Background: Iron deficiency anemia (IDA) is a prevalent yet underdiagnosed condition with a significant impact on quality of life. Oral iron supplementation is often poorly tolerated or yields inadequate response, requiring the use of intravenous iron (IVI) in some patients. Administration of certain IVI preparations has been associated with decreases in serum phosphate levels and clinically significant hypophosphatemia, which has been reported to lead to adverse events including serious fatigue and osteomalacia. Objective: The purpose of this study was to systematically assess the prevalence, clinical consequences, and reporting of treatment-emergent hypophosphatemia within literature investigating IVI therapies marketed in the United States (US). Methods: A systematic literature review (SLR) was conducted using the PubMed database to identify publications reporting serum phosphate levels or rates of hypophosphatemia within adult IDA patient populations receiving current US-marketed IVIs. Results: The SLR yielded 511 unique publications, with 40 records meeting the final inclusion criteria. Most studies did not report phosphate monitoring methodology or an explicit definition of hypophosphatemia. Hypophosphatemia rates ranged from 0.0% to 92.1% for ferric carboxymaltose (FCM), 0.0% to 40.0% for iron sucrose, 0.4% for ferumoxytol, and 0.0% for low-molecular-weight (LMW) iron dextran. Randomized controlled studies described hypophosphatemia as "asymptomatic" or did not report on other associated sequelae. Eleven case reports detailed treatment-emergent hypophosphatemia in patients treated with FCM. Patients with acute hypophosphatemia primarily developed severe fatigue; those with repeated FCM dosing developed chronic hypophosphatemia associated with osteomalacia and bone deformities. Conclusion: Studies analyzed in this SLR reported a range of hypophosphatemia rates, with the highest consistently seen in patients treated with FCM. Across the clinical literature, there appeared to be minimal standardization of phosphate monitoring and definitions of hypophosphatemia. Although multiple cases have documented serious clinical consequences of hypophosphatemia associated with certain IVIs, current trials neither consistently nor adequately assess the frequency and severity of treatment-emergent hypophosphatemia and may underestimate its prevalence.

Pathogenic bacteria that establish chronic infections in immunocompromised patients frequently undergo adaptation or selection for traits that are advantageous for their growth and survival. Clinical isolates of , a Gram-negative, opportunistic bacterial pathogen, exhibit a temporal transition from a motile to a nonmotile phenotype through loss of flagellar motility during the course of chronic infection. This progressive loss of motility is associated with increased resistance to both antibiotic and immune clearance. We have previously shown that loss of bacterial motility enables to evade phagocytic clearance both and and fails to activate the phosphatidylinositol 3-kinase (PI3K)/Akt-dependent phagocytic pathway. Therefore, we tested the hypothesis that clearance of phagocytosis-resistant bacteria could be induced by exogenously pretreating innate immune cells with the Akt-activating molecule phosphatidylinositol-(3,4,5)-trisphosphate (PIP). Here, we demonstrate that PIP induces the uptake of nonmotile by primary human neutrophils>25-fold, and this effect is phenocopied with the use of murine phagocytes. However, surprisingly, mechanistic studies revealed that the induction of phagocytosis by PIP occurs because polyphosphoinositides promote bacterial binding by the phagocytes rather than bypassing the requirement for PI3K. Moreover, this induction was selective since the uptake of other nonmotile Gram-negative, but not Gram-positive, bacteria can also be induced by PIP Since there is currently no treatment that effectively eradicates chronic infections, these findings provide novel insights into a potential methodology by which to induce clearance of nonmotile pathogenic bacteria and into the endogenous determinants of phagocytic recognition of.

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Objectives: Systemic lupus erythematosus (SLE) has a complex and heterogeneous natural history. Our aim was to develop a conceptual model of SLE that characterizes the relationships between short-and long-term outcomes that could be applied in future economic evaluations and health technology assessments of new therapies. Methods: As per the ISPOR-SMDM Modeling Good Research Practices Task Force guidelines, a targeted literature review was conducted to identify any previously developed conceptual or economic models in SLE. A steering committee of clinical and economic experts was convened to review existing model frameworks and brainstorm a new conceptual model, building on revision and refinement of prior models. The relationships between patient characteristics, disease activity, commonly used treatments, organ damage, health-related quality of life (HRQoL), and mortality were all considered by the committee, as well as the likely data available to parameterize the model in the future. Results: Based on the existing literature and consensus among committee members, the key components of the conceptual model included disease activity, corticosteroid use, and organ damage by individual system. Relationships not present in prior models included stratifying short-term disease activity by level (e.g., low, moderate, high)and corticosteroid use influencing subsequent disease activity. Higher disease activity levels (i.e., flare) would trigger higher short-term corticosteroid use and increased risk of long-term organ damage. Higher doses of corticosteroids should decrease disease activity in the short-term, while raising the risk of long-term organ damage. Relevant covariates identified included demographics, age at onset, cardiovascular comorbidities, baseline organ damage, history of lupus nephritis, and anti-malarial/other immunosuppressant use. Long-term outcomes include organ damage, mortality, HRQoL, and costs. Conclusions: By linking short-and long-term outcomes, this conceptual model provides a foundation on which to conduct future economic evaluations of new SLE therapies. The next step is to conduct a model validation using real world data.