Miracle-dz/UniFAR-FTUs huggingface dataset:
Obesity and Longer Term Risks of Dementia in 65–74 Year Olds

Abstract Background overweight or obesity at ages <65 years associates with increased dementia incidence, but at ≥65 years estimates are paradoxical. Weight loss before dementia diagnosis, plus smoking and diseases causing weight loss may confound associations. Objective to estimate weight loss before dementia diagnosis, plus short and longer-term body mass index associations with incident dementia in 65–74 year olds within primary care populations in England. Methods we studied dementia diagnosis free subjects: 257,523 non-smokers without baseline cancer, heart failure or multi-morbidity (group A) plus 161,927 with these confounders (group B), followed ≤14.9 years. Competing hazard models accounted for mortality. Results in group A, 9,774 were diagnosed with dementia and in those with repeat weight measures, 54% lost ≥2.5 kg during 10 years pre-diagnosis. During <10 years obesity (≥30.0 kg/m2) or overweight (25.0 to <30.0) were inversely associated with incident dementia (versus 22.5 to <25.0). However, from 10 to 14.9 years, obesity was associated with increased dementia incidence (hazard ratio [HR] 1.17; 95% CI: 1.03–1.32). Overweight protective associations disappeared in longer-term analyses (HR, 1.01; 95% CI: 0.90–1.13). In group B, (n = 6,070 with incident dementia), obesity was associated with lower dementia risks in the short and longer-term. Conclusions in 65–74 year olds (free of smoking, cancer, heart failure or multi-morbidity at baseline) obesity associates with higher longer-term incidence of dementia. Paradoxical associations were present short-term and in those with likely confounders. Reports of protective effects of obesity or overweight on dementia risk in older groups may reflect biases, especially weight loss before dementia diagnosis.
Parental career expectations: effect on medical students’ career attitudes over time

Motivation to become a doctor has typically been conceived as arising from personal interests. However, it is not uncommon, particularly amongst those from collectivist cultures, for career choice to be motivated by a desire or need to fulfil parent expectations. Whether or not this motivation has longer term effects on the career satisfaction and performance of medical students is unknown.
Evaluating the Evidence: Is There a Rigid Hierarchy?

Health outcomes research applies a wide range of methods to identify optimal approaches to determine optimal approaches to determine the effects of healthcare interventions and policies. Critical evaluation skills are necessary to navigate the evidence and identify studies that should influence clinical decision making and policy. A hierarchical “pyramid of evidence” that emphasizes randomized controlled clinical trials (RCTs) has been promulgated as the approach to judging study design and quality. Whereas this hierarchy may be suitable for the evaluation of efficacy, it may be inappropriate for many health outcomes research questions. This article examines the relevance of this construct to questions beyond those of therapeutic efficacy and discusses the essential role of study designs beyond RCTs. The strengths and weaknesses of study designs commonly encountered in the medical literature are reviewed. The article concludes with 2 case studies that apply the concepts reviewed and illustrate the need to match the study design with the research question. Of note, the concepts of internal validity, external validity, confounding, and bias are central to the discussion of the strengths and weaknesses of study designs in the medical literature. Readers not familiar with these concepts should refer to the Appendix in the online-only Data Supplement for clarification. ### The Pyramid of Evidence: A Useful Construct? Traditionally, the design of a study has been considered a principal barometer of the validity of its findings. In this construct, different study designs are considered in the context of a pyramid of evidence, in which studies most susceptible to threats to internal validity reside at the bottom and those least prone reside at the top (Figure). This hierarchy is widely used in discussions about the quality of medical studies and is integrated into the grading of evidence in practice guidelines.1 However, although the pyramid of evidence is undoubtedly well suited for questions of therapeutic efficacy, …
The Effect of Different Exercise Modes on Domain-Specific Cognitive Function in Patients Suffering from Parkinson's Disease: A Systematic Review of Randomized Controlled Trials.

BACKGROUND Supervised exercise training alleviates motor symptoms in people with Parkinson's disease (PD). However, the efficacy of exercise to improve nonmotor symptoms such as cognitive function is less well known. OBJECTIVE To systematically review evidence on the efficacy of different exercise modes (coordination exercise, resistance exercise, aerobic exercise) on domain-specific cognitive function in patients with PD. METHODS Parallel-group randomized controlled trials published before March 2018 were included. Primary outcome measures included global cognitive function and its subdomains, and the Unified Parkinson's Disease Rating Scale was included as a secondary outcome. Methodological quality was assessed using the Physiotherapy Evidence Database scale. RESULTS The literature search yielded 2,000 articles, of which 11 met inclusion criteria. 508 patients (mean age 68±4 years) were included with a disease severity from 1 to 4 on the Hoehn & Yahr stage scale. Overall study quality was modest (mean 6±2, range 3-8/10). In 5 trials a significant between-group effect size (ES) was identified for tests of specific cognitive domains, including a positive effect of aerobic exercise on memory (ES = 2.42) and executive function (ES = 1.54), and of combined resistance and coordination exercise on global cognitive function (ES = 1.54). Two trials found a significant ES for coordination exercise (ES = 0.84-1.88), which led to improved executive function compared with that of non-exercising control subjects. CONCLUSION All modes of exercise are associated with improved cognitive function in individuals with PD. Aerobic exercise tended to best improve memory; however, a clear effect of exercise mode was not identified.
Creative Expertise Is Associated With Transcending the Here and Now

Human imagination is bounded. As situations become more distant in time, place, perspective, and likelihood, they also become more difficult to simulate. What underlies the ability to successfully engage in distal simulations? Here we examine the psychological and neural mechanisms underlying distal simulation by studying individuals known for transcending these limits: creative experts. First, 2 behavioral studies establish that creative experts indeed succeed at engaging in vivid distal simulations, compared to less creative individuals. Performance on a traditional measure of creativity (Study 1) and real-world success in creative pursuits (Study 2) corresponded with more vivid distal simulations across temporal, spatial, social, and hypothetical domains. Study 3 used neuroimaging to identify the neural mechanism supporting creative experts’ simulation success. Whereas creative experts and controls recruit the same neural mechanism (the medial prefrontal cortex) while simulating common or proximal events, creative experts preferentially engage a distinct neural mechanism (the dorsomedial subsystem of the default network) while simulating distal events. Moreover, creative experts showed greater functional connectivity within this network at rest, suggesting they may be prepared to engage this mechanism, by default. Studying creative expertise provides new insight into the ability to mentally transcend the here and now.
The von Restorff Effect in Amnesia: The Contribution of the Hippocampal System to Novelty-Related Memory Enhancements

The ability to detect novelty is a characteristic of all mammalian nervous systems (Sokolov, 1963), and it plays a critical role in memory in the sense that items that are novel, or distinctive, are remembered better than those that are less distinct (von Restorff, 1933). Although several brain areas are sensitive to stimulus novelty, it is not yet known which regions play a role in producing novelty-related effects on memory. In the current study, we investigated novelty effects on recognition memory in amnesic patients and healthy control subjects. The control subjects demonstrated better recognition for items that were novel (i.e., presented in an infrequent color), and this effect was found for both recollection and familiarity-based responses. However, the novelty advantage was effectively eliminated in patients with extensive medial temporal lobe damage, mild hypoxic patients expected to have relatively selective hippocampal damage, and in a patient with thalamic lesions. The results indicate that the human medial temporal lobes play a critical role in producing normal novelty effects in memory.
A novel mechanism for the anticancer activity of aspirin and salicylates

Epidemiological studies indicate that long-term aspirin usage reduces the incidence of colorectal cancer (CRC) and may protect against other non-CRC associated adenocarcinomas, including oesophageal cancer. A number of hypotheses have been proposed with respect to the molecular action of aspirin and other non-steroidal anti-inflammatory drugs in cancer development. The mechanism by which aspirin exhibits toxicity to CRC has been previously investigated by synthesising novel analogues and derivatives of aspirin in an effort to identify functionally significant moieties. Herein, an early effect of aspirin and aspirin-like analogues against the SW480 CRC cell line was investigated, with a particular focus on critical molecules in the epidermal growth factor (EGF) pathway. The present authors proposed that aspirin, diaspirin and analogues, and diflunisal (a salicylic acid derivative) may rapidly perturb EGF and EGF receptor (EGFR) internalisation. Upon longer incubations, the diaspirins and thioaspirins may inhibit EGFR phosphorylation at Tyr1045 and Tyr1173. It was additionally demonstrated, using a qualitative approach, that EGF internalisation in the SW480 cell line may be directed to endosomes by fumaryldiaspirin using early endosome antigen 1 as an early endosomal marker and that EGF internalisation may also be perturbed in oesophageal cell lines, suggestive of an effect not only restricted to CRC cells. Taken together and in light of our previous findings that the aspirin-like analogues can affect cyclin D1 expression and nuclear factor-κB localisation, it was hypothesized that aspirin and aspirin analogues significantly and swiftly perturb the EGFR axis and that the protective activity of aspirin may in part be explained by perturbed EGFR internalisation and activation. These findings may also have implications in understanding the inhibitory effect of aspirin and salicylates on wound healing, given the critical role of EGF in the response to tissue trauma.
Nitrogen application is required to realize wheat yield stimulation by elevated CO2 but will not remove the CO2‐induced reduction in grain protein concentration

Elevated CO2 (eCO2) generally promotes increased grain yield (GY) and decreased grain protein concentration (GPC), but the extent to which these effects depend on the magnitude of fertilization remains unclear. We collected data on the eCO2 responses of GY, GPC and grain protein yield and their relationships with nitrogen (N) application rates across experimental data covering 11 field grown wheat (Triticum aestivum) cultivars studied in eight countries on four continents. The eCO2‐induced stimulation of GY increased with N application rates up to ~200 kg/ha. At higher N application, stimulation of GY by eCO2 stagnated or even declined. This was valid both when the yield stimulation was expressed as the total effect and using per ppm CO2 scaling. GPC was decreased by on average 7% under eCO2 and the magnitude of this effect did not depend on N application rate. The net effect of responses on GY and protein concentration was that eCO2 typically increased and decreased grain protein yield at N application rates below and above ~100 kg/ha respectively. We conclude that a negative effect on wheat GPC seems inevitable under eCO2 and that substantial N application rates may be required to sustain wheat protein yields in a world with rising CO2.
The Effect of Pedaling Cadence on Skeletal Muscle Oxygenation During Cycling at Moderate Exercise Intensity

Abstract The aim of this study was to assess the changes determined by increased cadence on skeletal muscle oxygenation during cycling at an exercise intensity equal to the ventilatory threshold (Tvent). Nine healthy, active individuals with different levels of cycling experience exercised at a power output equal to Tvent, pedaling at cadences of 40, 50, 60, 70, 80 and 90 rpm, each for 4 min. Cadences were tested in a randomized counterbalanced sequence. Cardiopulmonary and metabolic responses were studied using an ECG for heart rate, and gas calorimetry for pulmonary oxygen uptake and carbon dioxide production. NIRS was used to determine the tissue saturation index (TSI), a measure of vastus lateralis oxygenation. TSI decreased from rest to exercise; the magnitude of this TSI reduction was significantly greater when pedaling at 90 rpm (−14±4%), compared to pedaling at 40 (−12±3%) and 50 (−12±3%) rpm (P=0.027 and 0.017, respectively). Albeit small, the significant decrease in ΔTSI at increased cadence recorded in this study suggests that skeletal muscle oxygenation is relatively more affected by high cadence when exercise intensity is close to Tvent.
Risk of smoking and receipt of cessation services among veterans with mental disorders.

OBJECTIVE The purpose of this study was to determine rates of smoking and receipt of provider recommendations to quit smoking among patients with mental disorders treated in U.S. Department of Veterans Affairs (VA) treatment settings. METHODS The authors conducted a secondary analysis of the yearly, cross-sectional 2007 Veterans Health Administration Outpatient Survey of Healthcare Experiences of Patients (N=224,193). Logistic regression was used to determine the independent association of mental health diagnosis and the dependent variables of smoking and receipt of provider recommendations to quit smoking. RESULTS Patients with mental disorders had greater odds of smoking, compared with those without mental disorders (p<.05). Those with various mental disorders reported similar rates of receiving services (more than 60% to 80% reported receiving selected services), compared with those without these disorders, except that those with schizophrenia had more than 30% lower odds of receiving advice to quit smoking from their physicians (p<.05). Moreover, those who had co-occurring posttraumatic stress disorder or substance use disorders had significantly greater odds of reporting that they received advice to quit, recommendations for medications, and physician discussions of quitting methods, compared with those without these disorders (p<.05). Older patients, male patients, members of ethnic minority groups, those who were unmarried, those who were disabled or unemployed, and those living in rural areas had lower odds of receiving selected services (p<.05). CONCLUSIONS The majority of patients with mental disorders served by the VA reported receiving cessation services, yet their smoking rates remained high, and selected groups were at risk for receiving fewer cessation services, suggesting the continued need to disseminate cessation services.
Measuring, analyzing, and managing drug adherence in resistant hypertension.

The management of hypertension is based on 2 major approaches: a modification of lifestyle and the lifelong prescription of antihypertensive drugs.1,2 All hypertension guidelines recognize that “…the most effective therapy prescribed by the most careful clinician will control hypertension only if the patient is motivated to take the prescribed medication and to establish and maintain a health-promoting lifestyle. ” This statement clearly emphasizes the importance of supporting drug adherence (ie, adherence to the prescribed dosing regimens for prescribed medications) for patients to gain the maximal benefits of their therapy. Unfortunately, drug adherence in cardiovascular prevention remains low in the population. Thus, in a recent meta-analysis of data on 376 162 patients from 20 studies assessing drug adherence using prescription refill frequency for 7 preventive drug classes (aspirin, statins, and 5 antihypertensive drug classes) prescribed for primary and secondary prevention of cardiovascular diseases, mean adherence over all studies was only 57% after a median of 2 years. Furthermore, mean drug adherence was substantively and statistically significantly lower in primary than in secondary prevention.3 The role of drug adherence is particularly relevant in clinical situations in which drug therapies do not provide the expected results. This is typically so in resistant hypertension, commonly defined as the failure to reach blood pressure goals in patients adhering to adequate or maximal doses of an appropriate 3-drug regimen that includes a diuretic. Obviously, this definition of resistant hypertension implies that patients fully adhere to their therapy. This might actually be one of the reasons why the true prevalence of patients with resistant hypertension in the population remains largely ambiguous.4,5 In clinical trials, 10% to 30% of patients are estimated to present with resistant hypertension.6 In the National Health and Nutrition Examination Survey conducted between 2003 and 2008, 8.9% of …
Effects of Stepwise Lung Recruitment Maneuvers in Patients with Early Acute Respiratory Distress Syndrome: A Prospective, Randomized, Controlled Trial

Since the clinical benefit of lung recruitment maneuvers (LRMs) is still conflicting, we performed this prospective, randomized, controlled study to investigate whether LRMs should be used in the routine management of acute respiratory distress syndrome (ARDS). This trial was conducted in four intensive care units (ICUs) to compare application of a modified stepwise LRMs with solely lung-protective ventilation in patients with moderate to severe ARDS within 72 h from the onset. The primary outcome was 28-day mortality, and the secondary outcomes were ventilator-free days and ICU-free days. We collected data on 120 ARDS patients from 2009 to 2012, and there was no difference in 28-day mortality between the two groups (28.3% vs. 30.0%, p = 0.84). However, among survivors, patients in the LRM group had a significant longer median duration of ventilator-free days (18 vs. 13 days; p = 0.04) and ICU-free days (16 vs. 11 days; p = 0.03) at 28 days than in the control group. The respiratory system compliance was significantly higher in the LRM group from day 1 to day 7. The occurrence rate of barotrauma was similar in both groups. We concluded that LRMs combined with lung-protective ventilation in early ARDS may improve patient outcomes.
GABA‐containing compound gammapyrone protects against brain impairments in Alzheimer’s disease model male rats and prevents mitochondrial dysfunction in cell culture

Neuroinflammation, oxidative stress, decreased glucose/energy metabolism, and disrupted neurotransmission are changes that occur early in sporadic Alzheimer’s disease (AD), manifesting as mild cognitive impairment. Recently, the imbalanced function of the gamma‐aminobutyric acid (GABA) system was identified as a critical factor in AD progression. Thus, maintaining balance among neurotransmitter systems, particularly the GABA system, can be considered a beneficial strategy to slow AD progression. The present study investigated the effects of the compound gammapyrone, a molecule containing three GABA moieties: “free” moiety attached to the position 4 of the 1,4‐dihydropyridine (DHP) ring, and two “crypto” moieties as part of the DHP scaffold. The “free” and “crypto” GABA moieties are linked by a peptide bond (–CONH–), resulting in a peptide‐mimicking structure. In a nontransgenic male rat AD model generated by intracerebroventricular (icv) streptozocin (STZ) administration, gammapyrone (0.1 and 0.5 mg/kg ip) mitigated the impairment of spatial learning and memory, prevented astroglial and microglial neuroinflammation, and normalized acetylcholine breakdown and GABA biosynthesis. In PC12 cells, gammapyrone protected against oxidative stress, mitochondrial dysfunction and apoptosis caused by the mitochondrial toxin di‐2‐ethylhexyl phthalate (DEHP). Gammapyrone did not bind to GABA‐A and GABA‐B receptors in vitro; therefore, we cannot attribute its neuroprotective action to a specific interaction with GABA receptors. Nevertheless, we suggest that the peptide‐like regulatory mechanisms of gammapyrone or its allosteric modulatory properties are essential for the observed effects. Since, the icv STZ model resembles the early stages of AD, gammapyrone, and/or its congeners could be useful in the design of anti‐dementia drugs.
An Epidemiological Study of Hemodialysis Patients Based on the European Fresenius Medical Care Hemodialysis Network: Results of the ARO Study

Background/Aims: ARO, an observational study of hemodialysis (HD) patients in Europe, aims to enhance our understanding of patient characteristics and practice patterns to improve patient outcome. Methods: HD patients (n = 8,963) from 134 Fresenius Medical Care facilities treated between 2005 and 2006 were randomly selected from 9 European countries (Czech Republic, France, Hungary, Italy, Poland, Portugal, Spain, Slovak Republic and Slovenia) and Turkey. Information was captured on demographics, comorbidities, medications, laboratory and dialysis parameters, and outcome. Results: Patients were followed for 1.4 ± 0.7 years. Wide variation by country was observed for age, sex and diabetes as a cause of chronic kidney disease. Cardiovascular disease was present in 73% of patients. Dialysis parameters were homogeneous across countries. Arteriovenous fistulas were frequently used (73%). More incident patients had hemoglobin <11 g/dl than prevalent patients (50 vs. 33%, respectively). Phosphatemia and intact parathyroid hormone were similar between incident and prevalent patients (4.7 ± 1.2 mg/dl and 190 vs. 213 ng/l, respectively). Medication use varied widely by country. In total, 5% of patients underwent renal transplantation. Overall death rate was 124/1,000 patient-years. Conclusion: ARO revealed differences in HD practice patterns and patient characteristics in the 10 participating countries. Future ARO studies will fill gaps in the knowledge about the care of European HD patients.