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Abstract. Background:. Microsatellite instability (MSI) is a key biomarker for cancer immunotherapy and prognosis. Integration of MSI testing into a next-generation-sequencing (NGS) panel could save tissue sample, reduce turn-around time and cost, and provide MSI status and comprehensive genomic profiling in single test. We aimed to develop an MSI calling model to detect MSI status along with the NGS panel-based profiling test using tumor-only samples. Methods:. From January 2019 to December 2020, a total of 174 colorectal cancer (CRC) patients were enrolled, including 31 MSI-high (MSI-H) and 143 microsatellite stability (MSS) cases. Among them, 56 paired tumor and normal samples (10 MSI-H and 46 MSS) were used for modeling, and another 118 tumor-only samples were used for validation. MSI polymerase chain reaction (MSI-PCR) was performed as the gold standard. A baseline was built for the selected microsatellite loci using the NGS data of 56 normal blood samples. An MSI detection model was constructed by analyzing the NGS data of tissue samples. The performance of the model was compared with the results of MSI-PCR. Results:. We first intersected the target genomic regions of the NGS panels used in this study to select common microsatellite loci. A total of 42 loci including 23 mononucleotide repeat sites and 19 longer repeat sites were candidates for modeling. As mononucleotide repeat sites are more sensitive and specific for detecting MSI status than sites with longer length motif and the mononucleotide repeat sites performed even better than the total sites, a model containing 23 mononucleotide repeat sites was constructed and named Colorectal Cancer Microsatellite Instability test (CRC-MSI). The model achieved 100% sensitivity and 100% specificity when compared with MSI-PCR in both training and validation sets. Furthermore, the CRC-MSI model was robust with the tumor content as low as 6%. In addition, 8 out of 10 MSI-H samples showed alternations in the four mismatch repair genes (MLH1, MSH2, MSH6, and PMS2). Conclusion:. MSI status can be accurately determined along the targeted NGS panels using only tumor samples. The performance of mononucleotide repeat sites surpasses loci with longer repeat motif in MSI calling.

Objective: To provide a comprehensive and latest overview of susceptibility-weighted imaging (SWI) in the application of thrombolysis in acute ischemic stroke, and to update the decision-making effect and clinical value of SWI on identifying stroke patients suitable for thrombolytic therapy and possible benefits and risks followed. Data Sources: Literatures referred to this review were collected from PubMed, Medline, and EMBASE published till May 2017, using the search terms including susceptibility-weighted imaging, gradient-echo, T2*, thrombolysis, recombinant tissue plasminogen activator (rt-PA), thrombolytic therapy, and stroke. Study Selection: Papers in English or with available English abstracts were considered, with no limitation of study design. References were also identified from the bibliographies of identified articles and the authors' files. Results: SWI is of guiding significance for thrombolytic therapy in stroke patients, it can predict the location and length of thrombus and ischemic penumbra. It is worthy of noting that susceptibility vessel sign (SVS) on SWI can be used to predict recanalization after thrombolytic therapy and whether it is better to implement endovascular thrombolectomy in combination or alone. SWI is sensitive in detecting cerebral microbleed (CMB), and CMB might not be a contraindication for thrombolytic therapy, yet CMBs in multiple foci could possibly be related to intracranial hemorrhage (ICH) after thrombolysis. SVS and CMB on SWI sequence are of instructive value in performing antiplatelet therapy after thrombolytic therapy. Cerebral venous change on SWI is related to lower recanalization rate and poor outcome after thrombolysis. Conclusions: It seems that SWI can be applied to guide individualized thrombolytic therapies and assist clinicians in making better decisions by weighing benefits and risks. However, there still exist controversies about the relationship between signs on SWI and thrombolytic therapy.

Objective: Parkinson's disease (PD) is featured with motor disorder and nonmotor manifestations including psychological symptoms, autonomic nervous system dysfunction, and paresthesia, which results in great inconvenience to the patients' life. The apolipoprotein (Apo) superfamily, as a group of potentially modifiable biomarkers in clinical practice, is of increasing significance in the diagnosis, evaluation, and prognosis of PD. The present review summarized the current understanding and emerging findings of the relationship between Apo superfamily and PD. Data Sources: All literatures were identified by systematically searching PubMed, Embase, and Cochrane electronic databases with terms “Parkinson disease,” “apolipoprotein,” and their synonyms until May 2017. Study Selection: We have thoroughly examined titles and abstracts of all the literatures that met our search strategy and the full text if the research is identified or not so definite. Reference lists of retrieved articles were also scrutinized for additional relevant studies. Results: The levels of plasma ApoA1 are inversely correlated with the risk of PD and the lower levels of ApoA1 trend toward association with poorer motor performance. Higher ApoD expression in neurons represents more puissant protection against PD, which is critical in delaying the neurodegeneration process of PD. It is suggested that APOE alleles are related to development and progression of cognitive decline and age of PD onset, but conclusions are not completely identical, which may be attributed to different ApoE isoforms. APOJ gene expressions are upregulated in PD patients and it is possible that high ApoJ level is an indicator of PD dementia and correlates with specific phenotypic variations in PD. Conclusions: The Apo superfamily has been proved to be closely involved in the initiation, progression, and prognosis of PD. Apos and their genes are of great value in predicting the susceptibility of PD and hopeful to become the target of medical intervention to prevent the onset of PD or slow down the progress. Therefore, further large-scale studies are warranted to elucidate the precise mechanisms of Apos in PD.

Background: Little is known about the long-term outcomes of severe acute respiratory distress syndrome (ARDS) patients requiring extracorporeal membrane oxygenation (ECMO). This study aimed to investigate the 1-year outcomes of these patients or patients receiving mechanical ventilation (MV) and compare their health-related quality of life (HRQoL) to the general population. Methods: Severe ARDS survivors admitted to two ICUs in China between January 2012 and January 2014 were enrolled. Of the severe ARDS survivors enrolled, 1-year postdischarge, HRQoL assessment using the Short-Form 36 (SF-36) and EuroQol questionnaire dimensions, 6-min walking distance, chest computed tomography scan, pulmonary function, and arterial blood gas analysis were compared for ARDS patients with or without ECMO. Results: ARDS patients receiving ECMO had a significantly higher Acute Physiology and Chronic Health Evaluation II score (30.3 ± 6.7 vs. 26.5 ± 7.3, P= 0.036), lung injury score (3.3 ± 0.4 vs. 2.8 ± 0.5, P= 0.000), Sequential Organ Failure Assessment score (10.8 ± 3.5 vs. 7.9 ± 3.1, P= 0.000), lower PaO2/FiO2ratio ([mmHg, 1 mmHg = 0.133 kPa], 68.3 ± 16.1 vs. 84.8 ± 16.5, P= 0.000), and increased extrapulmonary organ failure (2 [1, 3] vs. 1 [1, 1], P= 0.025) compared with patients not receiving ECMO. ECMO and non-ECMO survivors showed similar pulmonary function, morphological abnormalities, resting arterial blood gas values, and 6-min walking distance. Mild pulmonary dysfunction and abnormal morphology were observed in a few survivors. In addition, ECMO and non-ECMO survivors showed a similar quality of life. ECMO survivors showed lower SF-36 physical functioning and role-physical domain scores (minimum clinically significant difference at least 5 points), and non-ECMO survivors had similar outcome. Conclusions: One-year posthospital discharge, severe ARDS survivors receiving ECMO or MV demonstrated comparable outcomes. Compared with the general population, ARDS survivors showed reduced HRQoL. Pulmonary function and lung morphology revealed sufficient recovery with minor lung impairment.

Background: There has been no external validation of survival prediction models for severe adult respiratory distress syndrome (ARDS) with extracorporeal membrane oxygenation (ECMO) therapy in China. The aim of study was to compare the performance of multiple models recently developed for patients with ARDS undergoing ECMO based on Chinese single-center data. Methods: A retrospective case study was performed, including twenty-three severe ARDS patients who received ECMO from January 2009 to July 2015. The PRESERVE (Predicting death for severe ARDS on VV-ECMO), ECMOnet, Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) score, a center-specific model developed for inter-hospital transfers receiving ECMO, and the classical risk-prediction scores of Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) were calculated. In-hospital and six-month mortality were regarded as the endpoints and model performance was evaluated by comparing the area under the receiver operating characteristic curve (AUC). Results: The RESP and APACHE II scores showed excellent discriminate performance in predicting survival with AUC of 0.835 (95% confidence interval [CI], 0.659–1.010, P = 0.007) and 0.762 (95% CI, 0.558–0.965, P = 0.035), respectively. The optimal cutoff values were risk class 3.5 for RESP and 35.5 for APACHE II score, and both showed 70.0% sensitivity and 84.6% specificity. The excellent performance of these models was also evident for the pneumonia etiological subgroup, for which the SOFA score was also shown to be predictive, with an AUC of 0.790 (95% CI, 0.571–1.009, P = 0.038). However, the ECMOnet and the score developed for externally retrieved ECMO patients failed to demonstrate significant discriminate power for the overall cohort. The PRESERVE model was unable to be evaluated fully since only one patient died six months postdischarge. Conclusions: The RESP, APCHAE II, and SOFA scorings systems show good predictive value for intra-hospital survival of ARDS patients treated with ECMO in our single-center evaluation. Future validation should include a larger study with either more patients' data at single-center or by integration of domestic multi-center data. Development of a scoring system with national characteristics might be warranted.

Background: The antagonistic actions of anticholinesterase drugs on non-depolarizing muscle relaxants are theoretically related to the activity of acetylcholinesterase (AChE) in the neuromuscular junction (NMJ). However, till date the changes of AChE activity in the NMJ during sepsis have not been directly investigated. We aimed to investigate the effects of sepsis on the antagonistic actions of neostigmine on rocuronium (Roc) and the underlying changes of AChE activity in the NMJ in a rat model of cecal ligation and puncture (CLP). Methods: A total of 28 male adult Sprague-Dawley rats were randomized to undergo a sham surgery (the sham group, n = 12) or CLP (the septic group, n = 16). After 24 h, the time-response curves of the antagonistic actions of 0.1 or 0.5 μmol/L of neostigmine on Roc (10 μmol/L)-depressed diaphragm twitch tension were measured. Meanwhile, the activity of AChE in the NMJ was detected using a modified Karnovsky and Roots method. The mRNA levels of the primary transcript and the type T transcript of AChE (AChET) in the diaphragm were determined by real-time reverse transcription-polymerase chain reaction. Results: Four of 16 rats in the septic group died within 24 h. The time-response curves of both two concentrations of neostigmine in the septic group showed significant upward shifts from those in the sham group (P < 0.001 for 0.1 μmol/L; P = 0.009 for 0.5 μmol/L). Meanwhile, the average optical density of AChE in the NMJ in the septic group was significantly lower than that in the sham group (0.517 ± 0.045 vs. 1.047 ± 0.087, P < 0.001). The AChE and AChETmRNA expression levels in the septic group were significantly lower than those in the sham group (P = 0.002 for AChE; P = 0.001 for AChET). Conclusions: Sepsis strengthened the antagonistic actions of neostigmine on Roc-depressed twitch tension of the diaphragm by inhibiting the activity of AChE in the NMJ. The reduced content of AChE might be one of the possible causes of the decreased AChE activity in the NMJ.

Background: This study was to establish a disease differentiation model for ST-segment elevation myocardial infarction (STEMI) youth patients experiencing ischemia and reperfusion via ultra-performance liquid chromatography and mass spectrometry (UPLC/MS) platform, which searches for closely related characteristic metabolites and metabolic pathways to evaluate their predictive value in the prognosis after discharge. Methods: Forty-seven consecutive STEMI patients (23 patients under 45 years of age, referred to here as “youth,” and 24 “elderly” patients) and 48 healthy control group members (24 youth, 24 elderly) were registered prospectively. The youth patients were required to provide a second blood draw during a follow-up visit one year after morbidity (n = 22, one lost). Characteristic metabolites and relative metabolic pathways were screened via UPLC/MS platform base on the Kyoto encyclopedia of genes and genomes (KEGG) and Human Metabolome Database. Receiver operating characteristic (ROC) curves were drawn to evaluate the predictive value of characteristic metabolites in the prognosis after discharge. Results: We successfully established an orthogonal partial least squares discriminated analysis model (R2X = 71.2%, R2Y = 79.6%, and Q2 = 55.9%) and screened out 24 ions; the sphingolipid metabolism pathway showed the most drastic change. The ROC curve analysis showed that ceramide [Cer(d18:0/16:0), Cer(t18:0/12:0)] and sphinganine in the sphingolipid pathway have high sensitivity and specificity on the prognosis related to major adverse cardiovascular events after youth patients were discharged. The area under curve (AUC) was 0.671, 0.750, and 0.711, respectively. A follow-up validation one year after morbidity showed corresponding AUC of 0.778, 0.833, and 0.806. Conclusions: By analyzing the plasma metabolism of myocardial infarction patients, we successfully established a model that can distinguish two different factors simultaneously: pathological conditions and age. Sphingolipid metabolism is the top most altered pathway in young STEMI patients and as such may represent a valuable prognostic factor and potential therapeutic target.

Objective: The objective was to evaluate the protective effects of dexmedetomidine (DEX), a selective agonist of α2-adrenergic receptor, on sepsis-induced diaphragm injury and the underlying molecular mechanisms. Data Sources: The data used in this review were mainly from PubMed articles published in English from 1990 to 2015. Study Selection: Clinical or basic research articles were selected mainly according to their level of relevance to this topic. Results: Sepsis could induce severe diaphragm dysfunction and exacerbate respiratory weakness. The mechanism of sepsis-induced diaphragm injury includes the increased inflammatory cytokines and excessive oxidative stress and superfluous production of nitric oxide (NO). DEX can reduce inflammatory cytokines, inhibit nuclear factor-kappaB signaling pathways, suppress the activation of caspase-3, furthermore decrease oxidative stress and inhibit NO synthase. On the basis of these mechanisms, DEX may result in a shorter period of mechanical ventilation in septic patients in clinical practice. Conclusions: Based on this current available evidence, DEX may produce extra protective effects on sepsis-induced diaphragm injury. Further direct evidence and more specific studies are still required to confirm these beneficial effects.

Background: Low molecular weight heparin (LMWH), as one of anticoagulant drugs, has been used for the treatment of chronic obstructive pulmonary disease (COPD) with prethrombotic state, but the specific use time is unclear. The aim of the study is to observe the effect of LMWH at two different periods of prethrombotic state in COPD in rats and to find the optimal time to use LMWH., Methods: Forty Wistar rats were randomly divided into 4 groups: normal control, raised for 55 days without any treatment; COPD control without LMWH, cigarette inhalation plus intratracheal instillation of lipopolysaccharide and hypodermic injection of normal saline once a day for 10 days; COPD control given LMWH 150 U/kg subcutaneous injection, once a day for 10 days starting day 15 (LMWH-d15); COPD control given LMWH 150 U/kg subcutaneous injection, once a day for 10 days starting day 29 (LMWH-d29)., Results: Comparing LMWH-d15 with LMWH-d29, plasma viscosity, whole blood viscosity, von Willebrand factor, serum fibrinogen, plasminogen activator inhibitor-1 and fibrin D-dimer were each significantly reduced; but thrombin plasminogen activator increased significantly whilst arterial PO2 and PCO2 improved significantly., Conclusion: The better time to use LMWH is the time when coagulation and fibrinolytic indices begin to change in COPD.