Cancer-associated venous thromboembolism (VTE) represents a major source of morbidity and mortality among patients receiving systemic chemotherapy. Based largely on the results of a single, large randomized trial and several smaller studies, the National Comprehensive Cancer Network (NCCN) has recommended low-molecular-weight heparin (LMWH) over vitamin K antagonists for the treatment of VTE in this patient group. Despite this, however, vitamin K antagonists continue to be used worldwide for the treatment of cancer-associated VTE. In this multinational randomized control trial, 900 patients with active cancer, life expectancy >6 months, and acute symptomatic proximal deep vein thrombosis (DVT), pulmonary embolism, or both, were randomized to receive either 1) tinzaparin (175 IU/kg) once daily for 6 months or 2) tinzaparin (175 IU/kg) once daily for 5-10 days until an international normalized ratio (INR) of 2.0 for two consecutive days is achieved, followed by warfarin for 6 months. Study participants were followed up for 30 and 180 days after last medication dose to compare the efficacy and safety of these treatment options. With respect to efficacy, researchers found that recurrent VTE occurred more frequently in the warfarin group; however these results were not statistically significant. In terms of safety-related outcomes, researchers found that the incidence of major bleeding events between the two treatment arms were similar. However, non-major bleeding occurred less frequently among patients in the tinzaparin only group (HR 0.58, 95% CI 0.40-0.84). Differences in mortality rates between the treatment groups were not statistically significant. This study therefore shows that in treating cancer-associated VTE, full-dose tinzaparin does not significantly reduce the risk of recurrent VTE, major bleeding or overall mortality when compared to 6-month warfarin treatment. The risk of experiencing a non-major bleeding event, however, is relatively reduced among patients administered full-dose tinzaparin daily.
The incidence of both depression and dementia increase exponentially with advancing age. Several studies have suggested that the high levels of cortisol often observed in depressed patients may have neurotoxic effects on the hippocampus. The hippocampus normally has an inhibitory role in regulating the hypothalamic-pituitary-adrenal (HPA) axis. As such, atrophy of this structure ultimately results in further cortisol release, hippocampal atrophy, and ultimately contributes to the development of clinical dementia. In this subset analysis of the Age, Gene/Environment Susceptibility (AGES)–Reykjavik Study cohort, researchers investigated the relationship between morning and evening salivary cortisol levels, regional brain volumes and cognitive functioning in 4,255 older adults without dementia who had neurocognitive testing, brain MRIs, and saliva cortisol collections. Upon stratifying participants into 3 cortisol level groups, researchers found that higher evening cortisol levels (>3.3nmoL/L) were significantly associated with smaller total and regional brain volumes (p<0.05). Compared to participants in the lowest cortisol level group, individuals with higher cortisol levels also demonstrated poorer cognitive functioning (memory, speed, executive functioning). Researchers also found that compared to white matter, gray matter was considerably more affected by high evening cortisol levels (p<0.001). Morning cortisol levels were not linked to total brain volume. However, higher cortisol levels were marginally associated with less white matter volume reduction compared to the lowest morning cortisol subgroup (p<0.05). Gray matter regions were not associated with morning cortisol levels, with the exception of frontal gray matter, where participants within the highest cortisol group exhibited slightly smaller frontal gray matter (p<0.05). Based on multilevel models, white matter was considerably more affected by morning cortisol than gray matter (p = 0.008). Finally, while no significant association was found between morning cortisol levels and memory, higher morning cortisol levels were associated with better speed and executive functioning when compared to the lowest morning cortisol group (p<0.05). This study therefore shows that morning and evening cortisol levels may be differentially associated with cognitive function and brain volume in certain gray and white matter structures.
The American Society of Clinical Oncology (ASCO) recommends routine risk assessment as a means of engaging women in informed decision-making surrounding therapies that may reduce their breast cancer risk. However, risk assessment is not routinely performed and few risk models incorporate important benign findings. Given that breast density and benign breast disease (BBD) are important risk factors for incident breast cancer, this raises concern surrounding the accuracy of risk assessment. Currently, the Breast Cancer Surveillance Consortium (BCSC) risk prediction model is the only risk assessment tool that utilizes Breast Imaging Reporting and Data System (BI-RADS) density categories. It does not, however, incorporate BBD findings determined through biopsy. In this retrospective cohort study, 1,135,977 women age 35-74 years old that had at least one mammogram with BI-RADS density reported were followed up for incident breast cancer as part of updating and validating a BCSC risk prediction model with BBD diagnoses. BBD diagnoses were classified as nonproliferative, proliferative without atypia, proliferative with atypia or lobular carcinoma in situ (LCIS). In developing a competing-risk model, researchers found that age had several important interactions with other risk factors in the model, where breast cancer risk was associated with race/ethnicity (p for interaction <0.001), family history (p for interaction = 0.007) and BI-RADS density (p for interaction <0.001) declined with increasing age. Calibration of the newly constructed model revealed a slight underestimation of breast cancer rates in women age 35-39, as well as women of Asian or Hispanic descent. Overall, the model slightly overestimated breast cancer risk in this cohort (expected-to-observed ratio 1.04, 95% CI 1.03-1.06). The area under the curve (AUC) for this model was 0.665, only marginally greater than the BCSC model without BBD. However, among women with a known biopsy result, the AUC increased from 0.650 to 0.660. This corresponded to a 7% increase in the proportion of women with a 5-year risk of invasive breast cancer of 3% or more. Among women with proliferative findings, the addition of BBD to the model increased the proportion of women with an estimated 5-year risk of 3% or more from 9.3% to 27.8% (p<0.001). This study therefore shows that while inclusion of BBD may have only minimal impact on risk discrimination, it may significantly change the risk estimated for women with biopsy results, particularly if results indicate proliferative disease.
Chronic obstructive pulmonary disease (COPD) is increasingly recognized as a multisystem disease, associated with a number of comorbidities that may contribute or cause moderate to severe exacerbations requiring hospitalization. Several randomized trials have suggested that the use of beta-blockers may be associated with a reduction in mortality and frequency of exacerbations, however previous research findings have indicated that these medications may be unsafe for patients with severe COPD on home oxygen. In this multicenter retrospective cohort study, 3,464 participants with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2-4 COPD were followed up for a median of 2.1 years to assess total and severe exacerbation rates in patients given beta-blockers, compared to other treatments. Propensity scoring was used to adjust for covariates associated with beta-blocker use (i.e. coronary artery disease, chronic heart failure). Researchers found that the use of beta-blockers was associated with a significantly lower rate of total exacerbations (incidence risk ratio (IRR) 0.73, 95% CI 0.60-0.90) and severe exacerbations (IRR 0.67, 95% CI 0.48-0.93). In a subanalysis of participants with GOLD stage 3-4 on home oxygen, the use of β-blockers was also associated with a reduction in the rate of total exacerbations (IRR 0.33, 95% CI 0.19 to 0.58) and severe exacerbations (IRR 0.35, 95% CI 0.16 to 0.76). There was no difference in all-cause mortality with β-blocker use. This study therefore shows that the use of beta-blockers may significantly reduce exacerbations in patients with COPD, including patients with severe disease requiring home oxygen.
Iron deficiency is a leading cause of anemia in sub-Saharan Africa. While iron supplementation is regarded as the gold standard in addressing this type of anemia, recent trials among children have raised concerns surrounding the safety of supplementation in regions that are malaria-endemic. In this randomized controlled trial, 1,500 iron-replete, nonanemic women were randomized to receive either 60 mg of iron or placebo to study safety and efficacy of iron supplementation during pregnancy in a malaria-endemic region. All study participants also received standard prenatal care every 4 weeks, including malaria screening and prophylaxis with a combination of sulfadoxine and pyrimethamine, and treatment as needed. Primary outcome measures were placental malaria, maternal hemoglobin level at delivery and birth weight. Researchers found that the prevalence of placental malaria between the groups did not significantly differ (RR 1.03, 95% CI 0.65-1.65). There was also no increased risk of microscopic (RR 1.14, 95% CI 0.49-2.65) or submicroscopic (RR 1.12, 95% CI 0.65-1.92) placental malaria associated with iron supplementation. Risk of maternal death was also not significantly affected by iron supplementation (RR 0.67, 95% CI 0.11-3.98), and although there were fewer maternal hospitalizations in the iron group (RR 0.57, 95% CI 0.32-1.02), no single type of hospitalization was significantly associated with iron supplementation. At the time of delivery, women in the iron group had significantly higher hemoglobin levels than the placebo group (mean 11.8g/dL vs. 10.9g/dL, p<0.001) and had a decreased risk of anemia (RR 0.60, 95% CI 0.51-0.71). Iron supplementation did not, however, decrease the risk of severe anemia at delivery (RR 0.68, 95% CI 0.41-1.14). Among live births, iron supplementation did not affect birth weight or risk of low birth weight (RR 0.91, 95% CI 0.62-1.34), fetal loss (RR 1.26, 95% CI 0.86-1.92), early child mortality (RR 1.28, 95% CI 0.67-2.45) or preterm birth. This study therefore demonstrates a lack of harm from prenatal iron supplementation in iron-replete nonanemic women where good malaria control is present.
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