Computed Tomography-Based Predictive Model for the Probability of Lymph Node Metastasis in Gastric Cancer: A Meta-analysis.

OBJECTIVES: Whether or not a gastric cancer (GC) patient exhibits lymph node metastasis (LNM) is critical to accurately guiding their treatment and prognostic evaluation, necessitating the ability to reliably predict preoperative LNM status. The present meta-analysis sought to examine the diagnostic value of computed tomography (CT)-based predictive models as a tool to gauge the preoperative LNM status of patients with GC. METHODS: Relevant articles were identified in the PubMed, Web of Science, and Wanfang databases. These studies were used to conduct pooled analyses examining sensitivity, specificity, positive likelihood ratio (PLR), and negative likelihood ratio (NLR) values, and area under the curve values were computed for summary receiver operating characteristic curves. RESULTS: The final meta-analysis incorporated data from 15 studies, all of which were conducted in China, enrolling 3,817 patients with GC (LNM+: 1790; LNM-: 2027). The developed CT-based predictive model exhibited respective pooled sensitivity, specificity, PLR, and NLR values of 84% (95% confidence interval [CI], 0.79-0.87), 81% (95% CI, 0.76-0.85), 4.39 (95% CI, 3.40-5.67), and 0.20 (95% CI, 0.16-0.26). The identified results were not associated with significant potential for publication bias ( P = 0.071). Similarly, CT-based analyses of LN status exhibited respective pooled sensitivity, specificity, PLR, and NLR values of 62% (95% CI, 0.53-0.70), 77% (95% CI, 0.72-0.81), 2.71 (95% CI, 2.20-3.33), and 0.49 (95% CI, 0.40-0.61), with no significant risk of publication bias ( P = 0.984). CONCLUSIONS: Overall, the present meta-analysis revealed that a CT-based predictive model may outperform CT-based analyses alone when assessing the preoperative LNM status of patients with GC, offering superior diagnostic utility.

Presurgical computed tomography-guided localization of lung ground glass nodules: comparing hook-wire and indocyanine green.

BACKGROUND: Presurgical computed tomography (CT)-guided localization is frequently employed to reduce the thoracotomy conversion rate, while increasing the rate of successful sublobar resection of ground glass nodules (GGNs) via video-assisted thoracoscopic surgery (VATS). In this study, we compared the clinical efficacies of presurgical CT-guided hook-wire and indocyanine green (IG)-based localization of GGNs. METHODS: Between January 2018 and December 2021, we recruited 86 patients who underwent CT-guided hook-wire or IG-based GGN localization before VATS resection in our hospital, and compared the clinical efficiency and safety of both techniques. RESULTS: A total of 38 patients with 39 GGNs were included in the hook-wire group, whereas 48 patients with 50 GGNs were included in the IG group. There were no significant disparities in the baseline data between the two groups of patients. According to our investigation, the technical success rates of CT-based hook-wire- and IG-based localization procedures were 97.4% and 100%, respectively (P = 1.000). Moreover, the significantly longer localization duration (15.3 ± 6.3 min vs. 11.2 ± 5.3 min, P = 0.002) and higher visual analog scale (4.5 ± 0.6 vs. 3.0 ± 0.5, P = 0.001) were observed in the hook-wire patients, than in the IG patients. Occurrence of pneumothorax was significantly higher in hook-wire patients (27.3% vs. 6.3%, P = 0.048). Lung hemorrhage seemed higher in hook-wire patients (28.9% vs. 12.5%, P = 0.057) but did not reach statistical significance. Lastly, the technical success rates of VATS sublobar resection were 97.4% and 100% in hook-wire and IG patients, respectively (P = 1.000). CONCLUSIONS: Both hook-wire- and IG-based localization methods can effectively identified GGNs before VATS resection. Furthermore, IG-based localization resulted in fewer complications, lower pain scores, and a shorter duration of localization.

Cost of Acute and Sequelae Care for Japanese Encephalitis Patients, Bangladesh, 2011-2021.

Japanese encephalitis (JE) is associated with an immense social and economic burden. Published cost-of-illness data come primarily from decades-old studies. To determine the cost of care for patients with acute JE and initial and long-term sequelae from the societal perspective, we recruited patients with laboratory-confirmed JE from the past 10 years of JE surveillance in Bangladesh and categorized them as acute care, initial sequalae, and long-term sequelae patients. Among 157 patients, we categorized 55 as acute, 65 as initial sequelae (53 as both categories), and 90 as long-term sequelae. The average (median) societal cost of an acute JE episode was US $929 ($909), of initial sequelae US $75 ($33), and of long-term sequelae US $47 ($14). Most families perceived the effect of JE on their well-being to be extreme and had sustained debt for JE expenses. Our data about the high cost of JE can be used by decision makers in Bangladesh.

Cost-effectiveness analysis of dinutuximab ß for the treatment of high-risk neuroblastoma in China.

BACKGROUND: Dinutuximab ß can be used to treat children with high-risk neuroblastoma (NB). Due to its high price, whether dinutuximab ß is cost-effective for the treatment of high-risk NB remains uncertain. Therefore, assessing the cost-effectiveness of dinutuximab ß in children with high-risk NB is of high importance. METHODS: The health utilities and economic outcomes in children with high-risk NB were projected using a partitioned survival model. The individual patient data (IPD) of add-on treatment with dinutuximab ß (GD2 group) were derived from the literature, while the IPD of traditional therapy (TT group) were obtained from retrospective data of Shanghai Children's Medical Center. Treatment costs included drugs, adverse event-related expenses, and medical resource use. Utility values were obtained from the literature. Costs and quality-adjusted life-years (QALYs) were measured over a 10-year time horizon. Deterministic sensitivity analyses (DSA) and probabilistic sensitivity analyses (PSA) were also conducted. RESULTS: Compared with the TT group, QALY increased in the GD2 group by 0.72 with an increased cost of $171,269.70, leading to an incremental cost-effectiveness ratio of 236,462.75$/QALY. DSA showed that the price of dinutuximab ß was the main factor on the results than other parameters. Compared with the TT group, the GD2 group could not be cost-effective in the PSA at the $37,920/QALY threshold. CONCLUSION: Results found that dinutuximab ß is not a cost-effective treatment option for children with high-risk NB unless its price is significantly reduced.

Initial forces acting on the maxillary teeth with aligner activation of canine distalization on the basis of different initial canine tips in vitro.

INTRODUCTION: The objective of this study was to investigate the 3-dimensional forces exerted on the maxillary teeth with aligner activation of maxillary canine distalization on the basis of different initial canine tips in vitro. METHODS: A force/moment measurement system was used to measure the forces exerted by the corresponding aligners with the same activation of 0.25 mm for canine distalization on the basis of the 3 initial canine tips. The 3 groups included: (1) group T1, with canine inclined mesially 10° on the basis of the standard tip; (2) group T2, with canine maintained standard tip; and (3) Group T3, inclined distally 10° on the basis of the standard tip. A sample size of 12 aligners was tested for each of the 3 groups. RESULTS: The canines were subjected to distomedial forces and labiolingual and vertical components, which are minimal in group T3. As the anterior anchorage for canine distalization, the incisors were mainly subjected to labial and medial reaction forces, with the most significant reaction forces in group T3, and the lateral incisors were subjected to greater forces than the central incisors. The posterior teeth mainly received medial forces, which were greatest when the pretreatment canines were distally tipped. The forces on the second premolar are greater than those on the first molar and the molars. CONCLUSIONS: The results demonstrate that attention to the pretreatment canine tip is necessary when performing canine distalization with aligners, and further work, both in vitro and clinically based, investigating the effect of the canine initial tip on maxillary teeth during canine distalization would greatly aid in better treatment protocol with aligners.

Risk probability and influencing factors of stroke in followed-up hypertension patients.

OBJECTIVE: To explore the risk probability and main influencing factors of stroke in followed-up hypertension patients through the analysis of long-term followed-up cohort data. METHODS: The method of followed-up observation cohort was used to collect the information of 168,417 followed-up hypertension patients from 2002 to 2020 in Jiading District in Shanghai. Kaplan-Meier method was used to analyze the risk probability of stroke complications in long-term followed-up HTN patients, and the influencing factors were analyzed by Cox proportional risk model. RESULTS: Among 168,417 followed-up hypertension patients, 11,143 cases had suffered stroke, and the cumulative incidence rate of stroke was 6.62% (male was 6.87%, female was 6.37%). With the extension of the hypertension years, the cumulative risk probability of stroke in HTN patients would continue to increase and the interval was not equidistant. The total cumulative risk probability of stroke in HTN patients was 78.9% (male was 91.0%, female was 70.7%). During the period of hypertension, the risk occurring probability of stroke was not fixed, but fluctuating. There were 4 onset peaks, which were in 8 years (probability was 4.2%), 15 years (probability was 14.0%), 22 years (probability was 6.0%) and 26 years (probability was 13.9%). The highest risk probability of male patients was in 26 years (probability was 23.1%), and the second peak was in 15 years (probability was 15.6%). The highest risk probability of female patients was in 15 years (probability was 12.9%), and the second peak was in 26 years (probability was 8.7%). The risk probability of different gender, BP grade and BMI was different, the male were at higher risk than the female, stage 3 HTN was higher than stage 2 and stage 1 HTN, obese people and underweight people were at higher risk than those who have normal weight. The main factors closely related to the occurrence of stroke complications were age (RR = 2.917, p < 0.001), body mass index (RR = 1.654, p < 0.001), family history of stroke (RR = 1.386, p < 0.001) and blood pressure grade (RR = 1.148, p < 0.001). CONCLUSION: The risk probability of stroke among hypertension patients was high in followed-up hypertension patients (total 78.9%, male 91.0%, female 70.7%), and would continue to increase disproportionately during period of hypertension (4 different onset peaks). With the persistence of hypertension, the risk probability of stroke would increase continuously. Multivariate Cox regression analysis showed that male patients, patients with HBP, abnormal BMI and positive family history were main factors closely related to the occurrence of stroke complications.

Application of 16 G Biopsy Needle in Transperineal Template-Guided Prostate Biopsy.

BACKGROUND: The aim of this study was to evaluate the clinical value of 16 G biopsy needle in transperineal template-guided prostate biopsy (TTPB), compared with 18 G biopsy needle. METHODS: The patients who underwent TTPB from August 2020 to February 2021 were randomized into 2 groups using a random number table. The control group (n = 65) and the observation group (n = 58) performed biopsy with 18 G (Bard MC l820) and 16 G (Bard MC l616) biopsy needles, respectively. Positive rate of biopsy, Gleason score, complications, and pain score were statistically analyzed. RESULTS: The age, prostate volume, PSA, and the number of cores were comparable between the 2 groups. The positive rate of biopsy in the observation group was 68.9% (40/58), meanwhile the control group was 46.2% (30/65). There was statistical difference between the 2 groups (p = 0.011). Gleason score of the observation group (8 [7-9]) was higher than that of the control group (8 [6-9]) (p = 0.038). There was no significant difference in pain score and complications including hematuria, hematospermia, perineal hematoma, infection, and urinary retention between the 2 groups (p > 0.05). CONCLUSIONS: 16 G biopsy needle significantly improved the positive rates and accurately evaluate the nature of lesions, meanwhile did not increase the incidence of complications compared with 18 G biopsy needle.

E-TBNet: Light Deep Neural Network for Automatic Detection of Tuberculosis with X-ray DR Imaging.

Currently, the tuberculosis (TB) detection model based on chest X-ray images has the problem of excessive reliance on hardware computing resources, high equipment performance requirements, and being harder to deploy in low-cost personal computer and embedded devices. An efficient tuberculosis detection model is proposed to achieve accurate, efficient, and stable tuberculosis screening on devices with lower hardware levels. Due to the particularity of the chest X-ray images of TB patients, there are fewer labeled data, and the deep neural network model is difficult to fully train. We first analyzed the data distribution characteristics of two public TB datasets, and found that the two-stage tuberculosis identification (first divide, then classify) is insufficient. Secondly, according to the particularity of the detection image(s), the basic residual module was optimized and improved, and this is regarded as a crucial component of this article's network. Finally, an efficient attention mechanism was introduced, which was used to fuse the channel features. The network architecture was optimally designed and adjusted according to the correct and sufficient experimental content. In order to evaluate the performance of the network, it was compared with other lightweight networks under personal computer and Jetson Xavier embedded devices. The experimental results show that the recall rate and accuracy of the E-TBNet proposed in this paper are better than those of classic lightweight networks such as SqueezeNet and ShuffleNet, and it also has a shorter reasoning time. E-TBNet will be more advantageous to deploy on equipment with low levels of hardware.

A novel system based on artificial intelligence for predicting blastocyst viability and visualizing the explanation.

Purpose: The purpose of the study was to invent and evaluate the novel artificial intelligence (AI) system named Fertility image Testing Through Embryo (FiTTE) for predicting blastocyst viability and visualizing the explanations via gradient-based localization. Methods: The authors retrospectively analyzed 19 342 static blastocyst images with related inspection histories from 9961 infertile patients who underwent in vitro fertilization. Among these data, 17 984 cycles of single-blastocyst transfer were used for training, and data from 1358 cycles were used for testing purposes. Results: The prediction accuracy for clinical pregnancy achieved by a control model using conventional Gardner scoring system was 59.8%, and area under the curve (AUC) was 0.62. FiTTE improved the prediction accuracy by using blastocyst images to 62.7% and AUC of 0.68. Additionally, the accuracy achieved by an ensemble model using image plus clinical data was 65.2% and AUC was 0.71, representing an improvement in prediction accuracy. The visualization algorithm showed brighter colors with blastocysts that resulted in clinical pregnancy. Conclusions: The authors invented the novel AI system, FiTTE, which could provide more precise prediction of the probability of clinical pregnancy using blastocyst images secondary to single embryo transfer than the conventional Gardner scoring assessments. FiTTE could also provide explanation of AI prediction using colored blastocyst images.

Computed tomography-guided coil localization for scapular-blocked lung nodules.

PURPOSE: To investigate the clinical efficacy, feasibility, and safety of the preoperative computed tomography (CT)-guided coil localization (CL) approach for scapula-blocked lung nodules (SBLNs). MATERIAL AND METHODS: A total of 123 patients with LNs were treated via CT-guided CL and subsequent VATS-guided wedge resection from January 2015 to June 2020. Of these patients, 12 (9.8%) exhibited SBLNs and underwent CT-guided CL. Technical success of localization and video-assisted thoracoscopic surgery (VATS)-guided wedge resection, and localization-related complications were recorded and analyzed. RESULTS: The technical success rate of CT-guided CL was 100%. Each patient was placed with one coil. The mean duration of CT-guided CL was 14.7 ± 2.7 min. One patient (8.3%) developed asymptomatic pneumothorax, which has not impacted the subsequent VATS procedure. Successful VATS-guided wedge resection of these SBLNs was achieved in all patients, with no instances of conversion to thoracotomy. Additional lobectomy was performed in three patients. The mean duration of the VATS procedure and blood loss were 143.8 ± 95.5 min and 110.0 ± 82.0 ml, respectively. CONCLUSIONS: The approach of CT-guided CL could be safely and easily utilized to facilitate high rates of success when conducting the VATS-guided wedge resection of SBLNs.

MiR-134-5p attenuates neuropathic pain progression through targeting Twist1.

Neuropathic pain is a kind of chronic pain because of dysfunctions of somatosensory nerve system. Recently, many studies have demonstrated that microRNAs (miRs) play crucial roles in neuropathic pain development. This study was designed to investigate the effects of miR-134-5p on the process of neuropathic pain progression in a rat model established by chronic sciatic nerve injury (CCI). First, we observed that miR-134-5p was significantly decreased in CCI rat models. Overexpression of miR-134-5p strongly alleviated neuropathic pain behaviors including mechanical and thermal hyperalgesia. Meanwhile, inflammatory cytokine expression, such as IL-6, IL-1ß and TNF-α in CCI rats were greatly repressed by upregulation of miR-134-5p. Twist1 has been widely regarded as a poor prognosis biomarker in diverse diseases. Here, by using bioinformatic analysis, 3'-untranslated region (UTR) of Twist1 was predicted to be a downstream target of miR-134-5p in our study. Here, we found that overexpression of miR-134-5p was able to suppress Twist1 dramatically. Furthermore, it was exhibited that Twist1 was increased in CCI rats time-dependently and Twist1 was inhibited in vivo. Subsequently, downregulation of Twist1 in CCI rats could depress neuropathic pain progression via inhibiting neuroinflammation. In conclusion, our current study indicated that miR-134-5p may inhibit neuropathic pain development through targeting Twist1. Our findings suggested that miR-134-5p might provide a novel therapeutic target for neuropathic pain.

Endemic Severe Fever with Thrombocytopenia Syndrome, Vietnam.

Severe fever with thrombocytopenia syndrome (SFTS), a tickborne viral disease, has been identified in China, South Korea, and Japan since 2009. We found retrospective evidence of SFTS virus (SFTSV) infection in Vietnam, which suggests that SFTSV infections also occur in Vietnam, where the virus has not been known to be endemic.

Structured sparsity regularized multiple kernel learning for Alzheimer's disease diagnosis.

Multimodal data fusion has shown great advantages in uncovering information that could be overlooked by using single modality. In this paper, we consider the integration of high-dimensional multi-modality imaging and genetic data for Alzheimer's disease (AD) diagnosis. With a focus on taking advantage of both phenotype and genotype information, a novel structured sparsity, defined by ℓ 1, p-norm (p > 1), regularized multiple kernel learning method is designed. Specifically, to facilitate structured feature selection and fusion from heterogeneous modalities and also capture feature-wise importance, we represent each feature with a distinct kernel as a basis, followed by grouping the kernels according to modalities. Then, an optimally combined kernel presentation of multimodal features is learned in a data-driven approach. Contrary to the Group Lasso (i.e., ℓ 2, 1-norm penalty) which performs sparse group selection, the proposed regularizer enforced on kernel weights is to sparsely select concise feature set within each homogenous group and fuse the heterogeneous feature groups by taking advantage of dense norms. We have evaluated our method using data of subjects from Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The effectiveness of the method is demonstrated by the clearly improved prediction diagnosis and also the discovered brain regions and SNPs relevant to AD.

Enterovirus-associated changes in blood transcriptomic profiles of children with genetic susceptibility to type 1 diabetes.

AIMS/HYPOTHESIS: Enterovirus infections have been associated with the development of type 1 diabetes in multiple studies, but little is known about enterovirus-induced responses in children at risk for developing type 1 diabetes. Our aim was to use genome-wide transcriptomics data to characterise enterovirus-associated changes in whole-blood samples from children with genetic susceptibility to type 1 diabetes. METHODS: Longitudinal whole-blood samples (356 samples in total) collected from 28 pairs of children at increased risk for developing type 1 diabetes were screened for the presence of enterovirus RNA. Seven of these samples were detected as enterovirus-positive, each of them collected from a different child, and transcriptomics data from these children were analysed to understand the individual-level responses associated with enterovirus infections. Transcript clusters with peaking or dropping expression at the time of enterovirus positivity were selected as the enterovirus-associated signals. RESULTS: Strong signs of activation of an interferon response were detected in four children at enterovirus positivity, while transcriptomic changes in the other three children indicated activation of adaptive immune responses. Additionally, a large proportion of the enterovirus-associated changes were specific to individuals. An enterovirus-induced signature was built using 339 genes peaking at enterovirus positivity in four of the children, and 77 of these genes were also upregulated in human peripheral blood mononuclear cells infected in vitro with different enteroviruses. These genes separated the four enterovirus-positive samples clearly from the remaining 352 blood samples analysed. CONCLUSIONS/INTERPRETATION: We have, for the first time, identified enterovirus-associated transcriptomic profiles in whole-blood samples from children with genetic susceptibility to type 1 diabetes. Our results provide a starting point for understanding the individual responses to enterovirus infections in blood and their potential connection to the development of type 1 diabetes. DATA AVAILABILITY: The datasets analysed during the current study are included in this published article and its supplementary information files ( www.btk.fi/research/computational-biomedicine/1234-2 ) or are available from the Gene Expression Omnibus (GEO) repository (accession GSE30211).

Patients with out-of-hospital cardiac arrest show decreased human leucocyte antigen-DR expression on monocytes and B and T lymphocytes after return of spontaneous circulation.

Immune disorders are an important feature of patients with out-of-hospital cardiac arrest (OHCA) after return of spontaneous circulation (ROSC). However, the precise immune alterations in patients with OHCA that occur immediately after ROSC are unclear. In this study, we investigated human leucocyte antigen-DR (HLA-DR) expression on circulatory monocytes and B and T lymphocytes. Sixty-eight consecutive patients with OHCA with ROSC >12 hours were enrolled. Clinical data and 28-day survival were recorded. Peripheral blood samples after ROSC days 1 and 3 were analysed to evaluate HLA-DR expression. Fifty healthy individuals were enrolled as controls. Compared with levels in healthy individuals, HLA-DR expression on monocytes and B lymphocytes, but not on T lymphocytes, decreased on days 1 and 3 after ROSC. No significant difference in HLA-DR expression was detected between survivors and non-survivors on day 1. For 41 patients with expression data for days 1 and 3, HLA-DR expression on monocytes and B lymphocytes in non-survivors was lower than that in survivors on day 3. In non-survivors, the mean fluorescence intensities of HLA-DR on B lymphocytes and percentages of HLA-DR+ T lymphocytes were lower on day 3 than on day 1. On days 1 and 3, there were significant correlations between HLA-DR expression on monocytes and B lymphocytes and clinical indicators, such as time to ROSC, adrenaline dose, acute physiology, chronic health evaluation II and the sequential organ failure assessment. The decreases in HLA-DR expression on circulatory monocytes and B and T lymphocytes after ROSC may be involved in the observed immunosuppression in patients with OHCA.

Individual serum bile acid profiling in rats aids in human risk assessment of drug-induced liver injury due to BSEP inhibition.

Drug-induced liver injury (DILI) has been the most frequent cause of post-marketing drug withdrawals in the last 50years. The multifactorial nature of events that precede severe liver injury in human patients is difficult to model in rodents due to a variety of confounding or contributing factors that include disease state, concurrent medications, and translational species differences. In retrospective analyses, a consistent risk factor for DILI has been the inhibition of the Bile Salt Export Pump (BSEP). One compound known for potent BSEP inhibition and severe DILI is troglitazone. The purpose of the current study is to determine if serum profiling of 19 individual bile acids by liquid chromatography-mass spectrometry (LC/MS) can detect perturbations in bile acid homeostasis in rats after acute intravenous (IV) administration of vehicle or 5, 25, or 50mg/kg troglitazone. Minimal serum transaminase elevations (approximately two-fold) were observed with no evidence of microscopic liver injury. However, marked changes in individual serum bile acids occurred, with dose-dependent increases in the majority of the bile acids profiled. When compared to predose baseline values, tauromuricholic acid and taurocholic acid had the most robust increase in serum levels and dynamic range, with a maximum fold increase from baseline of 34-fold and 29-fold, respectively. Peak bile acid increases occurred within 2hours (h) after dosing and returned to baseline values before 24h. In conclusion, serum bile acid profiling can potentially identify a mechanistic risk of clinical DILI that could be poorly detected by traditional toxicity endpoints.

Connectivity strength-weighted sparse group representation-based brain network construction for MCI classification.

Brain functional network analysis has shown great potential in understanding brain functions and also in identifying biomarkers for brain diseases, such as Alzheimer's disease (AD) and its early stage, mild cognitive impairment (MCI). In these applications, accurate construction of biologically meaningful brain network is critical. Sparse learning has been widely used for brain network construction; however, its l1 -norm penalty simply penalizes each edge of a brain network equally, without considering the original connectivity strength which is one of the most important inherent linkwise characters. Besides, based on the similarity of the linkwise connectivity, brain network shows prominent group structure (i.e., a set of edges sharing similar attributes). In this article, we propose a novel brain functional network modeling framework with a "connectivity strength-weighted sparse group constraint." In particular, the network modeling can be optimized by considering both raw connectivity strength and its group structure, without losing the merit of sparsity. Our proposed method is applied to MCI classification, a challenging task for early AD diagnosis. Experimental results based on the resting-state functional MRI, from 50 MCI patients and 49 healthy controls, show that our proposed method is more effective (i.e., achieving a significantly higher classification accuracy, 84.8%) than other competing methods (e.g., sparse representation, accuracy = 65.6%). Post hoc inspection of the informative features further shows more biologically meaningful brain functional connectivities obtained by our proposed method. Hum Brain Mapp 38:2370-2383, 2017. © 2017 Wiley Periodicals, Inc.

From a novel HTS hit to potent, selective, and orally bioavailable KDM5 inhibitors.

A high-throughput screening (HTS) of the Genentech/Roche library identified a novel, uncharged scaffold as a KDM5A inhibitor. Lacking insight into the binding mode, initial attempts to improve inhibitor potency failed to improve potency, and synthesis of analogs was further hampered by the presence of a C-C bond between the pyrrolidine and pyridine. Replacing this with a C-N bond significantly simplified synthesis, yielding pyrazole analog 35, of which we obtained a co-crystal structure with KDM5A. Using structure-based design approach, we identified 50 with improved biochemical, cell potency and reduced MW and lower lipophilicity (LogD) compared with the original hit. Furthermore, 50 showed lower clearance than 9 in mice. In combination with its remarkably low plasma protein binding (PPB) in mice (40%), oral dosing of 50 at 5mg/kg resulted in unbound Cmax ∼2-fold of its cell potency (PC9 H3K4Me3 0.96µM), meeting our criteria for an in vivo tool compound from a new scaffold.

Efficacy of vasopressin-epinephrine compared to epinephrine alone for out of hospital cardiac arrest patients: A systematic review and meta-analysis.

OBJECTIVE: The aim of this study was to conduct a meta-analysis to evaluate the efficacy of vasopressin-epinephrine compared to epinephrine alone in patients who suffered out-of-hospital cardiac arrest (OHCA). METHODS: Relevant studies up to February 2017 were identified by searching in PubMed, EMBASE, the Cochrane Library, Wanfang for randomized controlled trials(RCTs) assigning adults with cardiac arrest to treatment with vasopressin-epinephrine (VEgroup) vs adrenaline (epinephrine) alone (E group). The outcome point was return of spontaneous circulation (ROSC) for patients suffering from OHCA. Heterogeneity, subgroup analysis, sensitivity analysis and publication bias were explored. RESULTS: Individual patient data were obtained from 5047 participants who experienced OHCA in nine studies. Odds ratios (ORs) were calculated using a random-effects model and results suggested that vasopressin-epinephrine was associated with higher rate of ROSC (OR=1.67, 95% CI=1.13-2.49, P<0.00001, and total I2=83%). Subgroup showed that vasopressin-epinephrine has a significant association with improvements in ROSC for patients from Asia (OR=3.30, 95% CI=1.30-7.88); but for patients from other regions, there was no difference between vasopressin-epinephrine and epinephrine alone (OR=1.07, 95% CI=0.72-1.61). CONCLUSION: According to the pooled results of the subgroup, combination of vasopressin and adrenaline can improve ROSC of OHCA from Asia, but patients from other regions who suffered from OHCA cannot benefit from combination of vasopressin and epinephrine.

Deep Auto-context Convolutional Neural Networks for Standard-Dose PET Image Estimation from Low-Dose PET/MRI.

Positron emission tomography (PET) is an essential technique in many clinical applications such as tumor detection and brain disorder diagnosis. In order to obtain high-quality PET images, a standard-dose radioactive tracer is needed, which inevitably causes the risk of radiation exposure damage. For reducing the patient's exposure to radiation and maintaining the high quality of PET images, in this paper, we propose a deep learning architecture to estimate the high-quality standard-dose PET (SPET) image from the combination of the low-quality low-dose PET (LPET) image and the accompanying T1-weighted acquisition from magnetic resonance imaging (MRI). Specifically, we adapt the convolutional neural network (CNN) to account for the two channel inputs of LPET and T1, and directly learn the end-to-end mapping between the inputs and the SPET output. Then, we integrate multiple CNN modules following the auto-context strategy, such that the tentatively estimated SPET of an early CNN can be iteratively refined by subsequent CNNs. Validations on real human brain PET/MRI data show that our proposed method can provide competitive estimation quality of the PET images, compared to the state-of-the-art methods. Meanwhile, our method is highly efficient to test on a new subject, e.g., spending ~2 seconds for estimating an entire SPET image in contrast to ~16 minutes by the state-of-the-art method. The results above demonstrate the potential of our method in real clinical applications.