Identification of Fibrinogen as a Plasma Protein Binding Partner for Lecanemab Biosimilar IgG: Implications for Alzheimer's Disease Therapy.

OBJECTIVE: Recombinant monoclonal therapeutic antibodies like lecanemab, which target amyloid beta in Alzheimer's disease, offer a promising approach for modifying the disease progression. Due to its relatively short half-life, Lecanemab, administered as a bi-monthly infusion (typically 10mg/kg) has a relatively brief half-life. Interaction with abundant plasma proteins binder in the bloodstream can affect pharmacokinetics of drugs, including their half-life. In this study we investigated potential plasma protein binding interaction to lecanemab using lecanemab biosimilar. METHODS: Lecanemab biosimilar used in this study was based on publicly available sequences. ELISA and Western blotting were used to assess lecanemab biosimilar immunoreactivity in the fractions human plasma sample obtained through size exclusion chromatography. The binding of lecanemab biosimilar to candidate binders was confirmed by Western blotting, ELISA, and surface plasmon resonance analysis. RESULTS: Using a combination of equilibrium dialysis, ELISA, and Western blotting in human plasma, we first describe the presence of likely plasma protein binding partner to lecanemab biosimilar, and then identify fibrinogen as one of them. Utilizing surface plasmon resonance, we confirmed that lecanemab biosimilar does bind to fibrinogen, although with lower affinity than to monomeric amyloid beta. CONCLUSION: In the context of lecanemab therapy, these results imply that fibrinogen levels could impact the levels of free antibodies in the bloodstream and that fibrinogen might serve as a reservoir for lecanemab. More broadly, these results indicate that plasma protein binding may be an important consideration when clinically utilizing therapeutic antibodies in neurodegenerative disease.

Effectiveness of animal-assisted therapy and pet-robot interventions in reducing depressive symptoms among older adults: A systematic review and meta-analysis.

BACKGROUND: Systematic reviews suggest that animal-assisted therapy (AAT) and pet-robot interventions (PRI) achieve a reduction in mental health variables such as depressive symptoms. However, these systematic reviews include both randomised and non-randomised studies, which prevents an adequate assessment of the effect of confounding variables. OBJECTIVE: This systematic review and meta-analysis aimed to evaluate the comparative effectiveness of AAT and PRI through randomized controlled trials (RCTs) in reducing depression in older adults. METHODS: Our study is a systematic review. We searched three databases of scientific articles: SCOPUS, Web of Science and PubMed. We included studies that their population was older adults, aged 65 years or older, with or without a clinical condition, clinical diagnosis based on mental examination/test or documentation from medical records, accredited by the facilities' staff. We included trials in which the comparator was a passive intervention or an active intervention. We used the Cochrane risk-of-bias tool for randomised trials (RoB 2) to assess the risk of bias for each study. Our study was registered in PROSPERO (CRD42023393740). RESULTS: Twenty-three studies were included in this systematic review. However, only 19 trials were included in the meta-analysis. At the overall risk of bias level, 78.9% of the studies were at high risk of bias (n = 15). We found that AAT (g= -0.72; 95%CI -1.13 to -0.31; p = 0.001) has a moderate and statistically significant effect as an intervention to reduce depressive symptoms in older adults. However, the PRIs do not show a significant effect on reducing depressive symptoms in older adults. In addition, a sub-analysis based on dog-assisted therapy (g= -0.65; 95%CI -1.21 to -0.08; p = 0.025), a specific type of AAT, showed a modest effect on reducing depressive symptoms. CONCLUSIONS: Our study concluded that AAT and DAT had a moderate and statistically significant effect as interventions to reduce depressive symptoms in older adults. On the other hand, PRI did not show a significant effect in reducing depressive symptoms.

The clinical and financial impact of remote clinical oncology pharmacist engagement in community-based practices within The US Oncology Network.

INTRODUCTION: The integration of clinical oncology pharmacists into multidisciplinary healthcare teams is not well-described in the community practice setting. This study aims to analyze the clinical and financial impact of a remote-based clinical oncology pharmacist in four community oncology practices within The US Oncology Network. METHODS: Oncology-trained clinical pharmacists electronically reviewed chemotherapy orders for clinical optimization and financial stewardship within four community oncology practices. Each pharmacist was appointed at 0.5 full-time equivalents per practice. Financial, clinical, and workload metrics were tracked to monitor the impact of pharmacist engagement. RESULTS: Over 12 months, 5716 order reviews were completed with an intervention rate of 57%. The most common interventions identified by the pharmacists were interventions with clinical impact on the patient (36%), followed by dose rounding (35%) and therapeutic interchange (30%). Overall, interventions improved the cumulative practice margins by $1,455,033 and reduced total medication costs by $5,962,551. The average program return on investment was 415% (range 100-915%). CONCLUSION: Community oncology practices seek to provide high-value care in a lean, resource-constrained model. An oncology clinical pharmacist is a cost-effective and clinically invaluable care team member in community oncology practice. Pharmacists in this setting identified opportunities to improve medication safety and regimen optimization and demonstrated a significant tremendous financial impact on small-scale budgets in community oncology.

Experimental Models for Rare Melanoma Research-The Niche That Needs to Be Addressed.

Melanoma, the tumor arising from the malignant transformation of pigment-producing cells-the melanocytes-represents one of the most severe cancer types. Despite their rarity compared to cutaneous melanoma, the extracutaneous subtypes such as uveal melanoma (UM), acral lentiginous melanoma (ALM), and mucosal melanoma (MM) stand out due to their increased aggressiveness and mortality rate, demanding continuous research to elucidate their specific pathological features and develop efficient therapies. Driven by the emerging progresses made in the preclinical modeling of melanoma, the current paper covers the most relevant in vitro, in vivo, and in ovo systems, providing a deeper understanding of these rare melanoma subtypes. However, the preclinical models for UM, ALM, and MM that were developed so far remain scarce, and none of them is able to completely simulate the complexity that is characteristic to these melanomas; thus, a continuous expansion of the existing library of experimental models is pivotal for driving advancements in this research field. An overview of the applicability of precision medicine in the management of rare melanoma subtypes is also provided.

Characterizing Out-of-Pocket Payments and Financial Assistance for Patients Prescribed Abiraterone and Enzalutamide at an Academic Cancer Center Specialty Pharmacy.

PURPOSE: Abiraterone and enzalutamide are commonly used oral cancer therapies for patients with prostate cancer, both with potentially high out-of-pocket costs for patients. We investigated the prevalence of financial assistance mechanisms used to alleviate out-of-pocket costs and the association of these mechanisms with timing of treatment initiation of abiraterone or enzalutamide. METHODS: Using data from the medical center's specialty pharmacy, we identified first prescriptions for abiraterone or enzalutamide between January 1, 2017, and March 31, 2019. Prescriptions dispensed at an external pharmacy or that were discontinued for reasons unrelated to cost were excluded. Patient demographics, insurance coverage, out-of-pocket cost, and number of days between prescribed date and pill-to-mouth date were collected. RESULTS: Among 220 prescriptions in our final cohort, 185 were filled through our internal specialty pharmacy, 23 through a manufacturer-sponsored patient assistance program (PAP), and 12 were never filled because of cost. One third of the prescriptions in our final cohort (n = 66) were filled with financial assistance: PAP (10%), copay cards (9%), and grants (11%). The median amount of assistance received for the first fill was $2,860 US dollars (USD) (interquartile range $1,856-$10,717 USD). Prescriptions with an out-of-pocket cost < $100 USD were filled in the shortest time (median 5 days), whereas those filled through a PAP had the longest time to initiation (median 30.5 days). CONCLUSION: Among patients prescribed oral therapies for prostate cancer at a single institution, one third of patients received financial assistance. Although receiving assistance is likely to improve financial toxicity, waiting for assistance may lead to longer time to initiation of medication.

Group B streptococcus sepsis in an infant presented with cellulitis of soft tissue of neck.

We report a case of cellulitis of the soft tissue of the neck with group B streptococcus (GBS) sepsis in a 4-week-old baby boy presented with a 1-day history of fever, irritability and feed refusal. While in the hospital, a left-sided submandibular swelling extending to preauricular area started emerging, which progressed dramatically. Ultrasound scan of the neck confirmed inflammation of the underlying soft tissue while revealing multiple enlarged lymph nodes without any abscess formation and overlying soft tissue oedema. Blood cultures were flagged positive at 9 hours for GBS. The infant was treated with intravenous antibiotics for 2 weeks. GBS is considered a common cause of early-onset sepsis in neonates. However, it can also lead to late-onset sepsis in infancy with variable presentations. In our case, GBS sepsis manifested with cellulitis of the soft tissue of the neck along with swelling of local lymph nodes.

The deubiquitinase CYLD controls protective immunity against helminth infection by regulation of Treg cell plasticity.

BACKGROUND: Type 2 immunity can be modulated by regulatory T (Treg) cell activity. It has been suggested that the deubiquitinase cylindromatosis (CYLD) plays a role in the development or function of Treg cells, implying that it could be important for normal protective immunity, where type 2 responses are prevalent. OBJECTIVE: We sought to investigate the role of CYLD in Treg cell function and TH2 cell immune responses under steady-state conditions and during helminth infection. METHODS: Foxp3-restricted CYLD conditional knockout (KO) mice were examined in mouse models of allergen-induced airway inflammation and Nippostrongylus brasiliensis infection. We performed multiplex magnetic bead assays, flow cytometry, and quantitative PCR to understand how a lack of CYLD affected cytokine production, homing, and suppression in Treg cells. Target genes regulated by CYLD were identified and validated by microarray analysis, coimmunoprecipitation, short hairpin RNA knockdown, and transfection assays. RESULTS: Treg cell-specific CYLD KO mice showed severe spontaneous pulmonary inflammation with increased migration of Treg cells into the lung. CYLD-deficient Treg cells furthermore produced high levels of IL-4 and failed to suppress allergen-induced lung inflammation. Supporting this, the conditional KO mice displayed enhanced protection against N brasiliensis infection by contributing to type 2 immunity. Treg cell conversion into IL-4-producing cells was due to augmented mitogen-activated protein kinase and nuclear factor κB signaling. Moreover, Scinderin, a member of the actin-binding gelsolin family, was highly upregulated in CYLD-deficient Treg cells, and controlled IL-4 production through forming complexes with mitogen-activated protein kinase kinase/extracellular receptor kinase. Correspondingly, both excessive IL-4 production in vivo and the protective role of CYLD-deficient Treg cells against N brasiliensis were reversed by Scinderin ablation. CONCLUSIONS: Our findings indicate that CYLD controls type 2 immune responses by regulating Treg cell conversion into TH2 cell-like effector cells, which potentiates parasite resistance.

Treatment of severe hypertriglyceridemia with continuous insulin infusion.

Severe hypertriglyceridemia (SH) represents a therapeutic emergency because of the possibility of developing cardiovascular events and hyperlipemic acute pancreatitis (PA). Most patients with SH suffer primary or genetic abnormality in lipid metabolism in combination with a precipitating factor such as uncontrolled diabetes mellitus, alcoholism, and drug intake. The standard treatment of hypertriglyceridemia (HTG) with omega 3 fatty acids and fibrates, along with dietary changes, has no effect on an emergency situation. There are no clinical guidelines to SH, but therapy with insulin, heparin, a combination of both, plasmapheresis, or octreotide have been tested succesfully. We report the case of a 10-year-old girl with clinical acute pancreatitis and diabetic ketoacidosis debut, along with incidental finding of an SH, who had a good outcome after treatment with insulin intravenous infusion.