Impact of the Alberta Stroke Program CT Score subregions on long-term functional outcomes in acute ischemic stroke: Results from two multicenter studies in China.

Background and Objectives: The Alberta Stroke Program CT Score (ASPECTS) is a widely used rating system for assessing infarct extent and location. We aimed to investigate the prognostic value of ASPECTS subregions' involvement in the long-term functional outcomes of acute ischemic stroke (AIS). Materials and Methods: Consecutive patients with AIS and anterior circulation large-vessel stenosis and occlusion between January 2019 and December 2020 were included. The ASPECTS score and subregion involvement for each patient was assessed using posttreatment magnetic resonance diffusion-weighted imaging. Univariate and multivariable regression analyses were conducted to identify subregions related to 3-month poor functional outcome (modified Rankin Scale scores, 3-6) in the reperfusion and medical therapy cohorts, respectively. In addition, prognostic efficiency between the region-based ASPECTS and ASPECTS score methods were compared using receiver operating characteristic curves and DeLong's test. Results: A total of 365 patients (median age, 64 years; 70% men) were included, of whom 169 had poor outcomes. In the reperfusion therapy cohort, multivariable regression analyses revealed that the involvement of the left M4 cortical region in left-hemisphere stroke (adjusted odds ratio [aOR] 5.39, 95% confidence interval [CI] 1.53-19.02) and the involvement of the right M3 cortical region in right-hemisphere stroke (aOR 4.21, 95% CI 1.05-16.78) were independently associated with poor functional outcomes. In the medical therapy cohort, left-hemisphere stroke with left M5 cortical region (aOR 2.87, 95% CI 1.08-7.59) and caudate nucleus (aOR 3.14, 95% CI 1.00-9.85) involved and right-hemisphere stroke with right M3 cortical region (aOR 4.15, 95% CI 1.29-8.18) and internal capsule (aOR 3.94, 95% CI 1.22-12.78) affected were related to the increased risks of poststroke disability. In addition, region-based ASPECTS significantly improved the prognostic efficiency compared with the conventional ASPECTS score method. Conclusion: The involvement of specific ASPECTS subregions depending on the affected hemisphere was associated with worse functional outcomes 3 months after stroke, and the critical subregion distribution varied by clinical management. Therefore, region-based ASPECTS could provide additional value in guiding individual decision making and neurological recovery in patients with AIS.

Imaging Assessments and Clinical Significance of Brain Frailty in Moyamoya Disease.

BACKGROUND AND PURPOSE: Imaging assessment of brain frailty in ischemic stroke has been extensively studied, while the correlation between brain frailty and Moyamoya disease remains obscure. This study aimed to investigate the imaging characteristics of brain frailty and its clinical applications in Moyamoya disease. MATERIALS AND METHODS: This study included 60 patients with Moyamoya disease (107 hemispheres). All patients were divided into stroke and nonstroke groups based on clinical symptoms and imaging findings. The modified brain frailty score was adapted to consider 4 imaging signs: white matter hyperintensity, enlargement of perivascular space, old vascular lesions, and cerebral microbleed. The relative CBF of the MCA territory was quantified using pseudocontinuous arterial-spin labeling. Surgical outcome after revascularization surgery was defined by the Matsushima grade. RESULTS: The relative CBF of the MCA territory decreased as the modified brain frailty score and periventricular white matter hyperintensity grades increased (ρ = -0.22, P = .02; ρ = -0.27, P = .005). Clinically, the modified brain frailty score could identify patients with Moyamoya disease with stroke (OR = 2.00, P = .02). Although the modified brain frailty score showed no predictive value for surgical outcome, basal ganglia enlargement of the perivascular space had a significant correlation with the postoperative Matsushima grade (OR = 1.29, P = .03). CONCLUSIONS: The modified brain frailty score could reflect a cerebral perfusion deficit and clinical symptoms of Moyamoya disease, and its component basal ganglia enlargement of perivascular space may be a promising marker to predict surgical outcome and thus aid future clinical decision-making.

Association between plasma lysophosphatidic acid levels and bronchopulmonary dysplasia in extremely preterm infants: A prospective study.

BACKGROUND: Lysophosphatidic acid (LPA) is implicated in bronchopulmonary dysplasia (BPD) pathogenesis, but clinical evidence is lacking. This study aimed to investigate LPA levels in preterm infants with and without BPD and explore LPA as a biomarker for predicting BPD occurrence. METHODS: Premature infants with a gestational age of <28 weeks or a birth weight of <1000 g were enrolled. Blood samples were collected at postnatal day (PD) 7, 28, and postmenstrual age (PMA) 36 weeks, and plasma LPA levels were measured using a commercial ELISA kit. Receiver operating characteristic curve (ROC) curve analysis determined the PD 28 cutoff for LPA, and multivariable regression analyzed LPA's independent contribution to BPD and exploratory outcomes. RESULT: Among the 91 infants enrolled in this study, 35 were classified into the non-BPD group and 56 into the BPD group. Infants with BPD had higher plasma LPA levels at PD 28 (6.467 vs. 4.226 µg/mL, p = 0.034) and PMA 36 weeks (2.330 vs. 1.636 µg/mL, p = 0.001). PD 28 LPA level of 6.132 µg/mL was the cutoff for predicting BPD development. Higher PD 28 LPA levels (≥6.132 µg/mL) independently associated with BPD occurrence (OR 3.307, 95% CI 1.032-10.597, p = 0.044). Higher LPA levels correlated with longer oxygen therapy durations [regression coefficients (ß) 0.147, 95% CI 0.643-16.133, p = .034]. CONCLUSIONS: Infants with BPD had higher plasma LPA levels at PD 28 and PMA 36 weeks. Higher PD 28 LPA levels independently associated with an increased BPD risk.

Vascular and pulmonary effects of ibuprofen on neonatal lung development.

BACKGROUND: Ibuprofen is a nonsteroidal anti-inflammatory drug that is commonly used to stimulate closure of a patent ductus arteriosus (PDA) in very premature infants and may lead to aberrant neonatal lung development and bronchopulmonary dysplasia (BPD). METHODS: We investigated the effect of ibuprofen on angiogenesis in human umbilical cord vein endothelial cells (HUVECs) and the therapeutic potential of daily treatment with 50 mg/kg of ibuprofen injected subcutaneously in neonatal Wistar rat pups with severe hyperoxia-induced experimental BPD. Parameters investigated included growth, survival, lung histopathology and mRNA expression. RESULTS: Ibuprofen inhibited angiogenesis in HUVECs, as shown by reduced tube formation, migration and cell proliferation via inhibition of the cell cycle S-phase and promotion of apoptosis. Treatment of newborn rat pups with ibuprofen reduced pulmonary vessel density in the developing lung, but also attenuated experimental BPD by reducing lung inflammation, alveolar enlargement, alveolar septum thickness and small arteriolar wall thickening. CONCLUSIONS: In conclusion, ibuprofen has dual effects on lung development: adverse effects on angiogenesis and beneficial effects on alveolarization and inflammation. Therefore, extrapolation of the beneficial effects of ibuprofen to premature infants with BPD should be done with extreme caution.

Decreased plasma levels of PDGF-BB, VEGF-A, and HIF-2α in preterm infants after ibuprofen treatment.

Introduction: Ibuprofen is one of the most common non-steroidal anti-inflammatory drugs used to close patent ductus arteriosus (PDA) in preterm infants. PDA is associated with bronchopulmonary dysplasia (BPD), while PDA closure by ibuprofen did not reduce the incidence of BPD or death. Previous studies have indicated an anti-angiogenesis effect of ibuprofen. This study investigated the change of angiogenic factors after ibuprofen treatment in preterm infants. Methods: Preterm infants with hemodynamically significant PDA (hsPDA) were included. After confirmed hsPDA by color doppler ultrasonography within 1 week after birth, infants received oral ibuprofen for three continuous days. Paired plasma before and after the ibuprofen treatment was collected and measured by ELISA to determine the concentrations of platelet-derived growth factor-BB (PDGF-BB) and vascular endothelial growth factor A (VEGF-A), and hypoxia-inducible factor-2α (HIF-2α). Results: 17 paired plasma from infants with hsPDA were collected. The concentration of PDGF-BB and VEGF-A significantly decreased after ibuprofen treatment (1,908 vs. 442 pg/mL for PDGF-BB, 379 vs. 174 pg/mL for VEGF-A). HIF-2α level showed a tendency to decrease after ibuprofen treatment, although the reduction was not statistically significant (p = 0.077). Conclusion: This study demonstrated decreased vascular growth factors after ibuprofen exposure in hsPDA infants.

Platelets are indispensable for alveolar development in neonatal mice.

Previous studies suggest that platelets are involved in fetal and adult lung development, but their role in postnatal lung development especially after premature birth is elusive. There is an urgent need to scrutinize this topic because the incidence of bronchopulmonary dysplasia (BPD), a chronic lung disease after premature birth, remains high. We have previously shown impaired platelet biogenesis in infants and rats with BPD. In this study, we investigated the role of anti-CD41 antibody-induced platelet depletion during normal postnatal lung development and thrombopoietin (TPO)-induced platelet biogenesis in mice with experimental BPD. We demonstrate that platelet deficient mice develop a BPD-like phenotype, characterized by enlarged alveoli and vascular remodeling of the small pulmonary arteries, resulting in pulmonary arterial hypertension (PAH)-induced right ventricular hypertrophy (RVH). Vascular remodeling was potentially caused by endothelial dysfunction demonstrated by elevated von Willebrand factor (vWF) concentration in plasma and reduced vWF staining in lung tissue with platelet depletion. Furthermore, TPO-induced platelet biogenesis in mice with experimental BPD improved alveolar simplification and ameliorated vascular remodeling. These findings demonstrate that platelets are indispensable for normal postnatal lung development and attenuation of BPD, probably by maintaining endothelial function.

Dose-dependent immunomodulatory effects of metformin on human neonatal monocyte-derived macrophages.

While the association of inflammation with bronchopulmonary dysplasia (BPD) has long been appreciated, M1 proinflammatory macrophage population is emerging as the key element in driving the BPD inflammatory environment. Previous study suggests that low-dose metformin elicits an anti-inflammatory response, possibly through modulating macrophages, to improve disease outcome in a rat BPD model. To investigate this concept further, we examined the dose-dependent immunomodulatory function of metformin directly on human macrophages derived from cord blood (CB) monocytes. We demonstrate that low-dose metformin promotes expansion of M2 anti-inflammatory macrophages, contrasted with high-dose treatment, which exacerbates inflammation by favoring M1 polarization and restricting M2 phenotype. These findings highlight that metformin hold immunomodulatory ability by regulating macrophage polarization in a dose-dependent manner, and only when applied at low dose, exhibiting potential for beneficial anti-inflammatory adjuvant in BPD setting.

Deep learning with weak annotation from diagnosis reports for detection of multiple head disorders: a prospective, multicentre study.

BACKGROUND: A large training dataset with high-quality annotations is necessary for building an accurate and generalisable deep learning system, which can be difficult and expensive to prepare in medical applications. We present a novel deep-learning-based system, requiring no annotator but weak annotation from a diagnosis report, for accurate and generalisable performance in detecting multiple head disorders from CT scans, including ischaemia, haemorrhage, tumours, and skull fractures. METHODS: Our system was developed on 104 597 head CT scans from the Chinese PLA General Hospital, with associated textual diagnosis reports. Without expert annotation, we used keyword matching on the reports to automatically generate disorder labels for each scan. The labels were inaccurate because of the unreliable annotator-free strategy and inexact because of scan-level annotation. We proposed RoLo, a novel weakly supervised learning algorithm, with a noise-tolerant mechanism and a multi-instance learning strategy to address these issues. RoLo was tested on retrospective (2357 scans from the Chinese PLA General Hospital), prospective (650 scans from the Chinese PLA General Hospital), cross-centre (1525 scans from the Brain Hospital of Hunan Province), cross-equipment (1484 scans from the Chinese PLA General Hospital), and cross-nation (CQ500 public dataset from India) test datasets. Four radiologists were tested on the prospective test dataset before and after viewing system recommendations to assess whether the system could improve diagnostic performance. FINDINGS: The area under the receiver operating characteristic curve for detecting the four disorder types was 0·976 (95% CI 0·976-0·976) for retrospective, 0·975 (0·974-0·976) for prospective, 0·965 (0·964-0·966) for cross-centre, and 0·971 (0·971-0·972) for cross-equipment test datasets, and 0·964 (0·964-0·966) for CQ500 (with only haemorrhage and fracture). The system achieved similar performance to four radiologists and helped to improve sensitivity and specificity by 0·109 (95% CI 0·086-0·131) and 0·022 (0·017-0·026), respectively. INTERPRETATION: Without expert annotated data, our system achieved accurate and generalisable performance for head disorder detection. The system improved the diagnostic performance of radiologists. Because of its accuracy and generalisability, our computer-aided diganostic system could be used in clinical practice to improve the accuracy and efficiency of radiologists in different hospitals. FUNDING: National Key R&D Program of China, National Natural Science Foundation of China, and Beijing Natural Science Foundation.

Correlation of visual area with tremor improvement after MRgFUS thalamotomy in Parkinson's disease.

OBJECTIVE: MRI-guided focused ultrasound (MRgFUS) thalamotomy is a novel and minimally invasive alternative for medication-refractory tremor in Parkinson's disease (PD). However, the impact of MRgFUS thalamotomy on spontaneous neuronal activity in PD remains unclear. The purpose of the current study was to evaluate the effects of MRgFUS thalamotomy on local fluctuations in neuronal activity as measured by the fractional amplitude of low-frequency fluctuations (fALFF) in patients with PD. METHODS: Participants with PD undergoing MRgFUS thalamotomy were recruited. Tremor scores were assessed before and 3 and 12 months after treatment using the Clinical Rating Scale for Tremor. MRI data were collected before and 1 day, 1 week, 1 month, 3 months, and 12 months after thalamotomy. The fALFF was calculated. A whole-brain voxel-wise paired t-test was used to identify significant changes in fALFF at 12 months after treatment compared to baseline. Then fALFF in the regions with significant differences were extracted from fALFF maps of patients for further one-way repeated-measures ANOVA to investigate its dynamic alterations. The association between fALFF changes induced by thalamotomy and tremor improvement were evaluated using the nonparametric Spearman rank test. RESULTS: Nine participants with PD (mean age ± SD 64.7 ± 6.1 years, 8 males) were evaluated. Voxel-based analysis showed that fALFF in the left occipital cortex (Brodmann area 17 [BA17]) significantly decreased at 12 months after thalamotomy compared to baseline (voxel p < 0.001, cluster p < 0.05 family-wise error [FWE] corrected). At baseline, fALFF in the left occipital BA17 in patients was elevated compared with that in 9 age- and gender-matched healthy subjects (p < 0.05). Longitudinal analysis displayed the dynamic changes of fALFF in this region (F (5,40) = 3.61, p = 0.009). There was a significant positive correlation between the falling trend in fALFF in the left occipital BA17 and hand tremor improvement after treatment over 3 time points (Spearman's rho = 0.44, p = 0.02). CONCLUSIONS: The present study investigated the impact of MRgFUS ventral intermediate nucleus thalamotomy on spontaneous neural activity in medication-refractory tremor-dominant PD. The visual area is, for the first time, reported as relevant to tremor improvement in PD after MRgFUS thalamotomy, suggesting a distant effect of MRgFUS thalamotomy and the involvement of specific visuomotor networks in tremor control in PD.

Accelerate gas diffusion-weighted MRI for lung morphometry with deep learning.

OBJECTIVES: Multiple b-value gas diffusion-weighted MRI (DW-MRI) enables non-invasive and quantitative assessment of lung morphometry, but its long acquisition time is not well-tolerated by patients. We aimed to accelerate multiple b-value gas DW-MRI for lung morphometry using deep learning. METHODS: A deep cascade of residual dense network (DC-RDN) was developed to reconstruct high-quality DW images from highly undersampled k-space data. Hyperpolarized 129Xe lung ventilation images were acquired from 101 participants and were retrospectively collected to generate synthetic DW-MRI data to train the DC-RDN. Afterwards, the performance of the DC-RDN was evaluated on retrospectively and prospectively undersampled multiple b-value 129Xe MRI datasets. RESULTS: Each slice with size of 64 × 64 × 5 could be reconstructed within 7.2 ms. For the retrospective test data, the DC-RDN showed significant improvement on all quantitative metrics compared with the conventional reconstruction methods (p < 0.05). The apparent diffusion coefficient (ADC) and morphometry parameters were not significantly different between the fully sampled and DC-RDN reconstructed images (p > 0.05). For the prospectively accelerated acquisition, the required breath-holding time was reduced from 17.8 to 4.7 s with an acceleration factor of 4. Meanwhile, the prospectively reconstructed results showed good agreement with the fully sampled images, with a mean difference of -0.72% and -0.74% regarding global mean ADC and mean linear intercept (Lm) values. CONCLUSIONS: DC-RDN is effective in accelerating multiple b-value gas DW-MRI while maintaining accurate estimation of lung microstructural morphometry, facilitating the clinical potential of studying lung diseases with hyperpolarized DW-MRI. KEY POINTS: • The deep cascade of residual dense network allowed fast and high-quality reconstruction of multiple b-value gas diffusion-weighted MRI at an acceleration factor of 4. • The apparent diffusion coefficient and morphometry parameters were not significantly different between the fully sampled images and the reconstructed results (p > 0.05). • The required breath-holding time was reduced from 17.8 to 4.7 s and each slice with size of 64 × 64 × 5 could be reconstructed within 7.2 ms.

Pulmonary ACE2 expression in neonatal and adult rats.

Children show a distinct presentation of COVID-19, characterized by a lower incidence and mild phenotype, but the reason for this is still unknown. The angiotensin-converting enzyme 2 (ACE2) functions as the primary cell entry receptor for Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is thought to cause distinct clinical features between children and old people. The primary purpose of this study was to determine whether differences exist in the level of expression and distribution of ACE2 between neonatal and adult rat lungs. The lung tissues from rats of various ages were used to investigate the expression patterns of ACE2. Western blot, immunohistochemistry, and immunofluorescence were used to quantify or identify the localization of ACE2 in rat lungs. ACE2 was homogenously expressed in fewer alveolar type II (AT2) cells in the neonatal lung, with no polarization to the alveolar space and additional expression in pulmonary endothelium when compared to adult rat lungs. These findings suggest that the patterns of ACE2 distribution and cellular localization in rat lungs change with age.

Close Association Between Platelet Biogenesis and Alveolarization of the Developing Lung.

Bronchopulmonary dysplasia (BPD) is a neonatal chronic lung disease characterized by an arrest in alveolar and vascular development. BPD is secondary to lung immaturity, ventilator-induced lung injury, and exposure to hyperoxia in extremely premature infants, leading to a lifelong impairment of lung function. Recent studies indicate that the lung plays an important role in platelet biogenesis. However, the dynamic change of platelet production during lung development and BPD pathogenesis remains to be elucidated. We investigated the dynamic change of platelet parameters in extremely premature infants during BPD development, and in newborn rats during their normal development from birth to adulthood. We further studied the effect of hyperoxia exposure on platelet production and concomitant pulmonary maldevelopment in an experimental BPD rat model induced by prolonged exposure to hyperoxia. We detected a physiological increase in platelet count from birth to 36 weeks postmenstrual age in extremely premature infants, but platelet counts in extremely premature infants who developed BPD were persistently lower than gestational age-matched controls. In line with clinical findings, exposure to hyperoxia significantly decreased the platelet count in neonatal rats. Lung morphometry analysis demonstrated that platelet counts stabilized with the completion of lung alveolarization in rats. Our findings indicate a close association between platelet biogenesis and alveolarization in the developing lung. This phenomenon might explain the reduced platelet count in extremely premature infants with BPD.