The neurodevelopmental outcomes of young infants with hypoglycorrhachia that is comparable to glucose transporter 1 deficiency syndrome (GLUT1DS), i.e. cerebrospinal fluid (CSF) glucose ≤40 mg/dL and ...CSF lactate <2.2 mM without causes of secondary hypoglycorrhachia are unknown. This study investigated the developmental outcomes and possibility of GLUT1DS in infants with hypoglycorrhachia, or low CSF glucose concentration.
1655 neurologically asymptomatic infants aged <4 months had CSF examinations for fever workup from 2006 to 2016. Among the infants with normal CSF cell counts and without isolated pathogens, there were hypoglycorrhachia group who had CSF glucose levels that were comparable to GLUT1DS, and age- and gender-matched non-hypoglycorrhachia group. Both groups were at a mean age of 5.9 ± 2.4 years (ranged 1–10 years) at neurodevelopmental evaluation in 2017. Mutational analysis of solute-carrier-family 2, which facilitated the glucose transporter member 1 (SLC2A1) gene was performed.
Among the 722 infants with normal CSF cell counts and without isolated pathogens, 30 (4.2%) had hypoglycorrhachia that was comparable to GLUT1DS. In the 25 infants with hypoglycorrhachia available for follow-up, 4 (16%) had abnormal outcomes, of which 3 (12%) had the history of mixed-type developmental delay before age 6 and 1 (4%) had type 1 diabetes mellitus. In the non-hypoglycorrhachia control group (n = 50), 2 patients (4%) showed abnormal outcomes, both with the history of pure speech delay. The hypoglycorrhachia group had a higher rate of the history of mixed-type of developmental delay than the control group (12% vs. 0%, P = 0.034). No SLC2A1 pathogenic variants were observed in the hypoglycorrhachia group.
Hypoglycorrhachia may be a potential biomarker for neurodevelopmental delay instead of for GLUT1DS in neurologically asymptomatic young infants.
Deep mixed oils with secondary alterations have been widely discovered in the Tarim Basin, but current methods based on biomarkers and isotopes to de-convolute mixed oil cannot calculate the exact ...mixing proportion of different end-member oils, which has seriously hindered further exploration of deep hydrocarbons in the study area. To solve this problem, we constructed a novel method based on the carbon isotope (δ13C) of the group components to de-convolute mixed liquid hydrocarbons under the material balance principle. The results showed that the mixed oil in the Tazhong Uplift was dominantly contributed at an average proportion of 68% by an oil end-member with heavier δ13C that was believed to be generated from the Cambrian-Lower Ordovician source rocks, whereas the mixed oil in the Tabei Uplift was predominantly contributed at an average proportion of 61% by an oil end-member with lighter δ13C that was believed to be generated from the Middle-Upper Ordovician source rocks. This indicates that, on the basis of the detailed description of the distribution of effective source rocks, the proposed method will be helpful in realizing differential exploration and further improving the efficiency of deep liquid hydrocarbon exploration in the Tarim Basin. In addition, compared to traditional δ13C methods for whole oil and individual n-alkanes in de-convoluted mixed oil, the proposed method has a wider range of applications, including for mixed oils with variations in color and density, indicating potential for promoting the exploration of deep complex mixed oils in the Tarim Basin and even around the world.
S4 index is the rapid modification of signals when propagating through small-scale structures in the ionosphere, called ionospheric irregularities. The rapid modification of the signal causes the ...scintillation of the power. The purpose of this letter is to confirm the superposition property of the S4 index by using the ray-tracing method to simulate the signal propagation path through the ionospheric irregularities and then calculate the amplitude and S4 index of the received signal. The relation between the ionospheric scintillation S4 index and the signal propagation path can be understood. Then, the assimilation method for the S4 index can be developed to monitor the ionospheric irregularity in the future.
To promote environmental sustainability, recycled construction concrete is suggested for civil infrastructure works. The aim of this study was to investigate the effects of vegetation type on water ...infiltration under extreme rainfall conditions in a proposed three-layer landfill cover system containing recycled concrete. Three soil columns, namely bare, covered with shrub (
Schefflera arboricola
), and covered with grass (
Cynodon dactylon
), were subjected to ponding tests. Each column was compacted with a bottom layer of silty soil, an intermediate layer of coarse recycled concrete aggregate, and an upper layer of fine recycled concrete aggregate. Water breakthrough occurred only in the bare cover system after 48 h of ponding, equivalent to a rainfall return period of greater than 1000 years in Hong Kong. Under the vegetated covers, suction maintained in the bottom silty soil layer was higher than under the bare cover by 49–52 kPa and hence no percolation was observed after 48 h of ponding. Comparing the two vegetated cover systems, suction maintained under the shrub cover was 2–12 kPa higher (2%–8% lower volumetric water content) than that under the grassed cover in the layers of recycled concrete. This implies that shrub cover can be more effective than grass cover in reducing water infiltration in humid climates.
Accurate delineation of Gross Tumor Volume (GTV) is crucial for radiotherapy. Deep learning-driven GTV segmentation technologies excel in rapidly and accurately delineating GTV, providing a basis for ...radiologists in formulating radiation plans. The existing 2D and 3D segmentation models of GTV based on deep learning are limited by the loss of spatial features and anisotropy respectively, and are both affected by the variability of tumor characteristics, blurred boundaries, and background interference. All these factors seriously affect the segmentation performance. To address the above issues, a Layer-Volume Parallel Attention (LVPA)-UNet model based on 2D-3D architecture has been proposed in this study, in which three strategies are introduced. Firstly, 2D and 3D workflows are introduced in the LVPA-UNet. They work in parallel and can guide each other. Both the fine features of each slice of 2D MRI and the 3D anatomical structure and spatial features of the tumor can be extracted by them. Secondly, parallel multi-branch depth-wise strip convolutions adapt the model to tumors of varying shapes and sizes within slices and volumetric spaces, and achieve refined processing of blurred boundaries. Lastly, a Layer-Channel Attention mechanism is proposed to adaptively adjust the weights of slices and channels according to their different tumor information, and then to highlight slices and channels with tumor. The experiments by LVPA-UNet on 1010 nasopharyngeal carcinoma (NPC) MRI datasets from three centers show a DSC of 0.7907, precision of 0.7929, recall of 0.8025, and HD95 of 1.8702 mm, outperforming eight typical models. Compared to the baseline model, it improves DSC by 2.14 %, precision by 2.96 %, and recall by 1.01 %, while reducing HD95 by 0.5434 mm. Consequently, while ensuring the efficiency of segmentation through deep learning, LVPA-UNet is able to provide superior GTV delineation results for radiotherapy and offer technical support for precision medicine.
•Parallel 2D-3D strategy reduces anisotropy and spatial feature loss impacts.•Introduction of L(V)-MSCA addresses tumor variability and unclear edges.•Layer-Channel Attention elevates the network's focus on tumor-relevant structures.•LVPA-UNet has the potential to optimize radiation dose distribution planning.
Background
The goal of surveillance testing is to enable curative salvage therapy through early disease detection, however supporting evidence in gastroesophageal adenocarcinoma is limited. We ...evaluated frequency of successful salvage therapy and outcomes in patients who underwent surveillance.
Methods
A single‐site, retrospective cohort study was conducted to identify all patients who received curative resection for gastroesophageal adenocarcinoma. Surveillance testing were those investigations not triggered by abnormal symptoms, physical examination, or blood tests. Successful salvage therapy was any potentially curative therapy for disease recurrence which resulted in postrecurrence disease‐free survival ≥2 years. Time‐to‐event data were analyzed using the Kaplan‐Meier method and log rank tests.
Results
Between 2011 and 2016, 210 consecutive patients were reviewed. Esophageal (14%), gastroesophageal junction (40%), and gastric adenocarcinomas (45%) were treated with surgery alone (29%) or multimodality therapy (71%). Adjuvant therapy was administered in 35%. At median follow‐up of 38.3 months, 5‐year overall survival (OS) rate was 56%. Among 97 recurrences, 53% were surveillance‐detected, and 46% were symptomatic. None was detected by surveillance endoscopy. Median time‐to‐recurrence (TTR) was 14.8 months. Recurrences included locoregional only (4%), distant (86%), and both (10%). Salvage therapy was attempted in 15 patients, 4 were successful. Compared to symptomatic recurrences, patients with surveillance‐detected recurrences had longer median OS (36.2 vs 23.7 months, P = .004) and postrecurrence survival (PRS, 16.5 vs 4.6 months, P < .001), but similar TTR (16.2 vs 13.3 months, P = .40) and duration of palliative chemotherapy (3.9 vs 3.3 months, P = .64).
Conclusions
Among patients surveyed, 96% of recurrences were distant, and salvage therapy was successful in only 1.9% of patients. Longer OS in patients with surveillance‐detected compared to symptomatic recurrences was not associated with significant earlier disease detection, and may be contributed by differences in disease biology. Further prospective data are warranted to establish the benefit of surveillance testing in gastroesophageal adenocarcinoma.
For resected gastroesophageal adenocarcinoma treated at our institution, routine surveillance testing rarely enabled successful salvage therapy, did not detect recurrence earlier, and did not extend duration of palliative chemotherapy. Further prospected data is warranted to establish the role of surveillance testing in gastroesophageal adenocarcinoma.
Oncogenic KRAS (KRAS*) contributes to many cancer hallmarks. In colorectal cancer, KRAS* suppresses antitumor immunity to promote tumor invasion and metastasis. Here, we uncovered that KRAS* ...transforms the phenotype of carcinoma-associated fibroblasts (CAF) into lipid-laden CAFs, promoting angiogenesis and tumor progression. Mechanistically, KRAS* activates the transcription factor CP2 (TFCP2) that upregulates the expression of the proadipogenic factors BMP4 and WNT5B, triggering the transformation of CAFs into lipid-rich CAFs. These lipid-rich CAFs, in turn, produce VEGFA to spur angiogenesis. In KRAS*-driven colorectal cancer mouse models, genetic or pharmacologic neutralization of TFCP2 reduced lipid-rich CAFs, lessened tumor angiogenesis, and improved overall survival. Correspondingly, in human colorectal cancer, lipid-rich CAF and TFCP2 signatures correlate with worse prognosis. This work unveils a new role for KRAS* in transforming CAFs, driving tumor angiogenesis and disease progression, providing an actionable therapeutic intervention for KRAS*-driven colorectal cancer.
This study identified a molecular mechanism contributing to KRAS*-driven colorectal cancer progression via fibroblast transformation in the tumor microenvironment to produce VEGFA driving tumor angiogenesis. In preclinical models, targeting the KRAS*-TFCP2-VEGFA axis impaired tumor progression, revealing a potential novel therapeutic option for patients with KRAS*-driven colorectal cancer. This article is featured in Selected Articles from This Issue, p. 2489.
•Reported firstly about the mechanism of AHL-based aerobic granular stability.•Disintegration of aerobic granules due to inactivation of AHL was reported.•The AHLs content was significantly reduced ...in the presence of AHL-acylase.•Inactivation of AHLs led to the attachment potential of aerobic granules decrease.•Contents of extracellular PS and PN decreased due to the inactivation of AHL.
In this study, porcine kidney acylase, as N-acyl homoserine lactones (AHLs)-degradation enzyme, was employed for the first time to directly investigate the role of AHLs in the structure stability of aerobic granules. Results clearly showed that inactivation of AHLs by AHLs-acylase could weaken the stability of aerobic granule. In the presence of AHLs-acylase, AHLs were degraded by hydrolyzing the amide linkage, which resulted in aerobic granular attachment potential and activity of AHLs-based quorum sensing significantly reduced. In addition, it was also found that inactivation of AHLs led to reduction of extracellular polysaccharides and protein (PN), especially PN, and induced extracellular polymeric substances matrix damaged, which was hostile to stability of aerobic granules. This study provided direct evidence that AHLs played a key role in improving aerobic granular stability, and a potential way to enhance long-term stability of aerobic granules.
Abstract
Aims
Anticoagulation therapy is indicated to prevent stroke in atrial flutter (AFL) and atrial fibrillation (AF) patients. However, the outcomes of solitary AFL patients may differ from ...those with AFL who develop AF during follow-up. This study aimed to investigate the differences in clinical outcomes: (i) among patients with solitary AFL, AF, and AFL developing AF thereafter and (ii) between solitary AFL patients with vs. without anticoagulation therapy.
Methods and results
This nationwide cohort study enrolled patients with solitary AFL, solitary AF, and AFL developing AF from a 12 years National Health Insurance Research Database in Taiwan. There were 230 367 patients without anticoagulation therapy in the solitary AF cohort, 8064 in the solitary AFL cohort, and 4495 in the AFL with AF cohort. The AFL with AF and solitary AF cohorts had higher incidences of ischaemic stroke and major bleeding than the solitary AFL cohort. Solitary AFL patients with anticoagulation therapy had a lower ischaemic stroke rate than those without (P < 0.05) at the level of a CHA2DS2-VASc score ≥3. Solitary AFL patients with anticoagulation therapy had a higher intracranial haemorrhage rate than those without (P < 0.05) at the level of a CHA2DS2-VASc score ≤3. Net clinical outcomes including ischaemic stroke, systemic embolization, and major bleeding favoured anticoagulation use in solitary AFL patients with a CHA2DS2-VASc score ≥4.
Conclusion
Solitary AFL patients without anticoagulation therapy had better clinical outcomes than AFL patients developing AF in this study. Anticoagulation therapy may offer the best net clinical outcome for solitary AFL patients with a CHA2DS2-VASc score ≥4.
Sympathetic overactivity contributes to the pathogenesis of sepsis. The selective α2-adrenergic receptor agonist dexmedetomidine (DEX) is widely used for perioperative sedation and analgesia. We ...aimed to determine the central roles and mechanisms of DEX in attenuating sympathetic activity and inflammation in sepsis. Sepsis was induced by a single intraperitoneal injection of lipopolysaccharide (LPS) in rats. Effects of DEX were investigated 24 h after injection of LPS. Bilateral microinjection of DEX in the paraventricular nucleus (PVN) attenuated LPS-induced sympathetic overactivity, which was attenuated by the superoxide dismutase inhibitor DETC, cAMP analog db-cAMP or GABA
receptor antagonist gabazine. Superoxide scavenger tempol, NADPH oxidase inhibitor apocynin, adenylate cyclase inhibitor SQ22536 or PKA inhibitor Rp-cAMP caused similar effects to DEX in attenuating LPS-induced sympathetic activation. DEX inhibited LPS-induced superoxide and cAMP production, as well as NADPH oxidase, adenylate cyclase and PKA activation. The roles of DEX in reducing superoxide production and NADPH oxidase activation were attenuated by db-cAMP or gabazine. Intravenous infusion of DEX inhibited LPS-induced sympathetic overactivity, NOX activation, superoxide production, TNF-α and IL-1β upregulation in the PVN and plasma, as well as lung and renal injury, which were attenuated by the PVN microinjection of yohimbine and DETC. We conclude that activation of α2-adrenergic receptors with DEX in the PVN attenuated LPS-induced sympathetic overactivity by reducing NADPH oxidase-dependent superoxide production via both inhibiting adenylate cyclase-cAMP-PKA signaling and activating GABA
receptors. The inhibition of NADPH oxidase-dependent superoxide production in the PVN partially contributes to the roles of intravenous infusion of DEX in attenuating LPS-induced sympathetic activation, oxidative stress and inflammation.
PDF
