Cefiderocol and Intraventricular Colistin for Ventriculitis due to an Extensively Drug-Resistant Pseudomonas Aeruginosa.

Rheumatoid arthritis, an inflammatory rheumatic disease predominantly affecting small limb joints, frequently compromises the cervical spine, resulting in spinal instability and the potential surgical necessity. This may result in severe complications, such as ventriculitis, often associated with a high mortality rate and multidrug-resistant organisms. A major challenge lies in achieving therapeutic antimicrobial concentrations in the central nervous system. The authors present a case of a 65-year-old female, with cervical myelopathy due to severe rheumatoid arthritis. Following surgery, the patient developed ventriculitis caused by an extensively drug-resistant Pseudomonas Aeruginosa. Early diagnosis and prompt treatment played a crucial role in facilitating neurological and cognitive recovery.

Phosphorylation patterns in the AT1R C-terminal tail specify distinct downstream signaling pathways.

Different ligands stabilize specific conformations of the angiotensin II type 1 receptor (AT1R) that direct distinct signaling cascades mediated by heterotrimeric G proteins or ß-arrestin. These different active conformations are thought to engage distinct intracellular transducers because of differential phosphorylation patterns in the receptor C-terminal tail (the "barcode" hypothesis). Here, we identified the AT1R barcodes for the endogenous agonist AngII, which stimulates both G protein activation and ß-arrestin recruitment, and for a synthetic biased agonist that only stimulates ß-arrestin recruitment. The endogenous and ß-arrestin-biased agonists induced two different ensembles of phosphorylation sites along the C-terminal tail. The phosphorylation of eight serine and threonine residues in the proximal and middle portions of the tail was required for full ß-arrestin functionality, whereas phosphorylation of the serine and threonine residues in the distal portion of the tail had little influence on ß-arrestin function. Similarly, molecular dynamics simulations showed that the proximal and middle clusters of phosphorylated residues were critical for stable ß-arrestin-receptor interactions. These findings demonstrate that ligands that stabilize different receptor conformations induce different phosphorylation clusters in the C-terminal tail as barcodes to evoke distinct receptor-transducer engagement, receptor trafficking, and signaling.

Environmental impact of single-use versus reusable gastroscopes.

INTRODUCTION: The environmental impact of endoscopy is a topic of growing interest. This study aimed to compare the carbon footprint of performing an esogastroduodenoscopy (EGD) with a reusable (RU) or with a single-use (SU) disposable gastroscope. METHODS: SU (Ambu aScope Gastro) and RU gastroscopes (Olympus, H190) were evaluated using life cycle assessment methodology (ISO 14040) including the manufacture, distribution, usage, reprocessing and disposal of the endoscope. Data were obtained from Edouard Herriot Hospital (Lyon, France) from April 2023 to February 2024. Primary outcome was the carbon footprint (measured in Kg CO2 equivalent) for both gastroscopes per examination. Secondary outcomes included other environmental impacts. A sensitivity analysis was performed to examine the impact of varying scenarios. RESULTS: Carbon footprint of SU and RU gastroscopes were 10.9 kg CO2 eq and 4.7 kg CO2 eq, respectively. The difference in carbon footprint equals one conventional car drive of 28 km or 6 days of CO2 emission of an average European household. Based on environmentally-extended input-output life cycle assessment, the estimated per-use carbon footprint of the endoscope stack and washer was 0.18 kg CO2 eq in SU strategy versus 0.56 kg CO2 eq in RU strategy. According to secondary outcomes, fossil eq depletion was 130 MJ (SU) and 60.9 MJ (RU) and water depletion for 6.2 m3 (SU) and 9.5 m3 (RU), respectively. CONCLUSION: For one examination, SU gastroscope have a 2.5 times higher carbon footprint than RU ones. These data will help with the logistics and planning of an endoscopic service in relation to other economic and environmental factors.

Age-associated clonal B cells drive B cell lymphoma in mice.

Although cancer is an age-related disease, how the processes of aging contribute to cancer progression is not well understood. In this study, we uncovered how mouse B cell lymphoma develops as a consequence of a naturally aged system. We show here that this malignancy is associated with an age-associated clonal B cell (ACBC) population that likely originates from age-associated B cells. Driven by c-Myc activation, promoter hypermethylation and somatic mutations, IgM+ ACBCs clonally expand independently of germinal centers and show increased biological age. ACBCs become self-sufficient and support malignancy when transferred into young recipients. Inhibition of mTOR or c-Myc in old mice attenuates pre-malignant changes in B cells during aging. Although the etiology of mouse and human B cell lymphomas is considered distinct, epigenetic changes in transformed mouse B cells are enriched for changes observed in human B cell lymphomas. Together, our findings characterize the spontaneous progression of cancer during aging through both cell-intrinsic and microenvironmental changes and suggest interventions for its prevention.

Impact of allergic rhinitis control on work productivity and costs: a real-world data MASK-air study.

BACKGROUND: Allergic rhinitis (AR) has a substantial socioeconomic impact associated with impaired work productivity. OBJECTIVE: To study the impact of AR on work productivity and estimate the corresponding indirect costs for 40 countries. METHODS: We conducted a cross-sectional study using direct patient data from the MASK-air® app on users with self-reported AR. We used the Work Productivity and Activity Impairment Questionnaire: Allergy Specific to measure the impact of AR on work productivity (presenteeism and absenteeism). Weekly indirect costs were estimated per country, for each level of rhinitis control and considering patients with and without asthma. RESULTS: We assessed data from 677 weeks (364 patients), 280 of which were reported by patients with asthma. Regarding presenteeism, the median impact of AR in weeks of poor disease control was 60.7% (P25-P75=24.9-74.2%), while partial and good disease control were respectively associated with an impact of 25.0% (P25-P75=12.1-42.4%) and 4.4% (P25-75=0.8-12.9%). In poorly-controlled weeks, presenteeism was associated with indirect costs ranging from 65.7 US Dollars purchase power parity (US$ PPPs) (P25-P75=29.2-143.2) in Brazil to 693.6 US$ PPP (P25-P75=405.2-1094.9) in Iceland. Median absenteeism per week was of 0% for all levels of rhinitis control. Patients with AR+asthma showed higher overall work impairment than patients with AR alone, particularly in poorly-controlled weeks (median work impairment in AR alone=39.1% [P25-P75=12.5-71.9%]; median work impairment in AR+asthma=68.4% [P25-P75=54.6-80.2%]). CONCLUSION: Poor AR control was associated with decreased work productivity and increased indirect costs, particularly in patients with AR+asthma. The estimates from this study underpin the economic burden of AR.

Magneto-Enzymatic Microgels for Precise Hydrogel Sculpturing.

The inclusion of hollow channels in tissue-engineered hydrogels is crucial for mimicking the natural physiological conditions and facilitating the delivery of nutrients and oxygen to cells. Although bio-fabrication techniques provide diverse strategies to create these channels, many require sophisticated equipment and time-consuming protocols. Herein, collagenase, a degrading agent for methacrylated gelatin hydrogels, and magnetic nanoparticles (MNPs) are combined and processed into enzymatically active spherical structures using a straightforward oil bath emulsion methodology. The generated microgels are then used to microfabricate channels within biomimetic hydrogels via a novel sculpturing approach that relied on the precise coupling of protein-enzyme pairs (for controlled local degradation) and magnetic actuation (for directional control). Results show that the sculpting velocity can be tailored by adjusting the magnetic field intensity or concentration of MNPs within the microgels. Additionally, varying the magnetic field position or microgel size generated diverse trajectories and channels of different widths. This innovative technology improves the viability of encapsulated cells through enhanced medium transport, outperforming non-sculpted hydrogels and offering new perspectives for hydrogel vascularization and drug/biomolecule administration. Ultimately, this novel concept can help design fully controlled channels in hydrogels or soft materials, even those with complex tortuosity, in a single wireless top-down biocompatible step.

A replisome-associated histone H3-H4 chaperone required for epigenetic inheritance.

Faithful transfer of parental histones to newly replicated daughter DNA strands is critical for inheritance of epigenetic states. Although replication proteins that facilitate parental histone transfer have been identified, how intact histone H3-H4 tetramers travel from the front to the back of the replication fork remains unknown. Here, we use AlphaFold-Multimer structural predictions combined with biochemical and genetic approaches to identify the Mrc1/CLASPIN subunit of the replisome as a histone chaperone. Mrc1 contains a conserved histone-binding domain that forms a brace around the H3-H4 tetramer mimicking nucleosomal DNA and H2A-H2B histones, is required for heterochromatin inheritance, and promotes parental histone recycling during replication. We further identify binding sites for the FACT histone chaperone in Swi1/TIMELESS and DNA polymerase α that are required for heterochromatin inheritance. We propose that Mrc1, in concert with FACT acting as a mobile co-chaperone, coordinates the distribution of parental histones to newly replicated DNA.

Unveiling Dissolution Kinetics of CuO Nanofertilizer Using Bio-Based Ionic Liquids Envisaging Controlled Use Efficiency for Sustainable Agriculture.

The need for sustainable agriculture amid a growing population and challenging climatic conditions is hindered by the environmental repercussions of widespread fertilizer use, resulting in the accumulation of metal ions and the loss of micronutrients. The present study provides an approach to improve the efficiency of nanofertilizers by controlling the release of copper (Cu) ions from copper oxide (CuO) nanofertilizers through bioionic liquids based on plant growth regulators (PGR-ILs). A 7-day study was conducted to understand the kinetics of Cu ion release in aqueous solution of five different PGR-ILs, with choline ascorbate ([Cho][Asc]) or choline salicylate ([Cho][Sal]) leading to 200- to 700-fold higher dissolution of Cu ions in comparison to choline indole-3-acetate ([Cho][IAA]), choline indole-3-butyrate ([Cho][IBA]), and choline gibberellate ([Cho][GA3]). The tunable diffusion of Cu ions from CuO nanofertilizers using PGR-ILs is then applied in a foliar spray study, evaluating its impact on the growth phenotype, photosynthetic parameters, and carbon dioxide (CO2) sequestration in Nicotiana tabacum in a greenhouse. The results indicate that nanoformulations with lower concentrations of Cu ions in PGR-IL solutions exhibit superior outcomes in terms of plant length, net photosynthetic rate, dry biomass yield, and CO2 sequestration, emphasizing the critical role of dissolution kinetics in determining the effectiveness of PGR-IL-based nanoformulations for sustainable agriculture.

Non-invasive urine-based ELISA using a recombinant Leishmania protein to diagnose tegumentary leishmaniasis.

The diagnosis of tegumentary leishmaniasis (TL) is hampered by variable sensitivity and/or specificity of the tests. Serological assays are suitable to diagnose visceral leishmaniasis (VL); however, they present low performance for the detection of TL cases. Additionally, blood collection to obtain patient serum represents a challenge, as it is an invasive and uncomfortable procedure, requiring laboratorial infrastructure and trained professionals. In this context, the present study proposed to evaluate patient urine to detect TL, given that this analyte has proven to be effective in ELISA experiments for the detection of VL cases. For this, a Leishmania protein called LiHyV, two specific B-cell epitopes derived from protein amino acid sequence, and a Leishmania antigenic extract (SLA) were used as antigens. A total of 215 paired urine and serum samples were evaluated, and results showed that, when serum was employed as an analyte, rLiHyV, Peptide1, Peptide2, and SLA presented a sensitivity of 85 %, 29 %, 58 %, and 31 %, respectively, and a specificity of 97.5 %, 98 %, 100 %, and 97.5 %, respectively, in the diagnosis of TL. When urine was used, rLiHyV, Peptide1, Peptide2, and SLA presented a sensitivity of 95 %, 74 %, 67 %, and 52 %, respectively, and a specificity of 100 %, 99 %, 98 %, and 86 %, respectively. In conclusion, preliminary data suggest that urine could be considered as an alternative biological sample for the detection of TL cases.

Protocol for the systematic reviews on the desirable and undesirable effects of pharmacological treatments of allergic rhinitis informing the ARIA 2024 guidelines.

There is insufficient evidence regarding the comparative efficacy and safety of pharmacological treatments of allergic rhinitis (AR). In the context of informing the 2024 revision of the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines, we plan to perform three systematic reviews of randomized controlled trials (RCTs) comparing the desirable and undesirable effects (i) between intranasal and oral medications for AR; (ii) between combinations of intranasal and oral medications versus nasal or oral medications alone; and (iii) among different intranasal specific medications. We will search four electronic bibliographic databases and three clinical trials databases for RCTs examining patients ≥ 12 years old with seasonal or perennial AR. Assessed outcomes will include the Total Nasal Symptom Score, the Total Ocular Symptom Score, and the Rhinoconjunctivitis Quality-of-Life Questionnaire. We will assess the methodological quality of included primary studies by using the Cochrane risk-of-bias tool. If appropriate, we will perform a pairwise random-effects meta-analysis for each pair of assessed medication classes and outcomes, as well as a network meta-analysis to assess the comparative efficacy of intranasal medications among each other. Heterogeneity will be explored by sensitivity and subgroup analyses. This set of systematic reviews will allow for a comprehensive assessment of the effectiveness and safety of pharmacological interventions for AR and inform recommendations in the context of the ARIA guidelines.

Concepts for the development of person-centred, digitally-enabled, Artificial Intelligence-assisted ARIA care pathways (ARIA 2024).

The traditional healthcare model is focused on diseases (medicine and natural science) and does not acknowledge patients' resources and abilities to be experts in their own life based on their lived experiences. Improving healthcare safety, quality and coordination, as well as quality of life, are important aims in the care of patients with chronic conditions. Person-centred care needs to ensure that people's values and preferences guide clinical decisions. This paper reviews current knowledge to develop (i) digital care pathways for rhinitis and asthma multimorbidity and (ii) digitally-enabled person-centred care (1). It combines all relevant research evidence, including the so-called real-world evidence, with the ultimate goal to develop digitally-enabled, patient-centred care. The paper includes (i) Allergic Rhinitis and its Impact on Asthma (ARIA), a two-decade journey, (ii) Grading of Recommendations, Assessment, Development and Evaluation (GRADE), the evidence-based model of guidelines in airway diseases, (iii) mHealth impact on airway diseases, (iv) from guidelines to digital care pathways, (v) embedding Planetary Health, (vi) novel classification of rhinitis and asthma, (vi) embedding real-life data with population-based studies, (vii) the ARIA-EAACI strategy for the management of airway diseases using digital biomarkers, (viii) Artificial Intelligence, (ix) the development of digitally-enabled ARIA Person-Centred Care and (x) the political agenda. The ultimate goal is to propose ARIA 2024 guidelines centred around the patient in order to make them more applicable and sustainable.

Proteomic profiling of mesenchymal stem cell-derived extracellular vesicles: Impact of isolation methods on protein cargo.

Extracellular vesicles (EVs) are nanosized vesicles with a lipid bilayer that are secreted by cells and play a critical role in cell-to-cell communication. Despite the promising reports regarding their diagnostic and therapeutic potential, the utilization of EVs in the clinical setting is limited due to insufficient information about their cargo and a lack of standardization in isolation and analysis methods. Considering protein cargos in EVs as key contributors to their therapeutic potency, we conducted a tandem mass tag (TMT) quantitative proteomics analysis of three subpopulations of mesenchymal stem cell (MSC)-derived EVs obtained through three different isolation techniques: ultracentrifugation (UC), high-speed centrifugation (HS), and ultracentrifugation on sucrose cushion (SU). Subsequently, we checked EV marker expression, size distribution, and morphological characterization, followed by bioinformatic analysis. The bioinformatic analysis of the proteome results revealed that these subpopulations exhibit distinct molecular and functional characteristics. The choice of isolation method impacts the proteome of isolated EVs by isolating different subpopulations of EVs. Specifically, EVs isolated through the high-speed centrifugation (HS) method exhibited a higher abundance of ribosomal and mitochondrial proteins. Functional apoptosis assays comparing isolated mitochondria with EVs isolated through different methods revealed that HS-EVs, but not other EVs, induced early apoptosis in cancer cells. On the other hand, EVs isolated using the sucrose cushion (SU) and ultracentrifugation (UC) methods demonstrated a higher abundance of proteins primarily involved in the immune response, cell-cell interactions and extracellular matrix interactions. Our analyses unveil notable disparities in proteins and associated biological functions among EV subpopulations, underscoring the importance of meticulously selecting isolation methods and resultant EV subpopulations based on the intended application.

Huntingtin contains an ubiquitin-binding domain and regulates lysosomal targeting of mitochondrial and RNA-binding proteins.

Understanding the normal function of the Huntingtin (HTT) protein is of significance in the design and implementation of therapeutic strategies for Huntington's disease (HD). Expansion of the CAG repeat in the HTT gene, encoding an expanded polyglutamine (polyQ) repeat within the HTT protein, causes HD and may compromise HTT's normal activity contributing to HD pathology. Here, we investigated the previously defined role of HTT in autophagy specifically through studying HTT's association with ubiquitin. We find that HTT interacts directly with ubiquitin in vitro. Tandem affinity purification was used to identify ubiquitinated and ubiquitin-associated proteins that copurify with a HTT N-terminal fragment under basal conditions. Copurification is enhanced by HTT polyQ expansion and reduced by mimicking HTT serine 421 phosphorylation. The identified HTT-interacting proteins include RNA-binding proteins (RBPs) involved in mRNA translation, proteins enriched in stress granules, the nuclear proteome, the defective ribosomal products (DRiPs) proteome and the brain-derived autophagosomal proteome. To determine whether the proteins interacting with HTT are autophagic targets, HTT knockout (KO) cells and immunoprecipitation of lysosomes were used to investigate autophagy in the absence of HTT. HTT KO was associated with reduced abundance of mitochondrial proteins in the lysosome, indicating a potential compromise in basal mitophagy, and increased lysosomal abundance of RBPs which may result from compensatory up-regulation of starvation-induced macroautophagy. We suggest HTT is critical for appropriate basal clearance of mitochondrial proteins and RBPs, hence reduced HTT proteostatic function with mutation may contribute to the neuropathology of HD.

Effects of passive cycling on cerebrovascular reactivity in acute brain injured patients: A pilot study.

INTRODUCTION: Early mobilization benefits critically ill patients, but concerns persist, especially in neurologic intensive care unit patients with acute brain injuries. This study assesses early mobility's impact on cerebrovascular autoregulation (CA) and systemic hemodynamics. METHODS: This single-center retrospective study focused on adult neurologic intensive care unit patients undergoing passive cycle ergometry. Data were collected from December 2020 to April 2022. Physical therapists conducted sessions using a standardized protocol, monitoring mean arterial blood pressure (MAP) and intracranial pressure (ICP). The Pressure Reactivity Index (PRx) was calculated as a measure of CA. Statistical analysis included mixed models and repeated measures ANOVA. RESULTS: Eleven patients undergoing continuous physiologic monitoring and early mobility were included, primarily with subarachnoid hemorrhage or intracranial hemorrhage. Median time to protocol initiation was 4 days, with two patients discontinuing due to hemodynamic disturbances. Over a total of 11-hours of neuromonitoring data, passive cycling demonstrated a significant reduction in heart rate (HR), MAP, and ICP across different rotations per minute (RPM) settings compared to baseline. No significant alterations in PRx or cerebral perfusion pressure (CPP) were noted at various RPM levels. However, a significant difference in PRx emerged between patients who completed the protocol and those who did not, particularly at 10 RPM. DISCUSSION: This study offers preliminary insights into the impact of early mobility on CA in acute brain injured patients. While passive cycling demonstrates promise in preserving cerebral hemodynamics, its tolerability may not be uniform across all brain-injured patients. These findings highlight the need to determine optimal early mobilization timing and intensity in this population, emphasizing the necessity for larger prospective studies to validate these findings and inform clinical practice. DETAILS: This manuscript complies with all instructions to the authors. All coauthors meet the authorship requirements and have reviewed and approved the contents of the manuscript. The manuscript has not been published totally or partly, accepted for publication, or under editorial review for publication elsewhere. We have no conflicts of interest to disclose. STROBE checklist was reviewed prior to the submission of this paper. The manuscript adheres to ethical guidelines and was approved by Cleveland Clinic's institutional research board for retrospective study. There is no funding to disclose for this study.

Trimethoprim-Based multicomponent solid Systems: Mechanochemical Screening, characterization and antibacterial activity assessment.

In this work, multicomponent trimethoprim-based pharmaceutical solid systems were developed by mechanochemistry, using coformers from the GRAS list and other active pharmaceutical ingredients. The choice of coformers took into account their potential to increase the aqueous solubility/dissolution rate of TMP or its antibacterial activity. All the binary systems were characterized by thermal analysis, powder X-ray diffraction and infrared spectroscopy, and 3 equimolar systems with FTIR pointing to salts, and 4 eutectic mixtures were identified. The intrinsic dissolution rate of TMP in combination with nicotinic acid (a salt) and with paracetamol (eutectic mixture) were 25% and 5% higher than for pure TMP, respectively. For both Gram-positive and -negative strains, the antibacterial activity of TMP with some of the coformers was improved, since the dosage used was lower than the TMP control. A significant increase in antibacterial activity against E. coli was found for the eutectic mixture with curcumin, with the best results being obtained for the eutectic and equimolar mixtures with ciprofloxacin. Combining trimethoprim with coformers offers an interesting alternative to using trimethoprim alone: multicomponent forms with enhanced TMP dissolution rates were identified, as well as combinations showing enhanced antibacterial activity relatively to the pure drug.

Novel Relaxin Receptor RXFP1 Agonist AZD3427 in the Treatment of Heart Failure: A Phase 1a/b, First-in-Human, Randomized, Single-Blind, Placebo-Controlled Study.

BACKGROUND: Heart failure mortality remains high despite recent progress in pharmacological treatment. AZD3427 is a selective long-acting analog of relaxin, a vasodilatory hormone with antifibrotic effects. We assessed the safety, pharmacokinetics, and pharmacodynamics of AZD3427 in healthy volunteers and patients with heart failure on standard-of-care therapy. METHODS AND RESULTS: In this first-in-human, phase 1a/b, randomized, single-blind, placebo-controlled study, healthy volunteers were randomized 6:2 to receive a single dose of AZD3427 or placebo by subcutaneous injection in 5 mixed-ethnicity cohorts (5, 10, 30, 90, or 270 mg) and 1 Japanese-descent cohort (270 mg), or by intravenous injection in 1 cohort (15 mg). After confirming safety and tolerability in healthy volunteers, 3 cohorts of patients with heart failure and left ventricular ejection fraction ≤40% and 3 cohorts with ejection fraction ≥41% were randomized 6:2 to receive 5 weekly doses of AZD3427 (5, 15, or 45 mg) or placebo by subcutaneous injection. In total, 56 healthy volunteers and 48 patients with heart failure were randomized. AZD3427 was well tolerated at all doses. After subcutaneous administration, AZD3427 was absorbed slowly, and exposure was approximately linear across the dose range. In patients with heart failure, AZD3427 terminal half-life was 13 to 14 days and there were numerical increases in stroke volume and estimated glomerular filtration rate. No treatment-emergent antidrug antibodies were detected. CONCLUSIONS: AZD3427 had favorable safety and pharmacokinetic profiles. Hemodynamic changes in patients with heart failure were consistent with the anticipated effects of a relaxin analog. These findings support further development of AZD3427 as a novel long-term treatment for patients with heart failure. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04630067.

Platinum-based chemotherapy: trends in organic nanodelivery systems.

Despite the investment in platinum drugs research, cisplatin, carboplatin and oxaliplatin are still the only Pt-based compounds used as first line treatments for several cancers, with a few other compounds being approved for administration in some Asian countries. However, due to the severe and worldwide impact of oncological diseases, there is an urge for improved chemotherapeutic approaches. Furthermore, the pharmaceutical application of platinum complexes is hindered by their inherent toxicity and acquired resistance. Nanodelivery systems rose as a key strategy to overcome these challenges, with recognized versatility and ability towards improving the safety, bioavailability and efficacy of the available drugs. Among the known nanocarriers, organic systems have been widely applied, taking advantage of their potential as drug vehicles. Researchers have mainly focused on the development of lipidic and polymeric carriers, including supramolecular structures, with an overall improvement of encapsulated platinum complexes. Herein, an overview of recent trends and strategies is presented, with the main focus on the encapsulation of platinum compounds into organic nanocarriers, showcasing the evolution in the design and development of these promising systems. This comprehensive review highlights formulation methods as well as characterization procedures, providing insights that may be helpful for the development of novel platinum nanocarriers aiming at future pharmaceutical applications.