Purpose
Our aim is to examine the associations between high-sensitivity C-reactive protein (hsCRP) and hemoglobin A1c (HbA1c), common biomarkers of inflammation and insulin resistance, respectively, ...with breast cancer risk, while adjusting for measures of excess body size.
Methods
We conducted a nested case–control study within the Alberta’s Tomorrow Project cohort (Alberta, Canada) including 197 incident breast cancer cases and 394 matched controls. The sample population included both pre- and postmenopausal women. Serum concentrations of hsCRP and HbA1c were measured from blood samples collected at baseline, along with anthropometric measurements, general health and lifestyle data. Conditional logistic regression was used to evaluate associations between hsCRP, HbA1c, and breast cancer risk adjusted for excess body size (body fat percentage) and other risk factors for breast cancer.
Results
Higher concentrations of hsCRP were associated with elevated breast cancer risk (odds ratio OR 1.27; 95% confidence interval 95% CI 1.03–1.55). The observed associations were unchanged with adjustment for body fat percentage. Higher HbA1c concentrations were not significantly associated with an increased breast cancer risk (OR 1.22; 95% CI 0.17–8.75).
Conclusion
These data suggest that hsCRP may be associated with elevated breast cancer risk, independent of excess body size. However, elevated concentrations of HbA1c did not appear to increase breast cancer risk in apparently healthy women.
Current cancer prevention recommendations advise limiting red meat intake to <500 g/week and avoiding consumption of processed meat, but do not differentiate the source of processed meat. We examined ...the associations of processed meat derived from red v. non-red meats with cancer risk in a prospective cohort of 26 218 adults who reported dietary intake using the Canadian Diet History Questionnaire. Incidence of cancer was obtained through data linkage with Alberta Cancer Registry with median follow-up of 13·3 (interquartile range (IQR) 5·1) years. Multivariable Cox proportional hazards regression models were adjusted for covariates and stratified by age and sex. The median consumption (g/week) of red meat, processed meat from red meat and processed meat from non-red meat was 267·9 (IQR 269·9), 53·6 (IQR 83·3) and 11·9 (IQR 31·8), respectively. High intakes (4th Quartile) of processed meat from red meat were associated with increased risk of gastrointestinal cancer adjusted hazard ratio (AHR): 1·68 (95 % CI 1·09, 2·57) and colorectal cancers AHR: 1·90 (95 % CI 1·12, 3·22), respectively, in women. No statistically significant associations were observed for intakes of red meat or processed meat from non-red meat. Results suggest that the carcinogenic effect associated with processed meat intake may be limited to processed meat derived from red meats. The findings provide preliminary evidence towards refining cancer prevention recommendations for red and processed meat intake.
Overseas-born and newly arrived gay and bisexual men and men who have sex with men (GBMSM) are at higher risk of acquiring HIV in comparison to Australian-born GBMSM. Pre-exposure prophylaxis (PrEP) ...is subsidized by the Australian government under Medicare, Australia's universal health insurance scheme, however many members of this population are Medicare-ineligible, which could prevent them from accessing PrEP. We wanted to explore participants' knowledge of and attitudes toward PrEP and their opinions of new PrEP modalities, namely injectable PrEP and PrEP implants.
We conducted in-depth qualitative interviews between February 2021 to September 2021 with 22 overseas-born, newly arrived (<5 years in Australia) GBMSM of varying PrEP use. We asked their opinions of PrEP and their preferences of new PrEP modalities. Interviews were audio recorded and transcribed verbatim. We conducted a reflexive thematic analysis to interpret the data.
Participants' views reflect the intersections between systemic factors, such as Medicare ineligibility and the high cost of PrEP, with socio-cultural factors, such as lack of knowledge about PrEP, internalized stigma stemming from homo- and sex-negativity, and stigmatizing attitudes toward PrEP and PrEP users. For participants who were on PrEP, being community connected, having a positive relationship with doctors and nurses, and being informed of the option to purchase PrEP from overseas pharmacies at a low cost helped them to overcome some of these barriers. Additionally, there was a strong preference for injectable PrEP but not PrEP implants. Participants stressed the importance of providing a comprehensive information about PrEP specific to this population and to make PrEP free for all.
We concluded that resources about PrEP specific to this population that address both systemic and socio-cultural factors are needed, and for these resources to be available in languages other than English. This is to coincide with on-going advocacy to increase the capacity of publicly funded sexual health clinics to provide multilingual PrEP services for people without Medicare, and to make PrEP free for all. These combined strategies have the potential to increase PrEP knowledge and uptake among this population.
In this paper, we consider the role of inequality-based entry barriers on the formation of female-owned firms in Nigeria. With data from the 2010 World Enterprise Survey, we estimate the parameters ...of a simple model of female-owned firm entry to determine the role of inequality-based barriers on the number of female-owned firms across city-industry clusters in Nigeria. Parameter estimates from count data specifications of firm entry reveal that access to financing, land, and licenses/permits absolutely deter the entry of female-owned firms, as these entry barriers are proportional to the probability of observing no female-owned firms. In general, barriers to securing land constrain the entry of female-owned firms beyond the process determining absolute entry deterrence. This suggests that the market entry and underrepresentation of female-owned among firm-owners and entrepreneurs in Nigeria is, at least in part, caused by gender inequality in general. As private firm output dominates the gross domestic product of modern economies, our findings suggest that the reduction of gender inequality in Sub-Saharan Africa would result in more female-owned and entrepreneurs which would catalyze economic growth.
Abstract Background We hypothesized that recombinant B-type natriuretic peptide (BNP) (nesiritide) could improve urine output and neurohormonal markers of heart failure without worsening renal ...function in pediatric patients. Methods and Results We analyzed our experience involving 140 nesiritide infusions in 63 consecutive children. Serum levels of BNP and electrolytes were measured before and after therapy. Dosing was begun at 0.01 mcg·kg·min without a bolus and titrated to a maximum of 0.03 mcg·kg·min, in 0.005-mcg·kg·min increments. Blood pressure, heart rate, and heart rhythm were monitored. In a substudy, 20 patients with decompensated cardiomyopathy-related heart failure received 72 hours of nesiritide with prospective assessment of aldosterone, norepinephrine, plasma renin, and endothelin-1 levels before and after therapy. The heart rate decreased significantly ( P = .001). Urine output increased significantly on Days 1 and 3 ( P ≤ .001 and .004, respectively). The mean serum creatinine level decreased from 1.135 to 1.007 mg/dL ( P ≤ .001). In the substudy, aldosterone levels decreased from 37.5 ± 57.1 to 20.5 ± 41.9 ng/dL ( P = .005). Plasma renin, norepinephrine, and endothelin-1 levels decreased nonsignificantly. Two infusions were discontinued because of hypotension. Conclusions Nesiritide safely treated decompensated heart failure in children. Increased urine output reflected improving renal function. Improved neurohormonal markers were seen after 72 hours of therapy, and complications were uncommon.
Many diseases exhibit population-specific causal effect sizes with trans-ethnic genetic correlations significantly less than 1, limiting trans-ethnic polygenic risk prediction. We develop a new ...method, S-LDXR, for stratifying squared trans-ethnic genetic correlation across genomic annotations, and apply S-LDXR to genome-wide summary statistics for 31 diseases and complex traits in East Asians (average N = 90K) and Europeans (average N = 267K) with an average trans-ethnic genetic correlation of 0.85. We determine that squared trans-ethnic genetic correlation is 0.82× (s.e. 0.01) depleted in the top quintile of background selection statistic, implying more population-specific causal effect sizes. Accordingly, causal effect sizes are more population-specific in functionally important regions, including conserved and regulatory regions. In regions surrounding specifically expressed genes, causal effect sizes are most population-specific for skin and immune genes, and least population-specific for brain genes. Our results could potentially be explained by stronger gene-environment interaction at loci impacted by selection, particularly positive selection.
Triggering receptor expressed on myeloid cell-2 (TREM2) is a lipid and lipoprotein binding receptor expressed by cells of myeloid origin. Homozygous TREM2 mutations cause early onset progressive ...presenile dementia while heterozygous, point mutations triple the risk of Alzheimer's disease (AD). Although human genetic findings support the notion that loss of TREM2 function exacerbates neurodegeneration, it is not clear whether activation of TREM2 in a disease state would result in therapeutic benefits. To determine the viability of TREM2 activation as a therapeutic strategy, we sought to characterize an agonistic Trem2 antibody (AL002a) and test its efficacy and mechanism of action in an aggressive mouse model of amyloid deposition.
To determine whether agonism of Trem2 results in therapeutic benefits, we designed both intracranial and systemic administration studies. 5XFAD mice in the intracranial administration study were assigned to one of two injection groups: AL002a, a Trem2-agonizing antibody, or MOPC, an isotype-matched control antibody. Mice were then subject to a single bilateral intracranial injection into the frontal cortex and hippocampus and euthanized 72 h later. The tissue from the left hemisphere was histologically examined for amyloid-beta and microglia activation, whereas the tissue from the right hemisphere was used for biochemical analyses. Similarly, mice in the systemic administration study were randomized to one of the aforementioned injection groups and the assigned antibody was administered intraperitoneally once a week for 14 weeks. Mice underwent behavioral assessment between the 12- and 14-week timepoints and were euthanized 24 h after their final injection. The tissue from the left hemisphere was used for histological analyses whereas the tissue from the right hemisphere was used for biochemical analyses.
Here, we show that chronic activation of Trem2, in the 5XFAD mouse model of amyloid deposition, leads to reversal of the amyloid-associated gene expression signature, recruitment of microglia to plaques, decreased amyloid deposition, and improvement in spatial learning and novel object recognition memory.
These findings indicate that Trem2 activators may be effective for the treatment of AD and possibly other neurodegenerative disorders.
Patients with HER2-positive breast cancer who have received two or more previous therapies for advanced disease have few effective treatment options. The monarcHER trial aimed to compare the efficacy ...of abemaciclib plus trastuzumab with or without fulvestrant with standard-of-care chemotherapy of physician's choice plus trastuzumab in women with advanced breast cancer.
This phase 2, three-group, open-label trial was done across 75 hospitals, clinics, and medical centres in 14 countries. Eligible patients were women aged 18 years or older, who had hormone receptor-positive, HER2-positive advanced breast cancer with unresectable, locally advanced, recurrent or metastatic disease, Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received at least two HER2-targeted therapies for advanced disease. Patients were randomly assigned 1:1:1 to the abemaciclib, trastuzumab, and fulvestrant (group A), abemaciclib and trastuzumab (group B), or standard-of-care chemotherapy and trastuzumab (group C). Oral abemaciclib 150 mg 12 hourly was administered on days 1–21 of a 21-day cycle, intravenous trastuzumab 8 mg/kg on cycle 1 day 1, followed by 6 mg/kg on day 1 of each subsequent 21-day cycle, and intramuscular fulvestrant 500 mg on days 1, 15, and 29 and once every 4 weeks thereafter. Standard-of-care chemotherapy was administered as specified by the product label. Randomisation was by a computer-generated random sequence by means of an interactive web-response system and stratified by number of previous systemic therapies for advanced breast cancer and measurable versus non-measurable disease. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, first testing group A versus group C and, if this result was significant, then group B versus group C. Safety was assessed in all patients who had received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov (NCT02675231) and is ongoing for long-term survival follow-up.
Between May 31, 2016, and Feb 28, 2018, 325 patients were screened, of whom 237 eligible patients were enrolled and randomly assigned to groups A (n=79), B (n=79), and C (n=79). Median follow-up was 19·0 months (IQR 14·7–25·1). The study met its primary endpoint, showing a significant difference at the prespecified two-sided α of 0·2 in median progression-free survival between group A (8·3 months, 95% CI 5·9–12·6) and group C (5·7 months, 5·4–7·0; HR 0·67 95% CI 0·45–1·00; p=0·051). No difference was observed between median progression-free survival in group B (5·7 months, 95% CI 4·2–7·2) and group C (HR 0·94 0·64–1·38; p=0·77). The most common grade 3–4 treatment-emergent adverse event in groups A, B, and C was neutropenia (21 27% of 78 patients, 17 22% of 77, and 19 26% of 72). The most common serious adverse events were: in group A, pyrexia (three 4%), diarrhoea (two 3%), urinary tract infection (two 3%), and acute kidney injury (two 3%); in group B, diarrhoea (two 3%) and pneumonitis (two 3%); and in group C, neutropenia (four 6%) and pleural effusion (two 3%). Two deaths were attributed to treatment: one due to pulmonary fibrosis in group B and one due to febrile neutropenia in group C.
The combination of abemaciclib, fulvestrant, and trastuzumab significantly improved progression-free survival versus standard-of-care chemotherapy plus trastuzumab while showing a tolerable safety profile. Our results suggest that a chemotherapy-free regimen might potentially be an alternative treatment option for patients with hormone receptor-positive, HER2-positive advanced breast cancer.
Eli Lilly and Company.
Vascular contributions to cognitive impairment and dementia (VCID) are the second leading cause of dementia behind only Alzheimer's disease (AD); however, VCID is commonly found as a co-morbidity ...with sporadic AD. We have previously established a mouse model of VCID by inducing hyperhomocysteinemia in both wild-type and amyloid depositing mice. While we have shown the time course of neuropathological events in the wild-type mice with hyperhomocysteinemia, the effect of amyloid deposition on this time course remains unknown; therefore, in this study, we determined the time course of neuropathological changes in our mouse model of hyperhomocysteinemia-induced VCID in amyloid depositing mice.
APP/PS1 mice were placed on either a diet deficient in folate and vitamins B6 and B12 and enriched in methionine to induce hyperhomocysteinemia or a control diet for 2, 6, 10, 14, or 18 weeks. Immunohistochemistry and gene expression analysis were used to determine neuroinflammatory changes. Microhemorrhages and amyloid deposition were analyzed using histology and, finally, behavior was assessed using the 2-day radial arm water maze.
Neuroinflammation, specifically a pro-inflammatory phenotype, was the first pathological change to occur. Specifically, we see a significant increase in gene expression of tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, and interleukin 12a by 6 weeks. This was followed by cognitive deficits starting at 10 weeks. Finally, there is a significant increase in the number of microhemorrhages at 14 weeks on diet as well as redistribution of amyloid from the parenchyma to the vasculature.
The time course of these pathologies points to neuroinflammation as the initial, key player in homocysteine-induced VCID co-morbid with amyloid deposition and provides a possible therapeutic target and time points.
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