Reducing Carbapenem-Resistant Enterobacteriaceae Using the Targeted Solution Tool: A Quality Improvement Project.

BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) is a worldwide urgent health problem. Hand hygiene (HH) is an effective intervention to reduce the spread of CRE. LOCAL PROBLEM: In 2017, an increase in the rate of health care-associated (HA) CRE colonization was observed in a large multiorgan transplant center in Italy. This study aimed to reduce the HA-CRE colonization rates by improving HH compliance. METHODS: A pre-/post-intervention project was conducted from November 2017 through December 2020. INTERVENTIONS: The DMAIC (Define, Measure, Analyze, Improve, and Control) framework was used to implement the HH Targeted Solution Tool (TST). RESULTS: Hand hygiene compliance increased from 49% to 76.9% after the Improve phase ( P = .0001), and to 81.9% after the second Control phase ( P = .0001). The rate of HA-CRE decreased from 24.9% to 5.6% ( P = .0001). CONCLUSIONS: Using the DMAIC framework to implement the TST can result in significant improvements in HH compliance and HA-CRE colonization rates.

Joint Data Analysis in Nutritional Epidemiology: Identification of Observational Studies and Minimal Requirements.

Background: Joint data analysis from multiple nutrition studies may improve the ability to answer complex questions regarding the role of nutritional status and diet in health and disease. Objective: The objective was to identify nutritional observational studies from partners participating in the European Nutritional Phenotype Assessment and Data Sharing Initiative (ENPADASI) Consortium, as well as minimal requirements for joint data analysis. Methods: A predefined template containing information on study design, exposure measurements (dietary intake, alcohol and tobacco consumption, physical activity, sedentary behavior, anthropometric measures, and sociodemographic and health status), main health-related outcomes, and laboratory measurements (traditional and omics biomarkers) was developed and circulated to those European research groups participating in the ENPADASI under the strategic research area of "diet-related chronic diseases." Information about raw data disposition and metadata sharing was requested. A set of minimal requirements was abstracted from the gathered information. Results: Studies (12 cohort, 12 cross-sectional, and 2 case-control) were identified. Two studies recruited children only and the rest recruited adults. All studies included dietary intake data. Twenty studies collected blood samples. Data on traditional biomarkers were available for 20 studies, of which 17 measured lipoproteins, glucose, and insulin and 13 measured inflammatory biomarkers. Metabolomics, proteomics, and genomics or transcriptomics data were available in 5, 3, and 12 studies, respectively. Although the study authors were willing to share metadata, most refused, were hesitant, or had legal or ethical issues related to sharing raw data. Forty-one descriptors of minimal requirements for the study data were identified to facilitate data integration. Conclusions: Combining study data sets will enable sufficiently powered, refined investigations to increase the knowledge and understanding of the relation between food, nutrition, and human health. Furthermore, the minimal requirements for study data may encourage more efficient secondary usage of existing data and provide sufficient information for researchers to draft future multicenter research proposals in nutrition.

Strengths and limitations of non-disclosive data analysis: a comparison of breast cancer survival classifiers using VisualSHIELD.

Preserving data privacy is an important concern in the research use of patient data. The DataSHIELD suite enables privacy-aware advanced statistical analysis in a federated setting. Despite its many applications, it has a few open practical issues: the complexity of hosting a federated infrastructure, the performance penalty imposed by the privacy-preserving constraints, and the ease of use by non-technical users. In this work, we describe a case study in which we review different breast cancer classifiers and report our findings about the limits and advantages of such non-disclosive suite of tools in a realistic setting. Five independent gene expression datasets of breast cancer survival were downloaded from Gene Expression Omnibus (GEO) and pooled together through the federated infrastructure. Three previously published and two newly proposed 5-year cancer-free survival risk score classifiers were trained in a federated environment, and an additional reference classifier was trained with unconstrained data access. The performance of these six classifiers was systematically evaluated, and the results show that i) the published classifiers do not generalize well when applied to patient cohorts that differ from those used to develop them; ii) among the methods we tried, the classification using logistic regression worked better on average, closely followed by random forest; iii) the unconstrained version of the logistic regression classifier outperformed the federated version by 4% on average. Reproducibility of our experiments is ensured through the use of VisualSHIELD, an open-source tool that augments DataSHIELD with new functions, a standardized deployment procedure, and a simple graphical user interface.

Impact of the Organizational Model Adopted during the COVID-19 Pandemic on the Perceived Safety of Intensive Care Unit Staff.

BACKGROUND: The SARS-CoV-2 pandemic had a devastating health, social, and economic effect on the population. Organizational, technical and structural operations aimed at protecting staff, outpatients and inpatients were implemented in an Italian hospital with a COVID-19 dedicated intensive care unit. The impact of the organizational model adopted on the perceived safety among staff was evaluated. METHODS: Descriptive, structured and voluntary, anonymous, non-funded, self-administered cross-sectional surveys on the impact of the organizational model adopted during COVID-19 on the perceived safety among staff. RESULTS: Response rate to the survey was 67.4% (153 completed surveys). A total of 91 (59%) of respondents had more than three years of ICU experience, while 16 (10%) were employed for less than one year. Group stratification according to profession: 74 nurses (48%); 12 medical-doctors (7%); 11 physiotherapists (7%); 35 nurses-aides (22%); 5 radiology-technicians (3%); 3 housekeeping (1%); 13 other (8%). The organizational model implemented at ISMETT made them feel safe during their workday. A total of 113 (84%) agreed or strongly agreed with the sense of security resulting from the implemented measures. A vast majority of respondents perceived COVID-19 as a dangerous and deadly disease (94%) not only for themselves but even more as vectors towards their families (79%). A total of 55% of staff took isolation measures and moved away from their home by changing personal habits. The organizational model was perceived overall as appropriate (91%) to guarantee their health. CONCLUSION: The vast majority of respondents perceived the overall model applied during an unexpected, emergency situation as appropriate.

Reconstruction of the Cytokine Signaling in Lysosomal Storage Diseases by Literature Mining and Network Analysis.

Lysosomal storage diseases (LSDs) are characterized by the abnormal accumulation of substrates in tissues due to the deficiency of lysosomal proteins. Among the numerous clinical manifestations, chronic inflammation has been consistently reported for several LSDs. However, the molecular mechanisms involved in the inflammatory response are still not completely understood. In this study, we performed text-mining and systems biology analyses to investigate the inflammatory signals in three LSDs characterized by sphingolipid accumulation: Gaucher disease, Acid Sphingomyelinase Deficiency (ASMD), and Fabry Disease. We first identified the cytokines linked to the LSDs, and then built on the extracted knowledge to investigate the inflammatory signals. We found numerous transcription factors that are putative regulators of cytokine expression in a cell-specific context, such as the signaling axes controlled by STAT2, JUN, and NR4A2 as candidate regulators of the monocyte Gaucher disease cytokine network. Overall, our results suggest the presence of a complex inflammatory signaling in LSDs involving many cellular and molecular players that could be further investigated as putative targets of anti-inflammatory therapies.

QSPcc reduces bottlenecks in computational model simulations.

Mathematical models have grown in size and complexity becoming often computationally intractable. In sensitivity analysis and optimization phases, critical for tuning, validation and qualification, these models may be run thousands of times. Scientific programming languages popular for prototyping, such as MATLAB and R, can be a bottleneck in terms of performance. Here we show a compiler-based approach, designed to be universal at handling engineering and life sciences modeling styles, that automatically translates models into fast C code. At first QSPcc is demonstrated to be crucial in enabling the research on otherwise intractable Quantitative Systems Pharmacology models, such as in rare Lysosomal Storage Disorders. To demonstrate the full value in seamlessly accelerating, or enabling, the R&D efforts in natural sciences, we then benchmark QSPcc against 8 solutions on 24 real-world projects from different scientific fields. With speed-ups of 22000x peak, and 1605x arithmetic mean, our results show consistent superior performances.

History and Future Perspectives on the Discipline of Quantitative Systems Pharmacology Modeling and Its Applications.

Mathematical biology and pharmacology models have a long and rich history in the fields of medicine and physiology, impacting our understanding of disease mechanisms and the development of novel therapeutics. With an increased focus on the pharmacology application of system models and the advances in data science spanning mechanistic and empirical approaches, there is a significant opportunity and promise to leverage these advancements to enhance the development and application of the systems pharmacology field. In this paper, we will review milestones in the evolution of mathematical biology and pharmacology models, highlight some of the gaps and challenges in developing and applying systems pharmacology models, and provide a vision for an integrated strategy that leverages advances in adjacent fields to overcome these challenges.

Is the sublay self-gripping mesh effective for incisional ventral hernia repair? Our experience and a systematic review of the literature.

Sublay mesh repair seems to be the most effective method for treating incisional hernias (IHs). The aim of this study was to report our experience with retromuscular repair and self-gripping mesh for the treatment of midline IHs. In addition, we provided a systematic review of the literature regarding the use of this novel combination. All patients undergoing elective IH repair from June 2016 to November 2018 were included. The self-gripping mesh was placed in the sublay position. Demographic data, defect sizes, postoperative complications and follow-up durations were collected. A systematic review of the available literature was conducted in January 2020 using main databases. A total of 37 patients (20/17M/F) were included in this study, and the mean age and body mass index (BMI) were 58 years and 27 kg/m2, respectively. Minor complications occurred in six patients. Long-term follow-up demonstrated recurrence in three patients. Regarding the review, five publications were considered relevant. The highest complication rate was 28.6%, and the recurrence rate varied from 0 to 5.1%. This is the first review of the literature regarding sublay IH repair using a self-gripping mesh. The low rates of postoperative complications and recurrence in our experience and those reported by most of the reviewed articles demonstrate that this is a safe and effective method for repairing IHs.

DNA methylation during human adipogenesis and the impact of fructose.

BACKGROUND: Increased adipogenesis and altered adipocyte function contribute to the development of obesity and associated comorbidities. Fructose modified adipocyte metabolism compared to glucose, but the regulatory mechanisms and consequences for obesity are unknown. Genome-wide methylation and global transcriptomics in SGBS pre-adipocytes exposed to 0, 2.5, 5, and 10 mM fructose, added to a 5-mM glucose-containing medium, were analyzed at 0, 24, 48, 96, 192, and 384 h following the induction of adipogenesis. RESULTS: Time-dependent changes in DNA methylation compared to baseline (0 h) occurred during the final maturation of adipocytes, between 192 and 384 h. Larger percentages (0.1% at 192 h, 3.2% at 384 h) of differentially methylated regions (DMRs) were found in adipocytes differentiated in the glucose-containing control media compared to adipocytes differentiated in fructose-supplemented media (0.0006% for 10 mM, 0.001% for 5 mM, and 0.005% for 2.5 mM at 384 h). A total of 1437 DMRs were identified in 5237 differentially expressed genes at 384 h post-induction in glucose-containing (5 mM) control media. The majority of them inversely correlated with the gene expression, but 666 regions were positively correlated to the gene expression. CONCLUSIONS: Our studies demonstrate that DNA methylation regulates or marks the transformation of morphologically differentiating adipocytes (seen at 192 h), to the more mature and metabolically robust adipocytes (as seen at 384 h) in a genome-wide manner. Lower (2.5 mM) concentrations of fructose have the most robust effects on methylation compared to higher concentrations (5 and 10 mM), suggesting that fructose may be playing a signaling/regulatory role at lower concentrations of fructose and as a substrate at higher concentrations.

Laparo-endoscopic "Rendezvous" to treat cholecysto-choledocolithiasis: Effective, safe and simplifies the endoscopist's work.

AIM: To investigate our clinical experience with combined laparo-endoscopic Rendezvous (RV) for the treatment of patients affected by gallstones and common bile duct (CBD) stones and especially to study the never evaluated opinion of the endoscopist concerning the difficulty of the intraoperative endoscopic procedure during the RV in comparison with standard endoscopic retrograde cholangio-pancreatography (ERCP). METHODS: Eighty consecutive patients affected by cholecystolithiasis and diagnosed or suspected CBD stones were treated with a standardized "tailored" RV. The relevant technical features, the feasibility, the effectiveness in stone clearance, the safety but also the simple evaluation of difficulty and agreement of the endoscopist were analyzed with a questionnaire. RESULTS: The feasibility was 97.5% and the effectiveness 100% concerning CBD clearance and solution of coexisting problems at the papilla. Minor morbidity was 3.3%, the operating time was prolonged by a mean of 14 min, the mean hospital stay was 3.8 d and only one stone's recurrence occurred. The endoscopist evaluated the procedure to be simpler than standard ERCP-ES in 81.2% of the cases. CONCLUSION: Simultaneous RV carries high effectiveness and safety at least comparable to those reported for other options. The endoscopist is very often satisfied with this approach because of the minimization of some steps of the endoscopic procedure and avoidance of relevant iatrogenic risk factors. If the mandatory collaboration between surgeons and endoscopists is guaranteed, this approach can often be preferable for the patient, the surgeon, the endoscopist and the hospital.

A reverse metabolic approach to weaning: in silico identification of immune-beneficial infant gut bacteria, mining their metabolism for prebiotic feeds and sourcing these feeds in the natural product space.

BACKGROUND: Weaning is a period of marked physiological change. The introduction of solid foods and the changes in milk consumption are accompanied by significant gastrointestinal, immune, developmental, and microbial adaptations. Defining a reduced number of infections as the desired health benefit for infants around weaning, we identified in silico (i.e., by advanced public domain mining) infant gut microbes as potential deliverers of this benefit. We then investigated the requirements of these bacteria for exogenous metabolites as potential prebiotic feeds that were subsequently searched for in the natural product space. RESULTS: Using public domain literature mining and an in silico reverse metabolic approach, we constructed probiotic-prebiotic-food associations, which can guide targeted feeding of immune health-beneficial microbes by weaning food; analyzed competition and synergy for (prebiotic) nutrients between selected microbes; and translated this information into designing an experimental complementary feed for infants enrolled in a pilot clinical trial ( http://www.nourishtoflourish.auckland.ac.nz/ ). CONCLUSIONS: In this study, we applied a benefit-oriented microbiome research strategy for enhanced early-life immune health. We extended from "classical" to molecular nutrition aiming to identify nutrients, bacteria, and mechanisms that point towards targeted feeding to improve immune health in infants around weaning. Here, we present the systems biology-based approach we used to inform us on the most promising prebiotic combinations known to support growth of beneficial gut bacteria ("probiotics") in the infant gut, thereby favorably promoting development of the immune system.

ONS: an ontology for a standardized description of interventions and observational studies in nutrition.

BACKGROUND: The multidisciplinary nature of nutrition research is one of its main strengths. At the same time, however, it presents a major obstacle to integrate data analysis, especially for the terminological and semantic interpretations that specific research fields or communities are used to. To date, a proper ontology to structure and formalize the concepts used for the description of nutritional studies is still lacking. RESULTS: We have developed the Ontology for Nutritional Studies (ONS) by harmonizing selected pre-existing de facto ontologies with novel health and nutritional terminology classifications. The ONS is the result of a scholarly consensus of 51 research centers in nine European countries. The ontology classes and relations are commonly encountered while conducting, storing, harmonizing, integrating, describing, and searching nutritional studies. The ONS facilitates the description and specification of complex nutritional studies as demonstrated with two application scenarios. CONCLUSIONS: The ONS is the first systematic effort to provide a solid and extensible formal ontology framework for nutritional studies. Integration of new information can be easily achieved by the addition of extra modules (i.e., nutrigenomics, metabolomics, nutrikinetics, and quality appraisal). The ONS provides a unified and standardized terminology for nutritional studies as a resource for nutrition researchers who might not necessarily be familiar with ontologies and standardization concepts.

Graphical Modeling Meets Systems Pharmacology.

A main source of failures in systems projects (including systems pharmacology) is poor communication level and different expectations among the stakeholders. A common and not ambiguous language that is naturally comprehensible by all the involved players is a boost to success. We present bStyle, a modeling tool that adopts a graphical language close enough to cartoons to be a common media to exchange ideas and data and that it is at the same time formal enough to enable modeling, analysis, and dynamic simulations of a system. Data analysis and simulation integrated in the same application are fundamental to understand the mechanisms of actions of drugs: a core aspect of systems pharmacology.

Efficacy of the Laparoendoscopic "Rendezvous" to Treat Cholecystocholedocholithiasis in 210 Consecutive Patients: A Single Center Experience.

OBJECTIVE: The simultaneous laparoendoscopic "rendezvous" (LERV) represents an alternative to sequential or totally laparoscopic approaches for patients affected by cholecystocholedocholithiasis. The aim of this study was to analyze the results in a large series of 210 consecutive patients. MATERIALS AND METHODS: From 2002 to 2016 all patients affected by cholecystocholedocholithiasis were treated with a standardized "tailored" LERV. The relevant technical features of the procedure were recorded. An analysis of feasibility, effectiveness in stone clearance, and safety was performed. RESULTS: Among 214 patients with common bile duct stones, 210 were treated with LERV and 4 with open rendezvous approach. Intraoperative cholangiography confirmed common bile duct stones in 179 patients (85.2%) or sludge in 18 (8.5%) and in 98.9% stone clearance was obtained endoscopically. Endoscopic papilla cannulation was feasible in 161 patients (76.7%), whereas in 49 (23.3%) a transcystic guidewire was needed. The overall LERV feasibility was 96.6%. The conversion rate to open surgery was 3.3%. Minor morbidity was observed in 1.9% of cases, mortality in 0.47%, and the mean hospital stay was 4.3 days. CONCLUSIONS: These results confirm the high effectiveness of LERV. This approach to treat cholecystocholedocholithiasis should be preferred and therefore implemented where a strong collaboration between surgeons and endoscopists is possible.

Perspective: Essential Study Quality Descriptors for Data from Nutritional Epidemiologic Research.

Pooled analysis of secondary data increases the power of research and enables scientific discovery in nutritional epidemiology. Information on study characteristics that determine data quality is needed to enable correct reuse and interpretation of data. This study aims to define essential quality characteristics for data from observational studies in nutrition. First, a literature review was performed to get an insight on existing instruments that assess the quality of cohort, case-control, and cross-sectional studies and dietary measurement. Second, 2 face-to-face workshops were organized to determine the study characteristics that affect data quality. Third, consensus on the data descriptors and controlled vocabulary was obtained. From 4884 papers retrieved, 26 relevant instruments, containing 164 characteristics for study design and 93 characteristics for measurements, were selected. The workshop and consensus process resulted in 10 descriptors allocated to "study design" and 22 to "measurement" domains. Data descriptors were organized as an ordinal scale of items to facilitate the identification, storage, and querying of nutrition data. Further integration of an Ontology for Nutrition Studies will facilitate interoperability of data repositories.

Systems view of adipogenesis via novel omics-driven and tissue-specific activity scoring of network functional modules.

The investigation of the complex processes involved in cellular differentiation must be based on unbiased, high throughput data processing methods to identify relevant biological pathways. A number of bioinformatics tools are available that can generate lists of pathways ranked by statistical significance (i.e. by p-value), while ideally it would be desirable to functionally score the pathways relative to each other or to other interacting parts of the system or process. We describe a new computational method (Network Activity Score Finder - NASFinder) to identify tissue-specific, omics-determined sub-networks and the connections with their upstream regulator receptors to obtain a systems view of the differentiation of human adipocytes. Adipogenesis of human SBGS pre-adipocyte cells in vitro was monitored with a transcriptomic data set comprising six time points (0, 6, 48, 96, 192, 384 hours). To elucidate the mechanisms of adipogenesis, NASFinder was used to perform time-point analysis by comparing each time point against the control (0 h) and time-lapse analysis by comparing each time point with the previous one. NASFinder identified the coordinated activity of seemingly unrelated processes between each comparison, providing the first systems view of adipogenesis in culture. NASFinder has been implemented into a web-based, freely available resource associated with novel, easy to read visualization of omics data sets and network modules.

Totally implantable arterial device (TIAD): a questionable complication.

The authors report a complication of a totally implantable arterial device in a patient in which the device was inserted to prevent recurrence of hepatic metastasis. After intrahepatic chemotherapy, during the nursing of the totally implantable arterial device, the patient developed a mass close to the duodenal loop that disappeared seven months later. The spontaneous decrease of this mass suggests the hypothesis of a hematoma due to a rupture of a pseudoaneurysm of a small collateral artery.

Liver damage after transarterial chemoembolization without embolizing agent in unresectable hepatocellular carcinoma.

AIM AND BACKGROUND: Transarterial chemoembolization represents a therapy for hepatocellular carcinoma, but in cirrhotic patients affected by large or multifocal HCC with poor hepatic functional reserve, the procedure can damage normal parenchyma. We analyzed the effects on hepatic function of a modified chemoembolization consisting of ethiodized oil (Lipiodol Ultra Fluid) and epirubicin without gelatine sponge (C-LIP). METHODS: Of 90 patients with hepatocellular carcinoma observed from January 1995 to December 1999, 16 with a diagnosis of advanced (large or multifocal) disease underwent 19 C-LIP. The 30th post-C-LIP day was considered as a checkpoint of the biochemical parameters for a possible hepatic failure. The value of alpha-fetoprotein and the clinical finding of ascites were also considered after 30 days. RESULTS: Postoperative values of serum aspartate aminotrasferases, as well as alanine aminotransferase, were significantly higher than preoperative values (P = 0.002 and P = 0.019, respectively) (Table 1). In all patients, there was a significant increase in postoperative total serum bilirubin (P = 0.003). Statistical analysis showed a significant finding of postoperative ascites (P = 0.035) and the effectiveness of C-LIP on neoplastic tissue by a decrease of alpha-fetoprotein values at 30 days (P = 0.067). CONCLUSIONS: Transcatether arterial chemoembolization could represent an effective therapy against multifocal or advanced hepatocellular carcinoma, and its effectiveness is probably not decreased by using a modified procedure without embolizing agent (C-LIP). However, even when performing such a safe procedure, the hepatic functional reserve of the individual patient needs to be accurately evaluated in order to avoid liver failure.

Combination of fibrin glue protection with microsurgical technique for duct-to-mucosa pancreatico-jejunostomy reduces the incidence of leakages after pancreaticoduodenectomy.

The Achilles' heel of pancreatic surgery is the management of the pancreatic stump. Leakage from pancreatic anastomosis with subsequent fistula, abscess formation, sepsis, or bleeding is one of the most common causes of morbidity and mortality, and it also contributes significantly to prolonged hospitalization and increased hospital expenses. Many surgical methods have been developed aimed at reducing the incidence of post-operative pancreatic fistula. However, the best technique for pancreatico-enteric reconstruction continues to be disputed. Herein, we describe an interim analysis of 35 consecutive pancreatico-duodenectomies, all with the same standardized technique that combines microsurgical technique for duct-to-mucosa pancreatico-jejunostomy with the routine use of fibrin sealant. The rate of leakage of pancreaticojejunostomy was 5,7% (n=2), all of which were grade A fistulas, treated conservatively. The increased precision of magnification instruments and microsurgical technique for duct to mucosa anastomosis, combined with routine sealing of the pancreatic anastomosis are key factors to efficiently manage the pancreatic stump. The good results obtained and especially the minimal rate of fistula suggests that this technical solution is a safe, feasible and reliable approach for pancreatic reconstruction after pancreatico-duodenectomy.