Summary
Background
Medication non‐adherence seems to be a particular problem in younger patients with inflammatory bowel disease (IBD) and has a negative impact on disease outcome.
Aims
To assess ...whether non‐adherence, defined using thiopurine metabolite levels, is more common in young adults attending a transition clinic than adults with IBD and whether psychological co‐morbidity is a contributing factor. We also determined the usefulness of the Modified Morisky 8‐item Adherence Scale (MMAS‐8) to detect non‐adherence.
Methods
Seventy young adults 51% (36) male and 74 62% (46) male adults were included. Psychological co‐morbidity was assessed using the Hospital Anxiety Depression Scale (HADS) and self‐reported adherence using the MMAS‐8.
Results
Twelve percent (18/144) of the patients were non‐adherent. Multivariate analysis OR, (95% CI), P value confirmed that being young adult 6.1 (1.7–22.5), 0.001, of lower socio‐economic status 1.1 (1.0–1.1), <0.01 and reporting higher HADS‐D scores 1.2 (1.0–1.4), 0.01 were associated with non‐adherence. Receiver operator curve analysis of MMAS‐8 scores gave an area under the curve (95% CI) of 0.85 (0.77–0.92), (P < 0.0001): using a cut‐off of <6, the MMAS‐8 score has a sensitivity of 94% and a specificity of 64% to predict thiopurine non‐adherence. Non‐adherence was associated with escalation in therapy, hospital admission and surgeries in the subsequent 6 months of follow up.
Conclusions
Non‐adherence to thiopurines is more common in young adults with inflammatory bowel disease, and is associated with lower socio‐economic status and depression. The high negative predictive value of MMAS‐8 scores <6 suggests that it could be a useful screen for thiopurine non‐adherence.
To determine changes in the incidence of dementia between 1988 and 2015.
This analysis was performed in aggregated data from individuals >65 years of age in 7 population-based cohort studies in the ...United States and Europe from the Alzheimer Cohort Consortium. First, we calculated age- and sex-specific incidence rates for all-cause dementia, and then defined nonoverlapping 5-year epochs within each study to determine trends in incidence. Estimates of change per 10-year interval were pooled and results are presented combined and stratified by sex.
Of 49,202 individuals, 4,253 (8.6%) developed dementia. The incidence rate of dementia increased with age, similarly for women and men, ranging from about 4 per 1,000 person-years in individuals aged 65-69 years to 65 per 1,000 person-years for those aged 85-89 years. The incidence rate of dementia declined by 13% per calendar decade (95% confidence interval CI, 7%-19%), consistently across studies, and somewhat more pronouncedly in men than in women (24% 95% CI 14%-32% vs 8% 0%-15%).
The incidence rate of dementia in Europe and North America has declined by 13% per decade over the past 25 years, consistently across studies. Incidence is similar for men and women, although declines were somewhat more profound in men. These observations call for sustained efforts to finding the causes for this decline, as well as determining their validity in geographically and ethnically diverse populations.
Cognitive dysfunction is a common feature among patients with parkinsonism, including Parkinson disease (PD). However, there is a scarcity of data on cognitive functioning before parkinsonism ...diagnosis, a stage at which patients may still respond to putative disease-modifying interventions.
To assess whether poor cognitive functioning is associated with an increased risk of parkinsonism.
Between January 8, 2002, and December 14, 2008, baseline cognitive function was assessed in 7386 participants of the Rotterdam Study who were free of parkinsonism and dementia. Four tests were administered (Stroop color word test, letter-digit substitution, verbal fluency, and word learning) and a global cognition score was derived from principal component analysis. Subsequently, participants were followed up until January 1, 2015, for the onset of parkinsonism through serial in-person examinations and complete access to medical records. Parkinsonism was defined as the (1) presence of hypokinesia or bradykinesia plus at least 1 other cardinal sign and/or (2) clinical diagnosis by a neurologist or geriatrician. Patients with dementia diagnosis before parkinsonism diagnosis were considered to have probable PD.
Hazard ratios (HRs) for incident parkinsonism per SD decrease in global cognition, adjusted for age, sex, and study subcohort.
A total of 7386 patients were included in the analysis; of these, 4236 (57.4%) were women and mean (SD) age was 65.3 (10.2) years. During follow-up (median, 8.3 years; range, 0-15 years), 79 (1.1%) individuals received a diagnosis of incident parkinsonism; of these, 57 (72.2%) received a diagnosis of probable PD. Among patients with incident parkinsonism, 24 (30.4%) also developed dementia (10 before and 14 after parkinsonism onset). Poor global cognition at baseline was associated with a higher hazard of incident parkinsonism (hazard ratio HR, 1.79; 95% CI, 1.37-2.33). The association remained robust beyond the first 8 years (HR, 1.59; 95% CI, 1.01-2.59) and after removing individuals with dementia onset before parkinsonism (HR, 1.72; 95% CI, 1.28-2.27). Poor global cognition at baseline was also associated with incident probable PD (HR, 1.52; 95% CI, 1.11-2.08). Letter-digit substitution (HR, 1.59; 95% CI, 1.22-2.04), verbal fluency (HR, 1.61; 95% CI, 1.23-2.08), and inverted interference task Stroop color word test (HR, 1.56; 95% CI, 1.25-1.96) scores were each associated with incident parkinsonism, whereas the association with word learning delayed-task scores was weaker (HR, 1.18; 95% CI, 0.92-1.52).
Poor cognitive functioning is associated with an increased risk of incident parkinsonism, including probable PD. Cognition indicates the probability of parkinsonism over long intervals and extends beyond patients with onset of parkinsonism after dementia. The findings suggest that cognitive dysfunction can be considered a sign of prodromal PD.
Abstract
Background
To establish trajectories of cognitive and motor function, and to determine the sequence of change across individual tests in community-dwelling individuals aged 45–90 years.
...Method
Between 1997 and 2016, we repeatedly assessed cognitive function with 5 tests in 9514 participants aged 45–90 years from the population-based Rotterdam Study. Between 1999 and 2016, we measured motor function with 3 tests in 8297 participants. All participants were free from dementia, stroke, and parkinsonism. We assessed overall and education-specific cognitive and motor trajectories using linear mixed models with age as time scale. Next, we determined the sequence of change across individual tests.
Results
The number of assessments per participant ranged between 1 and 6 (mean interval, years SD: 5.1 1.4) for cognitive function, and 1 and 4 (5.4 1.4) for motor function. Cognitive and motor trajectories declined linearly between ages 45 and 65 years, followed by steeper declines after ages 65–70 years. Lower educated participants had lower cognitive function at age 45 years (baseline), and declined faster on most cognitive, but not on motor tests than higher educated participants. Up to a 25-year age difference between the fastest and slowest declining test scores was observed.
Conclusions
On a population-level, cognitive and motor function decline similarly. Compared to higher educated individuals, lower educated individuals had lower cognitive function at baseline, and a faster rate of decline thereafter. These educational-effects were not seen for motor function. These findings benefit the understanding of the natural course of cognitive and motor function during aging, and highlight the role of education in the preservation of cognitive but not motor function.
AMP-activated protein kinase (AMPK) acts as a cellular fuel gauge that responds to energy stress by suppressing cell growth and biosynthetic processes, thus ensuring that energy-consuming processes ...proceed only if there are sufficient metabolic resources. Malfunction of the AMPK pathway may allow cancer cells to undergo uncontrolled proliferation irrespective of their molecular energy levels. The aim of this study was to examine the state of AMPK phosphorylation histologically in primary breast cancer in relation to clinical and pathological parameters.
Immunohistochemistry was performed using antibodies to phospho-AMPK (pAMPK), phospho-Acetyl Co-A Carboxylase (pACC) an established target for AMPK, HER2, ERalpha, and Ki67 on Tissue Micro-Array (TMA) slides of two cohorts of 117 and 237 primary breast cancers. The quick score method was used for scoring and patterns of protein expression were compared with clinical and pathological data, including a minimum 5 years follow up.
Reduced signal, compared with the strong expression in normal breast epithelium, using a pAMPK antibody was demonstrated in 101/113 (89.4%) and 217/236 (91.9%) of two cohorts of patients. pACC was significantly associated with pAMPK expression (p = 0.007 & p = 0.014 respectively). For both cohorts, reduced pAMPK signal was significantly associated with higher histological grade (p = 0.010 & p = 0.021 respectively) and axillary node metastasis (p = 0.061 & p = 0.039 respectively). No significant association was found between pAMPK and any of HER2, ERalpha, or Ki67 expression, disease-free survival or overall survival.
This study extends in vitro evidence through immunohistochemistry to confirm that AMPK is dysfunctional in primary breast cancer. Reduced signalling via the AMPK pathway, and the inverse relationship with histological grade and axillary node metastasis, suggests that AMPK re-activation could have therapeutic potential in breast cancer.
There is growing interest in identifying individuals who are in the prodromal phase of Parkinson's disease (PD), as these individuals are potentially suitable for inclusion in intervention trials to ...prevent clinically manifest PD. However, it is less clear whether-and to what extent-cognitive deficits are present in prodromal PD.
A systematic query was conducted through PubMed and Embase for prospective observational cohort studies that (a) assessed cognitive performance in individuals free of manifest PD at baseline and (b) subsequently followed up participants for incident PD. We grouped the results by cognitive domain, and for domains that had been reported in at least three separate studies, we performed random-effects, inverse variance meta-analyses based on summary statistics.
We identified nine articles suitable for inclusion, with a total of 215 patients with phenoconversion and 13,524 individuals remaining disease-free at follow-up. The studies were highly heterogeneous in study design, study population, and cognitive test batteries. Studies that included only cognitive screening measures such as MMSE or MoCA reported no association between worse cognitive performance and onset of manifest PD (combined odds ratio 1.08; 95% confidence interval 0.66-1.77). By contrast, studies that used extensive cognitive testing batteries found that global cognitive deficits were associated with an increased risk of manifest PD. In domain-specific analyses, there was evidence for an association between worse executive functioning (OR 1.45; 95% CI 1.10-1.92), but not memory (OR 1.20; 95% CI 0.85-1.70) or attention (OR 0.98; 95% CI 0.23-4.26), and clinically manifest PD.
Although some caution due to high heterogeneity among published studies is warranted, the available evidence suggests that global and executive cognitive deficits are prodromal features of PD. Collaborative prospective studies with extensive cognitive test batteries are required to shed light on domain-specific deficits, temporal relations, and subgroup differences in prodromal cognitive deficits in PD.
Abstract Background Remote monitoring systems have the potential to measure symptoms and treatment effects in people with Parkinson's disease (PwP) in the home environment. However, information about ...user experience and long‐term compliance of such systems in a large group of PwP with relatively severe PD symptoms is lacking. Objective The aim was to gain insight into user experience and long‐term compliance of a smartwatch (to be worn 24/7) and an online dashboard to report falls and receive feedback of data. Methods We analyzed the data of the “Bringing Parkinson Care Back Home” study, a 1‐year observational cohort study in 200 PwP with a fall history. User experience, compliance, and reasons for noncompliance were described. Multiple Cox regression models were used to identify determinants of 1‐year compliance. Results We included 200 PwP (mean age: 69 years, 37% women), of whom 116 (58%) completed the 1‐year study. The main reasons for dropping out of the study were technical problems (61 of 118 reasons). Median wear time of the smartwatch was 17.5 h/day. The online dashboard was used by 77% of participants to report falls. Smartphone possession, shorter disease duration, more severe motor symptoms, and less‐severe freezing and balance problems, but not age and gender, were associated with a higher likelihood of 1‐year compliance. Conclusions The 1‐year compliance with this specific smartwatch was moderate, and the user experience was generally good, except battery life and data transfer. Future studies can build on these findings by incorporating a smartwatch that is less prone to technical issues.
The growth and spread of multidrug-resistant bacterial species, such as Klebsiella pneumoniae , pose a serious threat to human health and require the development of innovative antibacterial agents. ...The search for an acceptable, safe, and efficient antibacterial is a matter of significant concern. In the present work, silver-based metal–organic frameworks (Ag-MOFs) showed efficient antibacterial activity against multidrug-resistant K. pneumoniae (KBP 11) with a minimum inhibitory concentration and minimum bactericidal concentration of 10 μg mL −1 . Moreover, the Ag-MOF showed enhanced antibacterial activity compared to silver ions and silver nanoparticles. Our experimental investigation showed that the antibacterial efficacy is attributed to the production of reactive oxygen species and the release of cellular constituents, such as K + ions and proteins. The MOF scaffold enhances the stability and controlled release of silver ions, enabling sustained antibacterial activity and minimizing the risk of bacterial resistance development. Additionally, the MOF class, due to the high surface area and porous nature, enhances the transfer of bacteria into and on the surface of the MOF.
Metformin has therapeutic potential against breast cancer, but the mechanisms of action in vivo remain uncertain. This study examined biomarker effects of metformin in primary breast cancer in a ...preoperative window of opportunity trial. Non-diabetic women with operable invasive breast cancer were randomized to receive open label pre-operative metformin (500 mg daily for 1 week then 1 g twice daily for a further week) or as controls, not receiving metformin. Patients in both arms had a core biopsy pre-randomisation and again at the time of surgery. Immunohistochemistry for phospho-AMPK (pAMPK), phospho-Akt (pAkt), insulin receptor, cleaved caspase-3, and Ki67 was performed on formalin-fixed paraffin-embedded cores, scored blinded to treatment and analysed by paired
t
test. In metformin-treated patients, significant up-regulation of pAMPK (paired
t
test,
p
= 0.04) and down-regulation of pAkt (paired
t
test,
p
= 0.043) were demonstrated compared to the control group. Insulin receptor and serum insulin remained similar following metformin treatment compared with a rise in insulin receptor and insulin in controls. Significant falls in Ki67 and cleaved caspase-3 (paired
t
test,
p
= 0.044) were seen in the metformin-treated patients but not in the control group. Changes were independent of body mass index. These biomarker data suggest mechanisms for metformin action in vivo in breast cancer patients via up-regulation of tumor pAMPK, down-regulation of pAkt, and suppression of insulin responses reflecting cytostatic rather than cytotoxic mechanisms.
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