Changes in Patient Volumes and Outcomes After Adding Thrombectomy Capability.

BACKGROUND AND PURPOSE: With the rising demand for endovascular thrombectomy (EVT) and introduction of thrombectomy-capable stroke centers (TSC), there is interest among existing stroke hospitals to add EVT capability to attract and retain stroke patient referrals. In this work, we quantify changes in patient volumes and outcomes when adding EVT capability to an existing stroke center. METHODS: In MATLAB 2017a Simulink, we simulate a 3-center system comprising an EVT-capable comprehensive stroke center, an EVT-incapable primary stroke center, and an EVT-incapable primary stroke center that gains EVT capability (TSC). We model these changes in 2 geographic settings (urban and rural) using 2 routing paradigms (Nearest Center and Bypass). In Nearest Center, patients are sent to the nearest center regardless of EVT capability. In Bypass, patients with severe strokes are sent to the nearest EVT-capable center, and all others are sent to the nearest center. Probability of good clinical outcome is determined by type and timing of treatment using outcomes reported in clinical trials. RESULTS: Adding EVT capability in the Bypass model produced an absolute increase of 40.1% in total volume of patients with stroke and 31.2% to 31.9% in total volume of acute stroke treatments at the TSC. In the Nearest Center model, the total volume of patients with stroke did not change, but total volume of acute stroke treatment at the TSC had an absolute increase of 9.3% to 9.5%. Good clinical outcomes saw an absolute increase of 0.2% to 0.6% in the whole population and 0.3% to 1.8% in the TSC population. CONCLUSIONS: Adding EVT capability shifts patient and treatment volume to the TSC. However, these changes produce modest improvement in overall population health. Health systems should weigh relative hospital and patient benefits when considering adding EVT capability.

A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate.

Serine is both a proteinogenic amino acid and the source of one-carbon units essential for de novo purine and deoxythymidine synthesis. In the canonical pathway of glucose-derived serine synthesis, Homo sapiens phosphoglycerate dehydrogenase (PHGDH) catalyzes the first, rate-limiting step. Genetic loss of PHGDH is toxic toward PHGDH-overexpressing breast cancer cell lines even in the presence of exogenous serine. Here, we used a quantitative high-throughput screen to identify small-molecule PHGDH inhibitors. These compounds reduce the production of glucose-derived serine in cells and suppress the growth of PHGDH-dependent cancer cells in culture and in orthotopic xenograft tumors. Surprisingly, PHGDH inhibition reduced the incorporation into nucleotides of one-carbon units from glucose-derived and exogenous serine. We conclude that glycolytic serine synthesis coordinates the use of one-carbon units from endogenous and exogenous serine in nucleotide synthesis, and we suggest that one-carbon unit wasting thus may contribute to the efficacy of PHGDH inhibitors in vitro and in vivo.

SEER study of ablation versus partial nephrectomy in cT1A renal cell carcinoma.

AIM: Compare ablation versus partial nephrectomy (PN) in T1A renal cell carcinoma (RCC) treatment, using the SEER database. METHODS: Patients with diagnosed T1A RCC from 2004 to 2013 were identified. Propensity matching paired subjects with similar background variables. Kaplan-Meier and Cox proportional hazards regression were performed before and after matching. RESULTS: Cohort included 4592 patients (809 ablation, 3783 PN). PN compared with ablation group had significantly increased overall survival (OS; 93.6% vs 81.9% 5-year survival; p < 0.0001) and cancer-specific survival (CSS; p < 0.0001). After matching (1222 pairs), PN group had significantly increased OS (91.0% vs 86.3% 5-year survival; p = 0.0457) but similar CSS (p = 0.4023). CONCLUSION: Ablation offers similar CSS but lower OS as PN for T1A RCC in this SEER database.

Choline transporter-like protein 4 (CTL4) links to non-neuronal acetylcholine synthesis.

Synthesis of acetylcholine (ACh) by non-neuronal cells is now well established and plays diverse physiologic roles. In neurons, the Na(+) -dependent, high affinity choline transporter (CHT1) is absolutely required for ACh synthesis. In contrast, some non-neuronal cells synthesize ACh in the absence of CHT1 indicating a fundamental difference in ACh synthesis compared to neurons. The aim of this study was to identify choline transporters, other than CHT1, that play a role in non-neuronal ACh synthesis. ACh synthesis was studied in lung and colon cancer cell lines focusing on the choline transporter-like proteins, a five gene family choline-transporter like protein (CTL)1-5. Supporting a role for CTLs in choline transport in lung cancer cells, choline transport was Na(+) -independent and CTL1-5 were expressed in all cells examined. CTL1, 2, and 5 were expressed at highest levels and knockdown of CTL1, 2, and 5 decreased choline transport in H82 lung cancer cells. Knockdowns of CTL1, 2, 3, and 5 had no effect on ACh synthesis in H82 cells. In contrast, knockdown of CTL4 significantly decreased ACh secretion by both lung and colon cancer cells. Conversely, increasing expression of CTL4 increased ACh secretion. These results indicate that CTL4 mediates ACh synthesis in non-neuronal cell lines and presents a mechanism to target non-neuronal ACh synthesis without affecting neuronal ACh synthesis.

Population health impact of extended window thrombectomy in acute ischemic stroke.

BACKGROUND: Recent trials support endovascular thrombectomy (EVT) in select patients beyond the conventional 6-hour window. OBJECTIVE: In this work, we estimate the impact of extended window EVT on procedural volumes and population-level clinical outcomes using Monte Carlo simulation. METHODS: We simulated extending EVT eligibility in a system comprising an EVT-incapable primary stroke center (PSC) and EVT-capable comprehensive stroke center (CSC) using routing paradigms that initially direct patients to (1) the nearest center, (2) the CSC, or (3) either CSC or nearest center based on stroke severity. EVT eligibility and outcomes are based on HERMES, DEFUSE-3, and DAWN studies in the 0-6, 6-16, and 16-24 hour windows, respectively. Probability of good clinical outcome is determined by type and timing of treatment using clinical trial data. RESULTS: Relative increase in EVT volume in the three tested routing paradigms was 15.7-15.8%. The absolute increase in the rate of good clinical outcome 0.4% in all routing paradigms. NNT for extended window EVT was 239.9-246.4 among the entire stroke population. CONCLUSION: Extended window EVT with DEFUSE-3 and DAWN criteria increases EVT volume and modestly improves population-level clinical outcomes.

Effect of routing paradigm on patient-centered outcomes in acute ischemic stroke.

OBJECTIVE: To compare performance of routing paradigms for patients with acute ischemic stroke using clinical outcomes. METHODS: We simulated different routing paradigms in a system comprising one primary stroke center (PSC) and onecomprehensive stroke center (CSC), separated by distances representative of urban, suburban, and rural environments. In the Nearest Center paradigm, patients are initially sent to the nearest center, while in CSC First, patients are sent to the CSC. In Rhode Island and Distributive paradigms, patients with Field Assessment Stroke Triage for Emergency Destination (FAST-ED) score ≥4 are sent to the CSC, while others are sent to the nearest center or PSC, respectively. Performance and efficiency were compared using rates of good clinical outcome determined by type and timing of treatment using clinical trial data and number needed to bypass (NNB). RESULTS: Good clinical outcome was achieved in 43.67% of patients in Nearest Center and 44.62% in CSC First, Rhode Island, and Distributive in an urban setting; 42.79% in Nearest Center and 43.97% in CSC First and Rhode Island in a suburban setting; and 39.76% in Nearest Center, 41.73% in CSC First, and 41.59% in Rhode Island in a rural setting. In all settings, the NNB was considerably higher for CSC First than for Rhode Island or Distributive. CONCLUSION: Routing paradigms that allow bypass of nearer hospitals for thrombectomy-capable centers improve population-level patient outcomes. Differences are more pronounced with increasing distance between hospitals; therefore, the choice of model may have greater effect in rural settings. Selective bypass, as implemented in Rhode Island and Distributive paradigms, improves system efficiency with minimal effect on outcomes.

Effect of routing paradigm on patient centered outcomes in acute ischemic stroke.

BACKGROUND: To compare performance of routing paradigms for patients with acute ischemic stroke using clinical outcomes. METHODS: We simulated different routing paradigms in a system comprising one primary stroke center (PSC) and one comprehensive stroke center (CSC), separated by distances representative of urban, suburban, and rural environments. In the nearest center paradigm, patients are initially sent to the nearest center, while in CSC first, patients are sent to the CSC. In the Rhode Island and distributive paradigms, patients with a FAST-ED (Facial palsy, Arm weakness, Speech changes, Time, Eye deviation, and Denial/neglect) score ≥4 are sent to the CSC, while others are sent to the nearest center or PSC, respectively. Performance and efficiency were compared using rates of good clinical outcome, determined by type and timing of treatment using clinical trial data, and number needed to bypass (NNB). RESULTS: Good clinical outcome was achieved in 43.76% of patients in nearest center, 44.48% in CSC first, and 44.44% in Rhode Island and distributive in an urban setting; 43.38% in nearest center, 44.19% in CSC first, and 44.17% in Rhode Island in a suburban setting; and 41.10% in nearest center, 43.20% in CSC first, and 42.73% in Rhode Island in a rural setting. In all settings, NNB was generally higher for CSC first compared with Rhode Island or distributive. CONCLUSION: Routing paradigms that allow bypass of nearer hospitals for thrombectomy capable centers improve population level patient outcomes. Differences are more pronounced with increasing distance between hospitals; therefore, paradigm choice may be most impactful in rural settings. Selective bypass, as implemented in the Rhode Island and distributive paradigms, improves system efficiency with minimal impact on outcomes.

Direct puncture Onyx embolization of a large calvarial metastasis with intracranial extension: Case report.

We report a case of renal cell carcinoma (RCC) metastasis to the calvarium and describe a strategy for percutaneous embolization of hypervascular calvarial tumors with intracranial extension. An elderly patient with history of RCC presented with left-sided weakness. Imaging studies showed a large right frontoparietal calvarial mass with intra- and extracranial extension. The tumor was devascularized by direct puncture tumor embolization using Onyx 18, allowing subsequent operative resection without significant blood loss or the need for flap reconstruction of the scalp. Compared to more common endovascular approaches, direct-needle puncture embolization of transcalvarial masses may offer lower risk of injury to scalp vessels and underlying brain parenchyma.

Design, synthesis, and testing toward a 57-codon genome.

Recoding--the repurposing of genetic codons--is a powerful strategy for enhancing genomes with functions not commonly found in nature. Here, we report computational design, synthesis, and progress toward assembly of a 3.97-megabase, 57-codon Escherichia coli genome in which all 62,214 instances of seven codons were replaced with synonymous alternatives across all protein-coding genes. We have validated 63% of recoded genes by individually testing 55 segments of 50 kilobases each. We observed that 91% of tested essential genes retained functionality with limited fitness effect. We demonstrate identification and correction of lethal design exceptions, only 13 of which were found in 2229 genes. This work underscores the feasibility of rewriting genomes and establishes a framework for large-scale design, assembly, troubleshooting, and phenotypic analysis of synthetic organisms.