The deeper understanding of the complex hereditary basis of familial hypercholesterolemia (FH) has raised the rationale of genetic testing, which has been underutilized in clinical practice.
The ...present study aimed to explore the variant spectrum of FH in an expanding manner and compare its diagnostic performance.
A total of 169 Chinese individuals (124 index cases and 45 relatives) with clinical definite/probable FH were consecutively enrolled. Next-generation sequencing was performed for genetic analysis of 9 genes associated with hypercholesterolemia (major genes: LDLR, APOB, and PCSK9; minor genes: LDLRAP1, LIPA, STAP1, APOE, ABCG5, and ABCG8) including the evaluations of small-scale variants and large-scale copy number variants (CNVs).
Among the 169 clinical FH patients included, 98 (58.0%) were men. A total of 85 (68.5%) index cases carried FH-associated variants. The proportion of FH caused by small-scale variants in LDLR, APOB, and PCSK9 genes was 62.1% and then increased by 6.5% when other genes and CNVs were further included. Furthermore, the variants in LDLR, APOB, and PCSK9 genes occupied 75% of all FH-associated variants. Of note, there were 8 non-LDLR CNVs detected in the present study.
LDLR, APOB, and PCSK9 genes should be tested in the initial genetic screening, although variants in minor genes also could explain phenotypic FH, suggesting that an expanding genetic testing may be considered to further explain phenotypic FH.
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Abstract Background In the present study, we compared preservation of the hepatic artery flow during liver blood inflow occlusion with total portal triad blood flow clamping (the Pringle maneuver) to ...examine their effects on liver regeneration in rats after partial hepatectomy. Materials and methods Male Wistar rats were randomized to a control group (without hepatic inflow occlusion), an occlusion of the portal triad (OPT) group (OPT for 30 min under portal blood bypass), and an occlusion of the portal vein (OPV) group (OPV only for 30 min under portal blood bypass). All the rats underwent partial hepatectomy at the end of hepatic blood control. Liver regeneration was assessed on days 3 and 7 after hepatectomy. Liver damage, extracellular signal-regulated kinase-1/2 activation, and cytokine expression of the remnant liver in the first 24 h after hepatectomy were also assessed. Results Significantly greater liver regeneration, at a level similar to that of the control group, as indicated by the percentage of the initial liver weight, proliferating cell nuclear antigen and Ki-67 labeling indexes, and technetium-99m galactosyl human serum albumin liver uptake, was observed in the OPV group on day 3 after hepatectomy ( P < 0.05 versus the OPT group). Liver damage, as represented by alanine aminotransferase and aspartate aminotransferase measurement and histopathologic examination, was substantially alleviated in the OPV group compared with the OPT group. In contrast to the control and OPV groups, the OPT group had markedly increased extracellular signal-regulated kinase-1/2 activation, heat shock protein 70, and interleukin-6 expression in response to ischemia and partial hepatectomy. Conclusions Our results have indicated that compared with the Pringle maneuver, clamping the portal vein while preserving the hepatic artery flow during partial hepatectomy is better for remnant liver regeneration at an early posthepatectomy stage.
Abstract Background context No reports to date have accurately evaluated the management for acute spinal cord injury (SCI) caused by ossification of the posterior longitudinal ligament (OPLL) after ...minor trauma. Purpose To assess whether outcomes of laminoplasty is better than conservative treatment. Study design/setting A retrospective study. Patient sample Thirty-one patients underwent surgery (L group) and 29 patients underwent conservative treatment (C group). Outcome measures Disability, muscle strength, sensation, and general health status. Methods Patients were managed according to routine clinical practice and the results between groups were compared. Clinical and radiographic outcomes were assessed at admission, discharge, 6 months and at the final visit. Causes for trauma, duration of hospital stay, and complication were also evaluated. Results Causes for trauma included falling, traffic accidents and sports. Mixed and segmental types were the most frequent cause of OPLL resulting into SCI. Duration of hospital stay and complications were less in the L group. Motor and sensory scores increased in the L group at discharge (p<.05) and at 6 months (p<.05), and maintained thereafter (p>.05); scores improved significantly in the C group at 6 months (p<.05), with a slight deterioration with time (p>.05); scores in the L group were higher than in the C group at each time point after surgery (p<.05). Bodily pain and mental health in SF-36 improved at discharge in the L group (p<.05); all scores improved at 6 months in both the groups (p<.05), with better improvements in the L group (p<.05). The canal diameter increased and occupation ratio decreased in the L group (p<.05), and maintained thereafter (p<.05); a slight increase of occupation ratio was observed in the C group (p>.05). Lordotic angle and range of motion were maintained in both the groups, with no significance between groups (p>.05). High-signal intensity decreased at 6 months (p<.05) in the L group; no significant change was found in the C group during the follow-up (p>.05); Significant difference was detected between the groups at 6 months and at the final visit (p<.05). Conclusions Most of the OPLL patients displayed as incomplete SCI after minor trauma. Although spontaneous improvement of SCI without surgery is often observed, laminoplasty has more satisfactory outcomes, prevents late compression of cord, and reduces perioperative complications, although with no significant benefit in cervical alignment and range of motion.
To develop and validate an automated deep learning (DL)-based artificial intelligence (AI) platform for diagnosing and grading cataracts using slit-lamp and retroillumination lens photographs based ...on the Lens Opacities Classification System (LOCS) III.
Cross-sectional study in which a convolutional neural network was trained and tested using photographs of slit-lamp and retroillumination lens photographs.
One thousand three hundred thirty-five slit-lamp images and 637 retroillumination lens images from 596 patients.
Slit-lamp and retroillumination lens photographs were graded by 2 trained graders using LOCS III. Image datasets were labeled and divided into training, validation, and test datasets. We trained and validated AI platforms with 4 key strategies in the AI domain: (1) region detection network for redundant information inside data, (2) data augmentation and transfer learning for the small dataset size problem, (3) generalized cross-entropy loss for dataset bias, and (4) class balanced loss for class imbalance problems. The performance of the AI platform was reinforced with an ensemble of 3 AI algorithms: ResNet18, WideResNet50-2, and ResNext50.
Diagnostic and LOCS III-based grading prediction performance of AI platforms.
The AI platform showed robust diagnostic performance (area under the receiver operating characteristic curve AUC, 0.9992 95% confidence interval (CI), 0.9986–0.9998 and 0.9994 95% CI, 0.9989–0.9998; accuracy, 98.82% 95% CI, 97.7%–99.9% and 98.51% 95% CI, 97.4%–99.6%) and LOCS III-based grading prediction performance (AUC, 0.9567 95% CI, 0.9501–0.9633 and 0.9650 95% CI, 0.9509–0.9792; accuracy, 91.22% 95% CI, 89.4%–93.0% and 90.26% 95% CI, 88.6%–91.9%) for nuclear opalescence (NO) and nuclear color (NC) using slit-lamp photographs, respectively. For cortical opacity (CO) and posterior subcapsular opacity (PSC), the system achieved high diagnostic performance (AUC, 0.9680 95% CI, 0.9579–0.9781 and 0.9465 95% CI, 0.9348–0.9582; accuracy, 96.21% 95% CI, 94.4%–98.0% and 92.17% 95% CI, 88.6%–95.8%) and good LOCS III-based grading prediction performance (AUC, 0.9044 95% CI, 0.8958–0.9129 and 0.9174 95% CI, 0.9055–0.9295; accuracy, 91.33% 95% CI, 89.7%–93.0% and 87.89% 95% CI, 85.6%–90.2%) using retroillumination images.
Our DL-based AI platform successfully yielded accurate and precise detection and grading of NO and NC in 7-level classification and CO and PSC in 6-level classification, overcoming the limitations of medical databases such as few training data or biased label distribution.
Summary Our previous study has suggested an oncogenic role of eIF-5A2 in ovarian tumorigenesis. Abnormalities of eIF-5A2 , however, in colorectal carcinoma are unclear. In this study, amplification ...and overexpression of eIF-5A2 in colorectal carcinoma were studied by fluorescence in situ hybridization and immunohistochemistry using colorectal carcinoma tissue microarrays, including 139 primary colorectal carcinomas and their adjacent normal mucosa, 22 paired premalignant adenomas, and 42 metastatic tumors. The immunohistochemistry results showed that overexpression of EIF-5A2 was detected in none of normal epithelial mucosa, 35.3% of colorectal adenomas, 53.2% of primary colorectal carcinomas, and 67.6% of metastases. Amplification of eIF-5A2 was detected in 15.8% (16/101) of informative colorectal carcinomas, and most of them showed overexpression of EIF-5A2. In primary colorectal carcinomas, the frequency of EIF-5A2 overexpression was significantly higher in colorectal carcinomas with lymphovascular invasion (61.2%) than that in colorectal carcinomas without lymphovascular invasion (36.6%, P < .05). In addition, significant positive associations were found between EIF-5A2 overexpression and the tumors' later pN and pM stages, as well as increased tumor cell proliferation ( P < .05). These findings suggest that overexpression of EIF-5A2 in colorectal carcinomas may be important in the acquisition of a metastatic phenotype and plays an important role in colorectal carcinoma development and progression.
Lung cancer is a leading cause of cancer-related deaths worldwide. It mainly consists of 2 histological types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC, including squamous ...cell carcinoma and adenocarcinoma). The present study aimed to assess the role of serum progastrin-releasing peptide (ProGRP), neuron-specific enolase (NSE), and carcinoembryonic antigen (CEA) and their combinations in the histological diagnosis of lung cancer (specially SCLC), which is of great importance for the initiation of treatment and prognostic implications. Serum ProGRP, NSE, and CEA were determined by the electrochemiluminescence immunoassay (ECLIA) in 66 patients with SCLC, 73 with adenocarcinoma, 44 with squamous cell carcinoma, 45 with non-malignant pulmonary diseases, and 50 healthy controls. Receiver operating characteristic curves were constructed to compare the predictive ability of each biochemical marker and their combined detection models to discriminate among the patients with lung cancers of different histological groups, benign pulmonary diseases and healthy individuals. In the ECLIA detection system, ProGRP showed the sensitivity and specificity for SCLC diagnosis were 71.2% and 91.1% to 93.2%, respectively. Among the markers, the largest area under the ROCs was for ProGRP in discriminating SCLC from benign pulmonary diseases, squamous cell carcinoma and adenocarcinoma (0.815, 0.859, and 0.835, respectively), which indicated that ProGRP was the most efficient marker for identifying SCLC. Besides, ProGRP and NSE exhibited almost equivalent diagnostic performance in discriminating SCLC from benign diseases. As for squamous cell carcinoma, we recommended proGRP, while for adenocarcinoma, the combination of proGRP and CEA was preferred. Remarkably, when ProGRP ≤ 66 pg/mL, CEA was of great value in diagnosing SCLC and adenocarcinoma. If CEA ≤ 5 ng/mL, the patient was at higher risk for SCLC, whereas the patient was more likely to be diagnosed with adenocarcinoma. Our study provided promising information about the diagnostic values of serum ProGRP, NSE, CEA in distinguishing SCLC from benign pulmonary diseases and NSCLC, which was of crucial clinical significance in the early diagnosis and therapy of SCLC.
Abstract Background Everolimus-eluting stent (EES) are considered to have better clinical outcomes than other rapamycin derivative-eluting stents; however, the individual trials may not have ...sufficient power to prove it. This meta-analysis aimed to compare clinical outcomes of EES against other rapamycin derivative-eluting stents. Methods We searched Medline, the Cochrane Library, and other internet sources, without language or date restrictions for articles comparing clinical outcomes between EES and other rapamycin derivative-eluting stents. Safety endpoints were stent thrombosis (ST), mortality, cardiac death, and myocardial infarction (MI). Efficacy endpoints were major adverse cardiac events (MACE), target lesion revascularization (TLR), and target vessel revascularization (TVR). Results We identified 16 randomized controlled trials with 23,481 patients and a weighted mean follow-up of 18 months. Compared with other rapamycin derivative-eluting stents, EES were associated with a significant reduction in definite ST relative risk (RR): 0.45; 95% confidence interval (CI): 0.30–0.69; p < 0.001 and TLR (RR: 0.87; 95% CI: 0.77–0.99; p = 0.03). EES also showed a non-significant trend toward reduction in definite/probable ST (RR: 0.75; 95% CI: 0.56–1.01; p = 0.06). However, both groups had similar rates of mortality (RR: 0.95; 95% CI: 0.82–1.09; p = 0.45), MI (RR: 0.95; 95% CI: 0.82–1.10; p = 0.43), and MACE (RR: 0.94; 95% CI: 0.87–1.02; p = 0.35). The stratified analysis of the included trials showed that EES was associated with significantly lower rate of definite ST compared with either zotarolimus-eluting stent ( p = 0.012) or sirolimus-eluting stent ( p = 0.006), but not biolimus-eluting stent ( p = 0.16). In longer follow-up (>1 year) stratification, EES was associated with a significant reduction in risk of definite ST ( p < 0.001). Conclusions EES is associated with a significant reduction in definite ST and TLR for treating patients with coronary artery disease, compared with a pooled group of other rapamycin derivative-eluting stents. Biolimus-eluting stent had similar safety and efficacy for treating patients with coronary artery disease, compared with the EES.
Abstract Clopidogrel is a pro-drug that requires activation by the cytochrome P450 (CYP) enzyme system. Patients receiving clopidogrel are often treated with selective serotonin reuptake inhibitors ...(SSRIs) for co-existing depression. SSRIs that inhibit the CYP2C19 enzyme have the potential to reduce the effectiveness of clopidogrel. Using 5 US databases (1998-2013), we conducted a cohort study of adults who initiated clopidogrel while being treated with either an SSRI that inhibits CYP2C19 (fluoxetine and fluvoxamine) or a non-inhibiting SSRI. Patients were matched by propensity score and followed for as long as they were exposed to both clopidogrel and the index SSRI group (primary analysis) or for 180 days following clopidogrel initiation (sensitivity analysis). Outcomes included a composite ischemic event (myocardial infarction, ischemic stroke, or a revascularization procedure) and a composite major bleeding event (gastrointestinal bleed or hemorrhagic stroke). The final PS-matched cohort comprised 9,281 clopidogrel initiators on CYP2C19-inhibiting SSRIs and 44,278 clopidogrel initiators on a non-inhibiting SSRIs. As compared to those treated with a non-inhibiting SSRI, patients on a CYP2C19-inhibiting SSRI had an increased risk of ischemic events (hazard ratio (HR), 1.12; 95% confidence interval (CI), 1.01 to 1.24), which was more pronounced in patients 65 years of age and older (HR, 1.22; 95% CI, 1.00 to 1.48). The HR for major bleeding was 0.76 (95% CI, 0.50 to 1.17). In conclusion, the findings from this large, population-based study suggest that being treated with a CYP2C19-inhibiting SSRI when initiating clopidogrel may be associated with slight decrease in effectiveness of clopidogrel.
Transplantation of Autologous Endothelial Progenitor Cells May Be Beneficial in Patients With Idiopathic Pulmonary Arterial Hypertension: A Pilot Randomized Controlled Trial Xing-xiang Wang, Fu-rong ...Zhang, Yun-peng Shang, Jun-hui Zhu, Xu-dong Xie, Qian-min Tao, Jian-hua Zhu, Jun-zhu Chen The goal of this study was to investigate the feasibility, safety, and initial clinical outcome of intravenous infusion of autologous endothelial progenitor cells (EPCs) in patients with idiopathic pulmonary arterial hypertension (IPAH). We conducted a prospective, randomized trial comparing the effects of EPCs transplantation plus conventional therapy with those of conventional therapy alone in patients with IPAH. It is suggested that intravenous infusion of autologous EPCs seems to be feasible and safe, and might have beneficial effects on exercise capacity and pulmonary hemodynamics in patients with IPAH.
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