Miracle-dz/UniFAR-FTUs huggingface dataset:
Fluid Biomarkers in Clinical Trials of Alzheimer’s Disease Therapeutics

With the demographic shift of the global population toward longer life expectancy, the number of people living with Alzheimer’s disease (AD) has rapidly expanded and is projected to triple by the year 2050. Current treatments provide symptomatic relief but do not affect the underlying pathology of the disease. Therapies that prevent or slow the progression of the disease are urgently needed to avoid this growing public health emergency. Insights gained from decades of research have begun to unlock the pathophysiology of this complex disease and have provided targets for disease-modifying therapies. In the last decade, few therapeutic agents designed to modify the underlying disease process have progressed to clinical trials and none have been brought to market. With the focus on disease modification, biomarkers promise to play an increasingly important role in clinical trials. Six biomarkers have now been included in diagnostic criteria for AD and are regularly incorporated into clinical trials. Three biomarkers are neuroimaging measures – hippocampal atrophy measured by magnetic resonance imaging (MRI), amyloid uptake as measured by Pittsburg compound B positron emission tomography (PiB-PET), and decreased fluorodeoxyglucose (18F) uptake as measured by PET (FDG-PET) – and three are sampled from fluid sources – cerebrospinal fluid levels of amyloid β42 (Aβ42), total tau, and phosphorylated tau. Fluid biomarkers are important because they can provide information regarding the underlying biochemical processes that are occurring in the brain. The purpose of this paper is to review the literature regarding the existing and emerging fluid biomarkers and to examine how fluid biomarkers have been incorporated into clinical trials.
Heterogenous Quorum-Based Wake-Up Scheduling in Wireless Sensor Networks

We present heterogenous quorum-based asynchronous wake-up scheduling schemes for wireless sensor networks. The schemes can ensure that two nodes that adopt different quorum systems as their wake-up schedules can hear each other at least once in bounded time intervals. We propose two such schemes: cyclic quorum system pair (cqs-pair) and grid quorum system pair (gqs-pair). The cqs-pair which contains two cyclic quorum systems provides an optimal solution, in terms of energy saving ratio, for asynchronous wake-up scheduling. To quickly assemble a cqs-pair, we present a fast construction scheme which is based on the multiplier theorem and the (N,k,M, l)-difference pair defined by us. Regarding the gqs-pair, we prove that any two grid quorum systems will automatically form a gqs-pair. We further analyze the performance of both designs, in terms of average discovery delay, quorum ratio, and energy saving ratio. We show that our designs achieve better trade-off between the average discovery delay and quorum ratio (and thus energy consumption) for different cycle lengths. We implemented the proposed designs in a wireless sensor network platform of Telosb motes. Our implementation-based measurements further validate the analytically-established performance trade-off of our designs.
A survey of internal medicine residents' knowledge about Helicobacter pylori infection

OBJECTIVE:Despite recently published national guidelines, many physicians have only limited knowledge about Helicobacter pylori infection. We conducted this study to assess internal medicine residents' knowledge about H. pylori.METHODS:Two hundred and nineteen residents in seven accredited internal medicine training programs completed a self-administered questionnaire on personal demographics and practices related to testing for—and treating—H. pylori infection.RESULTS:Noon conferences (82%), ward teaching (66%), journals (70%), and sponsored symposia (27%) were their major sources of H. pylori-related information. Forty-eight percent had used office-based tests for the infection. Testing for (and treatment of) Helicobacter pylori infection was recommended by 97% (97%) for newly diagnosed duodenal ulcer, but by only 61% (63%) for a past history of duodenal ulcer. Many recommended testing in unproven conditions and might not have offered treatment to an infected patient. A proton pump inhibitor-based triple-drug regimen was the treatment of first choice of 55%; 20% recommended proton pump inhibitor-based dual regimens. Sixty-six percent and 80%, respectively, underestimated the rates of resistance to clarithromycin and metronidazole. In the absence of gastrointestinal symptoms, 22% would have ordered Helicobacter pylori testing but only 33% of these would undergo treatment if positive.CONCLUSIONS:Internal medicine residents usually test for Helicobacter pylori infection in appropriate conditions, but may not always treat the infection when the result is positive. Most use efficacious treatment regimens although many have inaccurate knowledge of resistance rates, which may adversely influence prescribing. Education should focus on practical issues surrounding Helicobacter pylori testing and treatment such as those contained in the American College of Gastroenterology's 1998 practice guidelines.
Targeting multiple pathogenic mechanisms with polyphenols for the treatment of Alzheimer's disease-experimental approach and therapeutic implications

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease of aging and currently has no cure. Its onset and progression are influenced by multiple factors. There is growing consensus that successful treatment will rely on simultaneously targeting multiple pathological features of AD. Polyphenol compounds have many proven health benefits. In this study, we tested the hypothesis that combining three polyphenolic preparations (grape seed extract, resveratrol, and Concord grape juice extract), with different polyphenolic compositions and partially redundant bioactivities, may simultaneously and synergistically mitigate amyloid-β (Aβ) mediated neuropathology and cognitive impairments in a mouse model of AD. We found that administration of the polyphenols in combination did not alter the profile of bioactive polyphenol metabolites in the brain. We also found that combination treatment resulted in better protection against cognitive impairments compared to individual treatments, in J20 AD mice. Electrophysiological examination showed that acute treatment with select brain penetrating polyphenol metabolites, derived from these polyphenols, improved oligomeric Aβ (oAβ)-induced long term potentiation (LTP) deficits in hippocampal slices. Moreover, we found greatly reduced total amyloid content in the brain following combination treatment. Our studies provided experimental evidence that application of polyphenols targeting multiple disease-mechanisms may yield a greater likelihood of therapeutic efficacy.
Impaired Pavlovian Conditioning and Altered Hippocampal N-methyl-D-aspartate Receptor Subunit Composition in a Rat Model of Fetal Alcohol Spectrum Disorder

Fetal Alcohol Spectrum Disorders (FASD), resulting from gestational alcohol consumption, is marked by physical and mental abnormalities, including persistent impairments in learning and memory. In this study, rat pups were intragastrically intubated with alcohol (5E rats; 5g/kg/day) or sham intubated across postnatal days 4-9. Adult 5E rats were significantly impaired in trace fear conditioning (TFC), a Pavlovian conditioning paradigm in which the conditioned stimulus (tone) and the unconditioned stimulus (foot shock) are separated by a stimulus-free interval of time. TFC requires hippocampal and prefrontal cortex N-methyl-D-aspartate receptor (NMDAR) activation. NMDARs contain four subunits: two mandatory NR1 subunits and two regulatory NR2 subunits. When activated, NR2B-containing NMDARs gate more calcium than NR2Acontaining NMDARs. Calcium acts as a second messenger in a molecular signaling cascade that contributes to the induction and maintenance of long-term potentiation (LTP), a learningmediated enhancement of neural signaling, on which successful TFC is reliant. Thus, NR2B subunits are proposed to enhance learning-dependent LTP more so than NR2A, and ethanolinduced alterations to NMDAR subunit composition could disrupt LTP maintenance and longterm memory storage. In support, whole cell lysate Western blotting revealed an elevated NR2A/NR2B ratio in dorsal hippocampus, but not in ventral hippocampus or medial prefrontal cortex, of adult 5E rats. Utilizing subcellular fractionation, Western blotting showed a significant reduction in synaptic and extrasynaptic NR2B subunits in dorsal hippocampus of 5E rats, which is proposed to impede the synaptic plasticity required for successful TFC. Results are expected to provide new and valuable knowledge regarding the etiology of FASD, and may lead to the use of novel pharmacological therapies targeting NMDARs to ameliorate cognitive deficits in FASD individuals.
Rethinking Parent and Child Conflict

This book is set in the context of contemporary life and depicts relationships among parents and children in four families living in a capital city in Australia. Because of the overabundance of manuals and the step-by-step advice that many provide, it is often assumed that parent and child conflict is easily resolved. The Hollywood film Parenthood implies that childrearing means a lifetime of anxiety for parents and goes as far as to suggest that after so many centuries, somebody must have found the formula for turning children into happy and successful adults. These are the capacities (innocence, naivety, vulnerability, etc.) that child development theorists have assumed are part of the child’s nature.
Expression of Class III Beta-Tubulin Correlates with Unfavorable Survival Outcome in Patients with Resected Non-small Cell Lung Cancer

Background: We analyzed the significance of class III beta-tubulin (TUBB3) expression in curatively resected non-small cell lung cancer as a prognostic marker along with previously reported excision repair cross complementation group 1 (ERCC1). Methods: One hundred and thirty-six consecutive patients were included in this retrospective study. Patients who received adjuvant chemotherapy were excluded. We used immunohistochemistry to evaluate TUBB3 and ERCC1 expression on tissue microarray in duplicate. Semiquantitative H score was used for the scoring of tumor staining. Results: Sixty percent of patients had stage I disease, 17% stage II, 18% stage IIIA, and 5% stage IIIB. TUBB3 H score showed bimodal distribution with the minimum at the value of 4, which was used as a cutoff value for determination of TUBB3 positivity. TUBB3 was expressed in 60 patients (44%). Patients with a positive TUBB3 expression survived shorter than did the patients with a negative expression (5-year overall survival [OS] rate was 40% versus 61%; p = 0.005/5-year disease-free survival rate was 34% versus 55%; p = 0.024). ERCC1 expression showed tendency for prolonged OS without reaching statistical significance. A multivariate analysis that incorporated covariates including TUBB3 expression, age, stage, EGFR mutation status, histology, and ERCC1 expression showed that TUBB3 was an independent unfavorable prognostic factor for OS (hazard ratio 2.083; p = 0.008) and relapse free survival (hazard ratio 1.978; p = 0.020). Conclusions: TUBB3 expression is an independent unfavorable prognostic marker in patients with curatively resected non-small cell lung cancer who did not receive adjuvant chemotherapy.
Acanthamoebae bind to rabbit corneal epithelium in vitro.

PURPOSE Selection of an appropriate animal model is crucial for the investigation of the pathogenesis of Acanthamoeba keratitis. To this end, it has been reported that fluorescein isothiocyanate (FITC)-labeled Acanthamoeba castellanii bind to human, pig, and hamster corneas, but not to rabbit corneas in organ culture. However, 35S-labeled A. polyphaga and A. culbertsoni have been found to bind to rabbit corneal epithelium grown in tissue culture. The purpose of the current study was to establish whether A. castellanii bind to rabbit corneal epithelium in organ culture. METHODS Two different adhesion assays were used to determine whether 35S-labeled and FITC-labeled A. castellanii bind to epithelium of corneal buttons in vitro and, if so, whether the binding is temperature-dependent, enhanced by injury, and inhibited by specific saccharides. Ameba binding to rabbit corneal epithelium was also evaluated by scanning electron microscopy. The binding of A. castellanii to corneal epithelium of three different species (human, pig, and rabbit) was compared. RESULTS Both 35S-labeled as well as FITC-labeled parasites were found to bind to epithelium of rabbit corneal buttons in vitro. Although the parasites bound avidly to the corneas at 25 degrees C and 35 degrees C, little binding was observed at 4 degrees C. Injury enhanced the binding. Methyl alpha-D-mannopyranoside, but not other saccharides (alpha-L-fucose and beta-galactose), inhibited binding of the parasites to the epithelium of rabbit corneas. By scanning EM, A. castellanii were found to adhere, invade, and penetrate the epithelium of rabbit corneas. Compared with rabbit corneas, ameba binding to pig, and human corneas was only 1.2 and 1.4 times higher, respectively. CONCLUSIONS Rabbit animal model may prove useful for investigation of the molecular mechanisms that mediate adhesion of Acanthamoeba to corneal epithelium.
Tongue-larynx interactions in the production of word initial laryngealization over different prosodic contexts: A repeated speech experiment

We report the results of a repeated speech experiment conducted to elicit laryngealization or full glottal stops before vowel-initial pseudo-words. In order to study potential interactions between the larynx and the tongue, we tested the effects of different vowels (high vs. low) and the effect of the presence of stress on the initial vowel, as well as the effect of the place of articulation of adjacent stop consonants. The results obtained are consistent with the idea that a retracted tongue root favors the production of laryngeal constriction. Indeed we found that laryngealization is stronger on unstressed initial vowels, where it co-occurs with a retracted back of the tongue.
Comparative safety and effectiveness of long-acting inhaled agents for treating chronic obstructive pulmonary disease: a systematic review and network meta-analysis

Objective To compare the safety and effectiveness of long-acting β-antagonists (LABA), long-acting antimuscarinic agents (LAMA) and inhaled corticosteroids (ICS) for managing chronic obstructive pulmonary disease (COPD). Setting Systematic review and network meta-analysis (NMA). Participants 208 randomised clinical trials (RCTs) including 134 692 adults with COPD. Interventions LABA, LAMA and/or ICS, alone or in combination, versus each other or placebo. Primary and secondary outcomes The proportion of patients with moderate-to-severe exacerbations. The number of patients experiencing mortality, pneumonia, serious arrhythmia and cardiovascular-related mortality (CVM) were secondary outcomes. Results NMA was conducted including 20 RCTs for moderate-to-severe exacerbations for 26 141 patients with an exacerbation in the past year. 32 treatments were effective versus placebo including: tiotropium, budesonide/formoterol, salmeterol, indacaterol, fluticasone/salmeterol, indacaterol/glycopyrronium, tiotropium/fluticasone/salmeterol and tiotropium/budesonide/formoterol. Tiotropium/budesonide/formoterol was most effective (99.2% probability of being the most effective according to the Surface Under the Cumulative RAnking (SUCRA) curve). NMA was conducted on mortality (88 RCTs, 97 526 patients); fluticasone/salmeterol was more effective in reducing mortality than placebo, formoterol and fluticasone alone, and was the most effective (SUCRA=71%). NMA was conducted on CVM (37 RCTs, 55 156 patients) and the following were safest: salmeterol versus each OF placebo, tiotropium and tiotropium (Soft Mist Inhaler (SMR)); fluticasone versus tiotropium (SMR); and salmeterol/fluticasone versus tiotropium and tiotropium (SMR). Triamcinolone acetonide was the most harmful (SUCRA=81%). NMA was conducted on pneumonia occurrence (54 RCTs, 61 551 patients). 24 treatments were more harmful, including 2 that increased risk of pneumonia versus placebo; fluticasone and fluticasone/salmeterol. The most harmful agent was fluticasone/salmeterol (SUCRA=89%). NMA was conducted for arrhythmia; no statistically significant differences between agents were identified. Conclusions Many inhaled agents are available for COPD, some are safer and more effective than others. Our results can be used by patients and physicians to tailor administration of these agents. Protocol registration number PROSPERO # CRD42013006725.
Life-history theory, chronic childhood illness and the timing of first reproduction in a British birth cohort

Life-history theoretical models show that a typical evolutionarily optimal response of a juvenile organism to high mortality risk is to reach reproductive maturity earlier. Experimental studies in a range of species suggest the existence of adaptive flexibility in reproductive scheduling to maximize fitness just as life-history theory predicts. In humans, supportive evidence has come from studies comparing neighbourhoods with different mortality rates, historical and cross-cultural data. Here, the prediction is tested in a novel way in a large (n = 9099), longitudinal sample using data comparing age at first reproduction in individuals with and without life-expectancy-reducing chronic disease diagnosed during childhood. Diseases selected for inclusion as chronic illnesses were those unlikely to be significantly affected by shifting allocation of effort away from reproduction towards survival; those which have comparatively large effects on mortality and life expectancy; and those which are not profoundly disabling. The results confirmed the prediction that chronic disease would associate with early age at first reproduction: individuals growing up with a serious chronic disease were 1.6 times more likely to have had a first child by age 30. Analysis of control variables also confirmed past research findings on links between being raised father-absent and early pubertal development and reproduction.
The Elliptical Cone of Uncertainty and Its Normalized Measures in Diffusion Tensor Imaging

Diffusion tensor magnetic resonance imaging (DT-MRI) is capable of providing quantitative insights into tissue microstructure in the brain. An important piece of information offered by DT-MRI is the directional preference of diffusing water molecules within a voxel. Building upon this local directional information, DT-MRI tractography attempts to construct global connectivity of white matter tracts. The interplay between local directional information and global structural information is crucial in understanding changes in tissue microstructure as well as in white matter tracts. To this end, the right circular cone of uncertainty was proposed by Basser as a local measure of tract dispersion. Recent experimental observations by Jeong et al. and Lazar et al. that the cones of uncertainty in the brain are mostly elliptical motivate the present study to investigate analytical approaches to quantify their findings. Two analytical approaches for constructing the elliptical cone of uncertainty, based on the first-order matrix perturbation and the error propagation method via diffusion tensor representations, are presented and their theoretical equivalence is established. We propose two normalized measures, circumferential and areal, to quantify the uncertainty of the major eigenvector of the diffusion tensor. We also describe a new technique of visualizing the cone of uncertainty in 3-D.
Output Spillovers from Fiscal Policy

In this paper, we estimate the cross-country spillover effects of government purchases on output for a large number of OECD countries. Following the methodology in Auerbach and Gorodnichenko (2012a, b), we allow these multipliers to vary smoothly according to the state of the economy and use real-time forecast data to purge policy innovations of their predictable components. We also consider the responses of other key macroeconomic variables. Our findings suggest that cross-country spillovers have an important impact, and also confirm those of our earlier papers that fiscal shocks have a larger impact when the affected country is in recession.
Economic impact of injuries according to type of injury.

AIM Analysis of the economic impact of injuries that occurred within a year in Motala district -- a World Health Organization Safe Community. METHOD A survey of all types of injury that occurred in an area with the total population of over 41,000 within a 12-month period (October 1, 1983, to September 30, 1984). All injuries that required medical care were noted. Included in the costs of injuries were the marginal costs to medical care, companies, and the health insurance system. RESULTS There were 4,926 injuries that required medical care. The costs of injuries were SEK 23.7 million (US$3.59 million) for the health care service (outpatient care, including primary health care and hospital care), SEK 79.7 million (US$12.08 million) for trade and industry, and SEK 9.1 million (US$1.38 million) for health insurance system. Home injuries accounted for the largest share of community costs (29%). Men accounted for the highest share of both the cost to the community (59%) and health insurance expenditures (70%) for injuries. In case of home injuries, the cost of medical care dominated among women (46%), whereas company costs dominated among men (77%). Serious injuries (Abbreviated Injury Scale - AIS-3) accounted for 16% of the total cost to the community, but constituted only 3% of all injuries. Moderate injuries (AIS-2) accounted for 69% of the cost and made up 48% of the injuries, whereas minor injuries (AIS-1) accounted for 12% of the cost and constituted 49% of all injuries. Injuries to the extremities accounted in all for 74% of the cost to the community. CONCLUSION The cost of injuries can be analyzed in relation to different characteristics of injuries, which can provide a comprehensive view of the injury profile and its economic impact according to the type of injury.
Current Status and Challenges in Identifying Disease Resistance Genes in Brassica napus

Brassica napus is an economically important crop across different continents including temperate and subtropical regions in Europe, Canada, South Asia, China and Australia. Its widespread cultivation also brings setbacks as it plays host to fungal, oomycete and chytrid pathogens that can lead to serious yield loss. For sustainable crop production, identification of resistance (R) genes in B. napus has become of critical importance. In this review, we discuss four key pathogens affecting Brassica crops: Clubroot (Plasmodiophora brassicae), Blackleg (Leptosphaeria maculans and L. biglobosa), Sclerotinia Stem Rot (Sclerotinia sclerotiorum), and Downy Mildew (Hyaloperonospora parasitica). We first review current studies covering prevalence of these pathogens on Brassica crops and highlight the R genes and QTL that have been identified from Brassica species against these pathogens. Insights into the relationships between the pathogen and its Brassica host, the unique host resistance mechanisms and how these affect resistance outcomes is also presented. We discuss challenges in identification and deployment of R genes in B. napus in relation to highly specific genetic interactions between host subpopulations and pathogen pathotypes and emphasize the need for common or shared techniques and research materials or tighter collaboration between researchers to reconcile the inconsistencies in the research outcomes. Using current genomics tools, we provide examples of how characterization and cloning of R genes in B. napus can be carried out more effectively. Lastly, we put forward strategies to breed resistant cultivars through introgressions supported by genomic approaches and suggest prospects that can be implemented in the future for a better, pathogen-resistant B. napus.