The natural history of prostate cancer is highly variable and difficult to predict. We report on the prognostic value of phosphatase and tensin homologue (PTEN) loss in a cohort of 675 men with ...conservatively managed prostate cancer diagnosed by transurethral resection of the prostate.
The PTEN status was assayed by immunohistochemistry (PTEN IHC) and fluorescent in situ hybridisation (PTEN FISH). The primary end point was death from prostate cancer.
The PTEN IHC loss was observed in 18% cases. This was significantly associated with prostate cancer death in univariate analysis (hazard ratio (HR)=3.51; 95% CI 2.60-4.73; P=3.1 × 10(-14)). It was highly predictive of prostate cancer death in the 50% of patients with a low risk score based on Gleason score, PSA, Ki-67 and extent of disease (HR=7.4; 95% CI 2.2-24.6; P=0.012) ), but had no prognostic value in the higher risk patients. The PTEN FISH loss was only weakly associated with PTEN IHC loss (κ=0.5). Both PTEN FISH loss and amplification were univariately predictive of death from prostate cancer, but this was not maintained in the multivariate analyses.
In low-risk patients, PTEN IHC loss adds prognostic value to Gleason score, PSA, Ki-67 and extent of disease.
To evaluate: (i) the impact of air-drying on bacterial, archaeal and fungal soil DNA profiles and (ii) the potential use of multiplex-terminal restriction fragment length polymorphism (M-TRFLP) as a ...tool for forensic comparison of soil. An M-TRFLP approach was used to profile bacterial, archaeal and fungal DNA profiles from five different soil sites. Air-drying soil significantly reduced the quantity of DNA but the number of operational taxanomic units (OTU) was unaffected. The impact of air-drying on soil DNA profiles was dependent on soil site and microbial primers. Fungal profiles were altered the least by air-drying. For prokaryotic profiles, air-drying altered the relative similarity/dissimilarity between soil sites. The M-TRFLP approach was more discriminatory compared with soil colour and single-taxa profiling, but did not significantly improve resolution between two similar soils. Of those tested, soil fungi were potentially the more robust target for application to soil forensic studies as they were altered less by air-drying and provided clear discrimination of soils from different sites. The M-TRFLP method demonstrated potential to achieve greater resolution, discriminating the soil sites based on both bacterial and fungal components. Soil DNA profiling has potential as a forensic tool, but sample condition and the appropriate selection of microbial target taxa must be considered.
Novel therapies have turned to delivering compounds to the brain using nasal sprays, bypassing the blood brain barrier, and enriching treatment options for brain aging and/or Alzheimer's disease. We ...conducted a series of in vivo experiments to test the impact of intranasal Apidra, a zinc-free insulin formulation, on the brain of young and aged F344 rats. Both single acute and repeated daily doses were compared to test the hypothesis that insulin could improve memory recall in aged memory-deficient animals. We quantified insulin signaling in different brain regions and at different times following delivery. We measured cerebral blood flow (CBF) using MRI and also characterized several brain metabolite levels using MR spectroscopy. We show that neither acute nor chronic Apidra improved memory or recall in young or aged animals. Within 2 hours of a single dose, increased insulin signaling was seen in ventral areas of the aged brains only. Although chronic Apidra was able to offset reduced CBF with aging, it also caused significant reductions in markers of neuronal integrity. Our data suggest that this zinc-free insulin formulation may actually hasten cognitive decline with age when used chronically.
Abstract only
Introduction:
Greater regularity in daily sleep and eating timing are independently and separately associated with lower carotid intima-media thickness (CIMT), a marker of subclinical ...atherosclerotic development in early adulthood. Not known is the extent to which achieving regularity in
both
sleep
and
eating would be associated with a lower CIMT as compared to achieving regularity in either behavior alone, or neither. Such information could help identify behavioral target priorities for cardioprotective interventions.
Hypothesis:
We tested the hypothesis that individuals achieving both sleep and eating regularity would have a lower CIMT than individuals with either sleep or eating regularity, or neither.
Methods:
Healthy adults aged 18-45 years (N=65, 29.7±7.2 years, 63% female) completed 14 days of sleep and dietary assessments via wrist accelerometry and photo-assisted diet records, respectively. Mean time for sleep midpoint (midpoint time between sleep onset and offset) and caloric midpoint (time at which 50% of total daily calories are consumed), sleep regularity (i.e., a mean sleep midpoint standard deviation (SD) of <60 minutes), and eating regularity (i.e., caloric midpoint SD < median of 154 minutes) values were generated. A 4-level ‘sleep and eating regularity’ variable was generated that distinguished between participants achieving regularity in: (1) both sleep and eating, (2) only eating, (3) only sleep, or (4) neither. A linear regression model evaluating the association between sleep and eating regularity with CIMT adjusting for age, sex, systolic blood pressure, sleep duration, and total energy intake was estimated.
Results:
Participants who achieved regularity in both sleep and eating (n=23) had the lowest M
CIMT
=0.523mm (SD=0.043), those who achieved only sleep regularity (n=10) had a M
CIMT
=0.549mm (SD=0.078), only eating regularity (n=16) had a M
CIMT
=0.568mm (SD=0.065), and those achieving neither sleep or eating regularity (n=16) had the highest M
CIMT
=0.575mm (SD=0.074). In a controlled model, the 4-level sleep and eating regularity variable was significantly associated with CIMT (F=2.95, p=.04, model R
2
=.33), with regularity in both demonstrating pairwise significance as compared to neither (p = 0.02) and eating regularity only (p = 0.02). Given that a 1-SD increase in CIMT (~0.06-0.07mm) has been shown to confer a 40% increased risk for first-time CVD events in adults <45 years old, the ~0.05mm difference in CIMT between regular vs. irregular groups has clinical meaning.
Conclusions:
Regularity in sleep and eating may be associated with lower subclinical atherosclerosis as early as young adulthood. Future studies evaluating the cardioprotective effects of promoting regularity of modifiable behaviors (eating and sleep) in adults at elevated CVD risk are warranted.
Abstract only
Background:
Physical inactivity and poor adherence to healthy eating guidelines impact cardiovascular health (CVH) outcomes in African American (AAs). Our randomized controlled trial ...(RCT) testing the FAITH! App, an mHealth lifestyle intervention, showed efficacy in promoting ideal CVH, particularly diet and physical activity (PA) among AAs, warranting exploration of underlying factors. Psychosocial factors (e.g., self-regulation, self-efficacy, social support) are key to healthy behavior adoption.
Hypothesis:
The intervention group would have greater improvements in diet and PA-related psychosocial factors than the control group after using the FAITH! App.
Methods:
A 2-arm cluster RCT was conducted among AAs from 16 churches in Minnesota comparing the FAITH! App intervention to a delayed intervention control group. The FAITH! App included culturally relevant, CVH-focused education modules, diet/PA self-monitoring and a sharing board. The outcomes were change in diet and PA self-regulation and self-efficacy (primary) and social support and barriers (secondary) at 6 months post-intervention. The intervention effect was assessed using linear regression.
Results:
Sixty-eight participants were included (71% female; mean age SD: 54.7 12.6 years) (
Table 1
). The intervention group showed a significantly greater increase in diet self-regulation planning/tracking nutrition (+0.66, p<.03) and PA self-regulation step count strategies (+0.47, p=.003) than the control group. Within groups, the intervention group demonstrated significant improvements across diet and PA self-regulation measures, while the control group showed an improvement only in fruit/vegetable and grain intake. No effect was observed in self-efficacy, social support, or barriers.
Conclusions:
Our culturally tailored mHealth lifestyle intervention was associated with notable increases in diet and PA self-regulation, suggesting a potential mechanism by which the FAITH! App improves healthy eating and PA among AAs.
Abstract
Objective: We explored the prevalence of Composite Major Maternal Morbidity (CMMM) for patients with severe preeclampsia (SPRE) and each class or category of HELLP syndrome.
Methods: In a ...retrospective cohort study from 2000 to 2010, we reviewed maternal charts of patients categorized with complete or partial HELLP syndrome. From 2005 to 2007, the maternal charts for every patient with a diagnosis of SPRE without HELLP syndrome were also evaluated for comparison. The CMMM for each patient group included cardiopulmonary; hematologic/coagulation, central nervous system/visual, hepatic or renal complications. During the study interval patients with class 1 and class 2 HELLP syndrome received Mississippi Protocol management.
Results: Four hundred and ninety-five mothers had a form of HELLP syndrome in years 2000-2010; 688 mothers experienced a non-HELLP severe form of preeclampsia during 2005-2007. The prevalence of CMMM for each patient group was: class 1 = 44%; class 2 = 13%; class 3 = 24%; partial HELLP = 20% and SPRE = 18%. CMMM for class 1 HELLP syndrome is significantly higher than all other groups (p < 0.001).
Conclusions: Patients who develop class 1 HELLP syndrome have significantly higher CMMM. Avoiding this most advanced stage of HELLP syndrome and minimizing the development of new MMM becomes a measure of medical management effectiveness and a tool to assess overall quality of care.
The effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer risk for BRCA1 and BRCA2 mutation carriers is uncertain. Retrospective analyses have suggested a protective effect but may be ...substantially biased. Prospective studies have had limited power, particularly for BRCA2 mutation carriers. Further, previous studies have not considered the effect of RRSO in the context of natural menopause.
A multi-centre prospective cohort of 2272 BRCA1 and 1605 BRCA2 mutation carriers was followed for a mean of 5.4 and 4.9 years, respectively; 426 women developed incident breast cancer. RRSO was modelled as a time-dependent covariate in Cox regression, and its effect assessed in premenopausal and postmenopausal women.
There was no association between RRSO and breast cancer for BRCA1 (HR = 1.23; 95% CI 0.94-1.61) or BRCA2 (HR = 0.88; 95% CI 0.62-1.24) mutation carriers. For BRCA2 mutation carriers, HRs were 0.68 (95% CI 0.40-1.15) and 1.07 (95% CI 0.69-1.64) for RRSO carried out before or after age 45 years, respectively. The HR for BRCA2 mutation carriers decreased with increasing time since RRSO (HR = 0.51; 95% CI 0.26-0.99 for 5 years or longer after RRSO). Estimates for premenopausal women were similar.
We found no evidence that RRSO reduces breast cancer risk for BRCA1 mutation carriers. A potentially beneficial effect for BRCA2 mutation carriers was observed, particularly after 5 years following RRSO. These results may inform counselling and management of carriers with respect to RRSO.
Negative mood states experienced during the withdrawal stage of substance dependence have been associated with relapse in persons suffering from substance use disorder (SUD). Exercise is gaining ...attention as an adjunct therapy for SUD due to its ability to alleviate negative mood states experienced during withdrawal. The purpose of this study was to investigate the effects of acute, controlled bouts of aerobic and resistance exercise versus sedentary control (quiet reading) on positive affect (PA) and negative affect (NA) in females undergoing SUD treatment at inpatient facilities. Females (n=11; 34 ± 8 yrs) were randomly assigned to each condition in counterbalanced fashion. Aerobic exercise (AE) consisted of 20 minutes of steady-state moderate intensity (40-60% HRR) treadmill walking. Resistance exercise (RE) consisted of 20 minutes of standardized circuit weight training (1:1 work to rest ratio). The Positive and Negative Affect Scale (PANAS) was used to assess PA and NA pre- and post-interventions. Repeated measures ANOVAs indicated AE and RE significantly increased PA (p < 0.05) versus control, with no significant difference between AE and RE. Friedman's test revealed AE and RE significantly reduced NA (p < 0.05) versus control. Results indicate short bouts of aerobic and resistance exercise are equally effective for acute mood regulation and superior to a sedentary control in females undergoing inpatient SUD treatment.
Sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce progression of chronic kidney disease and the risk of cardiovascular morbidity and mortality in a wide range of patients. However, their ...effects on kidney disease progression in some patients with chronic kidney disease are unclear because few clinical kidney outcomes occurred among such patients in the completed trials. In particular, some guidelines stratify their level of recommendation about who should be treated with SGLT2 inhibitors based on diabetes status and albuminuria. We aimed to assess the effects of empagliflozin on progression of chronic kidney disease both overall and among specific types of participants in the EMPA-KIDNEY trial.
EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA), and included individuals aged 18 years or older with an estimated glomerular filtration rate (eGFR) of 20 to less than 45 mL/min per 1·73 m
, or with an eGFR of 45 to less than 90 mL/min per 1·73 m
with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher. We explored the effects of 10 mg oral empagliflozin once daily versus placebo on the annualised rate of change in estimated glomerular filtration rate (eGFR slope), a tertiary outcome. We studied the acute slope (from randomisation to 2 months) and chronic slope (from 2 months onwards) separately, using shared parameter models to estimate the latter. Analyses were done in all randomly assigned participants by intention to treat. EMPA-KIDNEY is registered at ClinicalTrials.gov, NCT03594110.
Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and then followed up for a median of 2·0 years (IQR 1·5-2·4). Prespecified subgroups of eGFR included 2282 (34·5%) participants with an eGFR of less than 30 mL/min per 1·73 m
, 2928 (44·3%) with an eGFR of 30 to less than 45 mL/min per 1·73 m
, and 1399 (21·2%) with an eGFR 45 mL/min per 1·73 m
or higher. Prespecified subgroups of uACR included 1328 (20·1%) with a uACR of less than 30 mg/g, 1864 (28·2%) with a uACR of 30 to 300 mg/g, and 3417 (51·7%) with a uACR of more than 300 mg/g. Overall, allocation to empagliflozin caused an acute 2·12 mL/min per 1·73 m
(95% CI 1·83-2·41) reduction in eGFR, equivalent to a 6% (5-6) dip in the first 2 months. After this, it halved the chronic slope from -2·75 to -1·37 mL/min per 1·73 m
per year (relative difference 50%, 95% CI 42-58). The absolute and relative benefits of empagliflozin on the magnitude of the chronic slope varied significantly depending on diabetes status and baseline levels of eGFR and uACR. In particular, the absolute difference in chronic slopes was lower in patients with lower baseline uACR, but because this group progressed more slowly than those with higher uACR, this translated to a larger relative difference in chronic slopes in this group (86% 36-136 reduction in the chronic slope among those with baseline uACR <30 mg/g compared with a 29% 19-38 reduction for those with baseline uACR ≥2000 mg/g; p
<0·0001).
Empagliflozin slowed the rate of progression of chronic kidney disease among all types of participant in the EMPA-KIDNEY trial, including those with little albuminuria. Albuminuria alone should not be used to determine whether to treat with an SGLT2 inhibitor.
Boehringer Ingelheim and Eli Lilly.
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