MMPs (Matrix metalloproteinases) and their endogenous tissue inhibitors may contribute to lung injury through extracellular matrix degradation and modulation of inflammation and fibrosis.
To test for ...an association between MMP pathway proteins and inflammation, endothelial dysfunction, and clinical outcomes.
We measured MMPs in plasma collected on acute respiratory distress syndrome (ARDS) Day 1 from 235 children at five hospitals between 2008 and 2017. We used latent class analysis to identify patients with distinct MMP profiles and then associated those profiles with markers of inflammation (IL-1RA, -6, -8, -10, and -18; macrophage inflammatory protein-1α and -1β; tumor necrosis factor-α and -R2), endothelial injury (angiopoietin-2, von Willebrand factor, soluble thrombomodulin), impaired oxygenation (Pa
/Fi
P/F ratio, oxygenation index), morbidity, and mortality.
In geographically distinct derivation and validation cohorts, approximately one-third of patients demonstrated an MMP profile characterized by elevated MMP-1, -2, -3, -7, and -8 and tissue inhibitor of metalloproteinase-1 and -2; and depressed active and total MMP-9. This MMP profile was associated with multiple markers of inflammation, endothelial injury, and impaired oxygenation on Day 1 of ARDS, and conferred fourfold increased odds of mortality or severe morbidity independent of the P/F ratio and other confounders (95% confidence interval, 2.1-7.6; P < 0.001). Logistic regression using both the P/F ratio and MMP profiles was superior to the P/F ratio alone in prognosticating mortality or severe morbidity (area under the receiver operating characteristic curve, 0.75; 95% confidence interval, 0.68-0.82 vs. area under the receiver operating characteristic curve, 0.66; 95% confidence interval, 0.58-0.73; P = 0.009).
Pediatric patients with ARDS have specific plasma MMP profiles associated with inflammation, endothelial injury, morbidity, and mortality. MMPs may play a role in the pathobiology of children with ARDS.
Background
Limited real‐world data exist on treatment patterns and outcomes in patients with metastatic castration‐sensitive prostate cancer (mCSPC).
Methods
A retrospective cohort study was ...conducted, using the Veterans Health Administration claims database (April 2013–March 2018). Among 369,734 prostate cancer patients, we selected all men who developed metastases within 90 days before or after medical/surgical castration and who received androgen deprivation therapy (ADT). Patients were categorized into four cohorts: ADT‐only (± <90‐day nonsteroidal anti‐androgen NSAA use), ADT + NSAA, ADT + docetaxel, and ADT + abiraterone. Main outcomes were treatment patterns, time‐to‐progression to metastatic castration‐resistant disease, and overall survival. Multivariable analysis and sensitivity analysis were conducted.
Results
Of 1395 patients, 874 (63%) received ADT‐only, 338 (24%) received ADT + NSAA, 108 (8%) received ADT + docetaxel, and 75 (5%) received ADT + abiraterone. Proportions on ADT‐only and ADT + NSAA declined (from 66% to 60% and from 31% to 17%, respectively) over the study period, while proportions prescribed ADT + docetaxel or abiraterone increased from 3% to 9% and from 1% to 15%, respectively. Patients treated with ADT + NSAA had similar risks of castration‐resistant disease (hazard ratio HR 1.05; 95% confidence interval CI: 0.87, 1.26) and overall mortality (HR 1.22; 95% CI: 0.97, 1.54) as ADT‐only.
Conclusions
Most patients with mCSPC initiating ADT received ADT‐only or ADT + NSAA, despite the emergence of docetaxel and novel hormonal therapies. Even in the most recent period (2017 to early 2018), only 24% of men received intensified therapy with agents known to prolong survival versus ADT‐only. These data in real‐world clinical practice suggest substantial room for improved outcomes in patients with mCSPC.
A retrospective cohort study of 1395 men with metastatic castration‐sensitive prostate cancer initiating androgen deprivation therapy (ADT) found that the vast majority received ADT alone or with a first‐generation anti‐androgen. Despite the emergence of life‐prolonging treatments such as docetaxel and novel hormonal therapies, only a small proportion of patients received these treatments, indicating substantial room for improved outcomes in this population.
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e18766
Background: Waldenström macroglobulinemia (WM) is a rare, incurable non-Hodgkin lymphoma. Given limited real-world data on WM treatment utilization, this study evaluates ...real-world treatment patterns and associated outcomes in the US commercially insured population. Methods: A retrospective observational study was conducted using the IBM MarketScan commercial claims and Medicare supplement database. Adults with ≥2 WM diagnoses and ≥1 WM treatment between 2014 and 2019 were identified. Patients included were newly diagnosed, initiating treatment, and enrolled continuously for 6 months before and ≥60 days following the index date, defined as the first date of WM treatment. Treatment regimens were categorized as: rituximab monotherapy, chemotherapy-based (alone or in combination), proteasome inhibitor-based (alone or in combination with rituximab), ibrutinib (alone or in combination with rituximab), and other regimens. Treatment patterns were evaluated by frequency and duration of treatment regimen. Adherence is measured by discontinuation and switching rates. Healthcare resource utilization examined included inpatient, outpatient, and pharmacy visits. Total costs were calculated as sum of inpatient, outpatient and pharmacy costs per-patient-per-month (PPPM). Treatment regimens, costs, and hospitalizations were examined overall, and by line of therapy. Results: A total of 453 patients (mean age: 67 years, 51% male) received 1st-line therapy (mean duration: 246 days); 143 (32%) patients received 2nd-line therapy (mean duration: 231 days), and 24 (5%) received 3rd-line therapy (mean duration: 212 days). The most commonly used treatment regimens by line of therapy are shown in the treatment pattern table. Discontinuation rates were 43.3%, 50.4%, and 45.8%, and the switching rates were 25.4%, 10.5%, 20.8% during 1st, 2nd, and 3rd line of therapy, respectively. The overall hospitalization rate was 20% with an average length of stay (LOS) of 2.3 days. Approximately 17% (LOS: 1.4 days), 20% (LOS: 1.8 days), and 25% (LOS: 7.0 days) of patients had a hospitalization, during 1st, 2nd, and 3rd line of therapy, respectively. Mean total PPPM costs were $26,688 in overall population, and increased by line of therapy (1st: $18,682; 2nd: $19,171; and 3rd: $36,878). Conclusions: There remains a significant clinical and economic burden with suboptimal treatment adherence in US commercially-insured patients with WM. Future studies are needed to further understand factors associated with treatment selection. Table: see text
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Background: Androgen deprivation therapy (ADT) is the cornerstone of treatment for mCSPC patients. Clinical trials have recently shown that adding docetaxel (DOC) or novel hormonal ...therapies (NHT) to ADT improves survival in this population. Additionally, long-term (≥3 months) treatment with non-steroidal anti-androgens (AA) has been used to achieve combined androgen blockade. However, real-world evidence on survival outcomes in this setting is limited. Methods: Veterans Health Administration (VHA) claims data was used to compare time to metastatic castration-resistant prostate cancer (mCRPC) and overall survival (OS) in mCSPC men who initiated ADT alone or ADT with AA, DOC, or abiraterone (ABI) from April 1, 2014 to March 31, 2018. Propensity scores were calculated using logistics regression and adjusted for demographics (age, race) and patient characteristics at index (index year to ADT, radiation therapy, chronic corticosteroid use, Charlson Comorbidity Index score, select comorbidities, log(PSA), hemoglobin, alkaline phosphate, site of metastasis). Cox proportional hazard (CPH) models were used to evaluate time to progression to (mCRPC) and OS using stabilized inverse probability of treatment weighting (SIPTW) adjusting for body mass index, site of metastasis, time from metastatic diagnosis to index date, and log(PSA). Sensitivity analyses with CPH were conducted using propensity score matching (PSM). Results: The study included 1395 mCSPC men of which 874 (63%) were ADT only, 338 (24%) were ADT+AA (98% with bicalutamide), 75 (5%) were ADT+ABI, and 108 (8%) were ADT+DOC patients. Due to small sample sizes, adjusted survival analyses were not conducted on ADT+ABI and ADT+DOC cohorts. Post-SIPTW adjustment, patient characteristics were balanced between ADT+AA and ADT only cohorts. After treatment initiation, ADT+AA patients showed similar risk of progression to mCRPC (hazard ratio HR: 1.05 (95% CI: 0.87–1.26, P = .622), with a median time to mCRPC equal to 21.74 vs 22.5 months compared with ADT only. Patients treated with ADT+AA had similar risk of death compared to ADT only (HR: 1.22; 95% CI: 0.97–1.54, P = .093), with median survival not reached in both cohorts. Sensitivity analyses with PSM confirmed the results. Conclusions: Our study highlighted that most mCSPC patients in the VHA who initiated treatment between 2014 and 2018 were treated with ADT only despite the emergence of DOC or NHT combination therapies. Patients treated with ADT+AA had similar time to mCRPC and OS compared with ADT alone, but results should be treated with care as we could not adjust for all prognostic factors. Median time to mCRPC and OS in our study for both ADT and ADT+AA was similar to published data from corresponding placebo arms in NHT trials but inferior to outcomes in the treated arms of these trials, indicating significant room for survival improvement in the mCSPC population.
Real-world studies have evaluated the use of anticoagulants in obese patients with nonvalvular atrial fibrillation (NVAF), but they have been limited by sample size or the use of diagnosis codes on ...claims to define obesity. This retrospective study used body weight data of ≥100 kg or a body mass index of ≥30 kg/m2 to identify elderly (aged ≥65 years) NVAF patients with obesity in dually enrolled Veterans Affairs and fee-for-service Medicare patients. It evaluated the risk of stroke/systemic embolism (SE) and major bleeding (MB) in patients that initiated apixaban versus warfarin. Stabilized inverse probability treatment weighting was used to balance the baseline characteristics between patients prescribed apixaban and warfarin in obese patients. Cox models were used to evaluate the relative risk of stroke/SE and MB. Overall, 35.9% (n = 26,522) of the NVAF population were obese, of which 13,604 apixaban and 12,918 warfarin patients were included. After inverse probability treatment weighting, patient characteristics were balanced. The mean age was 75 years, the mean CHA2DS2-VASc score (Congestive Heart Failure, Hypertension, Age ≥75 Doubled, Diabetes Mellitus, Prior Stroke or Transient Ischemic Attack Doubled, Vascular Disease, Age 65–74, Female) was 3.8, the mean HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) Score was ∼2.6, and >98% of patients were males. Obese apixaban patients were associated with a similar risk of stroke/SE (hazard ratio: 0.82; 95% confidence interval: 0.66 to 1.03) and a significantly lower risk of MB (hazard ratio: 0.62; 95% confidence interval: 0.54 to 0.70) versus warfarin. No significant interaction was observed between treatment and obesity status (nonobese, obese/nonmorbid, obese/morbid) for stroke/SE (interaction p = 0.602) or MB (interaction p = 0.385). In obese patients with NVAF, apixaban was associated with a similar risk of stroke/SE and a significantly lower risk of MB versus warfarin.
Although bereaved parents suffer greatly, some may experience positive change referred to as post-traumatic growth.
Explore the extent to which parents perceive post-traumatic growth after their ...child's death in a pediatric intensive care unit (PICU), and associated factors.
Longitudinal parent survey conducted 6 and 13 months after a child's death. Surveys included the Post-traumatic Growth Inventory-Short Form (PTGI-SF), a 10-item measure with range of 0-50 where higher scores indicate more post-traumatic growth. Surveys also included the Inventory of Complicated Grief (ICG), the Patient Health Questionnaire-8 (PHQ-8) for depression, the Short Post-Traumatic Stress Disorder Rating Interview (SPRINT), a single item on perceived overall health, and sociodemographics.
One hundred fifty-seven parents of 104 children who died in 1 of 8 PICUs affiliated with the U.S. Collaborative Pediatric Critical Care Research Network.
Of participating parents, 62.4% were female, 71.6% White, 82.7% married, and 89.2% had at least a high school education. Mean PTGI-SF scores were 27.5 ± 12.52 (range 5-50) at 6 months and 28.6 ± 11.52 (range 2-49) at 13 months (
= 0.181). On multivariate modeling, higher education (compared with those not completing high school) and higher 6-month ICG scores (reflecting more complicated grief symptoms) were associated with lower 13-month PTGI-SF scores (
= 0.005 and 0.033, respectively).
Parents bereaved by their child's PICU death perceive a moderate degree of post-traumatic growth in the first 13 months after the death however variability is wide. Education level and complicated grief symptoms may influence parents' perception of post-traumatic growth.
Corticosteroids are commonly used in the treatment of pediatric septic shock without clear evidence of the potential benefits or risks. This study examined the association of early corticosteroid ...therapy with patient-centered clinically meaningful outcomes.
Subsequent cohort analysis of data derived from the prospective Life After Pediatric Sepsis Evaluation (LAPSE) investigation. Outcomes among patients receiving hydrocortisone or methylprednisolone on study day 0 or 1 were compared with those who did not use a propensity score-weighted analysis that controlled for age, sex, study site, and measures of first-day illness severity.
Twelve academic PICUs in the United States.
Children with community-acquired septic shock 1 month to 18 years old enrolled in LAPSE, 2013-2017. Exclusion criteria included a history of chronic corticosteroid administration.
None.
Among children enrolled in LAPSE, 352 of 392 met analysis inclusion criteria, and 155 of 352 (44%) received early corticosteroid therapy. After weighting corticosteroid therapy administration propensity across potentially confounding baseline characteristics, differences in outcomes associated with treatment were not statistically significant (adjusted effect or odds ratio 95% CI): vasoactive-inotropic support duration (-0.37 d -1.47 to 0.72; p = 0.503), short-term survival without new morbidity (1.37 0.83-2.28; p = 0.218), new morbidity among month-1 survivors (0.70 0.39-1.23; p = 0.218), and persistent severe deterioration of health-related quality of life or mortality at month 1 (0.70 0.40-1.23; p = 0.212).
This study examined the association of early corticosteroid therapy with mortality and morbidity among children encountering septic shock. After adjusting for variables with the potential to confound the relationship between early corticosteroid administration and clinically meaningful end points, there was no improvement in outcomes associated with this therapy. Results from this propensity analysis provide additional justification for equipoise regarding corticosteroid therapy for pediatric septic shock and ascertain the need for a well-designed clinical trial to examine benefit/risk for this intervention.
Based on the bioactive properties of certain compounds, such as antioxidant and anti‐inflammatory activities, an interesting subject of research are natural substances present in various parts of ...plants. The choice of the most appropriate method for separation and quantification of biologically active compounds from plants and natural products is a crucial step of any analytical procedure. The aim of this review article is to present an overview of a comprehensive literature study from the last 10 years (2007–2017), where relevant articles exposed the latest trends and the most appropriate methods applicable for separation and quantification of biologically active compounds from plant material and natural products. Consequently, various extraction methods have been discussed, together with the available procedures for purification and pre‐concentration and dedicated methods used for analysis.
Saponins are an important group of secondary metabolites naturally occurring in plants with important properties like: antibacterial, antiviral and antifungal. Moreover, they are widely used in the ...cosmetic industry and household chemistry. The sapogenins are saponin hydrolyses products, frequently used to facilitate saponin detection. In the present study, an improved methodology for isolation and separation of five sapogenins extracted from nettle (
L.), white dead-nettle (
L.), common soapwort (
L.) and washnut (
Gaertn.) was developed using ultra-high-performance liquid chromatography with an evaporative light-scattering detector (UHPLC-ELSD). Based on quantitative analysis, the highest content of hederagenin (999.1 ± 6.3 µg/g) and oleanolic acid (386.5 ± 27.7 µg/g) was found in washnut extracts. Good recoveries (71% ± 6 up to 99% ± 8) were achieved for four investigated targets, while just 22.2% ± 0.5 was obtained for the fifth one. Moreover, hederagenin and oleanolic acid of whose highest amount was detected in washnut (999.1 ± 6.3 µg/g and 386.5 ± 27.7 µg/g, respectively) were subject to another approach. Consequently, liquid chromatography coupled mass spectrometry (LC/MS) with multiple reaction monitoring mode (MRM) was used as an additional technique for fast and simultaneous identification of the mentioned targets.
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