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Open Access Publications from the University of California

Scholarly Works (5 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2008)

The left-handed parallel β-helix (LβH) is a structurally repetitive, highly regular, symmetrical fold, formed by coiling of elongated β-sheets into helical `rungs'. This canonical fold has recently received interest as a possible solution to the fibril structure of amyloid. However, sequence and structural requirements, and stability and folding of the LβH are not fully understood. To analyze this protein fold and investigate the possibility of its involvement in amyloid formations, combined approaches using computational and experimental methods were applied. (1) Sequence characteristics of the LβH were determined by analyzing known structures. A genome-wide sequence analysis was undertaken to determine the prevalence of this unique protein fold across the genomes. Molecular dynamics (MD) simulations were used to demonstrate the stabilizing effect of successive rungs and the hydrophobic core of the LβH. (2) An in-vivo folding assay using a known LβH protein was developed to investigate the residue tolerance and effect of mutations at structurally critical regions of the β-helical structure. Tyrosine fluorescence spectroscopy was also used to study the thermodynamic stability of the LβH protein. It showed that the β-helix could tolerate non-hydrophobic residues at interior positions, and proline residues in the β-helical domain were shown to be important, but not critical, in folding of the β-helix. A recombinant protein consisting of the LβH with a prion fragment was designed, constructed and tested. The results suggest that the amyloid prone PrP fragment may fold into a β-helix. (3) Modeling of possible monomeric subunits of the insulin amyloid fibril was conducted using β-solenoid folds, namely the β-helix and β-roll. While both the β-helix and β-roll models agreed with currently available biophysical data from misfolded insulin, MD simulations showed that the β-roll model was relatively more stable. Insulin monomeric subunit models were incorporated into plausible models of insulin fibrils. Simulated X-ray fiber diffraction patterns of these models demonstrated that the model fibers constructed from a β-solenoid subunit provided the reasonable fit to available experimental diffraction patterns.

    Cover page: Analysis of the left-handed β-helical fold toward understanding of amyloid fibril structure
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2015)

    Background and purpose

    We sought to assess the geographic proximity of patients with stroke in California to centers that performed specific threshold volumes of mechanical embolectomy procedures each year.

    Methods

    We identified all patients who were hospitalized for acute ischemic stroke at all nonfederal acute care hospitals in California from 2009 to 2010, and all hospitals that performed any mechanical embolectomy procedures by case volume during the same period, using nonpublic data from the Office of Statewide Health Planning and Development. We computed geographic service areas around each hospital on the basis of prespecified ground transport distance thresholds. We then calculated the proportion of hospitalized patients with stroke who lived within service areas for centers that performed a low volume and high volume of mechanical embolectomy procedures each year.

    Results

    During the 2-year study period, 15% (53/360) of hospitals performed at least 1 mechanical embolectomy for acute stroke, but only 19% (10/53) performed >10 cases per year. Most hospitalized patients with stroke (94%) lived within a 2-hour transport time (65 miles) to a hospital that performed ≥1 procedure during the 2-year period. Approximately 93% of the patients with stroke who received mechanical embolectomy lived within 20 miles from an embolectomy-capable hospital compared with 7% of those who lived >20 miles.

    Conclusions

    In California, most patients with stroke lived within reasonable ground transport distances from centers that performed ≥1 mechanical embolectomy in a 2-year period. The probability of receiving mechanical embolectomy for acute ischemic stroke was associated with living in close geographic proximity to these hospitals.
      Cover page: Regional availability of mechanical embolectomy for acute ischemic stroke in California, 2009 to 2010.
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2024)
      BACKGROUND AND OBJECTIVES: Mechanical thrombectomy (MT) improves outcomes for acute ischemic stroke (AIS) due to large vessel occlusion, but is time sensitive and requires specialized infrastructure. Professional organizations and certification bodies have promulgated minimum procedural volume standards for centers and for individual proceduralists but it is unclear whether enforcing these requirements would decrease geographic access to MT. Therefore, we sought to evaluate the potential impact of applying a minimum procedural volume threshold on geographic access to MT. METHODS: We identified all hospital discharges for stroke where an MT procedure was performed at any nonfederal hospital in Florida in 2019 using statewide hospital discharge data. We then generated geographic service area maps based on prespecified ground transport distances for the subset of hospitals that performed at least 1 MT and for those that performed at least 15 MTs that year, the minimum volume threshold required for thrombectomy capable and comprehensive stroke centers by the Joint Commission. Then, using zip code centroids and patient-level discharge hospital data, we computed the proportion of patients with AIS who lived within each of the generated service areas. RESULTS: A total of 105 of 297 hospitals performed MT; of those, 51 (17%) were low-volume centers (1-14 MTs/year) and 54 (18%) were high-volume centers (≥15 MTs/year). High-volume centers accounted for nearly 95% of all MTs performed in the state. Most patients hospitalized with AIS (87%) lived within 20 miles (or an estimated as a 1-hour driving time) of a hospital that performed at least 1 MT, and all (100%) lived within 115 miles (or estimated as 3-hour driving time). Setting a minimum MT volume threshold of 15 would decrease the proportion of stroke patients living within 1-hour driving time of an MT center from 87% to 77%. DISCUSSION: In 2019, most Florida stroke patients lived within a 1-hour ground transport time to a center that performed at least 1 MT and all lived within 3-hour driving time of an MT center, irrespective of whether a minimum procedural volume threshold of 15 cases per year was applied or not.
        Cover page: Geographic Access to High-Volume Mechanical Thrombectomy Centers in Florida, 2019.
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2021)

        Background

        We investigated the association between geographic proximity to hospitals and the administration rate of reperfusion therapy for acute ischemic stroke.

        Methods

        We identified patients with acute ischemic stroke who visited the hospital within 12 hours of symptom onset from a prospective nationwide multicenter stroke registry. Reperfusion therapy was classified as intravenous thrombolysis (IVT), endovascular therapy (EVT), or combined therapy. The association between the proportion of patients who were treated with reperfusion therapy and the ground transport time was evaluated using a spline regression analysis adjusted for patient-level characteristics. We also estimated the proportion of Korean population that lived within each 30-minute incremental service area from 67 stroke centers accredited by the Korean Stroke Society.

        Results

        Of 12,172 patients (mean age, 68 ± 13 years; men, 59.7%) who met the eligibility criteria, 96.5% lived within 90 minutes of ground transport time from the admitting hospital. The proportion of patients treated with IVT decreased significantly when stroke patients lived beyond 90 minutes of the transport time (P = 0.006). The proportion treated with EVT also showed a similar trend with the transport time. Based on the residential area, 98.4% of Korean population was accessible to 67 stroke centers within 90 minutes.

        Conclusion

        The use of reperfusion therapy for acute stroke decreased when patients lived beyond 90 minutes of the ground transport time from the hospital. More than 95% of the South Korean population was accessible to 67 stroke centers within 90 minutes of the ground transport time.
          Cover page: Effect of Transport Time on the Use of Reperfusion Therapy for Patients with Acute Ischemic Stroke in Korea
          • Article
          • Peer Reviewed
          UCLA Previously Published Works (2024)
          BACKGROUND: Recent clinical trials established the benefit of dual antiplatelet therapy with aspirin and clopidogrel (DAPT-AC) in early-presenting patients with minor ischemic stroke. However, the impact of these trials over time on the use and outcomes of DAPT-AC among the patients with nonminor or late-presenting stroke who do not meet the eligibility criteria of these trials has not been delineated. METHODS AND RESULTS: In a multicenter stroke registry, this study examined yearly changes from April 2008 to August 2022 in DAPT-AC use for stroke patients ineligible for CHANCE/POINT (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events/Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) clinical trials due to National Institutes of Health Stroke Scale >4 or late arrival beyond 24 hours of onset. A total of 32 118 patients (age, 68.1±13.1 years; male, 58.5%) with National Institutes of Health Stroke Scale of 4 (interquartile range, 1-7) were analyzed. In 2008, DAPT-AC was used in 33.0%, other antiplatelets in 62.7%, and no antiplatelet in 4.3%. The frequency of DAPT-AC was relatively unchanged through 2013, when the CHANCE trial was published, and then increased steadily, reaching 78% in 2022, while other antiplatelets decreased to 17.8% in 2022 (Ptrend<0.001). From 2011 to 2022, clinical outcomes nonsignificantly improved, with an average relative risk reduction of 2%/y for the composite of stroke, myocardial infarction, and all-cause mortality, both among patients treated with DAPT-AC and patients treated with other antiplatelets. CONCLUSIONS: Use of DAPT-AC in stroke patients with stroke ineligible for recent DAPT clinical trials increased markedly and steadily after CHANCE publication in 2013, reaching deployment in nearly 4 of every 5 patients by 2022. The secondary prevention in patients with ischemic stroke seems to be gradually improving, possibly due to the enhancement of risk factor control.
            Cover page: Trends in Dual Antiplatelet Therapy of Aspirin and Clopidogrel and Outcomes in Ischemic Stroke Patients Noneligible for POINT/CHANCE Trial Treatment.
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