Miracle-dz/UniFAR-FTUs huggingface dataset:
Global Case-Fatality Rates in Pediatric Severe Sepsis and Septic Shock: A Systematic Review and Meta-analysis

Importance The global patterns and distribution of case-fatality rates (CFRs) in pediatric severe sepsis and septic shock remain poorly described. Objective We performed a systematic review and meta-analysis of studies of children with severe sepsis and septic shock to elucidate the patterns of CFRs in developing and developed countries over time. We also described factors associated with CFRs. Data Sources We searched PubMed, Web of Science, Excerpta Medica database, Cumulative Index of Nursing and Allied Health Literature (CINAHL), and Cochrane Central systematically for randomized clinical trials and prospective observational studies from earliest publication until January 2017, using the keywords “pediatric,” “sepsis,” “septic shock,” and “mortality. ” Study Selection Studies involving children with severe sepsis and septic shock that reported CFRs were included. Retrospective studies and studies including only neonates were excluded. Data Extraction and Synthesis We conducted our systematic review and meta-analysis in close accordance to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Pooled case-fatality estimates were obtained using random-effects meta-analysis. The associations of study period, study design, sepsis severity, age, and continents in which studies occurred were assessed with meta-regression. Main Outcomes and Measures Meta-analyses to provide pooled estimates of CFR of pediatric severe sepsis and septic shock over time. Results Ninety-four studies that included 7561 patients were included. Pooled CFRs were higher in developing countries (31.7% [95% CI, 27.3%-36.4%]) than in developed countries (19.3% [95% CI, 16.4%-22.7%]; P < .001). Meta-analysis of CFRs also showed significant heterogeneity across studies. Continents that include mainly developing countries reported higher CFRs (adjusted odds ratios: Africa, 7.89 [95% CI, 6.02-10.32]; P < .001; Asia, 3.81 [95% CI, 3.60-4.03]; P < .001; South America, 2.91 [95% CI, 2.71-3.12]; P < .001) than North America. Septic shock was associated with higher CFRs than severe sepsis (adjusted odds ratios, 1.47 [95% CI, 1.41-1.54]). Younger age was also a risk factor (adjusted odds ratio, 0.95 [95% CI, 0.94-0.96] per year of increase in age). Earlier study eras were associated with higher CFRs (adjusted odds ratios for 1991-2000, 1.24 [95% CI, 1.13-1.37]; P < .001) compared with 2011 to 2016. Time-trend analysis showed higher CFRs over time in developing countries than developed countries. Conclusions and Relevance Despite the declining trend of pediatric severe sepsis and septic shock CFRs, the disparity between developing and developed countries persists. Further characterizations of vulnerable populations and collaborations between developed and developing countries are warranted to reduce the burden of pediatric sepsis globally.
Short- and Long-Term Stroke Risk after Urgent Management of Transient Ischaemic Attack: The Bologna TIA Clinical Pathway

Background: Rapid management can reduce the short stroke risk after transient ischaemic attack (TIA), but the long-term effect is still little known. We evaluated 3-year vascular outcomes in patients with TIA after urgent care. Methods: We prospectively enrolled all consecutive patients with TIA diagnosed by a vascular neurologist and referred to our emergency department (ED). Expedited assessment and best secondary prevention was within 24 h. Endpoints were stroke within 90 days, and stroke, myocardial infarction, and vascular death at 12, 24 and 36 months. Results: Between August 2010 and July 2013, we evaluated 686 patients with suspected TIA; 433 (63%) patients had confirmed TIA. Stroke at 90 days was 2.07% (95% confidence interval (CI), 1.1-3.9) compared with the ABCD2-predicted risk of 9.1%. The long-term stroke risk was 2.6% (95% CI, 1.1-4.2), 3.7% (95% CI, 1.6-5.9) and 4.4% (95% CI, 1.9-6.8) at 12, 24 and 36 months, respectively. The composite outcome of stroke, myocardial infarction, and vascular death was 3.5% (95% CI, 1.7-5.1), 4.9% (95% CI, 2.5-7.4), and 5.6% (95% CI, 2.8-8.3) at 12, 24, and 36 months, respectively. Conclusions: TIA expedited management driven by vascular neurologists was associated with a marked reduction in the expected early stroke risk and low long-term risk of stroke and other vascular events.
Neurophysiological Differences in Emotional Processing by Cochlear Implant Users, Extending Beyond the Realm of Speech.

OBJECTIVE Cochlear implants (CIs) restore a sense of hearing in deaf individuals. However, they do not transmit the acoustic signal with sufficient fidelity, leading to difficulties in recognizing emotions in voice and in music. The study aimed to explore the neurophysiological bases of these limitations. DESIGN Twenty-two adults (18 to 70 years old) with CIs and 22 age-matched controls with normal hearing participated. Event-related potentials (ERPs) were recorded in response to emotional bursts (happy, sad, or neutral) produced in each modality (voice or music) that were for the most part correctly identified behaviorally. RESULTS Compared to controls, the N1 and P2 components were attenuated and prolonged in CI users. To a smaller degree, N1 and P2 were also attenuated and prolonged in music compared to voice, in both populations. The N1-P2 complex was emotion-dependent (e.g., reduced and prolonged response to sadness), but this was also true in both populations. In contrast, the later portion of the response, between 600 and 850 ms, differentiated happy and sad from neutral stimuli in normal hearing but not in CI listeners. CONCLUSIONS The early portion of the ERP waveform reflected primarily the general reduction in sensory encoding by CI users (largely due to CI processing itself), whereas altered emotional processing (by CI users) could be found in the later portion of the ERP and extended beyond the realm of speech.
Comparison of Treatment Response in Idiopathic and Connective Tissue Disease-associated Pulmonary Arterial Hypertension.

RATIONALE Studies suggest that patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) have a poorer treatment response to therapies for PAH compared with patients with idiopathic PAH (IPAH), but individual randomized controlled trials (RCTs) have been underpowered to examine differences within these subgroups. OBJECTIVES To compare the effect of therapy for PAH in CTD-PAH versus IPAH. METHODS We obtained individual participant data from phase III placebo-controlled RCTs of therapies for PAH submitted to the U.S. Food and Drug Administration for drug approval. A treatment-by-diagnosis interaction term evaluated differences in treatment response between CTD-PAH and IPAH. Outcomes included change in 6-minute-walk distance (∆6MWD) from baseline to 12 weeks, clinical worsening, and all-cause mortality. MEASUREMENTS AND MAIN RESULTS The study sample included 827 participants with CTD-PAH and 1,935 with IPAH from 11 RCTs. Patients with CTD-PAH had less improvement in 6MWD when assigned to active treatment versus placebo compared with patients with IPAH (difference in treatment effect on ∆6MWD in CTD-PAH vs. IPAH, -17.3 m; 90% confidence interval, -31.3 to -3.3; P for interaction = 0.043). Treatment was less effective in reducing the occurrence of clinical worsening in CTD-PAH versus IPAH (P for interaction = 0.012), but there was no difference in the placebo-adjusted effect of treatment on mortality (P for interaction = 0.65). CONCLUSIONS Treatment for PAH was less effective in CTD-PAH compared with IPAH in terms of increasing 6MWD and preventing clinical worsening. The heterogeneity of treatment response supports the need for identifying therapies that are more effective for CTD-PAH.
Lexically-mediated syntactic priming effects in comprehension: Sources of facilitation

The nature of the facilitation occurring when sentences share a verb and syntactic structure (i.e., lexically-mediated syntactic priming) has not been adequately addressed in comprehension. In four eye-tracking experiments, we investigated the degree to which lexical, syntactic, thematic, and verb form repetition contribute to facilitated target sentence processing. Lexically-mediated syntactic priming was observed when primes and targets shared a verb and abstract syntactic structure, regardless of the ambiguity of the prime. In addition, repeated thematic role assignment resulted in syntactic priming (to a lesser degree), and verb form repetition facilitated lexical rather than structural processing. We conclude that priming in comprehension involves lexically associated abstract syntactic representations, and facilitation of verb and thematic role processes. The results also indicate that syntactic computation errors during prime processing are not necessary for lexically-mediated priming to occur during target processing. This result is inconsistent with an error-driven learning account of lexically-mediated syntactic priming effects.
VAPB depletion alters neuritogenesis and phosphoinositide balance in motoneuron-like cells: relevance to VAPB-linked amyotrophic lateral sclerosis

ABSTRACT VAPB and VAPA are ubiquitously expressed endoplasmic reticulum membrane proteins that play key roles in lipid exchange at membrane contact sites. A mutant, aggregation-prone, form of VAPB (P56S) is linked to a dominantly inherited form of amyotrophic lateral sclerosis; however, it has been unclear whether its pathogenicity is due to toxic gain of function, to negative dominance, or simply to insufficient levels of the wild-type protein produced from a single allele (haploinsufficiency). To investigate whether reduced levels of functional VAPB, independently from the presence of the mutant form, affect the physiology of mammalian motoneuron-like cells, we generated NSC34 clones, from which VAPB was partially or nearly completely depleted. VAPA levels, determined to be over fourfold higher than those of VAPB in untransfected cells, were unaffected. Nonetheless, cells with even partially depleted VAPB showed an increase in Golgi- and acidic vesicle-localized phosphatidylinositol-4-phosphate (PI4P) and reduced neurite extension when induced to differentiate. Conversely, the PI4 kinase inhibitors PIK93 and IN-10 increased neurite elongation. Thus, for long-term survival, motoneurons might require the full dose of functional VAPB, which may have unique function(s) that VAPA cannot perform. Summary: VAPB downregulation delays neurite elongation and increases Golgi- and acidic vesicle-associated phosphatidylinositol-4-phosphate in motoneuron-like cells, suggesting novel mechanisms for VAPB-linked amyotrophic lateral sclerosis.
Confirmatory Factor Analysis of the Disablement in the Physically Active Scale and Preliminary Testing of Short-Form Versions: A Calibration and Validation Study.

CONTEXT The Disablement in the Physically Active (DPA) scale is a patient-reported outcome instrument recommended for use in clinical practice and research. Analysis of the scale has indicated a need for further psychometric testing. OBJECTIVE To assess the model fit of the original DPA scale using a larger and more diverse sample and explore the potential for a short-form (SF) version. DESIGN Observational study. SETTING Twenty-four clinical settings. PATIENTS OR OTHER PARTICIPANTS Responses were randomly split into 2 samples: sample 1 (n = 690: 353 males, 330 females, and 7 not reported; mean age = 23.1 ± 9.3 years, age range = 11-75 years) and sample 2 (n = 690: 351 males, 337 females, and 2 not reported; mean age = 22.9 ± 9.3 years, age range = 8-74 years). Participants were physically active individuals who were healthy or experiencing acute, subacute, or persistent musculoskeletal injury. MAIN OUTCOME MEASURE(S) Confirmatory factor analysis was conducted to assess the factor structure of the original DPA scale. Exploratory factor, internal consistency, covariance modeling, correlational, and confirmatory factor analyses were conducted to assess potential DPA scale SFs. RESULTS The subdimensions of the disablement construct were highly correlated (≥0.89). The fit indices for the DPA scale approached recommended levels, but the first-order correlational values and second-order path coefficients provided evidence for multicollinearity, suggesting that clear distinctions between the disablement subdimensions cannot be made. An 8-item, 2-dimensional solution and a 10-item, 3-dimensional solution were extracted to produce SF versions. The DPA SF-8 was highly correlated (r = 0.94, P ≤ .001, R2 = 0.88) with the DPA scale, and the fit indices exceeded all of the strictest recommendations. The DPA SF-10 was highly correlated (r = 0.97, P ≤ .001, R2 = 0.94) with the DPA scale, and its fit indices values also exceeded the strictest recommendations. CONCLUSIONS The DPA SF-8 and SF-10 are psychometrically sound alternatives to the DPA scale.
Long‐term fertilization regimes change soil nitrification potential by impacting active autotrophic ammonia oxidizers and nitrite oxidizers as assessed by DNA stable isotope probing

Chemoautotrophic ammonia-oxidizers and nitrite-oxidizers are responsible for a significant amount of soil nitrate production. The identity and composition of these active nitrifiers in soils under different long-term fertilization regimes remain largely under-investigated. Based on that soil nitrification potential significantly decreased in soils with chemical fertilization (CF) and increased in soils with organic fertilization (OF), a microcosm experiment with DNA stable isotope probing was further conducted to clarify the active nitrifiers. Both ammonia-oxidizing archaea (AOA) and bacteria (AOB) were found to actively respond to urea addition in soils with OF and no fertilizer (CK), whereas only AOB were detected in soils with CF. Around 98% of active AOB were Nitrosospira cluster 3a.1 in all tested soils, and more than 90% of active AOA were Nitrososphaera subcluster 1.1 in unfertilized and organically fertilized soils. Nitrite oxidation was performed only by Nitrospira-like bacteria in all soils. The relative abundances of Nitrospira lineage I and VI were 32% and 61%, respectively, in unfertilized soils, and that of Nitrospira lineage II was 97% in fertilized soils, indicating long-term fertilization shifted the composition of active Nitrospira-like bacteria in response to urea. This finding indicates that different fertilizer regimes impact the composition of active nitrifiers, thus, impacting soil nitrification potential.
Promising Anti-Hepatitis C Virus Compounds from Natural Resources

Hepatitis C virus (HCV) infection is a major worldwide problem, which involves approximately 170 million people. High morbidity of patients is caused by chronic infection, which leads to liver cirrhosis, hepatocellular carcinoma and other HCV-related diseases. The sustained virological response (SVR) has been markedly improved to be >90% by the current standard interferon (IFN)-free treatment regimens with a combination of direct-acting antiviral agents (DAAs) targeting the viral NS3 protease, NS5A multi-function protein and NS5B RNA-dependent RNA polymerase, compared with 50–70% of SVR rates achieved by the previous standard IFN-based treatment regimens with or without an NS3 protease inhibitor. However, the emergence of DAA-resistant HCV strains and the limited access to the DAAs due to their high cost could be major concerns. Also, the long-term prognosis of patients treated with DAAs, such as the possible development of hepatocellular carcinoma, still needs to be further evaluated. Natural resources are considered to be good candidates to develop anti-HCV agents. Here, we summarize anti-HCV compounds obtained from natural resources, including medicinal plant extracts, their isolated compounds and some of their derivatives that possess high antiviral potency against HCV.
Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition

Heart failure affects ≈5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, &bgr;-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the US Food and Drug Administration approved the first of a new class of drugs for the treatment of heart failure: Valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses 2 of the pathophysiological mechanisms of heart failure: activation of the renin-angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared with enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacological properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension.
Analysis of ubiquitin recognition by the HECT ligase E6AP provides insight into its linkage specificity

Deregulation of the HECT-type ubiquitin ligase E6AP (UBE3A) is implicated in human papilloma virus-induced cervical tumorigenesis and several neurodevelopmental disorders. Yet the structural underpinnings of activity and specificity in this crucial ligase are incompletely understood. Here, we unravel the determinants of ubiquitin recognition by the catalytic domain of E6AP and assign them to particular steps in the catalytic cycle. We identify a functionally critical interface that is specifically required during the initial formation of a thioester-linked intermediate between the C terminus of ubiquitin and the ligase-active site. This interface resembles the one utilized by NEDD4-type enzymes, indicating that it is widely conserved across HECT ligases, independent of their linkage specificities. Moreover, we uncover surface regions in ubiquitin and E6AP, both in the N- and C-terminal portions of the catalytic domain, that are important for the subsequent reaction step of isopeptide bond formation between two ubiquitin molecules. We decipher key elements of linkage specificity, including the C-terminal tail of E6AP and a hydrophilic surface region of ubiquitin in proximity to the acceptor site Lys-48. Intriguingly, mutation of Glu-51, a single residue within this region, permits formation of alternative chain types, thus pointing to a key role of ubiquitin in conferring linkage specificity to E6AP. We speculate that substrate-assisted catalysis, as described previously for certain RING-associated ubiquitin–conjugating enzymes, constitutes a common principle during linkage-specific ubiquitin chain assembly by diverse classes of ubiquitination enzymes, including HECT ligases.
Obesity and Body Fat Distribution: Ethnic Differences and the Role of Socio-Economic Status

Objective: This study investigates differences in overweight and body fat distribution between Turkish and Moroccan migrants and the ethnic Dutch population, and the contribution of socio-economic status to their higher obesity prevalence. Methods: Data were collected as part of a general health survey, in Amsterdam, the Netherlands (2004). From 1,285 adults information on physical and psychological health, lifestyle and demographic background was obtained through health interviews. In a physical examination body height and weight as well as waist and hip circumference were measured. Results: Overweight was more common among Turkish migrants and Moroccan migrant women as compared to their Dutch counterparts. Obesity prevalence rates were more than twice as high among Turkish (39.6%) and Moroccan (39.1%) women than among Dutch women (16.5%). Controlling for level of education and unemployment attenuated ethnic differences in overweight. Abdominal obesity was more common among Turkish and Moroccan than among Dutch women. After controlling for BMI, migrant men had a relatively low waist circumference compared to Dutch men. Conclusion: Overweight is relatively common among Turkish and Moroccan migrants, especially women. Education and employment are relevant in explaining ethnic differences in overweight. Compared to Dutch men, migrant men seem to have a more favourable fat distribution with less abdominal fat.
The lesser anteater (Tamandua tetradactyla) is not tetradactyla, but pentadactyla

The name of the species tetradactyla means “four digits. ” In the literature, the hand of the lesser anteater (Tamandua tetradactyla) is described as having four digits (I, II, III and IV) with the absence of a fifth digit. The purpose of this study was to carry out an update adequately proposing an anatomical description of the T. tetradactyla hand. The present findings were analysed on the validation of Morse’s law for this species. In total, seven male cadavers were radiographed and dissected. We observed that the hand of the T. tetradactyla was formed by a carpus containing four bones in the proximal row, which in the medium lateral direction was the radial, intermediate, ulnar and accessory bones of the carpus, and the distal row was formed by carpal bones I, II, III and IV. There were five metacarpal bones (I, II, III, IV and V). The presence of five digits was verified but not confirmed with the literature. Digit I had two phalanges, the proximal and distal; digits II, III and IV had three phalanges: proximal, middle and distal. Digit five had only one phalanx, the proximal, but it was not externally visible. According to the findings of this study, the presence of the fifth digit raises the question of whether the term tetradactyla is the most appropriate to describe this species. This rudimentary fifth digit and the presence of a functional first digit show that the Morse’s law does not applies for the T. tetradactyla species.