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Over the past several years, multifaceted advances in the management of cancer have led to a significant improvement in survival rates. Throughout patients' oncological journeys, they will likely receive one or more implantable devices for the administration of fluids and medications as well as management of various comorbidities and complications related to cancer therapy. Infections associated with these devices are frequent and complex, often necessitating device removal, increasing health care costs, negatively affecting quality of life, and complicating oncological care, usually leading to delays in further life-saving cancer therapy. Herein, the authors comprehensively review multiple evidence-based recommendations along with best practices, expert opinions, and novel approaches for the prevention of diverse device-related infections. The authors present many general principles for the prevention of these infections followed by specific device-related recommendations in a systematic manner. The continuous involvement and meaningful cooperation between regulatory entities, industry, specialty medical societies, hospitals, and infection control-targeted interventions, along with primary care and consulting health care providers, are all vital for the sustained reduction in the incidence of these preventable infections.

Hypertrophic cardiomyopathy is an inherited disorder due to mutations in contractile proteins that results in a stiff, hypercontractile myocardium. To understand the role of cardiac stiffness in disease progression, here we create an in vitro model of hypertrophic cardiomyopathy utilizing hydrogel technology. Culturing wild-type cardiac myocytes on hydrogels with a Young’s Moduli (stiffness) mimicking hypertrophic cardiomyopathy myocardium is sufficient to induce a hypermetabolic mitochondrial state versus myocytes plated on hydrogels simulating healthy myocardium. Significantly, these data mirror that of myocytes isolated from a murine model of human hypertrophic cardiomyopathy (cTnI-G203S). Conversely, cTnI-G203S myocyte mitochondrial function is completely restored when plated on hydrogels mimicking healthy myocardium. We identify a mechanosensing feedback mechanism between the extracellular matrix and cytoskeletal network that regulates mitochondrial function under healthy conditions, but participates in the progression of hypertrophic cardiomyopathy pathophysiology resulting from sarcomeric gene mutations. Importantly, we pinpoint key ‘linker’ sites in this schema that may represent potential therapeutic targets.

Background Percutaneous nephrostomy tube infections (PCNIs) are complex, affect quality of life, necessitate implant exchanges, and increase health care costs. Here, we analyzed risk factors for recurrent PCNIs in patients treated with our standardized institutional algorithm. Methods At our institution, we prospectively evaluated consecutive patients with gynecological malignancies who developed PCNIs between July 2019 to September 2021. All patients were treated using our institutional algorithm for PCNI, which consists of obtaining blood cultures plus urine analyses and cultures from each percutaneous nephrostomy tube (PCN); utilizing ultrasound or abdominal pelvic computed tomography scans to rule out obstructive hydronephrosis, pyelonephritis, or renal abscess; exchanging the PCN once patients are receiving concordant antimicrobial therapy; and having patients complete an adequate course of targeted antimicrobials. Thereafter, patients were followed up until reinfection, routine PCN exchange at 3 months, being lost to follow-up, or death. Results We treated 100 patients. Their median age was 54 years; 53% were White. The most common malignancies were cervical (61%), ovarian (23%), and endometrial (13%), with 60% being metastatic. To analyze the risk factors for developing a recurrent PCNI, patients were placed in 3 different groups: those reinfected with the same organism (19%), reinfected with a different organism (17%), and not reinfected (64%). Overall, there were no differences among the patient groups regarding demographics, comorbidities, clinical presentation, infection timing, PCN exchange (Table 1) or microorganisms encountered (Table 2). However, patients with prior radiation therapy or pelvic fistulas (urinary-vaginal-rectal or their permutations) had higher rates for developing a recurrent PCNIs with the same organism (P< .002). Conclusion Patients with prior radiation therapy and underlying pelvic fistulas have an increased risk for reinfection with the same pathogen. Therefore, further studies should be performed to mitigate this increased risk of recurrent infections with more frequent PCN exchanges or, more invasive procedure such as ureteral embolization, sclerosis, or ligation to dissociate the upper and lower urinary tracts. Disclosures All Authors: No reported disclosures.

Replicating organizational principles that establish fine-scale tissue structure is critical to our capacity for building functional replacement tissues. Tissue boundaries such as epithelial-mesenchymal interfaces are engines for morphogenesisin vivo. However, despite a wealth of micropatterning approaches available to control tissue size, shape, and mechanical environmentin vitro, fine-scale spatial control of cell composition within tissue constructs remains an engineering challenge. To address this, we augment DNA “velcro” technology for selective patterning of ssDNA-labeled cells with long-term culture on mechanically defined polyacrylamide hydrogels. We co-functionalize photoactive benzophenone-containing polyacrylamide gels (BP-PA gels) with spatially precise ssDNA features that confer temporary cell adhesion and with extracellular matrix (ECM) proteins that confer long-term adhesion. We find that co-functionalization does not compromise ssDNA patterning fidelity or cell capture, nor hydrogel mechanical properties or mechanosensitive fibroblast spreading, enabling mechanobiology studies of precise cell interfaces. We then co-pattern colonies of fibroblasts and epithelial cells to study interface formation and extracellular signal-related kinase (ERK) activity at cellular contacts. Combining DNA velcro and ECM functionalization approaches provides independent control of initial cell placement, adhesion, and mechanical environment, constituting a new tool for studying biological interfaces and for programming multicellular interactions in engineered tissues.

Introduction Recent clinical trials of heart failure with preserved ejection fraction (HFpEF) have observed varying patient profiles by ejection fraction (EF), with attenuation of treatment benefits as EF increases. In routine clinical practice, the degree to which patients hospitalized for HF with EF≥60% may differ from those with lower EF is unknown. Purpose To compare patient characteristics, treatment patterns, and clinical outcomes across the range of EF among patients hospitalized for HFpEF. Methods Using the Humedica electronic medical records database between Jan 2010 and Dec 2020, patients hospitalized for a primary diagnosis of HF with EF>40% and who were haemodynamically stable at admission, without concurrent acute coronary syndrome or end-stage renal disease, and treated with intravenous (IV) diuretic agents within 48 h of admission were identified. Patient characteristics, treatment patterns, and clinical outcomes were compared by EF ranges of 41–49%, 50–59%, and ≥60%. Results Of 47,026 patients hospitalized with HFpEF, 6,335 (13%) had EF 41–49%, 18,603 (40%) had EF 50–59%, and 22,088 (47%) had EF≥60%. Across all 3 groups, patients were similar with respect to age (median 77 years for each group), race (83–84% White, 12–13% Black), systolic blood pressure (137–138 mmHg at admission), and eGFR (63–64 mL/min/1.73 m2 at admission). With progressively higher EF group, the proportion of women increased (45% vs 54% vs 65%) and median NT-proBNP decreased (4,221 vs 2,945 vs 2,234 pg/mL). Patients with EF ≥60% had the lowest rates of coronary artery disease and atrial fibrillation, and the highest rates of chronic pulmonary disease (Figure 1, Panel A). Discharge medications were generally similar, with exception of less beta-blocker use and more calcium channel blocker use among those with EF ≥60% (Figure 1, Panel B). Discharge use of angiotensin receptor-neprilysin inhibitor and sodium glucose cotransporter-2 inhibitor therapies were each Conclusion In a contemporary real-world population of US patients hospitalized for HF with EF >40%, nearly half had an EF≥60%. While clinical profiles and discharge medications varied, post-discharge outcomes were similarly poor irrespective of EF. There remain important opportunities to improve the care and outcomes for patients with HF across the range of preserved ejection fraction. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): MyoKardia, Inc., a wholly owned subsidiary of Bristol Myers Squibb

Cell phone and social media usage have become intriguing topics to explore and discuss over recent years. This research aims to review correlations of negative effects in mental and physical health caused by cell phone and social media use in the past two decades. The history of cell phones and their capabilities will be introduced. The need for human connection will be emphasized. Exploration of the connection between unbalanced use and different aspects of health will be evaluated such as addiction, social influences, brain changes, and multitasking. Lastly, resources and recommendations to find balance and support for anyone being adversely affected by cell phones and social media will be provided. Current literature reveals that there is a negative correlation between increased cell phone and social media use with human connection, mental health, and physical health.

Background:Procalcitonin (PCT) has been used to guide antibiotic therapy in bacterial infections. We aimed to determine the role of PCT in decreasing the duration of empiric antibiotic therapy among cancer patients admitted with COVID-19.Methods:This retrospective study included cancer patients admitted to our institution for COVID-19 between March 1, 2020, and June 28, 2021, with a PCT test done within 72 hr after admission. Patients were divided into two groups: PCT Results:The study included 530 patients (median age, 62 years [range, 13–91]). All the patients had ≥1 culture test within 7 days following admission. Patients with PCT 72 hr than were patients with PCT ≥0.25 ng/ml (45% [162/358] vs. 69% [119/172]; pConclusions:Among cancer patients with COVID-19, PCT level 72 hr may not be necessary. PCT could be useful in enhancing antimicrobial stewardship in cancer patients with COVID-19.Funding:This research was supported by the National Institutes of Health/National Cancer Institute under award number P30CA016672, which supports MD Anderson Cancer Center’s Clinical Trials Office.

The kidney develops through elaboration of ureteric bud tubules (the future urinary collecting ducts), stroma, and nephron progenitors in the cap mesenchyme that surround each tubule tip as they branch. Dynamic interactions between these tissues coordinate a balance between ureteric bud (UB) tip branching and nephron formation that sets nephron numbers for life, which impacts the likelihood of adult disease. How then is this balance achieved? Here we study the geometric and mechanical consequences of tubule tip crowding at the embryonic kidney surface and its effect on nephron formation. We find that kidney surface curvature reduces and tubule ‘tip domains’ pack more closely over developmental time. These together create a semi-crystalline geometry of tips at the kidney surface and a rigidity transition to more solid-like tissue properties at later developmental stages. New tips overcome mechanical resistance as they branch, expand, and displace close-packed neighbors, after which residual mechanical stress dissipates. This correlates with a changing nephrogenesis rate over the tip ‘life-cycle’. To draw a causal link between the two, we mimic a mechanical transient in human iPSC-derived nephron progenitor organoids and find increased cell commitment to early nephron aggregates. The data suggest that temporal waves of mechanical stress within nephron progenitor populations could constitute a pace-maker that synchronizes nephron formation and UB tubule duplication after E15. Ongoing efforts to understand the spatial and temporal regulation of nephron induction will clarify variation in nephron endowment between kidneys and advance engineered kidney tissues for regenerative medicine.

Mooring Integrity Management (MIM) is a key operational aspect for FPSO operators, mooring system designers and Recognized Classification Societies (RCS). MIM programs should include the capability to detect a mooring line failure. When direct or indirect measurement of line tension is available continuously and reliably over time, this requirement can be readily fulfilled. Current industry-wide experience shows it has been challenging to develop robust cost-effective real-time anchor line load monitoring systems for the offshore environment. To remedy this situation, Artificial Intelligence (AI) techniques are used to extract an intact or damage diagnosis for a spread moored unit offshore Brazil based on data readily available in situ. The Intelligent Agent (IA) developed has been reviewed by the Classification Society against Ref. [1] and [2]. Following this review a statement of maturity has been issued Ref. [3] qualifying the new technology.

BackgroundCardiovascular disease is the leading cause of death in Australia. Investment in research solutions has been demonstrated to yield health and a 9.8-fold return economic benefit. The sector, however, is severely challenged with success rates of traditional peer-reviewed funding in decline. Here, we aimed to understand the perceived challenges faced by the cardiovascular workforce in Australia prior to the COVID-19 pandemic.MethodsWe used an online survey distributed across Australian cardiovascular societies/councils, universities and research institutes over a period of 6 months during 2019, with 548 completed responses. Inclusion criteria included being an Australian resident or an Australian citizen who lived overseas, and a current or past student or employee in the field of cardiovascular research.ResultsThe mean age of respondents was 42±13 years, 47% were male, 85% had a full-time position, and 40% were a group leader or laboratory head. Twenty-three per cent (23%) had permanent employment, and 82% of full-time workers regularly worked >40 hours/week. Sixty-eight per cent (68%) said they had previously considered leaving the cardiovascular research sector. If their position could not be funded in the next few years, a staggering 91% of respondents would leave the sector. Compared to PhD- and age-matched men, women were less likely to be a laboratory head and to feel they had a long-term career path as a cardiovascular researcher, while more women were unsure about future employment and had considered leaving the sector (all pConclusionStrategic solutions, such as diversification of career pathways and funding sources, and moving from a competitive to a collaborative culture, need to be a priority to decrease reliance on government funding and allow cardiovascular researchers to thrive.

Significance Hypertrophic cardiomyopathy affects 1:500 of the general population. Current drug therapy is used to manage symptoms in patients. There is an unmet need for treatments that can prevent the cardiomyopathy. Here we identify biomarkers of hypertrophic cardiomyopathy resulting from causing cardiac troponin I mutation Gly203Ser, and present a safe, nontoxic, preventative approach for the treatment of associated cardiomyopathy., Currently there is an unmet need for treatments that can prevent hypertrophic cardiomyopathy (HCM). Using a murine model we previously identified that HCM causing cardiac troponin I mutation Gly203Ser (cTnI-G203S) is associated with increased mitochondrial metabolic activity, consistent with the human condition. These alterations precede development of the cardiomyopathy. Here we examine the efficacy of in vivo treatment of cTnI-G203S mice with a peptide derived against the α-interaction domain of the cardiac L-type calcium channel (AID-TAT) on restoring mitochondrial metabolic activity, and preventing HCM. cTnI-G203S or age-matched wt mice were treated with active or inactive AID-TAT. Following treatment, targeted metabolomics was utilized to evaluate myocardial substrate metabolism. Cardiac myocyte mitochondrial metabolic activity was assessed as alterations in mitochondrial membrane potential and flavoprotein oxidation. Cardiac morphology and function were examined using echocardiography. Cardiac uptake was assessed using an in vivo multispectral imaging system. We identified alterations in six biochemical intermediates in cTnI-G203S hearts consistent with increased anaplerosis. We also reveal that AID-TAT treatment of precardiomyopathic cTnI-G203S mice, but not mice with established cardiomyopathy, restored cardiac myocyte mitochondrial membrane potential and flavoprotein oxidation, and prevented myocardial hypertrophy. Importantly, AID-TAT was rapidly targeted to the heart, and not retained by the liver or kidneys. Overall, we identify biomarkers of HCM resulting from the cTnI mutation Gly203Ser, and present a safe, preventative therapy for associated cardiomyopathy. Utilizing AID-TAT to modulate cardiac metabolic activity may be beneficial in preventing HCM in “at risk” patients with identified Gly203Ser gene mutations.

The evolutionary acquisition of mitochondria has given rise to the diversity of eukaryotic life. Mitochondria have retained their ancestral α-proteobacterial traits through the maintenance of double membranes and their own circular genome. Their genome varies in size from very large in plants to the smallest in animals and their parasites. The mitochondrial genome encodes essential genes for protein synthesis and has to coordinate its expression with the nuclear genome from which it sources most of the proteins required for mitochondrial biogenesis and function. The mitochondrial protein synthesis machinery is unique because it is encoded by both the nuclear and mitochondrial genomes thereby requiring tight regulation to produce the respiratory complexes that drive oxidative phosphorylation for energy production. The fidelity and coordination of mitochondrial protein synthesis are essential for ATP production. Here we compare and contrast the mitochondrial translation mechanisms in mammals and fungi to bacteria and reveal that their diverse regulation can have unusual impacts on the health and disease of these organisms. We highlight that in mammals the rate of protein synthesis is more important than the fidelity of translation, enabling coordinated biogenesis of the mitochondrial respiratory chain with respiratory chain proteins synthesised by cytoplasmic ribosomes. Changes in mitochondrial protein fidelity can trigger the activation of the diverse cellular signalling networks in fungi and mammals to combat dysfunction in energy conservation. The physiological consequences of altered fidelity of protein synthesis can range from liver regeneration to the onset and development of cardiomyopathy.

Degeneration of the intervertebral disc (IVD) is known to occur naturally over time, with the severity of pain varying widely. Other components of the degenerative environment, including structural disruption and inflammatory cytokine levels, and their correlation with pain severity have been studied. However, the role of the inflammatory environment in activating degenerative changes that manifest as a pain phenotype has not been elucidated. Previous studies have aimed to recreate the sustained inflammatory environment exhibited during human disc degeneration in a rat model. Most commonly, a puncture injury has been used causing structural damage and only initiating an acute inflammatory response. This study utilized injection of lipopolysaccharide (LPS), a pro-inflammatory stimulus, into the rat disc in vivo to create the desired sustained inflammatory environment independent of physical disruption. LPS injections resulted in upregulation of pro-inflammatory cytokines and an immunogenic response. The structural integrity of the IVD was also altered demonstrated by changes in histological score, disc height, and mechanical properties. Ultimately, a sustained inflammatory environment led to both local and radiating mechanical sensitivity, demonstrating that the pain phenotype experienced during disc degeneration can be initiated solely by a sustained inflammatory profile. Markers indicative of nerve ingrowth into the IVD were also expressed suggesting a potential mechanism for the pain exhibited by animals. This rat injury model will allow for future study of the direct relationship between inflammation and pain in the degenerative environment.

Animal vocalizations have nonlinear characteristics responsible for features such as subharmonics, frequency jumps, biphonation, and deterministic chaos. This study describes the whistle repertoire of a short-beaked common dolphin (Delphinus delphis) group at Brazilian coast and quantifies the nonlinear features of these whistles. Dolphins were recorded for a total of 67 min around Cabo Frio, Brazil. We identify 10 basic categories of whistle, with 75 different types, classified according to their contour shape. Most (45) of these 75 types had not been reported previously for the species. The duration of the whistles ranged from 0.04 to 3.67 s, with frequencies of 3.05–29.75 kHz. Overall, the whistle repertoire presented here has one of the widest frequency ranges and greatest level of frequency modulation recorded in any study of D. delphis. All the nonlinear features sought during the study were confirmed, with at least one feature occurring in 38.4% of the whistles. The frequency jump was the most common feature (29.75% of the whistles) and the nonlinear time series analyses confirmed the deterministic chaos in the chaotic-like segments. These results indicate that nonlinearities are a relevant characteristic of these whistles, and that are important in acoustic communication.

Large-scale optimization problems that seek sparse solutions have become ubiquitous. They are routinely solved with various specialized first-order methods. Although such methods are often fast, they usually struggle with not-so-well conditioned problems. In this paper, specialized variants of an interior point-proximal method of multipliers are proposed and analyzed for problems of this class. Computational experience on a variety of problems, namely, multi-period portfolio optimization, classification of data coming from functional Magnetic Resonance Imaging, restoration of images corrupted by Poisson noise, and classification via regularized logistic regression, provides substantial evidence that interior point methods, equipped with suitable linear algebra, can offer a noticeable advantage over first-order approaches.

The physiological functions of several organs rely on branched tubular networks, but little is known about conflicts in development between building enough tubules for adequate function and geometric constraints imposed by organ size. We show that the mouse embryonic kidney epithelium negotiates a physical packing conflict between tubule tip duplication and limited area at the organ surface. Imaging, computational, and soft material modeling of tubule ‘families’ identifies six geometric packing phases, including two defective ones. Experiments in kidney explants show that a retrograde tension on tubule families is necessary and sufficient for them to avoid defects by switching to a vertical orientation that increases packing density. These results reveal developmental contingencies in response to physical limitations, and create a framework for classifying kidney defects.One-Sentence SummaryEpithelial branching in the kidney causes a geometric packing conflict that is resolved through internally generated tensions

BackgroundThe use of biological and targeted synthetic drugs has changed the outcomes of rheumatic diseases. The information on efficacy and safety provided by randomized controlled clinical trials does not always reflect the conditions of patients in real life. Data obtained from prospective registries, over extended periods and with real-world evidence, is a great contribution to the pharmacovigilance of these drugs.ObjectivesThe aim of this study is to describe adverse events (AE) and survival of treatments of patients included in the Argentine Registry of Adverse Events of Biological Therapies and Target Synthetic Drugs (BIOBADASAR 3.0).MethodsObservational, prospective and multicenter study of ten years of follow-up in patients with rheumatic diseases treated with original biological drugs, biosimilars or original and generic targeted synthetic therapies in Argentine. Those patients who received biological therapies were considered exposed while non-exposed patients represent the control group. All patients were evaluated at least once a year and whenever they experienced an AE or a change in treatment. Survival of treatments was evaluated by Kaplan Meier curves and the comparison between them was made by Log Rank Test analysis.ResultsA total of 6010 patients were included and 8810 treatment periods from 56 centers. 79.7% were female, mean age of 43.7 (SD 15.6) years. The most frequently reported rheumatological disease was rheumatoid arthritis (RA) (77.5%), followed by psoriatic arthritis (PsA) (8.2%), systemic lupus erythematosus (SLE) (3.1%), juvenile idiopathic arthritis (JIA) (2.6%) and ankylosing spondylitis (AS) (2.5%). The b-DMARD use frequencies were etanercept in 32.2%, followed by adalimumab in 18.7%, abatacept in 9.7%, certolizumab pegol in 8.7%, tofacitinib in 7.9%, rituximab in 7.3% and tocilizumab in 5.5%. The frequency of AE was 11.7% in the exposed group and 4.9% in controls (p=0.001). Infections were present in 41% in the exposed group vs 34% in controls (pConclusionWe found that the use of steroids and elderly patients are still being associated with a higher risk of presenting an AE and treatment discontinuing. This could be related to the fact that the use of steroids is frequently associated with active disease or severe conditions. Exposed patients have a lower AE-free survival and a lower treatment survival. This could be since unexposed patients have a longer follow-up time and a longer duration of their disease. This data from real-world Latin American patients of ten years of follow-up are extremely useful for monitoring and pharmacovigilance of biological therapies in patients with rheumatic diseases.References[1]De la Vega M, et al. The importance of rheumatology biologic registries in Latin America. Rheumatol Int. 2013;33(4):827-35. Rocha FA. Latin-American challenges and opportunities in rheumatology. Arthritis Res Ther. 2017;19(1):29.[2]Prior-Español A, et al. Clinical factors associated with discontinuation of ts/bDMARDs in rheumatic patients from the BIOBADASER III registry. Sci Rep. 2021 May 27;11(1):11091. doi: 10.1038/s41598-021-90442-w. PMID: 34045525; PMCID: PMC8159943.Disclosure of InterestsNone declared

BackgroundInfective endocarditis (IE) is more common in patients with cancer as compared with the general population. Due to an immunocompromised state, the need for invasive procedures, hypercoagulability and the presence of indwelling catheters, patients with cancer are particularly predisposed to the development of IE.ObjectivesLimited information exists about IE in patients with cancer. We aimed to evaluate the characteristics of patients with cancer and IE at our tertiary care centre, including a comparison of the microorganisms implicated and their association with mortality.MethodsA retrospective chart review of patients with cancer who had echocardiography for suspicion of endocarditis was conducted. A total of 56 patients with a confirmed diagnosis of cancer and endocarditis, based on the modified Duke criteria, were included in the study. Baseline demographics, risk factors for developing IE, echocardiography findings, microbiology and mortality data were analysed.ResultsFollowing the findings of vegetations by echocardiography, the median survival time was 8.5 months. Staphylococcus aureus was the most common organism identified as causing endocarditis. The mitral and aortic valves were the most commonly involved sites of endocarditis. Patients with S. aureus endocarditis (SAE) had a significantly poorer survival when compared with patients without SAE (p=0.0217) over the 12-month period from diagnosis of endocarditis.ConclusionsOverall survival of patients with cancer and endocarditis is poor, with a worse outcome in patients with SAE.

Description, A variant in an RNA processing enzyme predisposes to insulin resistance by reducing calcium release and insulin secretion., Mitochondrial energy metabolism plays an important role in the pathophysiology of insulin resistance. Recently, a missense N437S variant was identified in the MRPP3 gene, which encodes a mitochondrial RNA processing enzyme within the RNase P complex, with predicted impact on metabolism. We used CRISPR-Cas9 genome editing to introduce this variant into the mouse Mrpp3 gene and show that the variant causes insulin resistance on a high-fat diet. The variant did not influence mitochondrial gene expression markedly, but instead, it reduced mitochondrial calcium that lowered insulin release from the pancreatic islet β cells of the Mrpp3 variant mice. Reduced insulin secretion resulted in lower insulin levels that contributed to imbalanced metabolism and liver steatosis in the Mrpp3 variant mice on a high-fat diet. Our findings reveal that the MRPP3 variant may be a predisposing factor to insulin resistance and metabolic disease in the human population.

Nowadays nanoparticles are increasingly investigated for the targeted and controlled delivery of therapeutics, as suggested by the high number of research articles (2400 in 2000 vs 8500 in 2020). Among them, almost 2% investigated nanogels in 2020. Nanogels or nanohydrogels (NGs) are nanoparticles formed by a swollen three-dimensional network of synthetic polymers or natural macromolecules such as polysaccharides. NGs represent a highly versatile nanocarrier, able to deliver a number of therapeutics. Currently, NGs are undergoing clinical trials for the delivery of anti-cancer vaccines. Herein, the strategies to load low molecular weight drugs, (poly)peptides and genetic material into polysaccharide NGs as well as to formulate NGs-based vaccines are summarized, with a focus on the microfluidics approach., Carbohydrate Polymers, 266

A series of M41S type mesoporous molecular sieves modified with copper were synthesized through Template-Ion Exchange (TIE). The influence of hydrothermal treatment and mixing time at room temperature over the solids structural and chemical properties was evaluated in detail for a single Cu content. Characterization of the materials was carried out through various techniques: XRD, N2 adsorption-desorption, SEM, XPS, atomic absorption, UV–vis DR and TPR. It was found that different stirring times at room temperature had no significant influence over the physical and chemical characteristics of the final solid. However, hydrothermal treatment had a slight effect over the materials structure and metallic species distribution. In order to assess copper content influence, two other non-treated solids with different metallic contents were synthesized, characterized, and compared with hydrothermally treated samples. The catalytic performance of the hydrothermally treated and non-treated materials was tested in the liquid phase oxidation of limonene employing hydrogen peroxide (H2O2) as oxygen donor, an important fine chemical reaction. Only one of the evaluated Cu contents exhibited a minor difference in catalytic activity according to the applied synthesis conditions. Hence, a simple TIE procedure without hydrothermal treatment can be employed for the synthesis of Cu-MCM materials. By suppressing hydrothermal treatment, it is possible to save around 10% of the total energy requirement for the complete synthesis process. Fil: Vaschetti, Virginia María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigación y Tecnología Química. Universidad Tecnológica Nacional. Facultad Regional Córdoba. Centro de Investigación y Tecnología Química; Argentina Fil: Viola, Belén Melisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigación y Tecnología Química. Universidad Tecnológica Nacional. Facultad Regional Córdoba. Centro de Investigación y Tecnología Química; Argentina Fil: Barrera Diaz, Deicy Amparo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Física Aplicada "Dr. Jorge Andrés Zgrablich". Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto de Física Aplicada "Dr. Jorge Andrés Zgrablich"; Argentina Fil: Sapag, Manuel Karim. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Física Aplicada "Dr. Jorge Andrés Zgrablich". Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto de Física Aplicada "Dr. Jorge Andrés Zgrablich"; Argentina Fil: Eimer, Griselda Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigación y Tecnología Química. Universidad Tecnológica Nacional. Facultad Regional Córdoba. Centro de Investigación y Tecnología Química; Argentina Fil: Cánepa, Analía Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigación y Tecnología Química. Universidad Tecnológica Nacional. Facultad Regional Córdoba. Centro de Investigación y Tecnología Química; Argentina Fil: Casuscelli, Sandra Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigación y Tecnología Química. Universidad Tecnológica Nacional. Facultad Regional Córdoba. Centro de Investigación y Tecnología Química; Argentina

The proper functioning of central lines is imperative for the management of patients with cancer or on hemodialysis. However, these lifelines can become infected and can malfunction.Chelators such as citrate and EDTA have been widely studied alone or in combination with other antimicrobial agents in catheter lock solutions to prevent catheter-related bloodstream infections and to maintain catheter patency. Given their anticoagulation, antiplatelet aggregation, antibiofilm, antimicrobial activity, safety profile, as well as their low cost, chelators have long been considered alternatives to heparin and a vital component of catheter lock solutions. In this review, we present a detailed summary of the properties of chelators and in vitro and in vivo studies of chelator-containing lock solutions.

The enhanced recovery after surgery (ERAS) is nowadays a widely accepted multimodal programme of care in colorectal surgery, but still there is some reluctance in its application to very elderly patients. The aim of this study is to investigate short-term outcomes of laparoscopic resection for colorectal cancer in octogenarian patients within the ERAS programme. Data on 162 consecutive patients aged ≥ 80 years receiving elective minimally invasive colorectal resections within ERAS programme were collected in a multicentre, retrospective database in the period 2008–2017 in Italy. Univariate and multivariate analyses were performed to assess possible risk factors for poor clinical outcomes. The postoperative minor morbidity rate (Clavien–Dindo 1 and 2) was 25.9%. The incidence of postoperative major morbidity rate (severe medical and surgical complications defined as Clavien–Dindo 3 and 4) accounted 6.1% and only 1.8% had an anastomotic leakage. Reoperation rate was 5.5%, perioperative 30-day mortality was 1.8%, and 30-day readmission rate was 6.8%. On average, patients were released after 6 days. A univariate analysis showed that possible risk factors for severe medical complications were: low preoperative albumin level, high Charlson Age Comorbidity Index Score and number of days in the intensive care unit (ICU); risk factors for severe surgical complications were: low preoperative albumin level; risk factors for late hospital discharge were: multivisceral resections, number of days in ICU and body mass index (BMI) > 25 kg/m2. The multivariate analysis confirmed a low level of preoperative albumin and a longer ICU stay as independent risk factors for both postoperative severe surgical complications and late hospital discharge. The minimal invasive nature of the laparoscopic approach together with a multimodal analgesia therapy, the early resumption to oral diet and mobilisation could minimize the surgical stress and play an essential role in order to reduce medical morbidity in high-risk patients. Colorectal surgery within ERAS programme in octogenarians is a safe and flexible treatment in high-volume centres.

Changes in the rate and fidelity of mitochondrial protein synthesis impact the metabolic and physiological roles of mitochondria. Here we explored how environmental stress in the form of a high‐fat diet modulates mitochondrial translation and affects lifespan in mutant mice with error‐prone (Mrps12ep / ep ) or hyper‐accurate (Mrps12ha / ha ) mitochondrial ribosomes. Intriguingly, although both mutations are metabolically beneficial in reducing body weight, decreasing circulating insulin and increasing glucose tolerance during a high‐fat diet, they manifest divergent (either deleterious or beneficial) outcomes in a tissue‐specific manner. In two distinct organs that are commonly affected by the metabolic disease, the heart and the liver, Mrps12ep / ep mice were protected against heart defects but sensitive towards lipid accumulation in the liver, activating genes involved in steroid and amino acid metabolism. In contrast, enhanced translational accuracy in Mrps12ha / ha mice protected the liver from a high‐fat diet through activation of liver proliferation programs, but enhanced the development of severe hypertrophic cardiomyopathy and led to reduced lifespan. These findings reflect the complex transcriptional and cell signalling responses that differ between post‐mitotic (heart) and highly proliferative (liver) tissues. We show trade‐offs between the rate and fidelity of mitochondrial protein synthesis dictate tissue‐specific outcomes due to commonly encountered stressful environmental conditions or aging., This work reveals how trade‐offs between the rate and fidelity of mitochondrial protein synthesis dictate tissue‐specific outcomes to metabolic stress or aging. Error‐prone protein synthesis enhanced the rate of translation, protecting against heart defects but stimulated lipid accumulation in the liver. Enhanced translational accuracy protected liver function through activation of proliferation programs, but resulted in severe hypertrophic cardiomyopathy and reduced lifespan.

BackgroundComorbidities, particularly cardio-metabolic disorders, are highly prevalent in patients with psoriatic arthritis (PsA) and they were associated with an increased risk of atherosclerotic cardiovascular disease, which have been associated with higher morbidity and mortality. Whether PsA enhances the risk of SARS-CoV-2 infection or affects the disease outcome remains to be ascertained.ObjectivesTo describe the sociodemographic, clinical and treatment characteristics of patients with PsA with confirmed SARS-CoV-2 infection from the SAR-COVID registry and to identify the variables associated with poor COVID-19 outcomes, comparing them with those with rheumatoid arthritis (RA).MethodsCross-sectional observational study including patients ≥18 years old, with diagnosis of PsA (CASPAR criteria) and RA (ACR / EULAR 2010 criteria), who had confirmed SARS-CoV-2 infection (RT-PCR or serology) from the SAR-COVID registry. Recruitment period was between August 13, 2020 and July 31, 2021. Sociodemographic variables, comorbidities, and treatments were analyzed. To assess the severity of the infection, the ordinal scale of the National Institute of Allergy and Infectious Diseases (NIAID)1 was used, and it was considered that a patient met the primary outcome, if they presented criteria of categories 5 or higher on the severity scale. For this analysis, Chi2 test, Fisher’s test, Student’s test or Wilcoxon test, and binomial logistic regression using NIAID>=5 as dependent variable were performed.ResultsA total of 129 PsA patients and 808 with RA were included. Clinical characteristics are shown in Table 1. Regarding PsA treatment, 12.4% of PsA were receiving IL-17 inhibitors, 5.4% IL12-23 inhibitors, one patient apremilast and one abatacept. The frequency of NIAID≥5 was comparable between groups (PsA 19.5% vs RA 20.1%; p=0.976). (Figure 1).Table 1.Characteristics of patients with PsA and RA who presented COVID-19 in the SAR-COVID registry.Psoriatic arthritis (n=129)Rheumatoid arthritis (n=808)P valueTotal (n=937)Age (years), mean (SD)51.7 (12.7)53.1 (12.9)0.23952.9 (12.9)Female72 (55.8)684 (84.7)756 (80.7)Comorbidities65 (50.4)355 (43.9)0.203420 (44.8) Obesity (BMI ≥30)19 (15.2)102 (13.4)0.692121 (13.7) Morbid obesity (BMI ≥40)1 (0.8)10 (1.3)111 (1.25) Hypertension35 (28.5)205 (26.8)0.783240 (27.0) Diabetes16 (13.0)67 (8.8)0.18883 (9.39) Dyslipidemia24 (19.5)102 (13.5)0.106126 (14.4) Cardiovascular or cerebrovascular disease5 (11.4)32 (3.9)0.03337 (4.2)Two or more comorbidities55 (42.6)219 (27.1)274 (29.2)Current smoking4 (3.6)60 (8.4)0.7964 (7.7)High disease activity0 (0)29 (3.8)0.02729 (3.23)Glucocorticoids treatment5 (20.0)95 (60.1)100 (54.6)Conventional DMARDs47 (36.4)443 (54.8)490 (52.3)Biologic DMARDs60 (46.5)193 (23.9)253 (27.0)JAK inhibitors4 (3.10)72 (8.9)0.03876 (8.1)Full recovery of COVID-19105 (84.0)644 (81.7)0.127749 (82.0)COVID-19 complications16 (12.5)68 (8.7)0.22784 (9.2)Death due to COVID-191 (0.8)34 (4.3)0.07435 (3.8)Notes=values n (%) unless otherwise indicated; BMI: Body Mass Index; DMARDs: disease-modifying antirheumatic drugs; JAK inhibitors: Janus kinase inhibitors.PsA patients with NIAID≥5 in comparison with NIAIDConclusionAlthough PsA patients have a higher frequency of cardiovascular and metabolic comorbidities than those with RA, the COVID-19 severity was similar. Most of the patients had mild SARS-CoV-2 infection and a low death rate.References[1]Beigel JH, et al. Remdesivir for the Treatment of Covid-19 - Final Report. N Engl J Med. 2020 Nov 5;383(19):1813-1826.Disclosure of InterestsNone declared

BackgroundAdvances in rheumatology and new therapeutic options have certainly impacted patient survival, changing the age range, from youth to seniors. The differences between the age groups could influence the evolution of the disease and the adverse events (AEs) related to the treatments. There are few real-world data on the safety and efficacy of treatments in different age groups.ObjectivesTo evaluate the frequency of AEs and the survival of treatments according to the age in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or ankylosing spondylitis (AS).MethodsRetrospective, observational, multicenter study of real-life data of patients included in the BIOBADASAR 3.0 registry; exposed and not exposed to original biological treatments (b-DMARDs), biosimilars, targeted synthetic drugs (ts-DMARDs). The unexposed group received treatment with conventional disease-modifying drugs (cDMARDs). A Kaplan-Meier and Log Rank Test analysis was performed to study AEs-free survival and treatment in different age groups (young people 65). Factors related to treatment survival were evaluated using Cox regression models.Results5,297 patients were included, 80.3% female, mean age 43.7 years (SD 15.6) and median disease progression 14.3 [IQR 11.5]. RA 4658 (87.9%); APs 490 (9.25%) and EA 149 (2.8%). The main reason for treatment discontinuation was ineffectiveness, in 624 patients in the exposed group and in 53 (2.5%) patients in control group, followed by the presence of AEs in 352 (11.2%) and 83 (3.9%), respectively (p=0.001).A mean Charlson Score of 0.268 (SD 0.6) in the exposed group and 0.306 (SD 0.7) in the control group (p=0.095). Median EAs-free survival in the exposed group was 12.5 years [IQR 16.6] while in controls was 28 years [IQR 11], p0.017). The exposed group presented a median treatment survival in years of 11.25 years [IQR: 10] in young people; 12.5 years [IQR: 4.7] in young adults, 7.5 years [IQR: 12.1] in mature adults and 4.5 years [IQR: 1.14] in old adults (p>0.0001). Considering only the first line of treatment, a median survival of 11.5 years [IQR: 10] was evidenced in the age group 65 years old (p>0.004). (Figure 1). Considering the second line of treatment, the differences between the groups were not statistically significant (p=0.57). In the multivariate regression model for patients with RA, the factors with the greatest impact on treatment survival were female sex (HR 1.3, 95% CI 1.2-1.4), old age (HR 1.01, 95% CI 1.008-1.01), treatment with steroids (HR 1.19, 95% CI1.1-1.2) and longer disease duration (HR 1.01, 95% CI1.01 – 1.02).ConclusionIn the present study we were able to demonstrate a greater occurrence of AEs in old adults and mature adults compared to young people and young adults. Conversely, survival for b-DMARDs and ts-DMARDs were greater in youth and young adults. In patients with RA, female sex, corticosteroid therapy, old aged and longer disease duration were associated with treatment discontinuation.References[1]Souto A, et al. Rate of discontinuation and drug survival of biologic therapies in rheumatoid arthritis: a systematic review and meta-analysis of drug registries and health care databases. Rheumatology (Oxford). 2016;55(3):523–34.[2]Ray D, et al. Immune senescence, epigenetics and autoimmunity. Clin Immunol. 2018 Nov;196:59-63. doi: 10.1016/j.clim.2018.04.002. Epub 2018 Apr 11.[3]Vela P, et al. Influence of age on the occurrence of adverse events in rheumatic patients at the onset of biological treatment: data from the BIOBADASER III register. Arthritis Res Ther. 2020 Jun 15;22(1):143. doi: 10.1186/s13075-020-02231-x.Disclosure of InterestsNone declared

The development of disseminated cryptococcosis has historically occurred in patients living with advanced human immunodeficiency virus or other immunosuppressive conditions affecting T-cell function. Recently, patients with anti-cytokine neutralising autoantibodies have been recognised to be at risk for disseminated infections by opportunistic intracellular pathogens, including Cryptococcus species. Herein, we present a previously healthy 26-year-old man who was evaluated with disseminated cryptococcosis involving the bone, lung, mediastinum and brain. The patient's serum cryptococcal antigen titres were >1:1,100,000, and evaluation for an underlying immunodeficiency revealed high titres for anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies. We also review the literature of all published cases of disseminated cryptococcosis associated with the presence of anti-GM-CSF autoantibodies. Clinicians should have a heightened awareness of anti-cytokine autoantibodies in patients without a known immunodeficiency and development disseminated infections by opportunistic intracellular pathogens.

Background Oncological patients have several additional risk factors for developing a cardiac implantable electronic device (CIED)–related infection. Therefore, we evaluated the clinical impact of our comprehensive bundle approach that includes the novel minocycline and rifampin antimicrobial mesh (TYRX) for the prevention of CIED infections in patients living with cancer. Methods We retrospectively reviewed all consecutive patients who had a CIED placement at our institution during 2012–2017 who received preoperative vancomycin, intraoperative pocket irrigation with bacitracin and polymyxin B, plus TYRX antimicrobial mesh, followed by postoperative oral minocycline. Results A total of 154 patients had a CIED, with 97 permanent pacemakers (PPMs), 23 implantable cardioverter defibrillators (ICDs), and 34 cardiac resynchronization therapy (CRT) devices. An underlying solid cancer was present in 62% of patients, while 38% had a hematologic malignancy. Apart from a higher proportion of surgical interventions in the PPM group than in the ICD and CRT groups (P = .007), no other oncologic variables were statistically significantly different between groups. Despite an extensive median follow-up period (interquartile range) of 21.9 (6.7–33.8) months, 16 patients (10%) had a mechanical complication, while only 2 patients (1.3%) developed a CIED infection, requiring the device to be explanted. Conclusions Our comprehensive prophylactic bundle approach using TYRX antimicrobial mesh in an oncologic population at high risk for infections was revealed upon extensive follow-up to be both safe and effective in maintaining the rate of CIED infection at 1.3%, well within published averages in the broader population of CIED recipients.

European regulation changes have pushed electric machine manufacturers to request new materials suitable for impregnation of High Voltage motors and generators that are also compliant with European health restrictions. Until now, the most widely used materials for coils insulation are a blend of epoxy resin and anhydride that impregnates mica tapes, containing an epoxy binder with a Zinc naphthenate catalyst, which has the advantage of stability in storage tanks and good thermal and electrical properties. The development of a new impregnating resin, made with a hybrid epoxy-polyester chemistry, highlighted the need to find a way to improve compatibility with mica tapes. This new resin / tape combination has been visually evaluated, as first step, and then tested on bars, observing how dissipation factor versus voltage change after thermal ageing at high temperatures. Test bars made with new resin/tape combination withstood thermal ageing for a longer time than reference materials, confirming that compatibility between impregnating resin and mica tapes is a crucial factor influencing thermal resistance of a coil main wall insulation system.

Sarcomeric gene mutations are associated with the development of hypertrophic cardiomyopathy (HCM). Current drug therapeutics for HCM patients are effective in relieving symptoms, but do not prevent or reverse disease progression. Moreover, due to heterogeneity in the clinical manifestations of the disease, patients experience variable outcomes in response to therapeutics. Mechanistically, alterations in calcium handling, sarcomeric disorganization, energy metabolism and contractility participate in HCM disease progression. While some similarities exist, each mutation appears to lead to mutation‐specific pathophysiology. Furthermore, these alterations may precede or proceed development of the pathology. This review assesses the efficacy of HCM therapeutics from studies performed in animal models of HCM and human clinical trials. Evidence suggests that a preventative rather than corrective therapeutic approach may be more efficacious in the treatment of HCM. In addition, a clear understanding of mutation‐specific mechanisms may assist in informing the most effective therapeutic mode of action., Sarcomeric gene mutations are associated with the development of hypertrophic cardiomyopathy (HCM). Mechanistically, alterations in calcium handling, sarcomeric disorganization, energy metabolism and contractility participate in HCM disease progression. These alterations may precede or proceed development of the pathology. This review assesses the efficacy of preventative versus corrective HCM therapeutics from studies performed in animal models of HCM and human clinical trials.

The insulin/insulin-like growth factor signalling axis is an evolutionary ancient and highly conserved hormonal system involved in the regulation of metabolism, growth and lifespan in animals. Human insulin is stored in the pancreas, while insulin-like growth factor-1 (IGF-1) is maintained in blood in complexes with IGF-binding proteins (IGFBP1–6). Insect insulin-like polypeptide binding proteins (IBPs) have been considered as IGFBP-like structural and functional homologues. Here, we report structures of the Drosophila IBP Imp-L2 in its free form and bound to Drosophila insulin-like peptide 5 and human IGF-1. Imp-L2 contains two immunoglobulin-like fold domains and its architecture is unrelated to human IGFBPs, suggesting a distinct strategy for bioavailability regulation of insulin-like hormones. Similar hormone binding modes may exist in other insect vectors, as the IBP sequences are highly conserved. Therefore, these findings may open research routes towards a rational interference of transmission of diseases such as malaria, dengue and yellow fevers.

Current clinical trials demonstrate Duchenne muscular dystrophy (DMD) patients receiving phosphorodiamidate morpholino oligomer (PMO) therapy exhibit improved ambulation and stable pulmonary function; however, cardiac abnormalities remain. Utilizing the same PMO chemistry as current clinical trials, we have identified a non-toxic PMO treatment regimen that restores metabolic activity and prevents DMD cardiomyopathy. We propose that a treatment regimen of this nature may have the potential to significantly improve morbidity and mortality from DMD by improving ambulation, stabilizing pulmonary function, and preventing the development of cardiomyopathy.