Tissue informative cell-free DNA methylation sites in amyotrophic lateral sclerosis.

Cell-free DNA (cfDNA) is increasingly recognized as a promising biomarker candidate for disease monitoring. However, its utility in neurodegenerative diseases, like amyotrophic lateral sclerosis (ALS), remains underexplored. Existing biomarker discovery approaches are tailored to a specific disease context or are too expensive to be clinically practical. Here, we address these challenges through a new approach combining advances in molecular and computational technologies. First, we develop statistical tools to select tissue-informative DNA methylation sites relevant to a disease process of interest. We then employ a capture protocol to select these sites and perform targeted methylation sequencing. Multi-modal information about the DNA methylation patterns are then utilized in machine learning algorithms trained to predict disease status and disease progression. We applied our method to two independent cohorts of ALS patients and controls (n=192). Overall, we found that the targeted sites accurately predicted ALS status and replicated between cohorts. Additionally, we identified epigenetic features associated with ALS phenotypes, including disease severity. These findings highlight the potential of cfDNA as a non-invasive biomarker for ALS.

Incidence, associated disease burden and healthcare utilization due to Staphylococcus aureus prosthetic joint infection in European hospitals: the COMBACTE-NET ARTHR-IS multi-centre study.

BACKGROUND: The aim of this study was to estimate the incidence, associated disease burden and healthcare utilization due to Staphylococcus aureus prosthetic joint infections (SA-PJI) after primary hip and knee arthroplasty in European centres. METHODS: This study was conducted in patients who underwent primary hip and knee arthroplasty in 19 European hospitals between 2014 and 2016. The global incidence of PJI and SA-PJI was calculated. The associated disease burden was measured indirectly as infection-related mortality plus loss of function. For healthcare utilization, number and duration of hospitalizations, number and type of surgical procedures, duration of antibiotic treatments, and number of outpatient visits were collected. Subgroup and regression analyses were used to evaluate the impact of SA-PJI on healthcare utilization, controlling for confounding variables. RESULTS: The incidence of PJI caused by any micro-organism was 1.41%, and 0.40% for SA-PJI. Among SA-PJI, 20.7% were due to MRSA with substantial regional differences, and were more frequent in partial hip arthroplasty (PHA). Related deaths and loss of function occurred in 7.0% and 10.2% of SA-PJI cases, respectively, and were higher in patients with PHA. Compared with patients without PJI, patients with SA-PJI had a mean of 1.4 more readmissions, 25.1 more days of hospitalization, underwent 1.8 more surgical procedures, and had 5.4 more outpatient visits, controlling for confounding variables. Healthcare utilization was higher in patients who failed surgical treatment of SA-PJI. CONCLUSIONS: This study confirmed that the SA-PJI burden is high, especially in PHA, and provided a solid basis for planning interventions to prevent SA-PJI.

GAP score potential in predicting post-operative spinal mechanical complications: a systematic review of the literature.

PURPOSE: In 2017, the GAP score was proposed as a tool to reduce mechanical complications (MC) in adult spinal deformity (ASD) surgery: the reported MC rate for the GAP proportioned category was only 6%, which is clearly lower to the MC rate reported in the literature. The aim of this study is to analyse if the most recent literature confirms the promising results of the original article. MATERIALS AND METHODS: Using the PRISMA flow chart, we reviewed the literature to analyse GAP score capacity in predicting MC occurrence. We included articles clearly reporting ASD surgery MC stratified by GAP categories and the score's overall capacity to predict MC using the area under the curve (AUC). The quality of the included studies was evaluated using GRADE and MINORS systems. RESULTS: Eleven retrospective articles (1,517 patients in total) were included. The MC distribution per GAP category was as follows: GAP-P, 32.8%; GAP-MD, 42.3%; GAP-SD, 55.4%. No statistically significant difference was observed between the different categories using the Kruskal-Wallis test (p = 0.08) and the two-by-two Pearson-Chi square test (P Vs MD, p = 0.300; P Vs SD, p = 0.275; MD Vs SD, p = 0.137). The global AUC was 0.68 ± 0.2 (moderate accuracy). The included studies were of poor quality according to the GRADE system and had a high risk of bias based on the MINORS criteria. CONCLUSION: The actual literature does not corroborate the excellent results reported by the original GAP score article. Further prospective studies, possibly stratified by type of MC and type of surgery, are necessary to validate this score.

Pre-operative micronutrient deficiencies in patients with severe obesity candidates for bariatric surgery.

PURPOSE: In patients with obesity, micronutrient deficiencies have been reported both before and after bariatric surgery (BS). Obesity is a chronic pro-inflammatory status, and inflammation increases the risk of micronutrient malnutrition. Our objective was to assess in pre-BS patients the prevalence of micronutrient deficiencies and their correlation with blood values of C-reactive protein (CRP). METHODS: Anthropometric data, instrumental examinations, and blood variables were centrally measured in the first 200 patients undergoing a pre-BS evaluation at the "Città della Salute e della Scienza" Hospital of Torino, starting from January 2018. RESULTS: At least one micronutrient deficiency was present in 85.5% of pre-BS patients. Vitamin D deficiency was the most prevalent (74.5%), followed by folate (33.5%), iron (32%), calcium (13%), vitamin B12 (10%), and albumin (5.5%) deficiency. CRP values were high (> 5 mg/L) in 65% of the patients. These individuals showed increased rate of iron, folate, vitamin B12 deficiency, and a higher number of micronutrient deficiencies. In a multiple logistic regression model, increased CRP levels were significantly associated with deficiencies of vitamin B12 (OR = 5.84; 95% CI 1.25-27.2; p = 0.024), folate (OR = 4.02; 1.87-8.66; p < 0.001), and with the presence of ≥ 2 micronutrient deficiencies (OR = 2.31; 1.21-4.42; p = 0.01). CONCLUSIONS: Micronutrient deficiencies are common in patients with severe obesity undergoing BS, especially when inflammation is present. In the presence of increased CRP values before surgery, it might be advisable to search for possible multiple micronutrient deficiencies.

The IMEx coronavirus interactome: an evolving map of Coronaviridae-host molecular interactions.

The current coronavirus disease of 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus (SARS-CoV)-2, has spurred a wave of research of nearly unprecedented scale. Among the different strategies that are being used to understand the disease and develop effective treatments, the study of physical molecular interactions can provide fine-grained resolution of the mechanisms behind the virus biology and the human organism response. We present a curated dataset of physical molecular interactions focused on proteins from SARS-CoV-2, SARS-CoV-1 and other members of the Coronaviridae family that has been manually extracted by International Molecular Exchange (IMEx) Consortium curators. Currently, the dataset comprises over 4400 binarized interactions extracted from 151 publications. The dataset can be accessed in the standard formats recommended by the Proteomics Standards Initiative (HUPO-PSI) at the IntAct database website (https://www.ebi.ac.uk/intact) and will be continuously updated as research on COVID-19 progresses.

Prodigiosin-loaded electrospun nanofibers scaffold for localized treatment of triple negative breast cancer.

Hybrid composite nanofibers, with the potential to enhance cell adhesion while improving sustained drug release profiles, were fabricated by the blend electrospinning of poly(d,l-lactic-co-glycolic acid) (PLGA), gelatin, pluronic F127 and prodigiosin (PG). Scanning Electron Microscopy (SEM) images of the nanofibers revealed diameters of 1.031 ±â€¯0.851 µm and 1.349 ±â€¯1.264 µm, corresponding to PLGA/Ge-PG and PLGA/Ge-F127/Ge, respectively. The Young's moduli were also determined to be 1.446 ±â€¯0.496 kPa and 1.290 ±â€¯0.617 kPa, while the ultimate tensile strengths were 0.440 ±â€¯0.117 kPa and 0.185 ±â€¯0.480 kPa for PLGA/Ge-PG and PLGA/Ge-F127/Ge, respectively. In-vitro drug release profiles showed initial (burst) release for a period of 1 h to be 26.000 ±â€¯0.004% and 16.000 ±â€¯0.015% for PLGA/Ge and PLGA/Ge-F127 nanofibers, respectively. This was followed by 12 h of sustained release, and subsequent slow sustained release of PG from the composite nanofibers. The cumulative release of PG (for three days) was determined to be 82.0 ±â€¯0.1% for PLGA/Ge and 49.7 ±â€¯0.1% for PLGA/Ge-F127 nanofibers. The release exponents (n) show that both nanofibers exhibit diffusion-controlled release by non-Fickian (zeroth order) and quasi-Fickian diffusion in the initial and sustained release regimes, respectively. The suitability of the composite nanofibers for supporting cell proliferation and viability, as well as improving sustained release of the drug were explored. The in-vitro effects of cancer drug (PG) release were also studied on breast cancer cell lines (MCF-7 and MDA-MB-231 cells). The implications of the results are discussed for the potential applications of drug-nanofiber scaffolds as capsules for localized delivery of chemotherapeutic drugs for the treatment of triple negative breast cancer.

The IMEx Coronavirus interactome: an evolving map of Coronaviridae-Host molecular interactions.

The current Coronavirus Disease 2019 (COVID-19) pandemic, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has spurred a wave of research of nearly unprecedented scale. Among the different strategies that are being used to understand the disease and develop effective treatments, the study of physical molecular interactions enables studying fine-grained resolution of the mechanisms behind the virus biology and the human organism response. Here we present a curated dataset of physical molecular interactions, manually extracted by IMEx Consortium curators focused on proteins from SARS-CoV-2, SARS-CoV-1 and other members of the Coronaviridae family. Currently, the dataset comprises over 2,200 binarized interactions extracted from 86 publications. The dataset can be accessed in the standard formats recommended by the Proteomics Standards Initiative (HUPO-PSI) at the IntAct database website ( www.ebi.ac.uk/intact ), and will be continuously updated as research on COVID-19 progresses.

Retraction Note: An apoptosis-enhancing drug overcomes platinum resistance in a tumour-initiating subpopulation of ovarian cancer.

This Article has been retracted; see accompanying Retraction Note.

Increasing market opportunities for renewable energy technologies with innovations in aquifer thermal energy storage.

Heating and cooling using aquifer thermal energy storage (ATES) has hardly been applied outside the Netherlands, even though it could make a valuable contribution to the energy transition. The Climate-KIC project "Europe-wide Use of Energy from aquifers" - E-USE(aq) - aimed to pave the way for Europe-wide application of ATES, through the realization and monitoring of six ATES pilot plants across five different EU countries. In a preceding paper, based on preliminary results of E-USE(aq), conclusions were already drawn, demonstrating how the barriers for this form of shallow geothermal energy can be overcome, and sometimes even leveraged as opportunities. Based on final pilot project results, key economic and environmental outcomes are now presented. This paper starts with the analysis of specific technological barriers: unfamiliarity with the subsurface, presumed limited compatibility with existing energy provision systems (especially district heating), energy imbalances and groundwater contamination. The paper then shows how these barriers have been tackled, using improved site investigation and monitoring technologies to map heterogeneous subsoils. In this way ATES can cost-efficiently be included in smart grids and combined with other sources of renewable (especially solar) energy, while at the same time achieving groundwater remediation. A comparative assessment of economic and environmental impacts of the pilots is included, to demonstrate the sustainability of ATES system with different renewables and renewable-based technologies. The paper concludes with an assessment of the market application potential of ATES, including in areas with water scarcity, and a review of climate beneficial impact.

Sediment management in coastal infrastructures: Techno-economic and environmental impact assessment of alternative technologies to dredging.

The presence of anthropic activity in the coastal or riverine environment modifies the wave as well as the water and sediment current regime. In particular, the body of water around ports is an area where intense currents and sediment transport rates are usually present and can be affected by low water velocities that take place close to the entrance and inside the port basin. Consequently, sediment can be entrained and accumulated in such areas, creating problems to navigation. Ports and moorings are filled with fine sediments due to deposition resulting from solid transport. In particular, silt particles settle because of the weak vertical and lateral shearing of the velocity field. The result is that harbours frequently require ordinary maintenance dredging. The dredging process involves the removal of sediment in its natural deposited condition by using either mechanical or hydraulic equipment. Dredging is a consolidated and proven technology, but involves considerable drawbacks. In particular, dredging has a notable environmental impact on marine flora and fauna, contributes to the mobility and diffusion of contaminants and pollutants already present in the silted sediments, obstructs navigation and is characterized by relatively high and low predictable costs. This paper aims to provide an original structured overview of technologies alternative to dredging that have been tested in the past 50 years. More than 150 articles have been analysed to compare standard dredging technologies with market-ready competitors from techno-economic and environmental perspectives. In particular, the paper focuses on anti-sedimentation infrastructures and on innovative plant solutions characterized by low maintenance costs and by a very limited environmental impact. The final aim of the paper is to describe the currently available technologies that prevent port inlet and channel siltation and to classify them through a techno-economic and environmental impact assessment. The comparison shows that dredging has both the higher costs and environmental impact, while fixed sand by-passing plants are characterized by the lowest environmental impact and operation costs that are competitive with dredging.

Low carbon heating and cooling by combining various technologies with Aquifer Thermal Energy Storage.

A transition to a low carbon energy system is needed to respond to global challenge of climate change mitigation. Aquifer Thermal Energy Storage (ATES) is a technology with worldwide potential to provide sustainable space heating and cooling by (seasonal) storage and recovery of heat in the subsurface. However, adoption of ATES varies strongly across Europe, because of both technical as well as organizational barriers, e.g. differences in climatic and subsurface conditions and legislation respectively. After identification of all these barriers in a Climate-KIC research project, six ATES pilot systems have been installed in five different EU-countries aiming to show how such barriers can be overcome. This paper presents the results of the barrier analysis and of the pilot plants. The barriers are categorized in general barriers, and barriers for mature and immature markets. Two pilots show how ATES can be successfully used to re-develop contaminated sites by combining ATES with soil remediation. Two other pilots show the added value of ATES because its storage capacity enables the utilization of solar heat in combination with solar power production. Finally, two pilots are realized in countries with legal barriers where ATES systems have not previously been applied at all.

Chronic deltoid ligament insufficiency repair with Internal Brace™ augmentation.

BACKGROUND: Patients with chronic deltoid ligament insufficiency (CDLI) present a challenging situation. Although numerous procedures have been described, optimal treatment is still a matter of debate. While the treatment armamentarium ranges from simple ligament repair to complex reconstructions with or without realignment osteotomies, direct repair augmented with an Internal Brace™ device appears to be an attractive intermediate option. We investigated functional outcomes and complications in patients with CDLI operated on using Internal Brace™ augmentation. METHODS: A prospective study was conducted. Patients were included if they presented medial ankle pain and/or giving way, exhibited asymmetric flexible hindfoot valgus, failed conservative treatment, and had a positive MRI evaluated by an independent radiologist. Patients with stage IV flatfoot deformity, neuropathy and/or inflammatory arthritis were excluded. CDLI was confirmed intraoperatively with the arthroscopic drive-through sign. Patients were evaluated preoperatively and postoperatively using FAAM, SF-36 and grade of satisfaction. Paired t-tests were used to assess FAAM and SF-36 scores variation. RESULTS: Thirteen patients met inclusion criteria. No patient was lost to follow-up, with a mean follow-up time of 13.5 months (range 6-21). Preoperative FAAM and SF-36 scores improved from 58.7 to 75.3 and from 60.2 to 84.4 postoperatively, respectively (p<.01). Two implant failures were observed, with no apparent compromise of construct stability. No patient was re-operated. CONCLUSIONS: Our results suggest that deltoid ligament repair with Internal Brace™ augmentation in patients with CDLI is a reliable option with good functional outcomes and high satisfaction grade in short term follow-up. LEVEL OF EVIDENCE: Level IV.

Fetal cardiac growth is associated with in utero gut colonization.

BACKGROUND AND AIMS: Intra-uterine metabolic environment predicts newborns' cardiac morphology, metabolism and future health. In adults, gut microbiota composition relates to altered cardiac structure and metabolism. We investigated the relationship between gut microbiota colonization and fetal cardiac growth. METHODS AND RESULTS: Bacterial composition in meconium samples of 26 healthy, full-term newborns was assessed by 16S rDNA gene sequencing. Its relationship with birth echocardiographic parameters, and the interaction with cord blood levels of inflammatory markers were investigated. Correlative and cluster analysis, linear discriminant analysis effect size and predictive functional analysis based on Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were applied. Fetal left ventricle growth was related to gut microbiota composition at birth. Specifically, left ventricle posterior wall thickness (LVPW) greater than 4 mm was associated with lower microbiota beta and alpha diversity, depletion (LDA score > 3) of several bacteria at each taxonomic level, including Lactobacillales, and enrichment (LDA score > 5) in Enterobacteriales and Enterobacteriaceae. The latter was significantly related to cord blood gamma-glutamyltransferase levels (r = 0.58, p = 0.0057). Functionally, a thicker LVPW was related to up-regulation of pathways involved in lipopolysaccharide biosynthesis (+50%, p = 0.045 in correlative analysis) and energy metabolism (+12%, p = 0.028), and down-regulation of pathways involved in xenobiotic biodegradation (-21 to -53%, p = 0.0063-0.039), PPAR signaling (-24%, p = 0.021) and cardiac muscle contraction (-100%, p = 0.049). CONCLUSION: Fetal cardiac growth and gut colonization are associated. Greater neonatal LVPW thickness is related to lower diversity of the gut microbiota community, depletion of bacteria having anti-remodeling effects, and enrichment in bacteria functionally linked to inflammation.

Comparison of growth factor and interleukin content of adult peripheral blood and cord blood serum eye drops for cornea and ocular surface diseases.

INTRODUCTION: Various blood-derived products have been proposed for the topical treatment of ocular surface diseases. The aim of the study was to compare the different content of Growth Factors (GFs) and Interleukins (ILs) in peripheral blood (PB-S) and Cord Blood (CB-S) sera. MATERIALS AND METHODS: Sera were obtained from 105 healthy adult donors (PB-S) and 107 umbilical/placental veins at the time of delivery (CB-S). The levels of epithelial-GF (EGF), fibroblast-GF (FGF), platelet-derived-GF (PDGF), insulin-GF (IGF), transforming-GF alpha (TGF-α,) and beta 1-2-3 (TGF-ß1-ß2-ß3), vascular endothelial-GF (VEGF), nerve-GF (NGF), Interleukin (IL)-1ß,IL-4,IL-6,IL-10, and IL-13 were assessed by Bio-Plex Protein Array System (Bio-Rad Laboratories, CA, USA). The Mann-Whitney test for unpaired data was applied to compare GFs and ILs levels in the two sources. The associations among each GF/IL level and the obstetric data for CB-S and hematological characteristics for PB-S were also investigated. RESULTS: The levels of EGF, TGF-α, TGF-ß2, FGF, PDGF, VEGF, NGF, IL-1B, IL-4, IL-6, IL-10, and IL-13 were significantly higher in CB-S compared to PB-S. Conversely, the levels of IGF-1, IGF-2, and TGF-ß1 were significantly higher in PB-S. The female sex and the weight of the child showed a significant association in predicting EGF and PDGF levels. CONCLUSION: A significantly different content in those GFs and ILs was demonstrated in the two blood sources. Since each GF/IL selectively regulates different cellular processes involved in corneal healing, the use of PB-S or CB-S should be chosen on the basis of the cellular mechanism to be promoted in each clinical case.

Atelectasis is inversely proportional to transpulmonary pressure during weaning from ventilator support in a large animal model.

BACKGROUND: In mechanically ventilated, lung injured, patients without spontaneous breathing effort, atelectasis with shunt and desaturation may appear suddenly when ventilator pressures are decreased. It is not known how such a formation of atelectasis is related to transpulmonary pressure (PL ) during weaning from mechanical ventilation when the spontaneous breathing effort is increased. If the relation between PL and atelectasis were known, monitoring of PL might help to avoid formation of atelectasis and cyclic collapse during weaning. The main purpose of this study was to determine the relation between PL and atelectasis in an experimental model representing weaning from mechanical ventilation. METHODS: Dynamic transverse computed tomography scans were acquired in ten anaesthetized, surfactant-depleted pigs with preserved spontaneous breathing, as ventilator support was lowered by sequentially reducing inspiratory pressure and positive end expiratory pressure in steps. The volumes of gas and atelectasis in the lungs were correlated with PL obtained using oesophageal pressure recordings. Work of breathing (WOB) was assessed from Campbell diagrams. RESULTS: Gradual decrease in PL in both end-expiration and end-inspiration caused a proportional increase in atelectasis and decrease in the gas content (linear mixed model with an autoregressive correlation matrix; P < 0.001) as the WOB increased. However, cyclic alveolar collapse during tidal ventilation did not increase significantly. CONCLUSION: We found a proportional correlation between atelectasis and PL during the 'weaning process' in experimental mild lung injury. If confirmed in the clinical setting, a gradual tapering of ventilator support can be recommended for weaning without risk of sudden formation of atelectasis.

Hepatotoxicity of paracetamol and related fatalities.

Paracetamol, also known as acetaminophen, is the most commonly used antipyretic and pain reliever and since 1955 it is available over-the-counter as a single formulation or in combination with other substances and, as indicated by the World Health Organization, it can be used in all the three steps of pain intensity. Paracetamol toxicity is one of the most common causes of poisoning worldwide. While paracetamol is described as relatively nontoxic when administered in therapeutic doses, it is known to cause toxicity when taken in a single or repeated high dose, or after chronic ingestion. Repeated supratherapeutic misuse, non-intentional misuse, and intentional ingestion may all result in hepatic toxicity, the main cause of acute liver failure (ALF) in the United States and Europe. Since paracetamol is responsible for nearly half of the cases in the US of acute liver failure and remains the leading cause of liver transplantation, continued awareness promotion, education and research should be constantly undertaken. We herein review the literature on paracetamol toxicity with particular attention to aspects of liver damage and related fatalities.

Hepatotoxicity associated to synthetic cannabinoids use.

Synthetic cannabinoids (SCs) are psychotropic compounds, chemically created in laboratory to mimic cannabinergic brain activity of delta-9 tetrahydrocannabinol. The consumption of these compounds for recreational purposes can lead to a variety of adverse effects on health including overdose and deaths. Increasingly popular as substances of abuse since the 2000s, SCs were produced initially to bind and study cannabinoid receptors (they also can be called synthetic cannabimimetics) failing in eliminating the psychoactive effects. Currently, SCs are misused by students and young adults as "natural products" because of their herbal aspect. Actually, these apparently innocuous recreational substances hide toxic effects to health. Reported side effects are cardiovascular, gastrointestinal, neurological, renal, metabolic, ophthalmologic, pulmonary and psychoactive including dependence and withdrawal. A few cases of SCs ingestion have also been associated with liver failure. We herein review the recent literature on the SCs toxicity with particular attention to liver damage aspects.

Vaccines licensed and in clinical trials for the prevention of dengue.

Dengue has become a major global public health threat with almost half of the world's population living in at-risk areas. Vaccination would likely represent an effective strategy for the management of dengue disease in endemic regions, however to date there is only one licensed preventative vaccine for dengue infection. The development of a vaccine against dengue virus (DENV) has been hampered by an incomplete understanding of protective immune responses against DENV. The most clinically advanced dengue vaccine is the chimeric yellow fever-dengue vaccine (CYD) that employs the yellow fever virus 17D strain as the replication backbone (Chimerivax-DEN; CYD-TDV). This vaccine had an overall pooled protective efficacy of 65.6% but was substantially more effective against severe dengue and dengue hemorrhagic fever. Several other vaccine approaches have been developed including live attenuated chimeric dengue vaccines (DENVax and LAV Delta 30), DEN protein subunit V180 vaccine (DEN1-80E) and DENV DNA vaccines. These vaccines have been shown to be immunogenic in animals and also safe and immunogenic in humans. However, these vaccines are yet to progress to phase III trials to determine their protective efficacy against dengue. This review will summarize the details of vaccines that have progressed to clinical trials in humans.