Miracle-dz/UniFAR-FTUs huggingface dataset:
Mild cognitive impairment: narrative review of taxonomies and systematic review of their prediction of incident Alzheimer's disease dementia

Early detection of Alzheimer's disease is vital for developing novel treatments. Attempts to identify the intermediate state between normal cognition and dementia have evolved over the past 50 years. Current taxonomies of mild cognitive impairment (MCI) may be criticised for their imprecise operationalisation. With the advent of biomarkers such as amyloid-beta positron emission tomography imaging in established Alzheimer's disease, much research has focused on establishing which factors predict progression from MCI to Alzheimer's disease dementia. In this review, we discuss the historical context of MCI before reviewing the literature of MCI subtypes and their risk of progression to Alzheimer's disease dementia. Finally, we summarise the literature and discuss limitations and weaknesses of how the construct is operationalised and implemented, before offering suggestions for development of the concept of MCI. We conclude that MCI must be empirically defined for the sake of its predictive validity to identify Alzheimer's disease before dementia develops.
EVALUATION OF ANTI A60 IgM FOR THE DIAGNOSIS OF TUBERCULOSIS WITH ELISA METHOD

Evaluation of Anti Tuberculous IgM antibodies for rapid diagnosis of both pulmonary and extra-pulmonary tuberculosis. ELISA assay based on mycobacterial antigen A-60 (Anda Biologicals, France) was used on the sera obtained from 69 cases of Tuberculosis and 136 controls in the population of Karachi, Pakistan. Of 136 controls only 21.3 % were positive for IgM antibodies and showing 78.7% specificity. A very high sensitivity 72.2% was seen in sputum positive active pulmonary tuberculosis. Relatively low 56.2% sero positivity was seen in cases of sputum negative active pulmonary tuberculosis compared to those of sputum positive active pulmonary tuberculosis. In cases of extra pulmonary tuberculosis 57.8 % sensitivity was observed. In cases of healed tuberculosis only 18.7% were found positive for IgM. The estimation value of IgM against A-60 for the diagnosis of tuberculosis is proved from our data. Considering all the cases of active tuberculosis and the controls the global sensitivity of 62.2% and specificity of 78.7% was found when IgM estimation was taken into account.
Accelerating the Search for Interventions Aimed at Expanding the Health Span in Humans: The Role of Epidemiology.

BACKGROUND Extensive work in basic and clinical science suggests that biological mechanisms of aging are causally related to the development of disease and disability in late life. Modulation of the biological mechanisms of aging can extend both life span and health span in animal models, but translation to humans has been slow. METHODS Summary of workshop proceedings from the 2018-2019 Epidemiology of Aging Workshop hosted by the Intramural Research Program at the National Institute on Aging. RESULTS Epidemiologic studies play a vital role to progress in this field, particularly in evaluating new risk factors and measures of biologic aging that may influence health span, as well as developing relevant outcome measures that are robust and relevant for older individuals. CONCLUSIONS Appropriately designed epidemiological studies are needed to identify targets for intervention and to inform study design and sample size estimates for future clinical trials designed to promote health span.
Atomic structures of the RNA end-healing 5′-OH kinase and 2′,3′-cyclic phosphodiesterase domains of fungal tRNA ligase: conformational switches in the kinase upon binding of the GTP phosphate donor

Abstract Fungal tRNA ligase (Trl1) rectifies RNA breaks with 2′,3′-cyclic-PO4 and 5′-OH termini. Trl1 consists of three catalytic modules: an N-terminal ligase (LIG) domain; a central polynucleotide kinase (KIN) domain; and a C-terminal cyclic phosphodiesterase (CPD) domain. Trl1 enzymes found in all human fungal pathogens are untapped targets for antifungal drug discovery. Here we report a 1.9 Å crystal structure of Trl1 KIN-CPD from the pathogenic fungus Candida albicans, which adopts an extended conformation in which separate KIN and CPD domains are connected by an unstructured linker. CPD belongs to the 2H phosphotransferase superfamily by dint of its conserved central concave β sheet and interactions of its dual HxT motif histidines and threonines with phosphate in the active site. Additional active site motifs conserved among the fungal CPD clade of 2H enzymes are identified. We present structures of the Candida Trl1 KIN domain at 1.5 to 2.0 Å resolution—as apoenzyme and in complexes with GTP•Mg2+, IDP•PO4, and dGDP•PO4—that highlight conformational switches in the G-loop (which recognizes the guanine base) and lid-loop (poised over the nucleotide phosphates) that accompany nucleotide binding.
Genome-scale model-based identification of metabolite indicators for early detection of kidney toxicity.

Identifying early indicators of toxicant-induced organ damage is critical to provide effective treatment. To discover such indicators and the underlying mechanisms of toxicity, we used gentamicin as an exemplar kidney toxicant and performed systematic perturbation studies in Sprague Dawley rats. We obtained high-throughput data 7 and 13 h after administration of a single dose of gentamicin (0.5 g/kg) and identified global changes in genes in the liver and kidneys, metabolites in the plasma and urine, and absolute fluxes in central carbon metabolism. We used these measured changes in genes in the liver and kidney as constraints to a rat multi-tissue genome-scale metabolic network model to investigate the mechanism of gentamicin-induced kidney toxicity and identify metabolites associated with changes in tissue gene expression. Our experimental analysis revealed that gentamicin-induced metabolic perturbations could be detected as early as 7 h post-exposure. Our integrated systems-level analyses suggest that changes in kidney gene expression drive most of the significant metabolite alterations in the urine. The analyses thus allowed us to identify several significantly enriched injury-specific pathways in the kidney underlying gentamicin-induced toxicity, as well as metabolites in these pathways that could serve as potential early indicators of kidney damage.
Models of Traumatic Brain Injury in Aged Animals: A Clinical Perspective

Traumatic brain injury (TBI) is a major cause of morbidity and mortality in the United States, with advanced age being one of the major predictors of poor prognosis. To replicate the mechanisms and multifaceted complexities of human TBI and develop prospective therapeutic treatments, various TBI animal models have been developed. These models have been essential in furthering our understanding of the pathophysiology and biochemical effects on brain mechanisms following TBI. Despite these advances, translating preclinical results to clinical application, particularly in elderly individuals, continues to be challenging. This review aims to provide a clinical perspective, identifying relevant variables currently not replicated in TBI animal models, to potentially improve translation to clinical practice, especially as it applies to elderly populations. As background for this clinical perspective, we reviewed articles indexed on PubMed from 1970 to 2019 that used aged animal models for studying TBI. These studies examined end points relevant for clinical translation, such as neurocognitive effects, sensorimotor behavior, physiological mechanisms, and efficacy of neuroprotective therapies. However, compared with the higher incidence of TBI in older individuals, animal studies on the basic science of aging and TBI remain remarkably scarce. Moreover, a fundamental disconnect remains between experiments in animal models of TBI and successful translation of findings for treating the older TBI population. In this article, we aim to provide a clinical perspective on the unique attributes of TBI in older individuals and a critical appraisal of the research to date on TBI in aged animal models as well as recommendations for future studies.
Incidence of colorectal cancer in Eritrea: Data from the National Health Laboratory, 2011-2017

Introduction Recent studies have reported a significant increase in the prevalence of colorectal cancer (CRC) in Sub-Saharan Africa (SSA). Further, several studies employing disparate modelling algorithms have projected a significant rise in the frequency of CRC cases in the region. However, lack of good quality data on multiple themes related to CRC including incidence, among others, continues to be a problem in the region. Therefore, this study was designed to collect data on the incidence of CRC in Eritrea. Methods We conducted a retrospective analysis using data captured between 2011 and 2017 at the National Health Laboratory (NHL) in Asmara, Eritrea. Results 241 colorectal cases were identified in the Eritrean National Health Laboratory (NHL) database between 2011 and 2017. In the final analysis we included 94 patients confirmed cases giving an average of 18.8 patients per annum. The average age ± Standard deviation (SD) was 57.62 ± 17.14 with a male: female ratio of 58/36 (1: 1.61). The minimum and maximum age of the patients was 19 and 90 years, respectively. The rectum to colon ratio was 47/47 (1:1). The proportion of patients < 50 years in this cohort was significant. The age-standardized incidence rate (ASIR) in the study period was between 0.97 per 100 000 to 2.21 per 100 000. Similarly, the cumulative ASIR was 9.97 per 100 000. Analysis of trends did not reveal shifts over the study period (P<0.05). However, a strong correlation between incidence and age was established. Conclusion This study suggests that the incidence of CRC in Eritrea is relatively low. A significant number of patients were less than 50 years of age. Even then it’s our opinion that this study may underestimate the incidence of CRC.
Epidemiology and Diagnostics of Carbapenem Resistance in Gram-negative Bacteria

Abstract Carbapenem resistance in gram-negative bacteria has caused a global epidemic that continues to grow. Although carbapenemase-producing Enterobacteriaceae have received the most attention because resistance was first reported in these pathogens in the early 1990s, there is increased awareness of the impact of carbapenem-resistant nonfermenting gram-negative bacteria, such as Acinetobacter baumannii, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia. Moreover, evaluating the problem of carbapenem resistance requires the consideration of both carbapenemase-producing bacteria as well as bacteria with other carbapenem resistance mechanisms. Advances in rapid diagnostic tests to improve the detection of carbapenem resistance and the use of large, population-based datasets to capture a greater proportion of carbapenem-resistant organisms can help us gain a better understanding of this urgent threat and enable physicians to select the most appropriate antibiotics.
A characterization of ABL‐101 as a potential tracer for clinical fluorine‐19 MRI

The two main challenges that prevent the translation of fluorine‐19 (19F) MRI for inflammation monitoring or cell tracking into clinical practice are (i) the relatively low signal‐to‐noise ratio generated by the injected perfluorocarbon (PFC), which necessitates long scan times, and (ii) the need for regulatory approval and a high biocompatibility of PFCs that are also suitable for MRI. ABL‐101, an emulsion of perfluoro(t‐butylcyclohexane), is a third‐generation PFC that is already used in clinical trials, but has not yet been used for 19F MRI. The objective of this study was therefore to assess the performance of ABL‐101 as a 19F MRI tracer. At magnetic field strengths of 3, 9.4 and 14.1 T, the CF3 groups of ABL‐101 generated a large well‐separated singlet with T2/T1 ratios of >0.27, >0.14 and > 0.05, respectively. All relaxation times decreased with the increase in magnetic field strength. The detection limit of ABL‐101 in a 0.25 mm3 voxel at 3 T, 37°C and with a 3‐minute acquisition time was 7.21mM. After intravenous injection, the clearance half‐lives of the ABL‐101 19F MR signal in mouse (n = 3) spleen and liver were 6.85 ± 0.45 and 3.20 ± 0.35 days, respectively. These results demonstrate that ABL‐101 has 19F MR characteristics that are similar to those of PFCs developed specifically for MRI, while it has clearance half‐lives similar to PFCs that have previously been used in large doses in non‐MRI clinical trials. Overall, ABL‐101 is thus a very promising candidate tracer for future clinical trials that use 19F MRI for cell tracking or the monitoring of inflammation.
Triple Negative Breast Cancer: How Neurokinin-1 Receptor Antagonists Could Be Used as a New Therapeutic Approach.

Breast cancer (BC) is the most frequently diagnosed cancer and the leading cause of cancer death among females. BC cells not showing HER-2/Neu amplification and not expressing estrogen/progesterone receptors are named triple-negative BC (TNBC) cells. TNBC represents 10-15% of all BC and is associated with an aggressive clinical course. TNBC patient prognosis, survival and response to current therapies are poor and for this reason it is crucial to search new therapeutic targets in TNBC to develop new therapeutic strategies. One of these targets is the neurokinin-1 receptor (NK-1R). It is well known that the substance P (SP)/NK-1R system is involved in cancer progression. TNBC cells overexpress the NK-1R and, after binding to this receptor, SP promotes the proliferation/migration of TNBC cells. Non-peptide NK-1R antagonists (e.g., aprepitant) are known to exert, via the NK-1R, an antitumor action; TNBC cells die by apoptosis. In this review, we up-date the data on a promising therapeutic innovation: the use of NK-1R antagonists for the treatment of TNBC patients.
Co-administration of resveratrol and beta-aminopropionitrile attenuates liver fibrosis development via targeting lysyl oxidase in CCl4-induced liver fibrosis in rats

Abstract Objectives: In the current study, we aimed to investigate the effect of administration of resveratrol (RES) and beta-aminopropionitrile (BAPN) separately and together on the liver fibrosis progression via regulation of the gene expression and protein level of lysyl oxidase (LOX). Materials and methods: The six-week old Wistar rats received carbon tetrachloride (CCl4) intraperitoneally and RES and BAPN were administrated orally for eight weeks. The hepatoprotective effects of RES, BAPN, and combination treatment were evaluated. Then the hepatic protein and gene expression levels of LOX were measured. Results: Both RES and BAPN showed the antifibrotic effect through the reduction of collagen fiber bundles, hepatic hydroxyproline content, and protein level of LOX. The antifibrotic effect increased when RES and BAPN up-taken together. Conclusion: The co-administration of RES and BAPN can be considered as a promising therapeutic approach via targeting LOX.
The Global Ascendency of OXA-48-Type Carbapenemases

Surveillance studies have shown that OXA-48-like carbapenemases are the most common carbapenemases in Enterobacterales in certain regions of the world and are being introduced on a regular basis into regions of nonendemicity, where they are responsible for nosocomial outbreaks. OXA-48, OXA-181, OXA-232, OXA-204, OXA-162, and OXA-244, in that order, are the most common enzymes identified among the OXA-48-like carbapenemase group. SUMMARY Surveillance studies have shown that OXA-48-like carbapenemases are the most common carbapenemases in Enterobacterales in certain regions of the world and are being introduced on a regular basis into regions of nonendemicity, where they are responsible for nosocomial outbreaks. OXA-48, OXA-181, OXA-232, OXA-204, OXA-162, and OXA-244, in that order, are the most common enzymes identified among the OXA-48-like carbapenemase group. OXA-48 is associated with different Tn1999 variants on IncL plasmids and is endemic in North Africa and the Middle East. OXA-162 and OXA-244 are derivatives of OXA-48 and are present in Europe. OXA-181 and OXA-232 are associated with ISEcp1, Tn2013 on ColE2, and IncX3 types of plasmids and are endemic in the Indian subcontinent (e.g., India, Bangladesh, Pakistan, and Sri Lanka) and certain sub-Saharan African countries. Overall, clonal dissemination plays a minor role in the spread of OXA-48-like carbapenemases, but certain high-risk clones (e.g., Klebsiella pneumoniae sequence type 147 [ST147], ST307, ST15, and ST14 and Escherichia coli ST38 and ST410) have been associated with the global dispersion of OXA-48, OXA-181, OXA-232, and OXA-204. Chromosomal integration of blaOXA-48 within Tn6237 occurred among E. coli ST38 isolates, especially in the United Kingdom. The detection of Enterobacterales with OXA-48-like enzymes using phenotypic methods has improved recently but remains challenging for clinical laboratories in regions of nonendemicity. Identification of the specific type of OXA-48-like enzyme requires sequencing of the corresponding genes. Bacteria (especially K. pneumoniae and E. coli) with blaOXA-48, blaOXA-181, and blaOXA-232 are emerging in different parts of the world and are most likely underreported due to problems with the laboratory detection of these enzymes. The medical community should be aware of the looming threat that is posed by bacteria with OXA-48-like carbapenemases.
His bundle pacing: conduction system capture and clinical impact.

PURPOSE OF REVIEW It has been nearly 2 decades since His bundle pacing (HBP) was described and with very first randomized pilot study published, reviewing its impact on clinical practice is inevitable. RECENT FINDINGS Inclusion of HBP in the guidelines, along with long-term outcomes, outcomes comparing selective and non selective HBP and investigatory initiated randomized pilot comparing with cardiac resynchronization therapy, HBP has established itself as a feasible pacing alternative. SUMMARY HBP is an addition to the current armada of resynchronization techniques. HBP is an emerging area of interest, and is particularly relevant in patients, who require chronic ventricular pacing, but the long-term outcomes of this approach in large patient populations with low ejection fraction are still lacking. With several ongoing studies, in the near future we will have good-quality evidence to support native conduction system pacing as a viable alternative to improve meaningful outcomes.
The Role of Neck Circumference

apnea/hypopnea index (AHI) > 10/h, was significantly more frequent (60% vs 32%, 2 < 0.0001) and severe (mean SE, 25 26/h vs 12 19/h, p < 0.0001) in men than in women. Men had significantly larger NC than women, but the difference became much less pronounced when we normalized NC to body height (0.24 0.02 vs 0.23 0.03, p < 0.0001). Men had significantly higher AHI than women even after controlling for age, body mass index (BMI), and neck/height ratio (NHR); analysis of covariance showed that mean AHI was 24.4 0.4 in men vs 14.8 0.7 in women (p < 0.0001). This difference persisted even when we matched men and women for NHR and BMI. Finally, multiple regression analysis revealed the following: (1) NHR was the most significant predictor of AHI, accounting for 19% of the variability; and (2) the slope of AHI vs NHR was significantly higher in men than in women. Conclusions: We conclude the following: (1) the frequency and severity of sleep apnea in the sleep clinic population is greater in men than women, and (2) factors other than NC, age, and BMI must contribute to these gender differences. (CHEST 2003; 123:1544 –1550)
Annexin‐A1 deficiency exacerbates pathological remodelling of the mesenteric vasculature in insulin‐resistant, but not insulin‐deficient, mice

Arterial stiffness, a characteristic feature of diabetes, increases the risk of cardiovascular complications. Potential mechanisms that promote arterial stiffness in diabetes include oxidative stress, glycation and inflammation. The anti‐inflammatory protein annexin‐A1 has cardioprotective properties, particularly in the context of ischaemia. However, the role of endogenous annexin‐A1 in the vasculature in both normal physiology and pathophysiology remains largely unknown. Hence, this study investigated the role of endogenous annexin‐A1 in diabetes‐induced remodelling of mouse mesenteric vasculature.
CBX4 promotes the proliferation and metastasis via regulating BMI‐1 in lung cancer

Proliferation and metastasis are significantly malignant characteristics of human lung cancer, but the underlying molecular mechanisms are poorly understood. Chromobox 4 (CBX4), a member of the Polycomb group (PcG) family of epigenetic regulatory factors, enhances cellular proliferation and promotes cancer cell migration. However, the effect of CBX4 in the progression of lung cancer is not fully understood. We found that CBX4 is highly expressed in lung tumours compared with adjacent normal tissues. Overexpression of CBX4 significantly promotes cell proliferation and migration in human lung cancer cell lines. The knockdown of CBX4 obviously suppresses the cell growth and migration of human lung cancer cells in vitro. Also, the proliferation and metastasis in vivo are blocked by CBX4 knockdown. Furthermore, CBX4 knockdown effectively arrests cell cycle at the G0/G1 phase through suppressing the expression of CDK2 and Cyclin E and decreases the formation of filopodia through suppressing MMP2, MMP9 and CXCR4. Additionally, CBX4 promotes proliferation and metastasis via regulating the expression of BMI‐1 which is a significant regulator of proliferation and migration in lung cancer cells. Taken together, these data suggest that CBX4 is not only a novel prognostic marker but also may be a potential therapeutic target in lung cancer.
Síndrome de Brugada tipo II

El síndrome de Brugada es incluido dentro de las canalopatías. Fue descrito por primera vez en 1992 y se caracteriza por la presencia de síncope, arritmias ventriculares y, en ocasiones, muerte súbita en enfermos con un corazón estructuralmente sano, y por un patrón electrocardiográfi co caracterizado por la elevación del segmento ST de V1 a V3 y una morfología similar a la de un bloqueo de rama derecha.
Drivers’ Cue Utilization Predicts Cognitive Resource Consumption During a Simulated Driving Scenario

Objective This study was designed to examine whether cue utilization differentiates drivers’ consumption of cognitive resources during a simulated driving task. Background Outcomes from previous research have demonstrated that a general capacity for cue utilization differentiates cognitive load during novel process control tasks. However, it was previously unclear whether similar results would be demonstrated during familiar operational tasks. Method Based on an assessment of cue utilization within a driving context, participants were classified into higher or lower cue utilization typologies. During a simulated driving task, cognitive load was assessed through changes against baseline in cerebral oxygenation in the prefrontal cortex, through eye behavior metrics (fixation rates and fixation dispersion), and through driving performance (frequency of missed traffic signals and speed exceedances). Results Drivers with higher cue utilization recorded smaller mean fixation dispersions, smaller increases in cerebral oxygenation, and fewer missed traffic signals compared with drivers with lower cue utilization. These results suggest that compared with drivers with lower cue utilization, drivers with higher cue utilization experienced lower cognitive load during the simulated driving task while maintaining a higher level of performance. Conclusion The results provide support for the assertion that, among qualified operators, a greater capacity for cue utilization is associated with lower cognitive load during operational tasks. Application Cue-based assessments of driving may be beneficial in predicting performance and assisting in targeted training for recently qualified and/or older drivers.