Highlights • Binding of albumin to diuretics are key to delivery to the nephron, and low albumin levels diminish intravascular oncotic pressures necessary to maintain intravascular volume for ...effective diuresis. • Based on prospectively collected data from two acute heart failure clinical trials (DOSE-AHF and ROSE-AHF), this may not be the case in acute heart failure populations largely free of nephrotic syndrome or cirrhosis. • Our data from two well characterized cohorts of patients with acute heart failure suggest that serum albumin may not be a helpful tool to guide decongestion strategies or determine effectiveness of therapy.
More than half of youth treated with atypical antipsychotic (AAP) medications are also treated with concomitant antidepressants or stimulants. This study assessed the association between ...antidepressant or stimulant use concomitant with AAPs and the risk of incident type 2 diabetes mellitus (T2DM).
Medicaid Analytic eXtract data were used to conduct a retrospective cohort study of youth (aged 5-20 years) who initiated AAP treatment. In AAP-treated youth, concomitant antidepressant (selective serotonin reuptake inhibitors SSRI/serotonin-norepinephrine reuptake inhibitors SNRIs, tricyclic/other cyclic antidepressants TCAs, and other antidepressants) or stimulant use was assessed. The risk of incident T2DM was estimated using discrete time failure models, adjusting for disease risk score estimated using >125 baseline and time-dependent covariates.
Among 73,224 AAP initiators, 43.0% had concomitant antidepressant use (76.4% were SSRI/SNRIs) and 43.8% had concomitant stimulant use. The study cohort had an average follow-up of 24.8 months (median = 22.0 months, interquartile range IQR = 10.0-38.0 months). In current AAP-treated youth, concomitant SSRI/SNRI (relative risk RR = 1.84, 95% CI = 1.30-2.59) or TCA use (RR = 2.75, 95% CI = 1.28-5.87) was associated with an increased risk of T2DM. By contrast, concomitant use of other antidepressants or stimulants with AAPs was not associated with an increased risk of T2DM. In concomitant users of AAPs and SSRI/SNRIs, the risk of T2DM increased with the duration of SSRI/SNRI use (RR = 2.35, 95% CI = 1.15-4.83 for ≥180 days vs. 1-180 days) as well as with the cumulative SSRI/SNRI dose (RR = 1.99, 95% CI = 1.08-3.67 for >2,700 mg vs. 1-2,700 mg fluoxetine dose equivalents), after adjusting for the duration and cumulative dose of AAP use. By contrast, in concomitant users of AAPs and stimulants, neither duration nor cumulative dose of stimulants was associated with an increased risk of T2DM.
In AAP-treated Medicaid-insured youth, concomitant SSRI/SNRI use was associated with a heightened risk of T2DM, which intensified with increasing duration and dose.
Background Infiltration, accumulation, and degranulation of eosinophils in the lung are hallmarks of active allergic asthma. The pulmonary response to inhaled allergen triggers the secretion of ...eosinophil chemoattractants and antiapoptotic cytokines, including GM-CSF, IL-3, IL-4, IL-5, and eotaxin, among others. We recently showed that in vitro Pin1 regulated eosinophil production of and response to GM-CSF. Objective We sought to determine the effect of Pin1 inhibition on pulmonary eosinophilia after allergen challenge. Methods The Pin1 inhibitor juglone (5-hydroxy-1,4-naphthoquinone) was administered to allergen-sensitized and allergen-challenged Brown Norway rats. Bronchoalveolar lavage fluid and lungs were assessed for inflammation, cytokine expression, and Pin1 activity. Results Juglone-treated rats showed a dramatic reduction (approximately 75%) in bronchoalveolar lavage fluid and pulmonary eosinophilia but no change in lymphocyte, monocyte/macrophage, or neutrophil numbers. GM-CSF and IL-5 expression were also significantly reduced, whereas Pin1-independent cytokines, such as eotaxin or IL-4, as well as housekeeping mRNAs and proteins, including actin, were unaffected by juglone. The eosinophils present in the lung in juglone-treated rats showed significantly greater apoptosis. Conclusion These data suggest that in vivo Pin1 blockade attenuates GM-CSF and IL-5 production and can selectively reduce eosinophilic allergic inflammation. Clinical implications Eosinophils can be selectively reduced by Pin1 blockade, despite allergen challenge.
As immune checkpoint inhibitors (ICI) become increasingly used in frontline settings, identifying early indicators of response is needed. Recent studies suggest a role for circulating tumor DNA ...(ctDNA) in monitoring response to ICI, but uncertainty exists in the generalizability of these studies. Here, the role of ctDNA for monitoring response to ICI is assessed through a standardized approach by assessing clinical trial data from five independent studies.
Patient-level clinical and ctDNA data were pooled and harmonized from 200 patients across five independent clinical trials investigating the treatment of patients with non-small-cell lung cancer with programmed cell death-1 (PD-1)/programmed death ligand-1 (PD-L1)-directed monotherapy or in combination with chemotherapy. CtDNA levels were measured using different ctDNA assays across the studies. Maximum variant allele frequencies were calculated using all somatic tumor-derived variants in each unique patient sample to correlate ctDNA changes with overall survival (OS) and progression-free survival (PFS).
We observed strong associations between reductions in ctDNA levels from on-treatment liquid biopsies with improved OS (OS; hazard ratio, 2.28; 95% CI, 1.62 to 3.20;
< .001) and PFS (PFS; hazard ratio 1.76; 95% CI, 1.31 to 2.36;
< .001). Changes in the maximum variant allele frequencies ctDNA values showed strong association across different outcomes.
In this pooled analysis of five independent clinical trials, consistent and robust associations between reductions in ctDNA and outcomes were found across multiple end points assessed in patients with non-small-cell lung cancer treated with an ICI. Additional tumor types, stages, and drug classes should be included in future analyses to further validate this. CtDNA may serve as an important tool in clinical development and an early indicator of treatment benefit.
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