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Abstract Background Multiple sclerosis (MS) is a chronic autoimmune disease driven by sustained inflammation in the central nervous system. One of the pathological hallmarks of MS is extensive free radical production. However, the subsequent generation, potential pathological role, and detoxification of different lipid peroxidation-derived reactive carbonyl species during neuroinflammation are unclear, as are the therapeutic benefits of carbonyl quenchers. Here, we investigated the reactive carbonyl acrolein and (the therapeutic effect of) acrolein quenching by carnosine during neuroinflammation. Methods The abundance and localization of acrolein was investigated in inflammatory lesions of MS patients and experimental autoimmune encephalomyelitis (EAE) mice. In addition, we analysed carnosine levels and acrolein quenching by endogenous and exogenous carnosine in EAE. Finally, the therapeutic effect of exogenous carnosine was assessed in vivo (EAE) and in vitro (primary mouse microglia, macrophages, astrocytes). Results Acrolein was substantially increased in inflammatory lesions of MS patients and EAE mice. Levels of the dipeptide carnosine (β-alanyl-l-histidine), an endogenous carbonyl quencher particularly reactive towards acrolein, and the carnosine-acrolein adduct (carnosine-propanal) were ~ twofold lower within EAE spinal cord tissue. Oral carnosine treatment augmented spinal cord carnosine levels (up to > tenfold), increased carnosine-acrolein quenching, reduced acrolein-protein adduct formation, suppressed inflammatory activity, and alleviated clinical disease severity in EAE. In vivo and in vitro studies indicate that pro-inflammatory microglia/macrophages generate acrolein, which can be efficiently quenched by increasing carnosine availability, resulting in suppressed inflammatory activity. Other properties of carnosine (antioxidant, nitric oxide scavenging) may also contribute to the therapeutic effects. Conclusions Our results identify carbonyl (particularly acrolein) quenching by carnosine as a therapeutic strategy to counter inflammation and macromolecular damage in MS.

Rationale and Objectives: The aim of our retrospective study was to assess the safety and feasibility of cryoablation in high-risk patients with complex chest neoplastic lesions. Materials and Methods: Twenty patients with complex chest malignancies, both primary and secondary, located in the mediastinum, lung, and chest wall, underwent percutaneous CT-guided cryoablation treatments. Procedural success as well as complications were evaluated. Results: A total of 24 neoplastic lesions were treated (mean diameter: 27 mm; range: 7–54 mm). Technical success was obtained in all patients, without major complications or intraprocedural death. A pneumothorax not requiring a drainage tube placement was registered in 50% of patients, while 3/24 patients had a grade 3 pneumothorax requiring a chest tube placement. Conclusion: Percutaneous CT-guided cryoablation seems a safe and feasible treatment for complex thoracic lesions.

PURPOSEWe aimed to assess the use of transradial approach (TRA) among interventional radiologists (IRs) and its perceived advantages and disadvantages that have driven the decision to select or refuse this endovascular approach.METHODSA multicountry survey of 20 multiple-choice questions was conducted among interventional radiologists in Europe and the United States. Questions assessed demographic information of the participants and whether they performed TRA routinely, pre-procedural screening modalities for TRA, TRA technique, complications, reasons for adopting TRA and reasons for not adopting TRA. A total of 187 IRs completed the survey.RESULTSOne hundred respondents (53.5%) performed TRA routinely. TRA was chosen based on the procedure (90%, mostly embolization) and physical examination (75%). Patient preference (79%) and faster patient ambulation/discharge (73%) were the main drivers for TRA. Long learning curve (45%), lack of training (32%), prolonged procedural time (31%), potential risk for neurological complications (31%), and increase in radiation exposure (28%) were the most frequent detractors. TRA use was significantly higher in the US than in Europe (p < 0.001) and among male IRs than female IRs (p < 0.01). There was a declining trend in use of TRA with advanced age and more years of experience of IRs.CONCLUSIONTRA usage among IRs is limited by issues that can easily be addressed. This survey could help IRs to better understand the real advantages of TRA and how it can offer higher value in patient care.

Acute kidney injury is a frequent complication for critical newborns. Its management is a significant challenge, especially in extremely low-birth-weight (ELBW) infants. Currently, peritoneal dialysis (PD) is the most manageable treatment. However, data are lacking regarding when diuresis can be declared irreversible relative to the start of PD. A female infant born at 28 + 0 weeks with a birth weight of 800 g by monochorionic diamniotic pregnancy, complicated by twin-to-twin transfusion syndrome, developed acute renal failure on the second day of life because of long-term intrauterine hypoperfusion. PD was started on day 7. The patient remained anuric until the 52nd day of dialysis, when she presented adequate urine output of 2.5 mL/kg/h and PD was suspended for 11 days. After an episode of sepsis, PD was re-started, and after 50 days of treatment, given a urine output of 1.5 mL/kg/h, it was discontinued. The patient died on day 132 after a disseminate infection, which led to multiorgan failure. In ELBW infants, PD is a valid therapeutic instrument to treat patients with renal failure. Despite the evidence of low renal functional reserve in these patients, the duration of recovery from diuresis after a period of anuria can be very long.

Teeth include mesenchymal stem cells (MSCs), which are multipotent cells that promote tooth growth and repair. Dental tissues, specifically the dental pulp and the dental bud, constitute a relevant source of multipotent stem cells, known as dental-derived stem cells (d-DSCs): dental pulp stem cells (DPSCs) and dental bud stem cells (DBSCs). Cell treatment with bone-associated factors and stimulation with small molecule compounds are, among the available methods, the ones who show excellent advantages promoting stem cell differentiation and osteogenesis. Recently, attention has been paid to studies on natural and non-natural compounds. Many fruits, vegetables, and some drugs contain molecules that can enhance MSC osteogenic differentiation and therefore bone formation. The purpose of this review is to examine research work over the past 10 years that has investigated two different types of MSCs from dental tissues that are attractive targets for bone tissue engineering: DPSCs and DBSCs. The reconstruction of bone defects, in fact, is still a challenge and therefore more research is needed; the articles reviewed are meant to identify compounds useful to stimulate d-DSC proliferation and osteogenic differentiation. We only consider the results of the research which is encouraging, assuming that the mentioned compounds are of some importance for bone regeneration.

Acquired immune deficiency syndrome (AIDS) has been identified from US patients since 1981. AIDS is caused by infection with the human immunodeficiency virus type 1 (HIV-1) which is a retrovirus. HIV-1 gp120 can be recognized by the immune system because it is located outside the virion. The conserved region is identified in gp120, and it is recognized by an immune cell which then initiates specific immune responses, viral mutation escape, and increase vaccine protection coverage, a benefit derived from the conserved region-based vaccine design. However, previous researchers have little knowledge on this conserved region as a target for vaccine design. This paper explains how the conserved region of gp120 HIV-1 is a major target for vaccine design through a bioinformatics approach. The conserved region from gp120 was explored as a vaccine design target with a bioinformatics tool that consists of B-cell epitope mapping, vaccine properties, molecular docking, and dynamic simulation. The peptide vaccine candidate of B5 with the gp120 HIV-1 conserved region was found to provoke B-cell activation through a direct pathway, produce specific antibody, and increase protection from multi-strain viral infection.

Background Histidyl dipeptides such as carnosine are present in a micromolar to millimolar range in mammalian hearts. These dipeptides facilitate glycolysis by proton buffering. They form conjugates with reactive aldehydes, such as acrolein, and attenuate myocardial ischemia–reperfusion injury. Although these dipeptides exhibit multifunctional properties, a composite understanding of their role in the myocardium is lacking. Methods and Results To identify histidyl dipeptide–mediated responses in the heart, we used an integrated triomics approach, which involved genome‐wide RNA sequencing, global proteomics, and unbiased metabolomics to identify the effects of cardiospecific transgenic overexpression of the carnosine synthesizing enzyme, carnosine synthase (Carns), in mice. Our result showed that higher myocardial levels of histidyl dipeptides were associated with extensive changes in the levels of several microRNAs, which target the expression of contractile proteins, β‐fatty acid oxidation, and citric acid cycle (TCA) enzymes. Global proteomic analysis showed enrichment in the expression of contractile proteins, enzymes of β‐fatty acid oxidation, and the TCA in the Carns transgenic heart. Under aerobic conditions, the Carns transgenic hearts had lower levels of short‐ and long‐chain fatty acids as well as the TCA intermediate—succinic acid; whereas, under ischemic conditions, the accumulation of fatty acids and TCA intermediates was significantly attenuated. Integration of multiple data sets suggested that β‐fatty acid oxidation and TCA pathways exhibit correlative changes in the Carns transgenic hearts at all 3 levels. Conclusions Taken together, these findings reveal a central role of histidyl dipeptides in coordinated regulation of myocardial structure, function, and energetics.

Abstract Background Acute calculous cholecystitis (ACC) is the second most frequent surgical condition in emergency departments. The recommended treatment is the early laparoscopic cholecystectomy; however, the Tokyo Guidelines (TG) advocate for different initial treatments in some subgroups of patients without a strong evidence that all patients will benefit from them. There is no clear consensus in the literature about who is the unfit patient for surgical treatment. The primary aim of the study is to identify the risk factors for mortality in ACC and compare them with Tokyo Guidelines (TG) classification. Methods Retrospective unicentric cohort study of patients emergently admitted with and ACC during 1 January 2011 to 31 December 2016. The study comprised 963 patients. Primary outcome was the mortality after the diagnosis. A propensity score method was used to avoid confounding factors comparing surgical treatment and non-surgical treatment. Results The overall mortality was 3.6%. Mortality was associated with older age (68 + IQR 27 vs. 83 + IQR 5.5; P = 0.001) and higher Charlson Comorbidity Index (3.5 + 5.3 vs. 0+2; P = 0.001). A logistic regression model isolated four mortality risk factors (ACME): chronic obstructive pulmonary disease (OR 4.66 95% CI 1.7–12.8 P = 0.001), dementia (OR 4.12; 95% CI 1.34–12.7, P = 0.001), age > 80 years (OR 1.12: 95% CI 1.02–1.21, P = 0.001) and the need of preoperative vasoactive amines (OR 9.9: 95% CI 3.5–28.3, P = 0.001) which predicted the mortality in a 92% of the patients. The receiver operating characteristic curve yielded an area of 88% significantly higher that 68% (P = 0.003) from the TG classification. When comparing subgroups selected using propensity score matching with the same morbidity and severity of ACC, mortality was higher in the non-surgical treatment group. (26.2% vs. 10.5%). Conclusions Mortality was higher in ACC patients treated with non-surgical treatment. ACME identifies high-risk patients. The validation to ACME with a prospective multicenter study population could allow us to create a new alternative guideline to TG for treating ACC. Trial registration Retrospectively registered and recorded in Clinical Trials. NCT04744441

Abstract Background Prevention of incisional hernias with a prophylactic mesh in emergency surgery is controversial. The present study aimed to analyze the long-term results of prophylactic mesh used for preventing incisional hernia after emergency midline laparotomies. Methods This study was a registered (NCT04578561) retrospective analysis of patients who underwent an emergency midline laparotomy between January 2009 and July 2010 with a follow-up period of longer than 2 years. Long-term outcomes and risk factors for the development of incisional hernias between patients who received a prophylactic reinforcement mesh (Group M) and suture (Group S) were compared. Results From an initial 266 emergency midline laparotomies, 187 patients were included. The median follow-up time was 64.4 months (SD 35). Both groups had similar characteristics, except for a higher rate of previous operations (62 vs. 43.2%; P = 0.01) and operation due to a revision laparotomy (32.5 vs.13%; P = 0.02) in the M group. During follow-up, 29.9% of patients developed an incisional hernia (Group S 36.6% vs. Group M 14.3%; P = 0.002). Chronic mesh infections were diagnosed in 2 patients, but no mesh explants were needed, and no patient in the M group developed chronic pain. Long-term risk factors for incisional hernia were as follows: smoking (HR = 2.47; 95% CI 1.318–4.624; P = 0.05), contaminated surgery (HR = 2.98; 95% CI 1.142–7.8; P = 0.02), surgical site infection (SSI; HR = 3.83; 95% CI 1.86–7.86; P = 0.001), and no use of prophylactic mesh (HR = 5.09; 95% CI 2.1–12.2; P = 0.001). Conclusion Incidence of incisional hernias after emergency midline laparotomies is high and increases with time. High-risk patients, contaminated surgery, and surgical site infection (SSI) benefit from mesh reinforcement. Prophylactic mesh use is safe and feasible in emergencies with a low long-term complication rate. Trial registration: NCT04578561. www.clinicaltrials.gov

Reconstruction of bone defects and compensation of deficient repair mechanisms represent important goals within the field of regenerative medicine and require novel safe strategies for translation into the clinic. A non-viral osteogenic gene therapeutic vector system (‘hybrid vectors’) was generated, combining an improved bone morphogenetic protein 2 (BMP2) gene cassette and single pro-osteogenic microRNAs (miR-148b-3p, miR-20-5p, miR-590b-5p), driven by the U6 promoter. The vectors were tested in vitro for their osteogenic differentiation potential in C2C12 and C3H/10T1/2 cell lines, using BMP2 alone as control. After confirming BMP2 expression and miRNA transcription, increased osteogenic differentiation was observed by all hybrid vectors, but most consistently by BMP2/miR-590-5p, using alkaline phosphatase enzyme activity assays and osteogenic marker mRNA quantitation, including runt-related transcription factor 2 (Runx2), collagen type 1 (Col1a1) and osteocalcin. To visualise target mRNAs of the respective miRNAs, next generation sequencing was performed, confirming down-regulation of mRNA targets of the hybrid vectors. Since the hybrid vector consisting of BMP2 and miR-590-5p showed the largest increase in osteogenic differentiation in vitro, this was tested in a mouse ectopic-bone model. Mineralisation was more than with BMP2 alone. The present study showed hybrid vectors as a novel non-viral gene therapeutic plasmid system for combining therapeutic effects of recombinant protein expression and miRNA transcription that did not add to the burden of the translation machinery, while improving the therapeutic efficacies. In vivo proof-of-principle in the context of bone regeneration suggested that such hybrid vectors will be applicable in a wide array of gene therapeutic strategies.

Personalized cancer treatments help to deliver tailored and biologically driven therapies for cancer patients. Interventional oncology techniques are able to treat malignancies in a locoregional fashion, with a variety of mechanisms of action leading to tumor necrosis. Tumor destruction determines a great availability of tumor antigens that can be recognized by the immune system, potentially triggering an immune response. The advent of immunotherapy in cancer care, with the introduction of specific immune checkpoint inhibitors, has led to the investigation of the synergy of these drugs when used in combination with interventional oncology treatments. The aim of this paper is to review the most recent advances in the field of interventional oncology locoregional treatments and their interactions with immunotherapy.

Transjugular intrahepatic porto-systemic shunt (TIPSS) is an interventional radiology procedure whose aim is to create artificial communication between the portal and the hepatic blood flow in order to reduce the pressure gradient in portal hypertension. The indications to perform a TIPSS procedure can be framed in an elective or emergency setting: refractory ascites to diuretic therapy and secondary prophylaxis of variceal hemorrhage are the most frequent reasons for executing a TIPSS in an election context, while acute uncontrolled variceal bleeding is the principal indication that a TIPSS needs to be performed in an emergency setting. In recent years, the role of the TIPSS has been redefined for several conditions, such as ectopic varices, portal vein thrombosis, Budd–Chiari syndrome, hepatic veno-occlusive disease, and many others. This review aims to perform a deep analysis of when and why a TIPSS procedure should be carried out in an emergency, pointing out the related most common technical difficulties and complications.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease; patients’ long-term survival is strictly linked to the surgical resection of the tumor but only a minority of patients (2–3%) have a resectable disease at diagnosis. In patients with surgically unresectable disease, interventional radiology is taking on an increasing role in treatment with the application of loco-regional percutaneous therapies. The primary purposes of this narrative review are to analyze the safety and efficacy of ablative techniques in the management of borderline resectable and locally advanced diseases and to underline the role of the interventional radiologist in the management of patients with distant metastases. The secondary purpose is to focus on the synergy between immunotherapy and ablative therapies.

In this article, the link among the classes of stationary covariance functions, positive definite functions, and the class of functions defined through Bochner's theorem has been properly analyzed: indeed, in the literature, the relationship among the above classes of functions has often generated some misunderstanding. Moreover, in order to provide an exhaustive outline on the above classes, a generalization of Bochner's theorem has been pointed out. For what concerns all the properties and results given in this article for positive definite and strictly positive definite functions, it has been underlined which of them are very general, that is, they are valid for any covariance function, hence they are independent from Bochner's theorem and which of them are strictly related to Bochner's representation, which provides a complete characterization for the special subclass of continuous covariance functions. On the other hand, several applications in time series, in spatial and, more generally, in spatiotemporal literature utilize covariance models which are characterized by a discontinuity at the origin, that is, a nugget effect, or are zero almost everywhere, hence these covariance functions cannot be represented through Bochner's theorem. Some useful results on the subset of the covariance functions, which are strictly positive definite and occur in all the interpolation problems, have also been given. [ABSTRACT FROM AUTHOR]

The KRAS mutation stands out as one of the most influential oncogenic mutations, which directly regulates the hallmark features of cancer and interacts with other cancer-causing driver mutations. However, there remains a lack of precise information on their cooccurrence with mutated variants of KRAS and any correlations between KRAS and other driver mutations. To enquire about this issue, we delved into cBioPortal, TCGA, UALCAN, and Uniport studies. We aimed to unravel the complexity of KRAS and its relationships with other driver mutations. We noticed that G12D and G12V are the prevalent mutated variants of KRAS and coexist with the TP53 mutation in PAAD and CRAD, while G12C and G12V coexist with LUAD. We also noticed similar observations in the case of PIK3CA and APC mutations in CRAD. At the transcript level, a positive correlation exists between KRAS and PIK3CA and between APC and KRAS in CRAD. The existence of the co-mutation of KRAS and other driver mutations could influence the signaling pathway in the neoplastic transformation. Moreover, it has immense prognostic and predictive implications, which could help in better therapeutic management to treat cancer. [ABSTRACT FROM AUTHOR]

Sleep disorders affect millions of people around the world and have a high comorbidity with psychiatric disorders. While current hypnotics mostly increase non-rapid eye movement sleep (NREMS), drugs acting selectively on enhancing rapid eye movement sleep (REMS) are lacking. This polysomnographic study in male rats showed that the first-in-class selective melatonin MT1 receptor partial agonist UCM871 increases the duration of REMS without affecting that of NREMS. The REMS-promoting effects of UCM871 occurred by inhibiting, in a dose–response manner, the firing activity of the locus ceruleus (LC) norepinephrine (NE) neurons, which express MT1 receptors. The increase of REMS duration and the inhibition of LC-NE neuronal activity by UCM871 were abolished by MT1 pharmacological antagonism and by an adeno-associated viral (AAV) vector, which selectively knocked down MT1 receptors in the LC-NE neurons. In conclusion, MT1 receptor agonism inhibits LC-NE neurons and triggers REMS, thus representing a novel mechanism and target for REMS disorders and/or psychiatric disorders associated with REMS impairments. [ABSTRACT FROM AUTHOR]

All patients with Chronic Obstructive Pulmonary Disease (COPD), a multifactorial illness, have decreased post-bronchodilator lung function. While it was once believed that hyperresponsiveness and acute bronchodilator reversibility were characteristics of asthma, it is now generally acknowledged that these clinical features also occur in COPD. The current review provides an overview of corticosteroids' role in treating COPD signs. Both localized and systemic inflammations are key components of the pathophysiology of COPD. Inflammation occurs during an exacerbation and has been linked to a quicker course of COPD. Both systemic and local inflammations have been linked to COPD and using both Inhaled and Systemic Corticosteroids (ICS) has been found to be important when treating COPD. According to several current international documents on the management and therapy of COPD, patients at high risk of exacerbations-those with a Forced Expiratory Volume in one second (FEV1) of a fifty percent probability of exacerbation or more than one exacerbation per year-should receive ICS in addition to long-acting bronchodilators as maintenance treatment. In summary, systemic corticosteroids are the gold standard for treating Acute Exacerbations of COPD (AECOPD). Research has shown that using these drugs can improve lung function in the short term while reducing the likelihood of treatment failure, 30-day recurrence rates and length of hospital stay. [ABSTRACT FROM AUTHOR]

To critically explore experiences following thumb amputation and delineate elements of an ideal thumb prosthesis from the end user perspective. A qualitative study was undertaken with end user stakeholder groups, which included persons with a thumb amputation, rehabilitation professionals, and prosthetists. Analysis proceeded in line with conventional content analysis. Six patients with traumatic thumb amputation and eight healthcare providers (HCPs) were interviewed. Six themes were identified. The first theme discussed the impact of losing a thumb upon function, occupational activities, and mental wellbeing. The second theme reflected the idiosyncratic nature of thumb amputees, including their goals and nature of injury. The third theme stressed the costs associated with obtaining a thumb prosthesis. The fourth theme explored patient frustration and causes of device abandonment. Theme five summarized opinions on currently available thumb prostheses, and theme seven was the ideal design for a thumb prosthetic, including sensory elements and materials. Representative data from stakeholders mapped the current status of thumb prostheses. Preferences for an ideal thumb prosthesis included a simple, durable design with the ability to oppose, grasp, and sense pressure. Affordable cost and ease of fit emerged as systemic objectives. Provides insight into the experiences of individuals following thumb amputation. Identifies challenges that may lead to prosthetic abandonment so that these can be considered and addressed by rehabilitation professionals. Identifies positive elements and preferred materials in current prosthetics so that rehabilitation professionals may incorporate these more frequently. [ABSTRACT FROM AUTHOR]

Microplastic pollution is an emerging topic in environmental science. However, information about its prevalence in the freshwater ecosystems is still scarce. This study quantified and identified microplasticform and polymer types from surface sediments of the Molawin River. Sediment samples were collected from the upstream, midstream, and downstream stations of the river. Isolation of microplastics was performed through a modified granulometric approach, density separation, and filtration. Stereoscopic microscopy and Fourier-transform infrared spectroscopy (FTIR) were conducted to quantify and describe microplastics and identify the polymer types based on the infrared spectrum of absorption, respectively. Thehighest concentration of microplastics was found in the downstream station, with an average number of 97±12 items/100 g and 47.33±11.39 items/100 g sediment dry weight in the bank and channel, respectively. The isolated microplasticswere dominated by ≥100 to ≤200 μm size range. Based on stereoscopic microscopy, microfragments and microfibers were the most common microplastic type, while polyethylene (PE) and polypropylene (PP) were the polymer types identified based on FTIR analyses.This study revealed the presence of microplastics and confirmed the microplastics polymers present in the Molawin Watershed of Makiling Forest Reserve.