BACKGROUND: Transcranial Doppler (TCD) is a technique to assess blood flow velocity in the cerebral arteries. TCD is frequently used to monitor aneurysmal subarachnoid hemorrhage (aSAH) patients. This study compares TCD-criteria for vasospasm and its association with Delayed Cerebral Ischemia (DCI). An overall score based on flow velocities of various intracranial arteries was developed and evaluated.
METHODS: A retrospective diagnostic accuracy study was conducted between 1998 and 2017 with 621 patients included. Mean flow velocity (MFV) of the cerebral artery was measured between 2-5 days and between 6-9 days after ictus. Cutoff values from the literature, new cutoff values, and a new composite score (Combined Severity Score) were used to predict DCI. Sensitivity, specificity, and area under the curve (AUC) were determined, and logistic regression analysis was performed.
RESULTS: The Combined Severity Score showed an AUC 0.64 (95%CI 0.56-.71) at days 2-5, with sensitivity 0.53 and specificity 0.74. The Combined Severity Score had an adjusted Odds Ratio of 3.41 (95CI 1.86-6.32) for DCI. MCA-measurements yielded the highest AUC to detect DCI at day 2-5: AUC 0.65 (95%CI 0.58-0.73). Optimal cutoff MFV of 83 cm/s for MCA resulted in sensitivity 0.73 and specificity 0.50 at days 2-5.
CONCLUSIONS: TCD-monitoring of aSAH patients may be a valuable strategy for DCI risk stratification. Lower cutoff values can be used in the early phase after the ictus (day 2-5) than are commonly used now. The Combined Severity Score incorporating all major cerebral arteries may provide a meaningful contribution to interpreting TCD measurements.

OBJECTIVE: Bacterial efflux pumps are critical for resistance to antibiotics and for virulence. We previously identified small molecules that inhibit efflux pumps (efflux pump modulators, EPMs) and prevent pathogen replication in host cells. Here, we used medicinal chemistry to increase the activity of the EPMs against pathogens in cells into the nanomolar range. We show by cryo-electron microscopy that these EPMs bind an efflux pump subunit. In broth culture, the EPMs increase the potency (activity), but not the efficacy (maximum effect), of antibiotics. We also found that bacterial exposure to the EPMs appear to enable the accumulation of a toxic metabolite that would otherwise be exported by efflux pumps. Thus, inhibitors of bacterial efflux pumps could interfere with infection not only by potentiating antibiotics, but also by allowing toxic waste products to accumulate within bacteria, providing an explanation for why efflux pumps are needed for virulence in the absence of antibiotics.

New approaches for combatting microbial infections are needed. One strategy for disrupting pathogenesis involves developing compounds that interfere with bacterial virulence. A critical molecular determinant of virulence for Gram-negative bacteria are efflux pumps of the resistance-nodulation-division (RND) family, which includes AcrAB-TolC. We previously identified small molecules that bind AcrB, inhibit AcrAB-TolC, and do not appear to damage membranes. These efflux pump modulators (EPMs) were discovered in an in-cell screening platform called SAFIRE (Screen for Anti-infectives using Fluorescence microscopy of IntracellulaR Enterobacteriaceae). SAFIRE identifies compounds that disrupt the growth of a Gram-negative human pathogen, Salmonella enterica serotype Typhimurium (S. Typhimurium) in macrophages. We used medicinal chemistry to iteratively design ~200 EPM35 analogs and test them for activity in SAFIRE, generating compounds with nanomolar potency. Analogs were demonstrated to bind AcrB in a substrate binding pocket by cryo-electron microscopy (cryo-EM). Despite having amphipathic structures, the EPM analogs do not disrupt membrane voltage, as monitored by FtsZ localization to the cell septum. The EPM analogs had little effect on bacterial growth in standard Mueller Hinton Broth. However, under broth conditions that mimic the micro-environment of the macrophage phagosome, acrAB is required for growth, the EPM analogs are bacteriostatic, and increase the potency of antibiotics. These data suggest that under macrophage-like conditions the EPM analogs prevent the export of a toxic bacterial metabolite(s) through AcrAB-TolC. Thus, compounds that bind AcrB could disrupt infection by specifically interfering with the export of bacterial toxic metabolites, host defense factors, and/or antibiotics.

The SAFIRE grading scale is a novel, computable scale that predicts the outcome of aneurysmal subarachnoid hemorrhage (aSAH) patients in acute follow-up. However, this scale also may have prognostic significance in long-term follow-up and help guide further management.
The records of all patients enrolled in the Barrow Ruptured Aneurysm Trial (BRAT) were retrospectively reviewed, and the patients were assigned SAFIRE grades. Outcomes at 1 year and 6 years post-aSAH were analyzed for each SAFIRE grade level, with a poor outcome defined as a modified Rankin Scale score > 2. Univariate analysis was performed for patients with a high SAFIRE grade (IV or V) for odds of poor outcome at the 1- and 6-year follow-ups.
A total of 405 patients with confirmed aSAH enrolled in the BRAT were analyzed; 357 patients had 1-year follow-up, and 333 patients had 6-year follow-up data available. Generally, as the SAFIRE grade increased, so did the proportion of patients with poor outcomes. At the 1-year follow-up, 18% (17/93) of grade I patients, 22% (20/92) of grade II patients, 32% (26/80) of grade III patients, 43% (38/88) of grade IV patients, and 75% (3/4) of grade V patients were found to have poor outcomes. At the 6-year follow-up, 29% (23/79) of grade I patients, 24% (21/89) of grade II patients, 38% (29/77) of grade III patients, 60% (50/84) of grade IV patients, and 100% (4/4) of grade V patients were found to have poor outcomes. Univariate analysis showed that a SAFIRE grade of IV or V was associated with a significantly increased risk of a poor outcome at both the 1-year (OR 2.5, 95% CI 1.5-4.2; p < 0.001) and 6-year (OR 3.7, 95% CI 2.2-6.2; p < 0.001) follow-ups.
High SAFIRE grades are associated with an increased risk of a poor recovery at late follow-up.

OBJECTIVE: We hypothesized that cerebral CT angiogram performed using third-generation reconstruction algorithm and lower contrast dose-low-kVp technique (LD-CTA) will provide better image quality when compared with regular contrast dose CTA at 120 kVp using a sinogram-affirmed iterative reconstruction algorithm (ND-CTA).
METHODS: Retrospective imaging review of 100 consecutive patients (50 each in LD- and ND-CTA groups). Two readers independently assessed the subjective image quality across multiple vascular segments on a Likert-like scale. Differences in contrast dose, CT dose index (CTDI), and dose length product (DLP) were compared using Mann-Whitney U test. Fisher\'s exact test was used to compare subjective image quality. Similarly, contrast- and signal-to-noise ratios (CNR and SNR) were compared in the mid-M1 MCA vessels bilaterally and the mid-basilar artery using Mann-Whitney U test. Interclass correlation coefficient (ICC) was calculated for the SNR/CNR values.
RESULTS: Both observers showed excellent correlation in subjective image quality (mean percentage agreement of 95.2% for group 1 versus 89.2% for group 2). LD-CTA group showed better SNR and CNR (p < 0.0001) for both MCA vessels and the mid-basilar artery. Interclass correlation coefficient showed moderate correlation (0.51-0.63) between readers. LD-CTA group also used lower contrast (49 cc versus 97 cc in ND-CTA) and had lower radiation exposure (DLP/CTDI for both groups 268.3/80.7 vs 519.5/36.08, both < 0.0001).
CONCLUSIONS: Next-generation reconstruction algorithm and low-kV scanning significantly improved image quality on cerebral CTA images despite lower contrast dose and, in addition, have lower radiation exposure.

OBJECTIVE: We compared and analyzed the detectability performance pertaining to an abdominal phantom including a region of interest (ROI) according to a computed tomography (CT) reconstruction algorithm.
METHODS: Three types of reconstruction algorithms (FBP, SAFIRE, and ADMIRE) were used to evaluate the detectability performance using the abdominal phantom (phantom size: 25 × 18 × 28 cm3 ). The vendor default settings for routine multi-detector computed tomography abdominal scans were used. As the quantitative evaluation method, the contrast-to-noise ratio (CNR), difference in coefficient of variation (COV) with the normalization based on the FBP data, and the noise power spectrum (NPS) were measured.
RESULTS: The characteristic of the ADMIRE-3 reconstructed image was higher than those of the FBP and SAFIRE-3 reconstructed images. The CNR values of the SAFIRE and ADMIRE images were much higher than the corresponding values of the FBP images. The difference in COV values for the ADMIRE images was ~1.2 times lower than the corresponding values of the SAFIRE images.
CONCLUSIONS: The comparative analysis of the abdominal phantom low-contrast resolution differences for each CT exposure parameters showed that ADMIRE demonstrated better results than SAFIRE and FBP in terms of contrast, CNR, COV difference, and 1D NPS. This indicates that ADMIRE can provide a clearer observation even with the same number of contrast objects as compared to SAFIRE and FBP owing to its better contrast resolution in the central part of the contrast hole at low kV.

OBJECTIVE: Multislice computed tomography (MSCT) has been used for diagnosis of small intestinal diseases. However, the radiation dose is a big problem. This study was to investigate whether CARE Dose 4D combined with sinogram-affirmed iterative reconstruction (SAFIRE) can provide better image quality at a lower dose for imaging small intestinal diseases compared to MSCT.
METHODS: The noise reduction ability of SAFIRE was assessed by scanning the plain water mold using SOMATOM Definition Flash double-source spiral CT. CT images at each stage of radiography for 239 patients were obtained. The patients were divided into groups A and B were based on different tube voltage and current or the image recombination methods. The images were restructured using with filtered back projection (FBP) and SAFIRE (S1-S5). The contrast noise ratio (CNR), CT Dose index (CTDI), subjective scoring, and objective scoring were compared to obtain the best image and reformation parameters at different stages of CT.
RESULTS: Twenty-six restructuring patterns of tube voltage and current were obtained by FBP and SAFIRE. The average radiation dose using CARE Dose 4D combined with SAFIRE (S4-S5) reduced approximately 74.85% compared to conditions where the tube voltage of 100 kV and tube current of 131 mAs for patients with MSCT small intestinal CT enterography at plain CT scan, arterial stage, small intestine, and portal venous phase. The objective and subjective scoring were all significantly different among groups A and B at each stage.
CONCLUSIONS: Combination of CARE Dose 4D and SAFIRE is shown to decrease the radiation dose while maintaining image quality.

OBJECTIVE: Aim of the study was the comparison of high-pitch dual-source CTA of the aorta acquired with different tube currents and methods of image reconstruction in patients with Marfan Disease (MFS).
BACKGROUND: Patients with MFS receive repeatedly CT examinations of the entire aorta what leads to high cumulative lifetime radiation doses. Routine clinical use of low-kV-protocols in combination with iterative reconstruction for imaging of the aorta is still limited although this approach may be of great benefit for patients in need of serial follow-up scans.
METHODS: 106 patients with MFS received CTA of the entire aorta in a 2nd generation dual-source Flash-CT at 120, 100 or 80 kV. 120 kV images were reconstructed with FBP, low-kV images with an IR algorithm (SAFIRE) at different noise reduction levels. CTDIvol, DLP and effective dose were analyzed. Quantitative image analysis included comparison of SNR, CNR and Noise levels. For qualitative analysis, two blinded readers assessed noise, contour delineation, contrast, overall image quality and diagnostic confidence.
RESULTS: Effective dose was 9.4 (±1.5) mSv for 120 kV, 4.2 (±1.1) mSv for 100 kV and 1.9 (±0.42) mSv for 80 kV. 100 kV images showed the highest SNR and CNR values, followed by 80 kV and 120 kV. Qualitative image analysis showed the lowest scores for all evaluated aspects at 80 kV. Overall image quality and diagnostic confidence was excellent at all kV strengths.
CONCLUSIONS: In MFS patients low-kV CT protocols with IR allow for CTA of the entire aorta in excellent image quality and diagnostic confidence with a dose reduction of up to 80% compared to 120 kV. For baseline CT, we recommend 100 kV, for follow-up CT scans 80 kV as tube voltage.

OBJECTIVE: To prospectively compare image quality of cranial computed tomography (CCT) examinations with varying slice widths using traditional filtered back projection (FBP) versus sinogram-affirmed iterative image reconstruction (SAFIRE).
METHODS: 29 consecutive patients (14 men, mean age: 72 ± 17 years) referred for a total of 40 CCT studies were prospectively included. Each CCT raw data set was reconstructed with FBP and SAFIRE at 5 slice widths (1-5mm; 1mm increments). Objective image quality was assessed in three predefined regions of the brain (white matter, thalamus, cerebellum) using identical regions of interest (ROIs). Subjective image quality was assessed by 2 experienced radiologists. Objective and subjective image quality parameters were statistically compared between FBP and SAFIRE reconstructions.
RESULTS: SAFIRE reconstructions resulted in mean noise reductions of 43.8% in the white matter, 45.6% in the thalamus and 42.0% in the cerebellum (p<0.01) compared to FBP on non contrast-enhanced 1mm slice width images. Corresponding mean noise reductions on 1mm contrast-enhanced studies were 45.7%, 47.3%, and 45.0% in the white matter, thalamus, and cerebellum, respectively (p<0.01). There was no significant difference in mean attenuation of any region or slice width between the two reconstruction methods (all p>0.05). Subjective image quality of IR images was mostly rated higher than that of the FBP images.
CONCLUSIONS: Compared to FBP, SAFIRE provides significant reductions in image noise while increasing subjective image in CCT, particularly when thinner slices are used. Therefore, SAFIRE may allow utilization of thinner slices in CCT, potentially reducing partial volume effects and improving diagnostic accuracy.

BACKGROUND: Different iterative reconstruction (IR) techniques compensate increased noise from lower tube current-time product settings, yet the differences between IR settings remain unclear.
OBJECTIVE: Aim of this study was to test whether different IR settings have a clinically relevant influence on image quality and on the diagnostic accuracy of low-dose CT angiography in patients with a stent.
METHODS: Forty-two patients with 73 coronary stents were prospectively enrolled. Data were acquired with dual-source CT, and images were reconstructed with standard filtered back projection (FBP) and raw data-based IR with different settings (I3, I4, I5). Quantitative parameters, including CT-attenuation, noise, signal-to-noise ratio, contrast-to-noise ratio, as well as the presence of in-stent stenosis > 50% were determined. All patients had invasive angiography as reference standard.
RESULTS: Mean effective dose was 0.32 ± 0.02 mSv. Image noise decreased significantly compared with FBP (I3 = 29%; I4 = 38% and I5 = 45%), whereas signal-to-noise and contrast-to-noise ratios increased significantly (all IR settings P < .01). Subjective image quality was superior with all IR settings (P < .01). FBP sensitivity, specificity, positive predictive value, and negative predictive value were 83%, 71%, 36%, and 96% per stent compared with 100%, 76%, 44%, and 100%, respectively, in IR reconstructions independent of the IR setting applied.
CONCLUSIONS: In low-dose coronary CT angiography, higher IR settings significantly improved subjective and objective image quality but had no effect on accuracy.