Deterministic teleportation of a quantum gate between two logical qubits.

A quantum computer has the potential to efficiently solve problems that are intractable for classical computers. However, constructing a large-scale quantum processor is challenging because of the errors and noise that are inherent in real-world quantum systems. One approach to addressing this challenge is to utilize modularity-a strategy used frequently in nature and engineering to build complex systems robustly. Such an approach manages complexity and uncertainty by assembling small, specialized components into a larger architecture. These considerations have motivated the development of a quantum modular architecture, in which separate quantum systems are connected into a quantum network via communication channels1,2. In this architecture, an essential tool for universal quantum computation is the teleportation of an entangling quantum gate3-5, but such teleportation has hitherto not been realized as a deterministic operation. Here we experimentally demonstrate the teleportation of a controlled-NOT (CNOT) gate, which we make deterministic by using real-time adaptive control. In addition, we take a crucial step towards implementing robust, error-correctable modules by enacting the gate between two logical qubits, encoding quantum information redundantly in the states of superconducting cavities6. By using such an error-correctable encoding, our teleported gate achieves a process fidelity of 79 per cent. Teleported gates have implications for fault-tolerant quantum computation3, and when realized within a network can have broad applications in quantum communication, metrology and simulations1,2,7. Our results illustrate a compelling approach for implementing multi-qubit operations on logical qubits and, if integrated with quantum error-correction protocols, indicate a promising path towards fault-tolerant quantum computation using a modular architecture.

A multifaceted quality improvement intervention on venous thromboembolism prophylaxis compliance in hospitalized medical patients at a comprehensive cancer center.

INTRODUCTION: Previous studies suggest that quality improvement initiatives focused on hospital-acquired venous thromboembolism have a positive impact on prescribing rates of venous thromboembolism prophylaxis, especially those that incorporate computerized changes. METHODS: We conducted a quality improvement project to determine whether education and computerized prescriber order entry system changes affect venous thromboembolism prophylaxis compliance rates in hospitalized medical patients at a Comprehensive Cancer Center. Between 1 January 2021 and 31 January 2023, 37,739 non-surgical, adult patient encounters with a length of stay > 48 h were analyzed in our study. From 18 December 2021 to 8 March 2022, provider education was delivered to the three largest admitting services, and computerized prescriber order entry changes were implemented incorporating a mandatory requirement to either order venous thromboembolism prophylaxis or document a contraindication for all patients at moderate venous thromboembolism risk. RESULTS: Monthly venous thromboembolism prophylaxis compliance rates, as defined by the Centers for Medicare and Medicaid Services VTE-1 metric, increased from a mean of 74% to 93% after the interventions. This change was driven primarily by an increased utilization of mechanical venous thromboembolism prophylaxis from 37% to 53%. CONCLUSION: Our study demonstrated that a multi-faceted intervention incorporating provider education and computerized prescriber order entry system changes can significantly increase venous thromboembolism prophylaxis compliance rates in cancer patients.

Outpatient initiation of venetoclax in patients with acute myeloid leukemia.

INTRODUCTION: Venetoclax is a treatment option in patients with acute myeloid leukemia (AML) in both the front-line and relapsed/refractory settings. Initiation of therapy has been previously restricted to the inpatient setting at some institutions due to a risk of tumor lysis syndrome (TLS) and limitations in medication access efficiency given the high cost of therapy. METHODS: We assessed the safety of initiating venetoclax in the outpatient setting through a single-arm, retrospective study of adult AML patients between April 1, 2019 and June 30, 2020. RESULTS: Eighty-two patients started venetoclax during this time, with 47 (57%) patients initiated in the outpatient setting. Fifty-five percent of patients received venetoclax as first-line treatment for AML (n = 45) and 45% of patients received venetoclax for relapsed/refractory AML (n = 37). Successful initiation, defined as no hospitalizations secondary to TLS within seven days of therapy initiation, occurred in 98% of patients. The rate of TLS was 2.1% (n = 1) following venetoclax initiation. TLS symptoms were managed during hospitalization, requiring only one day of missed AML therapy. Median turnaround time for medication access was three days. Hospitalizations within seven days occurred in 17% of patients (n = 8), with the majority due to febrile neutropenia. CONCLUSIONS: The results of our study provide further evidence for the safety and feasibility of initiating venetoclax in the outpatient setting with a pharmacist-led interdisciplinary protocol.

Human cardiac myosin-binding protein C phosphorylation- and mutation-dependent structural dynamics monitored by time-resolved FRET.

Cardiac myosin-binding protein C (cMyBP-C) is a thick filament-associated protein of the sarcomere and a potential therapeutic target for treating contractile dysfunction in heart failure. Mimicking the structural dynamics of phosphorylated cMyBP-C by small-molecule drug binding could lead to therapies that modulate cMyBP-C conformational states, and thereby function, to improve contractility. We have developed a human cMyBP-C biosensor capable of detecting intramolecular structural changes due to phosphorylation and mutation. Using site-directed mutagenesis and time-resolved fluorescence resonance energy transfer (TR-FRET), we substituted cysteines in cMyBP-C N-terminal domains C0 through C2 (C0-C2) for thiol-reactive fluorescent probe labeling to examine C0-C2 structure. We identified a cysteine pair that upon donor-acceptor labeling reports phosphorylation-sensitive structural changes between the C1 domain and the tri-helix bundle of the M-domain that links C1 to C2. Phosphorylation reduced FRET efficiency by ~18%, corresponding to a ~11% increase in the distance between probes and a ~30% increase in disorder between them. The magnitude and precision of phosphorylation-mediated TR-FRET changes, as quantified by the Z'-factor, demonstrate the assay's potential for structure-based high-throughput screening of compounds for cMyBP-C-targeted therapies to improve cardiac performance in heart failure. Additionally, by probing C1's spatial positioning relative to the tri-helix bundle, these findings provide new molecular insight into the structural dynamics of phosphoregulation as well as mutations in cMyBP-C. Biosensor sensitivity to disease-relevant mutations in C0-C2 was demonstrated by examination of the hypertrophic cardiomyopathy mutation R282W. The results presented here support a screening platform to identify small molecules that regulate N-terminal cMyBP-C conformational states.

Safety comparison of minimally invasive abdomen-only esophagectomy versus minimally invasive Ivor Lewis esophagectomy: a retrospective cohort study.

BACKGROUND: We report mortality and post-operative complications from esophageal resection in the treatment of gastroesophageal adenocarcinoma or stricture, comparing a minimally invasive abdomen-only esophagectomy (MIAE) approach with a minimally invasive Ivor Lewis esophagectomy (MIILE) approach. METHODS: A single-center retrospective cohort study of patients with esophageal adenocarcinoma or stricture treated by either MIAE or MIILE was conducted. MIAE was offered for strictures less than five centimeters or cancers that were American Joint Committee on Cancer (AJCC) Stage ≤ T2 without lymphadenopathy. Patients treated with these surgical techniques were analyzed to assess pre-operative risk, intra and post-operative variables, adverse events, and overall survival. RESULTS: This study included 17 patients undergoing MIAE and 32 patients treated with MIILE. There were a fewer median number of lymph nodes resected (p < 0.001) and shorter operative duration (p < 0.001) for MIAE compared to MIILE. MIAE patients also had significantly higher Charlson Comorbidity Index scores and ACS National Surgical Quality Improvement Program (NSQIP) surgical risk values than MIILE patients (p < 0.05). There was no difference in median estimated blood loss, length of stay, pulmonary or cardiac complications between groups. There was no significant difference in 90-day survival. CONCLUSION: A minimally invasive abdomen-only approach in a specific patient population is comparable in safety to a minimally invasive Ivor Lewis approach, with associated shorter median operative duration. MIAE patients had significantly greater pre-operative comorbidities and higher calculated peri-operative risk of complication but demonstrated similar post-operative outcomes. This suggests that MIAE may be a suitable surgical approach for treating gastroesophageal adenocarcinoma or stricture in patients deemed unsuitable for MIILE.

Titania-catalyzed radiofluorination of tosylated precursors in highly aqueous medium.

Nucleophilic radiofluorination is an efficient synthetic route to many positron-emission tomography (PET) probes, but removal of water to activate the cyclotron-produced [(18)F]fluoride has to be performed prior to reaction, which significantly increases overall radiolabeling time and causes radioactivity loss. In this report, we demonstrate the possibility of (18)F-radiofluorination in highly aqueous medium. The method utilizes titania nanoparticles, 1:1 (v/v) acetonitrile-thexyl alcohol solvent mixture, and tetra-n-butylammonium bicarbonate as a phase-transfer agent. Efficient radiolabeling is directly performed with aqueous [(18)F]fluoride without the need for a drying/azeotroping step to significantly reduce radiosynthesis time. High radiochemical purity of the target compound is also achieved. The substrate scope of the synthetic strategy is demonstrated with a range of aromatic, aliphatic, and cycloaliphatic tosylated precursors.

Cytotoxic chemotherapy in the contemporary management of metastatic castration-resistant prostate cancer (mCRPC).

For several years, docetaxel was the only treatment shown to improve survival of patients with metastatic castration-resistant prostate cancer (mCRPC). There are now several novel agents available, although chemotherapy with docetaxel and cabazitaxel continues to play an important role. However, the increasing number of available agents will inevitably affect the timing of chemotherapy and therefore it may be important to offer this approach before declining performance status renders patients ineligible for chemotherapy. Patient selection is also important to optimise treatment benefit. The role of predictive biomarkers has assumed greater importance due to the development of multiple agents and resistance to available agents. In addition, the optimal sequence of treatments remains undefined and requires further study in order to maximize long-term outcomes. We provide an overview of the clinical data supporting the role of chemotherapy in the treatment of mCRPC and the emerging role in metastatic castration-sensitive prostate cancer. We review the key issues in the management of patients including selection of patients for chemotherapy, when to start chemotherapy, and how best to sequence treatments to maximise outcomes. In addition, we briefly summarise the promising new chemotherapeutic agents in development in the context of emerging therapies.

Corticosteroids in the management of prostate cancer: a critical review.

Corticosteroids have been used in the management of prostate cancer for over 30 years. Although daily oral corticosteroids have frequently used in conjunction with chemotherapy for metastatic castration-resistant prostate cancer, their independent impact on survival is unclear. However, corticosteroids confer palliative benefits and are associated with objective responses and circulating tumor cell (CTC) and PSA declines in a small minority of patients, although toxicities such as osteoporosis and immunosuppression complicate long-term use. Following the demonstration of a palliative benefit for mitoxantrone combined with corticosteroids compared with corticosteroids alone, subsequent trials that demonstrated a benefit for first-line docetaxel over mitoxantrone, and second-line cabazitaxel over mitoxantrone, administered concurrent daily oral corticosteroids with all of these agents to maintain uniformity. Conversely, improved outcomes were demonstrated with docetaxel without corticosteroids for metastatic castration-sensitive prostate cancer. Daily oral corticosteroids are routinely combined with abiraterone to mitigate symptoms of mineralocorticoid excess. In contrast daily corticosteroids are not essential when administering enzalutamide or radium-223, and there is a concern of deleterious immune effects concurrently with sipuleucel-T. Given emerging evidence for promotion of resistance mechanisms, routine administration of daily oral corticosteroids in settings other than abiraterone administration and palliation of symptoms is probably not required.

Size and histologic characteristics of lymph node material retrieved from tissue discarded after routine pathologic examination of lung cancer resection specimens.

Redissection of discarded lung resection specimens after routine pathology examination reveals missed lymph node metastasis. We sought to determine if size can be used to grossly select lymph nodes for microscopic examination. This is a prospective cohort study of lymph nodes retrieved from discarded lung resection specimens. The association between size and histologic characteristics of retrieved material was compared by the Wilcoxon-Mann-Whitney test. We retrieved 1094 grossly 'lymph node-like" tissue from 112 remnant lung resection specimens, of which 345 (32%) proved not to be lymph nodes and 71 (9%) of 749 lymph nodes had metastasis. Metastasis was present in discarded nodes in 26 (23%) of 112 patients. The non-lymph node tissue was significantly smaller than lymph nodes (P < .0001); lymph nodes with metastases were significantly larger than those without metastases (P < .0001). However, there was significant size overlap between the 3 types of grossly lymph node-like tissue. Thirty-two percent of nodes with metastasis were less than 1 cm; 15% of patients had at least 1 lymph node less than 1 cm with metastasis. The size difference between lymph nodes with and without metastasis is clinically unhelpful because of broad overlap. Size is insufficiently discriminatory and cannot be relied on to select materials for histologic examination. A third of grossly retrieved material was non-lymph node tissue. This probably occurs during routine pathologic examination and likely contributes to the low N1 lymph node count.

A Machine Learning Model to Predict Risk for Hepatocellular Carcinoma in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease.

Background and Aims: Hepatocellular carcinoma (HCC) incidence is increasing and correlated with metabolic dysfunction-associated steatotic liver disease (MASLD; formerly nonalcoholic fatty liver disease), even in patients without advanced liver fibrosis who are more likely to be diagnosed with advanced disease stages and shorter survival time, and less likely to receive a liver transplant. Machine learning (ML) tools can characterize large datasets and help develop predictive models that can calculate individual HCC risk and guide selective screening and risk mitigation strategies. Methods: Tableau and KNIME Analytics were used for descriptive analytics and ML tasks. ML models were developed using standard laboratory and clinical parameters. Sci-kit learn algorithms were used for model development. Data from University of California (UC), Davis, were used to develop and train a pilot predictive model, which was subsequently validated in an independent dataset from UC San Francisco. MASLD and HCC patients were identified by International Classification of Diseases-9/10 codes. Results: Of the patients diagnosed with MASLD (n = 1561 training; n = 686 validation), HCC developed in 14% (n = 227) of the UC Davis training cohort and 25% (n = 176) of the UC San Francisco validation cohort. Liver fibrosis determined by the noninvasive Fibrosis-4 score was the strongest single predictor for HCC in the model. Using the validation cohort, the model predicted HCC development at 92.06% accuracy with an area under the curve of 0.97, F1-score of 0.84, 98.34% specificity, and 74.41% sensitivity. Conclusion: ML models can aid physicians in providing early HCC risk assessment in patients with MASLD. Further validation will translate to cost-effective, personalized care of at-risk patients.

Revealing Vision-Language Integration in the Brain with Multimodal Networks.

We use (multi)modal deep neural networks (DNNs) to probe for sites of multimodal integration in the human brain by predicting stereoen-cephalography (SEEG) recordings taken while human subjects watched movies. We operationalize sites of multimodal integration as regions where a multimodal vision-language model predicts recordings better than unimodal language, unimodal vision, or linearly-integrated language-vision models. Our target DNN models span different architectures (e.g., convolutional networks and transformers) and multimodal training techniques (e.g., cross-attention and contrastive learning). As a key enabling step, we first demonstrate that trained vision and language models systematically outperform their randomly initialized counterparts in their ability to predict SEEG signals. We then compare unimodal and multimodal models against one another. Because our target DNN models often have different architectures, number of parameters, and training sets (possibly obscuring those differences attributable to integration), we carry out a controlled comparison of two models (SLIP and SimCLR), which keep all of these attributes the same aside from input modality. Using this approach, we identify a sizable number of neural sites (on average 141 out of 1090 total sites or 12.94%) and brain regions where multimodal integration seems to occur. Additionally, we find that among the variants of multimodal training techniques we assess, CLIP-style training is the best suited for downstream prediction of the neural activity in these sites.

Population Transformer: Learning Population-level Representations of Intracranial Activity.

We present a self-supervised framework that learns population-level codes for intracranial neural recordings at scale, unlocking the benefits of representation learning for a key neuroscience recording modality. The Population Transformer (PopT) lowers the amount of data required for decoding experiments, while increasing accuracy, even on never-before-seen subjects and tasks. We address two key challenges in developing PopT: sparse electrode distribution and varying electrode location across patients. PopT stacks on top of pretrained representations and enhances downstream tasks by enabling learned aggregation of multiple spatially-sparse data channels. Beyond decoding, we interpret the pretrained PopT and fine-tuned models to show how it can be used to provide neuroscience insights learned from massive amounts of data. We release a pretrained PopT to enable off-the-shelf improvements in multi-channel intracranial data decoding and interpretability, and code is available at https://github.com/czlwang/PopulationTransformer.

Development and Qualification of Analytical Methods to Support Low Concentration Drug Product in-use Studies.

The emergence of highly potent therapeutics with low expected clinical doses creates a challenge for analytical characterization of simulated drug product in-use samples. The low expected protein concentration (often µg/mL) and highly charged and sub-optimal sample matrices like 0.9% saline or 5% dextrose make ensuring dose solution stability and characterizing product quality changes difficult. Health authority expectations require analysis of low concentration in-use samples to be completed with suitable assays to ensure little to no changes are occurring during drug product dose preparation and administration, thus ensuring patient safety. However, characterization of these samples for protein concentration, size variants, charge variants and potency often necessitates additional analytical method development to improve sensitivity and compatibility with in-use samples. Here we report the development and qualification of reliable in-use methods to characterize simulated in-use samples to assist during drug product development.

Efficacy and Safety of Gilteritinib versus Sorafenib as Post-Transplant Maintenance in Patients With FLT3-ITD Acute Myeloid Leukemia.

BACKGROUND: FLT3-ITD AML is associated with an increased risk of relapse, leading many patients to receive an allogeneic hematopoietic stem cell transplantation (alloHCT) after induction. Unfortunately, relapse rate after alloHCT remains high and strategies are needed to improve outcomes. MATERIALS AND METHODS: We performed a retrospective analysis of adult patients with FLT3-ITD AML who received alloHCT from 6/1/2016 to 12/31/2020 and received gilteritinib (GILT) or sorafenib (SORA)as post-transplant maintenance, outside of a clinical trial. RESULTS: A total of 55 patients were treated with either GILT (n = 27) or SORA (n = 29) for post-HCT maintenance. One patient was treated with SORA after first alloHCT and GILT after second alloHCT. Patient characteristics were comparable between groups. FLT3 inhibitors were utilized in pre-alloHCT therapy in all but 1 patient. The median duration of time that patients remained on GILT was 385 days (range, 10-804) and on SORA 315 days (range, 3-1777). 1-year PFS and relapse incidence were similar between GILT and SORA; PFS was 66% versus 76% (P = .4) and relapse incidence was 19% versus 24% (P = .6), respectively.Both groups had high incidence of Grade 3-4 hematological toxicity, including neutropenia (45% GILT and 34% SORA) and thrombocytopenia (30% GILT and 52% SORA). Only 44% and 14% patients who received GILT and SORA did not discontinue maintenance, respectively. CONCLUSION: Our results revealed comparable PFS and a similar toxicity profile when SORA and GILT are used as post- HCT maintenance therapy.

Investigating the host binding signature on the Plasmodium falciparum PfEMP1 protein family.

The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family plays a central role in antigenic variation and cytoadhesion of P. falciparum infected erythrocytes. PfEMP1 proteins/var genes are classified into three main subfamilies (UpsA, UpsB, and UpsC) that are hypothesized to have different roles in binding and disease. To investigate whether these subfamilies have diverged in binding specificity and test if binding could be predicted by adhesion domain classification, we generated a panel of 19 parasite lines that primarily expressed a single dominant var transcript and assayed binding against 12 known host receptors. By limited dilution cloning, only UpsB and UpsC var genes were isolated, indicating that UpsA var gene expression is rare under in vitro culture conditions. Consequently, three UpsA variants were obtained by rosette purification and selection with specific monoclonal antibodies to create a more representative panel. Binding assays showed that CD36 was the most common adhesion partner of the parasite panel, followed by ICAM-1 and TSP-1, and that CD36 and ICAM-1 binding variants were highly predicted by adhesion domain sequence classification. Binding to other host receptors, including CSA, VCAM-1, HABP1, CD31/PECAM, E-selectin, Endoglin, CHO receptor "X", and Fractalkine, was rare or absent. Our findings identify a category of larger PfEMP1 proteins that are under dual selection for ICAM-1 and CD36 binding. They also support that the UpsA group, in contrast to UpsB and UpsC var genes, has diverged from binding to the major microvasculature receptor CD36 and likely uses other mechanisms to sequester in the microvasculature. These results demonstrate that CD36 and ICAM-1 have left strong signatures of selection on the PfEMP1 family that can be detected by adhesion domain sequence classification and have implications for how this family of proteins is specializing to exploit hosts with varying levels of anti-malaria immunity.

An update of the pharmacological treatment options for generalized myasthenia gravis in adults with anti-acetylcholine receptor antibodies.

PURPOSE: This review aims to provide an update on current pharmacological agents for the management of generalized myasthenia gravis (MG). SUMMARY: MG is an autoimmune disease characterized by impaired neuromuscular transmission and muscle weakness. Most patients have autoimmune antibodies to the nicotinic acetylcholine receptor, with treatments aimed at eliminating or decreasing levels of autoantibodies. Limitations of current treatments for generalized MG include limited efficacy and serious adverse effects, indicating a continued need for new treatments. Efgartigimod alfa, a biologic newly approved by the Food and Drug Administration, provides a novel treatment option for patients with chronic generalized MG. CONCLUSION: While the landscape for treatment of generalized MG has expanded over recent years, there is still an unmet need for patients for whom multiple lines of treatment have failed. The introduction of neonatal Fc receptor antagonists such as efgartigimod alfa may have an immediate impact in patients for whom standard-of-care therapy has failed.

Factors associated with hardware failure after lateral thoracolumbar fusions - A ten year case series.

OBJECTIVE: Thoracolumbar lateral interbody fusions (tLLIF) are one tool in the spine surgeon's toolbox to indirectly decompress neuroforamina while also improving segmental lordosis in a biomechanically distinct manner from posterior fusions. When part of a concomitant posterior construct, hardware failure (HF), sometimes requiring revision surgery, can occur. We sought to study the relationship between tLLIF and HF. METHODS: We conducted a retrospective study on consecutive patents who underwent tLLIF at a single academic center between January 2012 and December 2021 by seven unique neurosurgeons. Patients were excluded if they had no posterior instrumentation within their construct or if they had less than six months of follow-up. Hardware failure was defined as screw breakage or rod fracture seen on postoperative imaging. RESULTS: 232 patients were identified; 6 (2.6 %) developed HF throughout a mean follow-up of 1182 days (range =748-1647 days). Adjacent segment disease was the most common pathology addressed (75 patients (32.3 %)). The amount of posterior instrumentation both in the surgery in question and in the total construct were significantly higher in the HF cohort (4.33 ± 1.52 levels, 5.83 ± 3.36 levels) versus the non-HF cohort (2.08 ± 0.296 levels, p = 0.014; 2.86 ± 0.316 levels, p = 0.003, respectively). The number of interbody devices added in the index surgery and in the entire construct were both significantly higher in the HF cohort (3.33 ± 0.666 interbody devices, 3.33 ± 0.666 devices) than in the non-HF cohort (1.88 ± 0.152 interbody devices, p = 0.002; 2.31 ± 0.158 devices, p = 0.036, respectively). Higher amounts of lateral levels of fusion approached significance for association with HF (HF: 2.67 ± 0.844 levels, no HF: 1.73 ± 1.26 levels, p = 0.076). On multivariate analysis, only the number of interbody devices added in the index surgery was predictive of HF (Odds ratio=2.3, 95 % confidence interval=1.25-4.23, p = 0.007). CONCLUSION: Greater levels of posterior fusion, and greater numbers of interbody devices in an index surgery and in a construct as a whole, were associated with higher rates of HF in our cohort of patients with tLLIF. Greater numbers of lateral segments fused in this population may also be related to HF.

Traumatic Atrial Septal Defect Repair via Primary Endovascular Suture Method: Case Report and Operative Technique.

We report a case of a 20-year-old male with no prior medical history who was found to have an atrial septal defect on echocardiography following a motor vehicle accident (MVA). The patient underwent primary percutaneous defect closure using the NobleStitch EL (Heartstitch, Fountain Valley, California) cardiovascular suturing system with intra-operative Doppler echocardiogram showing no residual shunt or color flow. There were no operative complications. At five months follow-up, the patient reported no symptoms from the procedure. In the case of traumatic atrial septal defect repair, the NobleStitch EL system may be utilized as an alternative to open heart surgery.

A meta-analysis and systematic review of endovascular thrombectomy versus medical management for acute basilar artery occlusion.

OBJECTIVE: Acute basilar artery occlusion (BAO) is a devastating neurologic event. As endovascular thrombectomy (EVT) became more prevalent for anterior circulation strokes, investigations were conducted in the posterior circulation. Its success in improving outcomes compared to standard medical therapy (SMT) after BAO has been debated. METHODS: We conducted a systematic review and meta-analysis of all randomized controlled trials (RCTs) and observational cohort studies evaluating EVT compared to SMT in acute BAO. We queried PubMed, Embase, and Cochrane for studies. Primary outcome was good functional outcome at 90 days (modified Rankin scale (mRS) ≤ 3). We analyzed studies for risk of bias (ROB) and calculated pooled risk ratios (RRs), odds ratios (ORs), and mean differences (MDs) with 95% confidence intervals (95%CI) using the random effects model for our primary outcome and secondary positive outcomes and harms. RESULTS: We identified four RCTs (991 patients randomized) and three cohort studies (1030 patients treated in-trial) that fit inclusion criteria. Three RCTs had low ROB, one had serious ROB. One cohort study had high ROB, one had moderate ROB, and one had low ROB. EVT was statistically significantly more associated with good functional outcome than SMT in RCTs (RR=1.54, 95%CI=1.16-2.04, p = 0.003) and trended towards significance in cohort studies (RR=2.64, 95%CI=0.87-8.00, p = 0.09). Mean mRS at 90 days was lower in EVT patients in RCTs (MD=-0.65, 95%CI=-1.07--0.22, p = 0.003) though not cohort studies (MD =-0.84, 95%CI=-2.48-0.79, p = 0.31). Symptomatic intracerebral hemorrhage (sICH) was statistically significantly associated with EVT in RCTs (OR=6.36, 95%CI=2.24-18.07, p < 0.001) and statistically non-significantly in cohort studies (OR=4.51, 95CI=1.00-20.33, p = 0.05). Mortality at 90 days was statistically lower with EVT than with SMT in both RCTs (OR=0.76, 95%CI=0.65-0.88, p < 0.001) cohort studies (OR=0.36, 95%CI=0.26-0.50, p < 0.001) CONCLUSION: EVT is associated with greater rates of good functional outcomes and lower rates of death and disability despite higher rates of periprocedural sICH.

Functional characterization and localization of a Bacillus subtilis sortase and its substrate and use of this sortase system to covalently anchor a heterologous protein to the B. subtilis cell wall for surface display.

Sortases catalyze the covalent anchoring of proteins to the cell surface on Gram-positive bacteria. Bioinformatic analysis suggests the presence of structural genes encoding sortases and their substrates in the Bacillus subtilis genome. In this study, a ß-lactamase reporter was fused to the cell wall anchoring domain from a putative sortase substrate, YhcR. Covalent anchoring of this fusion protein to the cell wall was confirmed by using the eight-protease-deficient B. subtilis strain WB800 as the host. Inactivation of yhcS abolished the cell wall anchoring reaction. The amounts of fusion protein anchored to the cell wall were proportional to the levels of YhcS. These data demonstrate that YhcS and YhcR are the sortase and sortase substrate, respectively, in B. subtilis. Furthermore, yhcS is not essential for the survival of B. subtilis under the cultivation condition tested. YhcR fusions were distributed helically in the lateral cell wall. Interestingly, when viewed with an epifluorescence microscope, YhcS also appeared to form short helical arcs. This is the first report to illustrate such distribution of sortases in a rod-shaped bacterium. Models for the spatial distribution of both the sortase and its substrate are discussed. The amount of the reporters displayed on the surface was unambiguously quantified via a unique strategy. Under optimal conditions with the overproduction of YhcS, 47,300 YhcR fusions could be displayed per cell. Displayed reporters were biologically functional and surface accessible. Characterization of the sortase-substrate system allowed the successful development of a YhcR-based covalent surface display system. This system may have various biotechnological applications.