusion mismatch volumes (72 vs. 89 mL; P = 0.016). HIR was significantly correlated with DSA collaterals (-0.327; 95% confidence interval, -0.494 to -0.138; P = 0.01). An HIR cut-off of <0.4 best predicted good DSA collaterals with an odds ratio of 4.3 (95% confidence interval, 1.8-10.1) (sensitivity, 0.792; specificity, 0.560; area under curve, 0.708). CONCLUSION: The HIR is a robust indicator of angiographic collaterals and might be used as a surrogate of collateral assessment in patients undergoing magnetic resonance imaging. HIR <0.4 best predicted good DSA collaterals.

Accurate prediction of spontaneous lumbar curve correction following posterior selective thoracic fusion in adolescent idiopathic scoliosis using logistic regression models and clinical rationale.

INTRODUCTION: Accurate prediction of spontaneous lumbar curve correction (SLCC) after selective thoracic fusion (STF) remains difficult. This study sought to improve prediction accuracy of SLCC. The hypothesis was preoperative and intraoperative variables could predict SLCC < 20°. METHODS: A multicenter observational prospective analysis was conducted to determine predictors of SLCC in AIS patients that had posterior STF. Curve types included major thoracic curves (Lenke 1, 3-4).The primary outcome variable was to establish prediction models, and a postoperative lumbar curve (LC) ≤ 20° was defined as the target variable. Multivariate logistic regression models were established to study the relationship between selected variables and a LC ≤ 20° versus a LC > 20° at ≥ 2-year follow-up. Single and dual thresholds models in perspective of clinical rationales were applied to find models with the highest positive/negative predictive values (PPV/NPV). The secondary outcome measure was SRS scores at ≥ 2-year follow-up. RESULTS: 410 patients were included. At ≥ 2-year follow-up 282 patients had LC ≤ 20°. These patients had better SRS-22 scores than those with LC > 20° (P = 0.02). The postoperative LC and LC ≤ 20° were predicted by preoperative LC and LC-bending Cobb angle (P < 0.01, r = 0.4-0.6). Logistic regression models could be established to identify patients at risk for failing the target LC ≤ 20°.For preoperative LC and LC-bending, the prediction model achieved a NPV/PPV of 80%/72%. If the postoperative main thoracic curve is combined with the preoperative LC and a gray area for difficult decisions was allowed, model accuracy could even be improved (NPV/PPV = 96%/81%). CONCLUSION: An accurate prediction model for postoperative SLCC was established based on a large analysis of prospective STF cases. These models can support prediction and understanding of postoperative SLCC aiding in surgical decision making when contemplating a selective thoracic fusion. These slides can be retrieved under Electronic Supplementary Material.

Thrombectomy with Conscious Sedation Compared with General Anesthesia: A DEFUSE 3 Analysis.

BACKGROUND AND PURPOSE: The optimal patient sedation during mechanical thrombectomy for ischemic stroke in the extended time window is unknown. The purpose of this study was to assess the impact of patient sedation on outcome in patients undergoing thrombectomy 6-16 hours from stroke onset. MATERIALS AND METHODS: Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3 (DEFUSE 3) was a multicenter, randomized, open-label trial of thrombectomy for ICA and M1 occlusions in patients 6-16 hours from stroke onset. Subjects underwent thrombectomy with either general anesthesia or conscious sedation at the discretion of the treating institution. RESULTS: Of the 92 patients who were randomized to intervention, 26 (28%) underwent thrombectomy with general anesthesia and 66 (72%) underwent thrombectomy with conscious sedation. Baseline clinical and imaging characteristics were similar among all groups. Functional independence at 90 days was 23% for general anesthesia, 53% for conscious sedation, and 17% for medical management (P = .009 for general anesthesia versus conscious sedation). Conscious sedation was associated with a shorter time from arrival in the angiosuite to femoral puncture (median, 14 versus 18 minutes; P = 0.05) and a shorter time from femoral puncture to reperfusion (median, 36 versus 48 minutes; P = .004). Sixty-six patients were treated at sites that exclusively used general anesthesia (n = 14) or conscious sedation (n = 52). For these patients, functional independence at 90 days was significantly higher in the conscious sedation subgroup (58%) compared with the general anesthesia subgroup (21%) (P = .03). CONCLUSIONS: Patients who underwent thrombectomy with conscious sedation in the extended time window experienced a higher likelihood of functional independence at 90 days, a lower NIHSS score at 24 hours, and a shorter time from femoral puncture to reperfusion compared with those who had general anesthesia. This effect remained robust in institutions that only treated patients with a single anesthesia technique.

G protein ßγ subunits play a critical role in the actions of amphetamine.

Abnormal levels of dopamine (DA) are thought to contribute to several neurological and psychiatric disorders including drug addiction. Extracellular DA levels are regulated primarily via reuptake by the DA transporter (DAT). Amphetamine, a potent psychostimulant, increases extracellular DA by inducing efflux through DAT. Recently, we discovered that G protein ßγ subunits (Gßγ) interact with DAT, and that in vitro activation of Gßγ promotes DAT-mediated efflux. Here, we investigated the role of Gßγ in the actions of amphetamine in DA neurons in culture, ex vivo nucleus accumbens (NAc), and freely moving rats. Activation of Gßγ with the peptide myr-Ser-Ile-Arg-Lys-Ala-Leu-Asn-Ile-Leu-Gly-Tyr-Pro-Asp-Tyr-Asp (mSIRK) in the NAc potentiated amphetamine-induced hyperlocomotion, but not cocaine-induced hyperlocomotion, and systemic or intra-accumbal administration of the Gßγ inhibitor gallein attenuated amphetamine-induced, but not cocaine-induced hyperlocomotion. Infusion into the NAc of a TAT-fused peptide that targets the Gßγ-binding site on DAT (TAT-DATct1) also attenuated amphetamine-induced but not cocaine-induced hyperlocomotion. In DA neurons in culture, inhibition of Gßγ with gallein or blockade of the Gßγ-DAT interaction with the TAT-DATct1 peptide decreased amphetamine-induced DA efflux. Furthermore, activation of Gßγ with mSIRK potentiated and inhibition of Gßγ with gallein reduced amphetamine-induced increases of extracellular DA in the NAc in vitro and in freely moving rats. Finally, systemic or intra-accumbal inhibition of Gßγ with gallein blocked the development of amphetamine-induced, but not cocaine-induced place preference. Collectively, these results suggest that interaction between Gßγ and DAT plays a critical role in the actions of amphetamine and presents a novel target for modulating the actions of amphetamine in vivo.