Miracle-dz/UniFAR-FTUs huggingface dataset:
Rethinking Chronic Obstructive Pulmonary Disease. Chronic Pulmonary Insufficiency and Combined Cardiopulmonary Insufficiency

Abstract Almost 70 years ago, Drs. Baldwin, Cournand, and Richards defined chronic pulmonary insufficiency by the presence of respiratory symptoms, radiologic evidence of pulmonary emphysema on chest radiography, and physiologic gas trapping. A decade later, airflow obstruction on spirometry was added to the definition and insufficiency became a disease. Contemporary studies are reviving the diagnostic approach described by these early luminaries, with researchers finding that symptomatic smokers with preserved spirometry have increased exacerbations and that smokers and non‐smokers with normal spirometry but emphysema on chest computed tomography have increased mortality. Hence, the Baldwin‐Cournand‐Richards concept of disease defined by respiratory symptoms, radiologic findings, and physiology—regardless of spirometric criteria—is being rediscovered. Baldwin, Cournand, and Richards also stated that “functionally, it is obvious that the pulmonary and circulatory apparatus are one unit,” and they defined combined cardiopulmonary insufficiency as chronic pulmonary insufficiency with (left or right) cardiac and pulmonary artery enlargement. They appreciated the complexity of these interactions, which include the potential role of gas trapping in heart failure with reduced ejection fraction; the impact of emphysema on blood flow in heart failure with preserved ejection fraction; multiple contributions to cor pulmonale with increased pulmonary artery pressure; and cor pulmonale parvus in emphysema; all of which may be amenable to specific therapeutic interventions. Given the complexity of heart‐lung interactions originally identified by Baldwin, Cournand, and Richards and the potentially large therapeutic opportunities, large‐scale studies are still warranted to find specific therapies for subphenotypes of combined cardiopulmonary insufficiency.
The phylogenetic analysis of VP1 genomic region in foot-and-mouth disease virus serotype O isolates in Sri Lanka reveals the existence of 'Srl-97', a newly named endemic lineage

Foot and mouth disease (FMD) has devastated the cattle industry in Sri Lanka many times in the past. Despite its seriousness, limited attempts have been made to understand the disease to ameliorate its effects–current recommendation for vaccines being based solely on immunological assessments rather than on molecular identification. The general belief is that the cattle population in Sri Lanka acquired the FMD virus (FMDV) strains via introductions from India. However, there could be endemic FMDV lineages circulating in Sri Lanka. To infer the phylogenetic relationships of the FMDV strains in the island, we sequenced the VP1 genomic region of the virus isolates collected during the 2014 outbreak together with a few reported cases in 2012 and 1997 and compared them to VP1 sequences from South Asia. The FMDV strains collected in the 2014 outbreak belonged to the lineage, Ind-2001d, of the topotype, ME-SA. The strains collected in 2012 and 1997 belonged to another lineage called 'unnamed' by the World Reference Laboratory for Foot and Mouth Disease (WRLFMD). Based on the present analysis, we designate the lineage 'unnamed' as Srl-97 which we found endemic to Sri Lanka. The evolutionary rates of Srl-97 and Ind-2001d in Sri Lanka were estimated to be 0.0004 and 0.0046 substitutions/site/year, respectively, suggesting that Srl-97 evolves slowly.
Skin penetration enhancement techniques

17 1 CHAPTER 1 20 1.1 TRASDERMAL DRUG DELIVERY SYSTEMS 21 1.2 STRUCTURE AND FUNCTION OF HUMAN SKIN 21 1.2. 1 EPIDERMIS: 22 1.2. 1.1 STRATUM CORNEUM: 23 1.2. 1.2 STRATUM LUCIDUM: 24 1.2. 1.3 STRATUM GRANULOSUM: 24 1.2. 1.4 STRATUM SPINOSUM: 25 1.2. 1.5 STRATUM BASALE: 25 1.2. 2 DERMAL-EPIDERMAL JUNCTION: 25 1.2. 3 DERMIS: 26 1.2. 4 SUBCUTANEOUS FATTY LAYER: 26 1.3 ROUTES OF TRANSDERMAL DRUG DELIVERY 28 1.4 PERMEANT P HYSICOCHEMICAL CH ARACTERISTICS F OR SKIN DELIVERY 30 1.5 PENETRATION ENHANCEMENT TECHNIQUES 30 1.5. 1 CHEMICALS AS PENETRATION ENHANCERS 31 1.5. 2 HYDRATION (WATER AND OCCLUSION) 32 1.5. 3 CHEMICAL AND FORMULATION MODIFIERS 33 1.5. 4 VESICLE OR PARTICLE DELIVERY 33
A Comparison of Two Mouse Frailty Assessment Tools

The mouse clinical frailty index and the mouse frailty phenotype assessment are two recently developed tools used to assess frailty in mice. The objectives of this study were to investigate whether the same mice are identified as frail with both tools and to examine the association of each of the assessment tools with age and frailty-related outcomes. Frailty was measured using both tools in old (~24 months; n = 36) C57BL/6 male mice. After 2 weeks, blood pressure and heart rate were measured and serum samples were collected for analysis of alanine aminotransferase, creatinine, and albumin levels. The mouse frailty phenotype assessment identified no mice as frail but modification of the assessment tool identified six mice as frail. The mouse clinical frailty index identified 16 mice as frail and the agreement between the two scales was 50.0%. Increasing clinical frailty index scores were correlated with low serum alanine aminotransferase, as well as decreased heart rate, and reduced heart rate variance. We conclude that, consistent with equivalent frailty assessment scales in humans, both tools have value but do not necessarily identify the same mice as frail.
Systematic Review and Meta-analysis of the Safety of Antistaphylococcal Penicillins Compared to Cefazolin

ABSTRACT Recent studies and experience suggest that cefazolin might be equally as effective as antistaphylococcal penicillins for methicillin-susceptible Staphylococcus aureus (MSSA), with a better safety profile and lower cost. The objective of these meta-analyses was to compare the safeties of antistaphylococcal penicillins and cefazolin. The PubMed, Embase, and International Pharmaceutical Abstracts databases and websites for clinical trial registries through 23 June 2017 were searched. In addition, recent abstracts from infectious disease and pharmacy conferences were reviewed. We estimated Peto odds ratios (ORs) with 95% confidence intervals (CIs) using random-effects models. One analysis focused on hospitalized patients, and the other focused on outpatients. Eleven retrospective studies of hospitalized patients and three retrospective studies of outpatients were included. In hospitalized patients, lower rates of nephrotoxicity (Peto OR, 0.225; 95% CI, 0.127 to 0.513), acute interstitial nephritis (Peto OR, 0.189; 95% CI, 0.053 to 0.675), hepatotoxicity (Peto OR, 0.160; 95% CI, 0.066 to 0.387), and drug discontinuation due to adverse reactions (Peto OR, 0.192; 95% CI, 0.089 to 0.414) were found with cefazolin. In outpatients, lower rates of nephrotoxicity (Peto OR, 0.372; 95% CI, 0.192 to 0.722), hepatotoxicity (Peto OR, 0.313; 95% CI, 0.156 to 0.627), and hypersensitivity reactions (Peto OR, 0.372; 95% CI, 0.201 to 0.687) were observed with cefazolin. Compared to antistaphylococcal penicillins, cefazolin was associated with significant reductions in nephrotoxicity and hepatotoxicity in hospitalized patients and outpatients. Additionally, cefazolin was associated with lower likelihoods of discontinuation due to side effects in hospitalized patients and hypersensitivity reactions in outpatients. Cefazolin should be considered a first-line option for patients with MSSA infections for which efficacy is presumed to be similar to that of antistaphylococcal penicillin therapy.
Familiar Strangers: the Collective Regularity in Human Behaviors

The social phenomenon of familiar strangers was identified by Stanley Milgram in 1972 with a small-scale experiment. However, there has been limited research focusing on uncovering the phenomenon at a societal scale and simultaneously investigating the social relationships between familiar strangers. With the help of the large-scale mobile phone records, we empirically show the existence of the relationship in the country of Andorra. Built upon the temporal and spatial distributions, we investigate the mechanisms, especially collective temporal regularity and spatial structure that trigger this phenomenon. Moreover, we explore the relationship between social distances on the communication network and the number of encounters and show that larger number of encounters indicates shorter social distances in a social network. The understanding of the physical encounter network could have important implications to understand the phenomena such as epidemics spreading and information diffusion.
Adjusting Expected Value of Sample Information Using Realistic Expectations around Implementation

We thank Eckermann and Willan for their interest in our work. Although Eckermann and Willan recognize that our work represents a useful addition to the literature, they express concerns about the way that we have estimated the expected value of sample information (EVSI) under perfect implementation (we use the word ‘‘optimal’’ with regard to implementation). In particular, Eckermann and Willan assert that we have estimated the EVSI with perfect implementation ‘‘as though conducting no further research will result in implementation of the option with the lowest INB [incremental net benefit], rather than maximizing the INB given current evidence. ’’ Unfortunately, Eckermann and Willan seem to have misunderstood the way we have calculated EVSI with optimal implementation in our article. In estimating this figure, we agree that the ‘‘counterfactual’’ should be the option that maximizes the net monetary benefit (NMB; which they call INB) given current evidence. This is precisely the way we have calculated this EVSI figure: as the difference between the ‘‘factual’’ figure, representing the expected NMB if research takes place (£318.11 million, cell L in Table 2 of our article), and the ‘‘counterfactual’’ figure, representing the maximum NMB under current evidence (£293.12 million, cell C in Table 2). It should be obvious from our Table 2 that the figure we used for the counterfactual is indeed the highest of the NMB figures for current information. The resulting EVSI figure (£24.99 million) is given in Table 3 of our article. We, of course, agree with Eckermann and Willan that decision context is important; taking this into account and expressing EVSI in a way that more closely reflects the interplay between information and implementation is the key motivation for our article. In doing so, we account for the fact that availability of additional information is expected to improve implementation, but it will not necessarily lead to instantaneous and perfect implementation. Eckermann and Willan seem to share this view in their letter. Given this, one can easily see why EVSI with improved implementation (i.e., higher than ‘‘current’’ implementation but lower than ‘‘optimal’’ implementation) is expected to result in higher NMB than EVSI with current implementation and lower NMB than EVSI with optimal implementation. We thank Eckermann and Willan for recognizing the potential of our proposed framework to provide a useful tool for value of information analysis, and we hope that it is now clear to them that our calculations are correct, based on the counterfactual option that maximizes NMB given current evidence.
Stimulation of Na+-K+-2Cl-cotransporter in neuronal cells by excitatory neurotransmitter glutamate.

Na+-K+-2Cl-cotransporters are important in renal salt reabsorption and in salt secretion by epithelia. They are also essential in maintenance and regulation of ion gradients and cell volume in both epithelial and nonepithelial cells. Expression of Na+-K+-2Cl-cotransporters in brain tissues is high; however, little is known about their function and regulation in neurons. In this study, we examined regulation of the Na+-K+-2Cl-cotransporter by the excitatory neurotransmitter glutamate. The cotransporter activity in human neuroblastoma SH-SY5Y cells was assessed by bumetanide-sensitive K+ influx, and protein expression was evaluated by Western blot analysis. Glutamate was found to induce a dose- and time-dependent stimulation of Na+-K+-2Cl-cotransporter activity in SH-SY5Y cells. Moreover, both the glutamate ionotropic receptor agonist N-methyl-d-aspartic acid (NMDA) and the metabotropic receptor agonist (±)-1-aminocyclopentane- trans-1,3-dicarboxylic acid ( trans-ACPD) significantly stimulated the cotransport activity in these cells. NMDA-mediated stimulation of the Na+-K+-2Cl-cotransporter was abolished by the selective NMDA-receptor antagonist (+)-MK-801 hydrogen maleate. trans-ACPD-mediated effect on the cotransporter was blocked by the metabotropic receptor antagonist (+)-α-methyl-(4-carboxyphenyl)glycine. The results demonstrate that Na+-K+-2Cl-cotransporters in neurons are regulated by activation of both ionotropic and metabotropic glutamate receptors.
Role of the kidney in human leptin metabolism.

To assess the role of the human kidney in leptin metabolism, we measured renal leptin net balance and urinary leptin excretion in 16 normal postabsorptive volunteers with varying degrees of obesity. Arterial leptin concentrations (11.6 ± 2.7 ng/ml) significantly exceeded renal vein concentrations (10.3 ± 2.5 ng/ml, P < 0.001). Renal leptin fractional extraction averaged 13.1 ± 1.1%, and renal leptin net balance (uptake) averaged 1,070 ± 253 ng/min. Lineweaver-Burk analysis indicated that renal leptin uptake followed saturation kinetics with an apparent Michaelis-Menten constant of 10.9 ng/ml and maximal velocity of 1,730 ng/min. Leptin was generally undetectable in urine. Using literature values for systemic leptin clearance, we calculated that renal leptin uptake could account for ∼80% of all leptin removal from plasma. These data indicate that the human kidney plays a substantial role in leptin removal from plasma by taking up and degrading the peptide.
Kidney Function in Obesity-Challenges in Indexing and Estimation.

As the prevalence of obesity continues to increase worldwide, an increasing number of people are at risk for kidney disease. Thus, there is a critical need to understand how best to assess kidney function in this population, and several challenges exist. The convention of indexing glomerular filtration rate (GFR) to body surface area (BSA) attempts to normalize exposure to metabolic wastes across populations of differing body size. In obese individuals, this convention results in a significantly lower indexed GFR than unindexed GFR, which has practical implications for drug dosing. Recent data suggest that "unindexing" estimated GFR (multiplying by BSA/1.73 m2) for drug dosing may be acceptable, but pharmocokinetic data to support this practice are lacking. Beyond indexing, biomarkers commonly used for estimating GFR may induce bias. Creatinine is influenced by muscle mass, whereas cystatin C correlates with fat mass, both independent of kidney function. Further research is needed to evaluate the performance of estimating equations and other filtration markers in obesity, and determine whether unindexed GFR might better predict optimal drug dosing and clinical outcomes in patients whose BSA is very different than the conventional normalized value of 1.73 m2.
When the Nose Doesn’t Know: Canine Olfactory Function Associated With Health, Management, and Potential Links to Microbiota

The impact of health, management, and microbiota on olfactory function in canines has not been examined in review. The most important characteristic of the detection canine is its sense of smell. Olfactory receptors are primarily located on the ethmoturbinates of the nasal cavity. The vomeronasal organ is an additional site of odor detection that detects chemical signals that stimulate behavioral and/or physiological changes. Recent advances in the genetics of olfaction suggest that genetic changes, along with the unique anatomy and airflow of the canine nose, are responsible for the macrosmia of the species. Inflammation, alterations in blood flow and hydration, and systemic diseases alter olfaction and may impact working efficiency of detection canines. The scientific literature contains abundant information on the potential impact of pharmaceuticals on olfaction in humans, but only steroids, antibiotics, and anesthetic agents have been studied in the canine. Physical stressors including exercise, lack of conditioning, and high ambient temperature impact olfaction directly or indirectly in the canine. Dietary fat content, amount of food per meal, and timing of meals have been demonstrated to impact olfaction in mice and dogs. Gastrointestinal (GI) microbiota likely impacts olfaction via bidirectional communication between the GI tract and brain, and the microbiota is impacted by exercise, diet, and stress. The objective of this literature review is to discuss the specific effects of health, management, and microbiota shifts on olfactory performance in working canines.
The value of neutrophil-to-lymphocyte ratio for response and prognostic effect of neoadjuvant chemotherapy in solid tumors: A systematic review and meta-analysis

Introduction: The neutrophil-to-lymphocyte ratio (NLR) has been found to be an indicator of poor prognosis in many tumour types. However, little is known about the relationship between the NLR and patients with tumours who receive neoadjuvant chemotherapy (NAC) in terms of response rate and prognostic ability. We thus performed this meta-analysis to further investigate this relationship. Methods: An electronic systematic literature search for articles published before September 2017 was performed to explore the association between the pretreatment NLR and outcome in patients treated with NAC. Data were extracted by the reported odds ratios (ORs) and hazard ratios (HRs) with their 95% confidence intervals (CIs) for the response rate and the survival outcome, respectively. The results were pooled using the random-effect or fixed-effect model. Results: Thirty-three studies were eventually included in our study, and all were published no earlier than 2011. An NLR that was higher than the cut-off was associated with a lower pathological complete response (pCR) rate in patients with cancer (OR = 1.72, 95% CI, 1.26-2.33). A lower NLR was associated with better overall survival (OS) (HR = 1.58, 95% CI, 1.34-1.86), cancer-specific survival (CSS) (HR = 2.22, 95% CI, 1.32-3.74), disease-free survival (DFS) (HR = 1.32, 95% CI, 1.10-1.59) and recurrence-free survival (RFS) (HR = 1.90, 95% CI, 1.50-2.40). Conclusion: Overall, an NLR lower than the cut-off value indicated a greater chance for pCR and may predict good survival outcomes after NAC for patients with solid tumours. The use of the NLR for risk stratification before NAC should be further demonstrated by future large-scale prospective studies.
A DC-coupled 50 Gb/s 0.064 pJ/bit thin-oxide level shifter in 28 nm FDSOI CMOS

High-speed optical interconnects require compact, low-power driver electronics for optical modulators. Inverter based CMOS driver circuits show very low power consumption. However, the output swing is typically limited to the supply voltage which is typically insufficient for optical modulators, requiring a cascoded output driver and level shifter. In this work, we present a new DC-coupled thin-oxide level shifter topology in a 28 nm FDSOI CMOS technology enabling data rates up to 50 Gb/s with a power efficiency of 0.064 pJ/bit.
Effects of Intermittent Lighting on Breeder Chicks Provided with "In-Transit" Nutrients

In-transit supply of nutrients and water supplement is essential to maintaining good chick quality and well-being during long, international shipments. Although chicks require light to promote ingestion of nutrients, supply of continuous in-transit lighting is impractical. This study compared four intermittent lighting regimens of 1L:5D, 5L:10D,10L:10D, and 5L:15D applied to a three-day simulated transport period with regard to chick performance and energetics during the treatment period and a four-day subsequent growth period. The four lighting regimens produced similar seven-day chick performance, although chicks under 10L:10D had a somewhat higher body mass loss and metabolic rate than birds in other regimens during the three-day treatment period (P < 0.05). The results suggest the existence of flexibility in providing in-transit lighting for shipping chicks. Significant differences in the heat and moisture production rate of the chicks were observed between light and dark periods, with the response values being 21 to 27% lower in the dark period than in the light period. The results further suggest that chicks in transit would benefit the most from sufficient lighting to ingest necessary nutrients but then remaining in darkness to conserve body energy.
Paracoccidioides Spp.: Virulence Factors and Immune-Evasion Strategies

Paracoccidioides spp. are dimorphic fungal pathogens responsible for one of the most relevant systemic mycoses in Latin America, paracoccidioidomycosis (PCM). Their exact ecological niche remains unknown; however, they have been isolated from soil samples and armadillos (Dasypus novemcinctus), which have been proposed as animal reservoir for these fungi. Human infection occurs by inhalation of conidia or mycelia fragments and is mostly associated with immunocompetent hosts inhabiting and/or working in endemic rural areas. In this review focusing on the pathogen perspective, we will discuss some of the microbial attributes and molecular mechanisms that enable Paracoccidioides spp. to tolerate, adapt, and ultimately avoid the host immune response, establishing infection.
The Enigmatic Alphavirus Non-Structural Protein 3 (nsP3) Revealing Its Secrets at Last

Alphaviruses encode 4 non-structural proteins (nsPs), most of which have well-understood functions in capping and membrane association (nsP1), polyprotein processing and RNA helicase activity (nsP2) and as RNA-dependent RNA polymerase (nsP4). The function of nsP3 has been more difficult to pin down and it has long been referred to as the more enigmatic of the nsPs. The protein comprises three domains, an N-terminal macro domain, a central zinc-binding domain and a C-terminal hypervariable domain (HVD). In this article, we review old and new literature about the functions of the three domains. Much progress in recent years has contributed to a picture of nsP3, particularly through its HVD as a hub for interactions with host cell molecules, with multiple effects on the biology of the host cell at early points in infection. These and many future discoveries will provide targets for anti-viral therapies as well as strategies for modification of vectors for vaccine and oncolytic interventions.