[Application of quality function deployment technology in extracorporeal membrane oxygenation treatment of patients with critical cardiopulmonary disease].

OBJECTIVE: To accurately and effectively identify the most critical needs of extracorporeal membrane oxygenation (ECMO) treatment for patients with severe cardiopulmonary diseases, and to better carry out continuous improvement of medical service quality an patients' satisfaction. METHODS: Patients who underwent ECMO and transferred from 56 medical institutions in the Henan Provincial People's Hospital Critical Care Medicine Specialist Alliance [the patients who were transported before applying quality function deployment (QFD) from June 2017 to May 2018 were enrolled as the control group, and patients who were transported after applying QFD from June 2018 to May 2019 were the observation group], medical staff in the alliance hospitals, ECMO transfer teams and transfer driver teams were enrolled as the subjects of the survey. QFD was applied to convert the collected requirements into quality improvement elements for targeted improvement measures. RESULTS: A total of 125 questionnaires were distributed in this survey, and 116 valid questionnaires were collected, including 91 from patients (including 27 from the control group and 64 from the observation group), 10 from the medical staff of the alliance hospitals, 10 from the ECMO transport teams and 5 from the transport driver teams. The questionnaire recovery rate was 92.8%. The improvement elements of ECMO treatment for patients with critical cardiopulmonary diseases were ranked according to the importance, and the top five were as follows: the accuracy of the first diagnosis, the specialization of ECMO team, the guarantee of vehicle safety, the seamless responses, and the smooth coordinated rescue protocol. CONCLUSIONS: The top five improvement elements should be prioritized in ECMO treatment of patients with critical cardiopulmonary disease in all hospitals of the Alliance to ensure more accurate and timely treatment.

Collaborative calculation and application of interreal and real interval relations to protect privacy.

The determination of the relation between a number and a numerical interval is one of the core problems in the scientific calculation of privacy protection. The calculation of the relationship between two numbers and a numerical interval to protect privacy is also the basic problem of collaborative computing. It is widely used in data queries, location search and other fields. At present, most of the solutions are still fundamentally limited to the integer level, and there are few solutions at the real number level. To solve these problems, this paper first uses Bernoulli inequality generalization and a monotonic function property to extend the solution to the real number level and designs two new protocols based on the homomorphic encryption scheme, which can not only protect the data privacy of both parties involved in the calculation, but also extend the number domain to real numbers. In addition, this paper designs a solution to the confidential cooperative determination problem between real numbers by using the sign function and homomorphism multiplication. Theoretical analysis shows that the proposed solution is safe and efficient. Finally, some extension applications based on this protocol are given.

Comparing the Clinical Outcome of Peri-implant Hard and Soft Tissue Treated with Immediate Individualized CAD/CAM Healing Abutments and Conventional Healing Abutments for Single-Tooth Implants in Esthetic Areas Over 12 Months: A Randomized Clinical Trial.

PURPOSE: The purpose of this study was to compare the clinical influence of immediate individualized CAD/CAM healing abutments and conventional healing abutments on peri-implant soft and hard tissue in shaping the emergence profile. MATERIALS AND METHODS: Patients with a single maxillary incisor missing who accepted dental implantation were registered in this study. After implantation, individualized CAD/CAM healing abutments and regular prefabricated abutments were randomly inserted to shape the emergence profile. A radiograph was taken, and the pink esthetic score, papilla height, papilla proportion, and probing depth were recorded at 6 months after implant placement (T1), loading (T2, definitive restoration), and 1 year after loading (T3). Patient self-assessment scores were also evaluated through the visual analog scale. The data were analyzed statistically using the t test or repeated-measurements analysis of variance (ANOVA). RESULTS: Twenty patients were enrolled in this study, including 9 patients using individualized abutments and 11 patients using conventional abutments. The mean total marginal bone level in the individualized abutment group was 1.53 ± 0.65 mm at implant placement, 1.10 ± 0.47 mm at loading, and 0.76 ± 0.47 mm at 1 year after loading. In contrast, the mean total marginal bone level in the conventional abutment group was 0.62 ± 0.39 mm at implant placement, 0.14 ± 0.55 mm at loading, and -0.04 ± 0.53 mm at 1 year after loading. The differences between the individualized abutment group and conventional abutment group were statistically significant for the mesial and distal marginal bone level at three time points, respectively (P ≤ .05). Similarly, there were significant differences in probing depth, papilla height, and pink esthetic score between the two groups. CONCLUSION: This immediately individualized healing abutment protocol may significantly preserve the peri-implant marginal bone and soft tissue. The use of individualized CAD/CAM healing abutments for shaping the emergence profile shows better esthetic outcomes than conventional healing abutments.

Association between WNT-1-inducible signaling pathway protein-1 (WISP1) genetic polymorphisms and the risk of gastric cancer in Guangxi Chinese.

BACKGROUND: WNT1-inducible signaling pathway protein 1 (WISP1) is a member of the CCN protein family and a downstream target of ß-catenin. Aberrant WISP1 expression may be involved in carcinogenesis. To date, no studies have investigated the association between single-nucleotide polymorphisms (SNPs) of WISP1 and gastric cancer. Therefore, we conducted this study to explore their relationship. METHODS: Polymerase chain reaction-restriction fragment length polymorphism assay was used to analyze three SNPs of WISP1 in 204 gastric cancer patients and 227 controls. RESULTS: Overall, we could not identify a significant association between WISP1 SNPs and gastric cancer risk. However, the subgroup analysis demonstrated that the presence of the rs7843546 T allele was associated with a significantly decreased risk of gastric cancer in those of Han Chinese ethnicity (CT vs. CC: OR = 0.33, 95%CI 0.14-0.78; TT vs. CC: OR = 0.29, 95%CI 0.11-0.76; CT + TT vs. CC: OR = 0.32, 95%CI 0.14-0.74). In addition, patients with the rs7843546 TT genotype display a 0.34-fold lower risk of developing stage I/II gastric cancer than those with the CC genotype Furthermore, individuals ≥ 50 years old who carried the rs10956697 AC genotype had a significantly decreased risk of gastric cancer (OR = 0.58, 95%CI 0.35-0.98). Smokers with the rs10956697 AC and AC + AA genotypes exhibited a 0.28-fold lower and 0.32-fold lower risk of gastric cancer, respectively. CONCLUSIONS: The WISP1 SNPs rs7843546 and rs10956697 were, for the first time, found to reduce susceptibility to gastric cancer in various subgroups of Guangxi Chinese.

A digital approach for 1-step formation of the supraimplant emergence profile at the time of immediate implant placement.

An optimal soft tissue profile is essential for obtaining optimal esthetics in anterior implant-supported restorations. Commercially available cylindrical healing abutments do not mimic the shape of natural teeth and may create a poor peri-implant emergence. This article introduces a digital protocol to improve the formation of the supraimplant emergence profile with an individualized healing abutment fabricated by computer-aided design and computer-aided manufacture (CAD-CAM) at the time of implant placement. A benefit of this technique is obtaining optimal morphology of the peri-implant soft tissues, especially for teeth with increased horizontal overlap.

Improving Academic Performance Using an Innovative Cranial-Nerve Table.

To facilitate the review and retention of the complicated contents of the Head Block in the Dental Gross Anatomy course, an innovative cranial-nerve table was introduced to first-year dental students using an interactive self-retrieval format. Our analysis of exam data shows the efficacy of this learning tool.

Bayesian additive decision trees of biomarker by treatment interactions for predictive biomarker detection and subgroup identification.

Personalized medicine, or tailored therapy, has been an active and important topic in recent medical research. Many methods have been proposed in the literature for predictive biomarker detection and subgroup identification. In this article, we propose a novel decision tree-based approach applicable in randomized clinical trials. We model the prognostic effects of the biomarkers using additive regression trees and the biomarker-by-treatment effect using a single regression tree. Bayesian approach is utilized to periodically revise the split variables and the split rules of the decision trees, which provides a better overall fitting. Gibbs sampler is implemented in the MCMC procedure, which updates the prognostic trees and the interaction tree separately. We use the posterior distribution of the interaction tree to construct the predictive scores of the biomarkers and to identify the subgroup where the treatment is superior to the control. Numerical simulations show that our proposed method performs well under various settings comparing to existing methods. We also demonstrate an application of our method in a real clinical trial.

Quantitative reproducibility analysis for identifying reproducible targets from high-throughput experiments.

BACKGROUND: High-throughput assays are widely used in biological research to select potential targets. One single high-throughput experiment can efficiently study a large number of candidates simultaneously, but is subject to substantial variability. Therefore it is scientifically important to performance quantitative reproducibility analysis to identify reproducible targets with consistent and significant signals across replicate experiments. A few methods exist, but all have limitations. METHODS: In this paper, we propose a new method for identifying reproducible targets. Considering a Bayesian hierarchical model, we show that the test statistics from replicate experiments follow a mixture of multivariate Gaussian distributions, with the one component with zero-mean representing the irreproducible targets. RESULTS: A target is thus classified as reproducible or irreproducible based on its posterior probability belonging to the reproducible components. We study the performance of our proposed method using simulations and a real data example. CONCLUSION: The proposed method is shown to have favorable performance in identifying reproducible targets compared to other methods.

[Effect of Fuxin Mixture on The 01-AR-cAMP-PKA Pathway of Rats with Heart Failure].

Objective To observe the effect of Fuxin Mixture(FXM) on the ß,-AR(adrenergic receptor) -cAMP(cyclic adenosine monophosphate, cAMP) -PKA ( protein kinase A, PKA) pathway of rats with heart failure. Methods Male Wistar rats were randomly divided into blank control group, captopril group, FXM low dose group, FXM high dose group and model group.Models of CHF were established. After drug intervention for 6 weeks, the left ventricular mass index (LVMI) was analysed, the expression of ß1 - AR mRNA in myocardial tissue was measured,the level of cAMP in rat plasma,the OD value PKA content of spleen tissue homogenate were detected. Results Compared with the blank control group, the LVMI and the cAMP in plasma of model group were increased (P <0. 05), the expression of ß1,-AR mRNA, the OD value of spleen tissue homogenate and PKA were decreased (P <0. 01). Compared with the model group, the LVMI were decreased,and the expression of ß1-AR mRNA were increased in FXM high dose group and captopril group (P <0. 01 , P <0. 05) ; the level of cAMP in plasma of each drug group were decreased (P <0. 01) , the OD value of spleen tissue homogenate and PKA were increased (P <0. 01). Compared with the captopril group, the expression of ß1-AR mRNA, the OD value of spleen tissue homogenate and PKA were decreased, and the LVMI and the cAMP were increased in the FXM low dose group (P <0. 01 , P <0. 05). Compared with the FXM low dose group, the LVMI and the cAMP of FXM high dose group were decreased (P <0. 05), the expression of ß1-AR mRNA, the OD value of spleen tissue homogenate and PKA were increased (P <0. 01). Conclusion FXM could play the role of anti-heart fail- ure through regulating P1-AR-cAMP-PKA pathway.

The influence of a polymorphism in the gene encoding angiotensin converting enzyme (ACE) on treatment outcomes in late-onset Pompe patients receiving alglucosidase alfa.

Correlations between angiotensin-converting enzyme (ACE) genotype (I/I, I/D, D/D), disease severity at baseline and response to enzyme replacement therapy (ERT) were assessed in the Pompe disease Late-Onset Treatment Study (LOTS). No correlations were observed between ACE genotype and disease severity at baseline. However, D/D patients appeared to have a reduced response to alglucosidase alfa treatment than I/I or I/D patients, suggesting that ACE polymorphisms may influence the response to alglucosidase alfa treatment and warrants further investigation.

Differences in the timing and magnitude of Pkd1 gene deletion determine the severity of polycystic kidney disease in an orthologous mouse model of ADPKD.

Development of a disease-modifying therapy to treat autosomal dominant polycystic kidney disease (ADPKD) requires well-characterized preclinical models that accurately reflect the pathology and biochemical changes associated with the disease. Using a Pkd1 conditional knockout mouse, we demonstrate that subtly altering the timing and extent of Pkd1 deletion can have a significant impact on the origin and severity of kidney cyst formation. Pkd1 deletion on postnatal day 1 or 2 results in cysts arising from both the cortical and medullary regions, whereas deletion on postnatal days 3-8 results in primarily medullary cyst formation. Altering the extent of Pkd1 deletion by modulating the tamoxifen dose produces dose-dependent changes in the severity, but not origin, of cystogenesis. Limited Pkd1 deletion produces progressive kidney cystogenesis, accompanied by interstitial fibrosis and loss of kidney function. Cyst growth occurs in two phases: an early, rapid growth phase, followed by a later, slow growth period. Analysis of biochemical pathway changes in cystic kidneys reveals dysregulation of the cell cycle, increased proliferation and apoptosis, activation of Mek-Erk, Akt-mTOR, and Wnt-ß-catenin signaling pathways, and altered glycosphingolipid metabolism that resemble the biochemical changes occurring in human ADPKD kidneys. These pathways are normally active in neonatal mouse kidneys until repressed around 3 weeks of age; however, they remain active following Pkd1 deletion. Together, this work describes the key parameters to accurately model the pathological and biochemical changes associated with ADPKD in a conditional mouse model.

A Bayesian three-parameter logistic model for early- and late-onset DLTs in oncology Phase I studies.

We introduce a three-parameter logistic model to analyze the dose limiting toxicity (DLT) as a time-to-event endpoint in oncology Phase I trials. In the proposed model, patients are allowed to stay on trial without the constraint of a maximum follow-up time. Our model accommodates late-onset DLT as well as early-onset DLT, by both of which the dose recommendation is informed. A Bayesian approach is used to incorporate prior knowledge of the test treatment into dose recommendation. Simulation examples show that our proposed model has good operating characteristics in assessing the maximum tolerated dose (MTD).

Enhancing targeted tumor treatment by near IR light-activatable photodynamic-photothermal synergistic therapy.

For several decades, cancer has been one of the most life-threatening diseases. For enhancing anticancer efficiency with minimum side effects, combination therapy is envisioned. The current manuscript reports for the first time the development of a methylene blue (MB) bound nanoplatform, which is capable of delivering targeted diagnostic and combined synergistic photothermal and photodynamic treatment of cancer. Experimental data found that, once the nanoparticle binds with the target cell surface, it can detect LNCaP human prostate cancer cell selectively using fluorescence imaging. Our result shows that the therapeutic actions can be controlled with external NIR light. No cytotoxicity was observed in the absence of NIR light. Targeted photodynamic and photothermal treatment using 785 nm NIR light indicates that the multimodal treatment enhances the possibility of destroying LNCaP prostate cancer cells in vitro dramatically. We discuss the operating principle for the targeted imaging and possible mechanisms for combined therapeutic actions. Our experimental data show that NIR light activated combined therapy for cancer may become a highly effective treatment procedure in clinical settings.

Epigenetic reprogramming in Mist1(-/-) mice predicts the molecular response to cerulein-induced pancreatitis.

Gene expression is affected by modifications to histone core proteins within chromatin. Changes in these modifications, or epigenetic reprogramming, can dictate cell fate and promote susceptibility to disease. The goal of this study was to determine the extent of epigenetic reprogramming in response to chronic stress that occurs following ablation of MIST1 (Mist1(-/-) ), which is repressed in pancreatic disease. Chromatin immunoprecipitation for trimethylation of lysine residue 4 on histone 3 (H3K4Me3) in purified acinar cells from wild type and Mist1(-/-) mice was followed by Next Generation sequencing (ChIP-seq) or ChIP-qPCR. H3K4Me3-enriched genes were assessed for expression by qRT-PCR in pancreatic tissue before and after induction of cerulein-induced pancreatitis. While most of H3K4Me3-enrichment is restricted to transcriptional start sites, >25% of enrichment sites are found within, downstream or between annotated genes. Less than 10% of these sites were altered in Mist1(-/-) acini, with most changes in H3K4Me3 enrichment not reflecting altered gene expression. Ingenuity Pathway Analysis of genes differentially-enriched for H3K4Me3 revealed an association with pancreatitis and pancreatic ductal adenocarcinoma in Mist1(-/-) tissue. Most of these genes were not differentially expressed but several were readily induced by acute experimental pancreatitis, with significantly increased expression in Mist1(-/-) tissue relative to wild type mice. We suggest that the chronic cell stress observed in the absence of MIST1 results in epigenetic reprogramming of genes involved in promoting pancreatitis to a poised state, thereby increasing the sensitivity to events that promote disease.

Multifunctional nanoplatforms for targeted multidrug-resistant-bacteria theranostic applications.

The emergence of multidrug-resistant-bacteria (MDRB) infection poses a major burden to modern healthcare. Early detection in the bloodstream and a new strategy development for MDRB infection treatment without antibiotics are clinically significant to save millions of lives every year. To tackle the MDRB challenge, the current manuscript reports the design of "multifunctional nanoplatforms" consisting of a magnetic core-plasmonic shell nanoparticle, a methylene blue-bound aptamer, and an MDRB Salmonella DT104 specific antibody. The reported "multifunctional nanoplatform" is capable of targeted separation from a blood sample and sensing and multimodal therapeutic killing of MDRB. Experimental data using an MDRB-infected whole-blood sample show that nanoplatforms can be used for selective magnetic separation and fluorescence imaging. In vitro light-triggered photodestruction of MDRB, using combined photodynamic and photothermal treatment, shows that the multimodal treatment regime can enhance MDRB killing significantly. We discussed the possible mechanisms on combined synergistic therapy for killing MDRB. The "multifunctional nanoplatform" reported in this manuscript has great potential for the imaging and combined therapy of MDRB in clinical settings.

Multipronged approach to managing beta-glucan contaminants in the downstream process: control of raw materials and filtration with charge-modified nylon 6,6 membrane filters.

(1→3)-ß-D-Glucans (beta-glucans) have been found in raw materials used in the manufacture of recombinant therapeutics. Because of their biological activity, beta-glucans are considered process contaminants and consequently their level in the product needs to be controlled. Although beta-glucans introduced into the cell culture process can readily be removed by bind-and-elute chromatography process steps, beta-glucans can also be introduced into the purification process through raw materials containing beta-glucans as well as leachables from filters made from cellulose. This article reports a multipronged approach to managing the beta-glucan contamination in the downstream process. Raw material screening and selection can be used to effectively limit the level of beta-glucan introduced into the downstream process. Placement of a cellulosic filter upstream of the last bind-and-elute column step or effective preuse flushing can also limit the level of contaminant introduced. More importantly, this article reports the active removal of beta-glucan from the downstream process when necessary. It was discovered that the Posidyne(®) filter, a charge-modified nylon 6,6 membrane filter, was able to effectively remove beta-glucans from buffers at relatively low pH and salt concentrations. An approach of using low beta-glucan buffer components combined with filtration of the buffer with a Posidyne membrane has been successfully demonstrated at preparative scale. Additionally, the feasibility of active removal of beta-glucan from in-process product pools by Posidyne membrane filtration has also been demonstrated. Based on the data presented, a mechanism for binding is proposed, as well as a systematic approach for sizing of the Posidyne filter.

Evaluation of effects of Fc domain high-mannose glycan on antibody stability.

Elevated levels of CH2 domain N-linked high-mannose (HM) glycans are commonly observed in therapeutic monoclonal antibodies at various stages of the development. The effect of HM glycans on antibody stability was evaluated by using two approaches. In the first approach, immunoglobulin G (IgG) 1 material containing 21% HM was incubated at 29°C for 6 weeks and fractionated into monomeric and aggregate species by using size-exclusion chromatography (SEC). These fractions were analyzed for the levels of HM. No significant difference was observed in the amount of HM in aggregate and monomer fractions indicating that the HM-containing fractions did not have a greater tendency to form aggregates. In the second approach, both IgG1 material and IgG2 material were separated by Concanavalin-A affinity chromatography into a HM-enriched fraction and a HM-depleted fraction, respectively. Real-time and accelerated stability studies were carried out with these fractions together with untreated samples under standard formulation conditions. The stability of these fractions over time was monitored using SEC and cation-exchange chromatography. No significant difference was observed in rates of aggregation or charge variant formation. These data indicate that HM glycans had no effect on the IgG1 and IgG2 product's stability under the formulation conditions studied.

Differential distribution patterns from medial prefrontal cortex and dorsal raphe to the locus coeruleus in rats.

Locus coeruleus (LC) consists of a densely packed nuclear core and a surrounding plexus of dendritic zone, which is further divided into several subregions. Whereas many limbic-related structures topographically target specific subregions of the LC, the precise projections from two limbic areas, that is, medial prefrontal cortex (mPFC) and dorsal raphe (DR), have not been investigated. The goal of the present study is to identify and compare the distribution patterns of mPFC and DR afferent terminals to the LC nuclear core as opposed to specific pericoerulear dendritic regions (Peri-LC). To address these issues, anterograde tracer injections were combined with dopamine-ß-hydroxylase (DBH) immunofluorescent staining to reveal the distribution patterns around the LC nuclear complex. Our data suggest that both mPFC-LC and DR-LC projections exhibit selective afferent terminal patterns. More specifically, mPFC-LC projecting fibers mainly target the rostromedial Peri-LC, whereas DR-LC projecting fibers demonstrate a preference to the caudal juxtaependymal Peri-LC. Thus, our present findings provide further evidences that afferents to the LC are topographically organized. Understanding the relationship among different inputs to the LC may help to elucidate the organizing principle which likely governs the interactions between the broad afferent sources of the LC and its global efferent targets.

Risk-benefit evaluation of on-line high-performance liquid chromatography analysis for pooling decisions in large-scale chromatography.

In the production of a human therapeutic protein from inclusion bodies, product related impurities of very similar size and charge to the product are created as byproducts of the refold process. Their removal is usually challenging even when using chromatography with high performance resins and elution by shallow linear gradients. Additionally, performing this type of separation for commercial production adds increased complexity. To maximize productivity, columns are loaded so high that product elution profiles are not well separated from the impurities and pooling decisions are challenging. In this paper, conventional UV pooling based on fractionation or predefined absorbance based criteria will be compared to pooling based on fast on-line HPLC analytic. The development and implementation in a GMP process will be shown for a specific challenging separation by hydrophobic interaction chromatography. The different approaches have their unique complexities, timelines, uncertainties, and risks during development and implementation as well as during manufacturing. This study presents a probabilistic framework for quantitative comparison of two processes with unequal variability and uncertainty to evaluate the potential benefits of a PAT technology for its routine use in GMP Bioprocess manufacturing.

Coexpression of serotonin and nitric oxide in the raphe complex: cortical versus subcortical circuit.

Several lines of evidence have implicated a direct reciprocal interaction between serotonin and nitric oxide (NO). The goal of this investigation was, therefore, to examine the coexpression of tryptophan hydroxylase (TPH; the rate limiting enzyme for the synthesis of serotonin) and neuronal NO synthase (nNOS) in the ascending cortical projecting raphe nuclei (B6-B9 subgroups), when compared with the descending spinal cord projecting raphe nuclei (B1-B3 subgroups). Our data demonstrated that: (1) a significant number of raphe-cortical projecting neurons was identified not only in the midline subgroup of dorsal raphe (B6, 7) but also in the median raphe (B8), as well as in the supralemniscal nucleus (B9); (2) serotonergic cortical projecting neurons from these three raphe nuclei exhibited a high (>80%) percentage of coexpression with nNOS immunoreactivity; (3) similarly, serotonin transporter immunoreactive fibers in the medial prefrontal cortex were also double-labeled with nNOS immunoreactivity; (4) in contrast, the descending spinal cord projecting raphe nuclei revealed only TPH but not nNOS immunoreactivity. Our present findings suggest the existence of a direct interaction between serotonin and NO in the ascending cortical projecting raphe system. In contrast, a different strategy appears to operate the descending spinal cord projecting raphe system.