Miracle-dz/UniFAR-FTUs huggingface dataset:
Modeling Prevention of Malaria and Selection of Drug Resistance with Different Dosing Schedules of Dihydroartemisinin-Piperaquine Preventive Therapy during Pregnancy in Uganda

Dihydroartemisinin-piperaquine (DHA-PQ) is under study for intermittent preventive treatment during pregnancy (IPTp), but it may accelerate selection for drug resistance. Understanding the relationships between piperaquine concentration, prevention of parasitemia, and selection for decreased drug sensitivity can inform control policies and optimization of DHA-PQ dosing. ABSTRACT Dihydroartemisinin-piperaquine (DHA-PQ) is under study for intermittent preventive treatment during pregnancy (IPTp), but it may accelerate selection for drug resistance. Understanding the relationships between piperaquine concentration, prevention of parasitemia, and selection for decreased drug sensitivity can inform control policies and optimization of DHA-PQ dosing. Piperaquine concentrations, measures of parasitemia, and Plasmodium falciparum genotypes associated with decreased aminoquinoline sensitivity in Africa (pfmdr1 86Y, pfcrt 76T) were obtained from pregnant Ugandan women randomized to IPTp with sulfadoxine-pyrimethamine (SP) or DHA-PQ. Joint pharmacokinetic/pharmacodynamic models described relationships between piperaquine concentration and the probability of genotypes of interest using nonlinear mixed effects modeling. An increase in the piperaquine plasma concentration was associated with a log-linear decrease in risk of parasitemia. Our models predicted that higher median piperaquine concentrations would be required to provide 99% protection against mutant infections than against wild-type infections (pfmdr1: N86, 9.6 ng/ml; 86Y, 19.6 ng/ml; pfcrt: K76, 6.5 ng/ml; 76T, 19.6 ng/ml). Comparing monthly, weekly, and daily dosing, daily low-dose DHA-PQ was predicted to result in the fewest infections and the fewest mutant infections per 1,000 pregnancies (predicted mutant infections for pfmdr1 86Y: SP monthly, 607; DHA-PQ monthly, 198; DHA-PQ daily, 1; for pfcrt 76T: SP monthly, 1,564; DHA-PQ monthly, 283; DHA-PQ daily, 1). Our models predict that higher piperaquine concentrations are needed to prevent infections with the pfmdr1/pfcrt mutant compared to those with wild-type parasites and that, despite selection for mutants by DHA-PQ, the overall burden of mutant infections is lower for IPTp with DHA-PQ than for IPTp with SP. (This study has been registered at ClinicalTrials.gov under identifier NCT02282293.)
Increased Risk of Malaria During the First Year of Life in Small-for-Gestational-Age Infants: A Longitudinal Study in Benin

BACKGROUND According to the Developmental Origins of Health and Diseases paradigm, the fetal period is highly vulnerable and may have profound effects on later health. Few studies assessed the effect of small-for-gestational age (SGA), a proxy for fetal growth impairment, on risk of malaria during infancy in Africa. METHODS We used data from a cohort of 398 mother-child pairs, followed from early pregnancy to age 1 year in Benin. Malaria was actively and passively screened using thick blood smear. We assessed the effect of SGA on risk of malaria infection and clinical malaria from birth to 12 months, after stratifying on the infant's age using a logistic mixed regression model. RESULTS After adjustment for potential confounding factors and infant's exposure to mosquitoes, SGA was associated with a 2-times higher risk of malaria infection (adjusted odds ratio [aOR] = 2.16; 95% confidence interval [CI], 1.04-4.51; P = .039) and clinical malaria (aOR = 2.33; 95% CI, 1.09-4.98; P = .030) after age 6 months. CONCLUSION Results suggest higher risk of malaria during the second semester of life in SGA infants, and argue for better follow-up of these infants after birth, as currently for preterm babies.
IRS-1 increases TAZ expression and promotes osteogenic differentiation in rat bone marrow mesenchymal stem cells

ABSTRACT Whether insulin receptor substrate 1 (IRS-1) inhibits or promotes the osteogenic proliferation and differentiation in vitro remains controversial. Transcriptional co-activator with PDZ-binding motif (TAZ) plays a vital role in the osteogenesis of bone marrow mesenchymal stem cells (BMSCs), and strongly activates the expression of the osteogenic differentiation markers. In this study, we found that IRS-1 and TAZ followed similar increasing expression patterns at the early stage of osteogenic differentiation. Knocking down IRS-1 decreased the TAZ, RUNX2 and OCN expression, and overexpressing IRS induced the upregulation of the TAZ, RUNX2 and OCN expression. Furthermore, our results showed that it was LY294002 (the PI3K-Akt inhibitor), other than UO126 (the MEK-ERK inhibitor), that inhibited the IRS-1 induced upregulation of TAZ expression. Additionally, SiTAZ blocked the cell proliferation in G1 during the osteogenic differentiation of BMSCs. Taken together, we provided evidence to demonstrate that IRS-1 gene modification facilitates the osteogenic differentiation of rat BMSCs by increasing TAZ expression through the PI3K-Akt signaling pathway. This article has an associated First Person interview with the first author of the paper. Summary: Stem cell therapy has become a promising approach for bone tissue engineering. Our study reveals that IRS-1 gene modification of stem cells upregulates TAZ expression and osteogenesis.
Deep Learning in Cardiology

The medical field is creating large amount of data that physicians are unable to decipher and use efficiently. Moreover, rule-based expert systems are inefficient in solving complicated medical tasks or for creating insights using big data. Deep learning has emerged as a more accurate and effective technology in a wide range of medical problems such as diagnosis, prediction, and intervention. Deep learning is a representation learning method that consists of layers that transform data nonlinearly, thus, revealing hierarchical relationships and structures. In this review, we survey deep learning application papers that use structured data, and signal and imaging modalities from cardiology. We discuss the advantages and limitations of applying deep learning in cardiology that also apply in medicine in general, while proposing certain directions as the most viable for clinical use.
Trends and state variations in out-of-hospital births in the United States, 2004-2017.

BACKGROUND Out-of-hospital births have been increasing in the United States, although past studies have found wide variations between states. Our purpose was to examine trends in out-of-hospital births, the risk profile of these births, and state differences in women's access to these births. METHODS National birth certificate data from 2004 to 2017 were analyzed. Newly available national data on method of payment for the delivery (private insurance, Medicaid, self-pay) were used to measure access to out-of-hospital birth options. RESULTS After a gradual decline from 1990 to 2004, the number of out-of-hospital births increased from 35 578 in 2004 to 62 228 in 2017. In 2017, 1 of every 62 births in the United States was an out-of-hospital birth (1.61%). Home births increased by 77% from 2004 to 2017, whereas birth center births more than doubled. Out-of-hospital births were more common in the Pacific Northwest and less common in the southeastern states such as Alabama, Louisiana, and Mississippi. Women with planned home and birth center births were less likely to have a number of population characteristics associated with poor pregnancy outcomes, including teen births, smoking during pregnancy, obesity, and preterm, low birthweight, and multiple births. More than 2/3 of planned home births were self-paid, compared with 1/3 of birth center and just 3% of hospital births, with large variations by state. CONCLUSIONS Lack of insurance or Medicaid coverage is an important limiting factor for women desiring out-of-hospital birth in most states. Recent increases in out-of-hospital births despite important limiting factors highlight the strong motivation of some women to choose out-of-hospital birth.
Phenotypes in acute respiratory distress syndrome: moving towards precision medicine

Purpose of review To provide an overview of the current research in identifying homogeneous subgroups and phenotypes in ARDS. Recent findings In recent years, investigations have used either physiology, clinical data, biomarkers or a combination of these to stratify patients with ARDS into distinct subgroups with divergent clinical outcomes. In some studies, there has also been evidence of differential treatment response within subgroups. Physiologic approaches include stratification based on P/F ratio and ventilatory parameters; stratification based on P/F ratio is already being employed in clinical trials. Clinical approaches include stratification based on ARDS risk factor or direct vs. indirect ARDS. Combined clinical and biological data has been used to identify two phenotypes across five cohorts of ARDS, termed hyperinflammatory and hypoinflammatory. These phenotypes have widely divergent clinical outcomes and differential response to mechanical ventilation, fluid therapy, and simvastatin in secondary analysis of completed trials. Next steps in the field include prospective validation of inflammatory phenotypes and integration of high-dimensional ‘omics’ data into our understanding of ARDS heterogeneity. Summary Identification of distinct subgroups or phenotypes in ARDS may impact future conduct of clinical trials and can enhance our understanding of the disorder, with potential future clinical implications.
The evolutionary relationship among beak shape, mechanical advantage, and feeding ecology in modern birds *

Extensive research on avian adaptive radiations has led to a presumption that beak morphology predicts feeding ecology in birds. However, this ecomorphological relationship has only been quantified in a handful of avian lineages, where associations are of variable strength, and never at a broad macroevolutionary scale. Here, we used shape analysis and phylogenetic comparative methods to quantify the relationships among beak shape, mechanical advantage, and two measures of feeding ecology (feeding behavior and semiquantitative dietary preferences) in a broad sample of modern birds, comprising most living orders. We found a complex relationship, with most variables showing a significant relationship with feeding ecology but little explanatory power. For example, diet accounts for less than 12% of beak shape variation. Similar beak shapes are associated with disparate dietary regimes, even when accounting for diet‐feeding behavior relationships and phylogeny. Very few lineages optimize for stronger bite forces, with most birds exhibiting relatively fast, weak bites, even in large predatory taxa. The extreme morphological and behavioral flexibility of the beak in birds suggests that, far from being an exemplary feeding adaptation, avian beak diversification may have been largely contingent on trade‐offs and constraints.
Rethink and Redesign Meta learning

Recently, meta-learning has shown as a promising way to improve the ability to learn from few-data for many computer vision tasks. However, existing meta-learning approaches still fall behind human greatly, and like many deep learning algorithms, they also suffer from overﬁtting. We named this problem as Task-Over-Fitting (TOF) problem 1 that the meta-learner over-ﬁts to the training tasks, not to the training data. We human beings can learn from few-data, mainly due to that we are so smart to leverage past knowledge to understand the images of new categories rapidly. Furthermore, be beneﬁting from our ﬂexible attention mechanism, we can accurately extract and select key features from images and further solve few-shot learning tasks with excellent performance. In this paper, we rethink the meta-learning algorithm and ﬁnd that existing meta-learning approaches miss considering attention mechanism and past knowledge. To this end, we present a novel paradigm of meta-learning approach with three developments to introduce attention mechanism and past knowledge step by step. In this way, we can narrow the problem space and improve the performance of meta-learning, and the TOF problem can also be signiﬁcantly reduced. Extensive experiments demonstrate the effectiveness of our des-ignation and methods with state-of-the-art performance not only on several few-shot learning benchmarks but also on the Cross-Entropy across Tasks (CET) metric 2
Study on endocrine disruptors levels in raw milk from cow’s farms: Risk assessment

Diet represents the primary route for human exposure to bisphenol A (BPA). As endocrine disruptor (ED), BPA has raised concerns about its adverse effects on human health. Therefore, EFSA recommended a tolerable daily intake (t-TDI) of 4 μg/kg bw/day and the EU Regulation n. 2018/213 fixed a specific migration limit (SML) of 0.05 mg/kg for BPA in food from plastic materials intended to come in contact with food. BPA could be present in milk due to environmental contamination, and also as a result of the migration from contact materials used during milking and storage. Considering the widespread consumption of milk and milk products, the contamination of dairy products is a matter of public health concern. The aim of the study was to investigate the BPA contamination levels of raw cow’s milk from two farms located in Campania region, Italy. The milk samples (n=22), weekly collected from the cooling tank, were analyzed using liquid chromatography with fluorescence detection. In raw milk from both farms, preliminary results showed the occurrence of BPA levels lower than the SML limit, ranging from not detected to 2.34 μg/L. The consumer exposure, calculated considering a hypothetical raw milk consumption and three possible scenarios, was below the t-TDI. Despite the low levels of exposure through milk consumption, low doses can have lasting effects during human development. Thus, new approaches, methods, and plans should be applied to monitor ED contamination, such as BPA and other pollutants, and to assure milk safety.
Similar polyethylene wear between cemented and cementless Oxford medial UKA: a 5-year follow-up randomized controlled trial on 79 patients using radiostereometry

Background and purpose — Hydroxyapatite (HA)-coated implants have been associated with high polyethylene wear in hip arthroplasties. HA coating as a promoter of wear in knee arthroplasties has not been investigated. We compared the wear-rate of the polyethylene bearing for cemented and cementless HA-coated Oxford medial unicondylar knee arthroplasties (UKA). Secondarily, we investigated whether wear-rates were influenced by overhang or impingement of the bearing. Patients and methods — 80 patients (mean age 64 years), treatment-blinded, were randomized to 1 of 3 Oxford medial UKA versions: cemented with double-pegged or single-pegged femoral component or cementless HA-coated with double-pegged femoral component (ratios 1:1:1). We compared wear between the cemented (n = 55) and cementless group (n = 25) (ratio 2:1). Wear, impingement, and overhang were quantified between surgery and 5-year follow-up using radiostereometry. Clinical outcome was evaluated with the Oxford Knee Score. Results — The mean wear-rate for patients without bearing overhang was 0.04 mm/year (95% CI 0.02–0.07) for the cemented group and 0.05 mm/year (CI 0.02–0.08) for the cementless group. The mean difference in wear was 0.008 mm/year (CI –0.04 to 0.03). No impingement was identified. Half of the patients had medial bearing overhang, mean 2.5 mm (1–5). Wear increased by 0.014 mm/year for each mm increment in overhang. The mean Oxford Knee Score was 39 for the cementless group and 38 for the cemented group at the 5-year follow-up. Interpretation — The wear-rates were similar for the 2 fixation methods, which supports further use of the cementless Oxford medial UKA. However, a caveat is a relatively large 95% CI of the mean difference in wear-rate. Component size and position is important as half of the patients presented with an additional increase in wear-rate due to medial bearing overhang. Trial registration: ClinicalTrials.gov identifier: NCT00679120.
Elevated Temperature Does Not Substantially Modify the Interactive Effects Between Elevated CO2 and Diel CO2 Cycles on the Survival, Growth and Behavior of a Coral Reef Fish

Recent studies demonstrate that diel CO2 cycles, such as those prevalent in many shallow water habitats, can potentially modify the effects of ocean acidification conditions on marine organism. However, whether the interaction between elevated CO2 and diel CO2 cycles is further modified by elevated temperature is unknown. To test this, we reared juvenile spiny damselfish, Acanthochromis polyacanthus for 11 weeks in two stable (450 and 1000 µatm) and two diel- cycling elevated CO2 treatments (1000 ± 300 and 1000 ± 500 µatm) at both current-day (29°C) and projected future temperature (31°C). We measured the effects on survivorship, growth, behavioural lateralization, activity, boldness and escape performance (fast starts). A significant interaction between CO2 and temperature was only detected for survivorship. Survival was lower in the two cycling CO2 treatments at 31°C compared with 29°C but did not differ between temperatures in the two stable CO2 treatments. In other traits we observed independent effects of elevated CO2, and interactions between elevated CO2 and diel CO2 cycles, but these effects were not influenced by temperature. There was a trend towards decreased growth in fish reared under stable elevated CO2 that was counteracted by diel CO2 cycles, with fish reared under cycling CO2 being significantly larger than fish reared under stable elevated CO2. Diel CO2 cycles also mediated the negative effect of elevated CO2 on behavioural lateralization, as previously reported. Routine activity was reduced in the 1000 ± 500 μatm CO2 treatment compared to control fish. In contrast, neither boldness nor fast-starts were affected by any of the CO2 treatments. Elevated temperature had significant independent effects on growth, routine activity and fast start performance. Our results demonstrate that diel CO2 cycles can significantly modify the growth and behavioural responses of fish under elevated CO2 and that these effects are not altered by elevated temperature, at least in this species. Our findings add to a growing body of work that highlights the critical importance of incorporating natural CO2 variability in ocean In review 3 acidification experiments to more accurately assess the effects of ocean climate change on marine ecosystems.
Infection prevention in the operating room anesthesia work area

L. Silvia Munoz-Price MD, PhD, Andrew Bowdle MD, PhD, B. Lynn Johnston MD, Gonzalo Bearman MD, MPH, Bernard C. Camins MD, MSc, E. Patchen Dellinger MD, Marjorie A. Geisz-Everson PhD, CRNA, Galit Holzmann-Pazgal MD, Rekha Murthy MD, David Pegues MD, Richard C. Prielipp MD, MBA, FCCM, Zachary A. Rubin MD, Joshua Schaffzin MD, PhD, Deborah Yokoe MD, MPH and David J. Birnbach MD, MPH Froedtert & the Medical College of Wisconsin, Milwaukee, Wisconsin, University of Washington, Seattle, Washington, Dalhousie University, Halifax, Nova Scotia, Virginia Commonwealth University School of Medicine, Richmond, Virginia, University of Alabama at Birmingham, Birmingham, Alabama, University of Southern Mississippi, Hattiesburg, Mississippi, Baylor College of Medicine, Houston, Texas, Cedars-Sinai Medical Center, Los Angeles, California, University of Pennsylvania, Philadelphia, Pennsylvania, University of Minnesota, Minneapolis, Minnesota, David Geffen School of Medicine at UCLA, Los Angeles, California, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, University of California San Francisco School of Medicine, San Francisco, California and University of Miami Miller School of Medicine, Miami, Florida
Molecular basis for the acid-initiated uncoating of human enterovirus D68

Significance Enterovirus D68 (EV-D68) is an emerging pathogen that primarily causes childhood respiratory infections and is linked to neurological diseases. It was unclear how the virus uncoats and delivers its genome into a host cell to establish viral replication. Using high-resolution cryoelectron microscopy, we showed that acid induces structural rearrangements of EV-D68 to initiate genome release from the virus. Structural analyses delineated a viral uncoating pathway that involves multiple distinct conformational states. Particularly, the structure of a previously unknown uncoating intermediate enabled the identification of potential molecular determinants that facilitate EV-D68 uncoating. These results advance the knowledge of cell entry of EV-D68 and open up possibilities for developing antiviral therapeutics that impede structural rearrangements of the virus. Enterovirus D68 (EV-D68) belongs to a group of enteroviruses that contain a single positive-sense RNA genome surrounded by an icosahedral capsid. Like common cold viruses, EV-D68 mainly causes respiratory infections and is acid-labile. The molecular mechanism by which the acid-sensitive EV-D68 virions uncoat and deliver their genome into a host cell is unknown. Using cryoelectron microscopy (cryo-EM), we have determined the structures of the full native virion and an uncoating intermediate [the A (altered) particle] of EV-D68 at 2.2- and 2.7-Å resolution, respectively. These structures showed that acid treatment of EV-D68 leads to particle expansion, externalization of the viral protein VP1 N termini from the capsid interior, and formation of pores around the icosahedral twofold axes through which the viral RNA can exit. Moreover, because of the low stability of EV-D68, cryo-EM analyses of a mixed population of particles at neutral pH and following acid treatment demonstrated the involvement of multiple structural intermediates during virus uncoating. Among these, a previously undescribed state, the expanded 1 (“E1”) particle, shows a majority of internal regions (e.g., the VP1 N termini) to be ordered as in the full native virion. Thus, the E1 particle acts as an intermediate in the transition from full native virions to A particles. Together, the present work delineates the pathway of EV-D68 uncoating and provides the molecular basis for the acid lability of EV-D68 and of the related common cold viruses.
Metabolomic Analysis of Diet-Induced Obese Mice Supplemented with Eicosapentaenoic Acid

Abstract Eicosapentaenoic acid (EPA) is an omega-3 fatty acid with anti-inflammatory effects. To determine the effects of EPA on metabolic pathways in obese adipose tissues and liver, mice were fed normal chow diet (NCD), high-fat diet (HFD), or 3% EPA-containing high fat diet (HFD+EPA) for 8 weeks. Metabolomic analysis was performed using epididymal adipose tissues (epi WAT) and liver. Metabolites that were specifically elevated in HFD+EPA, were assessed for their anti-inflammatory properties using RAW264.7 macrophage cells. Body and adipose tissue weights were significantly higher in HFD than NCD, and lower in HFD+EPA than HFD. Plasma insulin levels were significantly higher in HFD than NCD, and lower in HFD+EPA compared with HFD. Plasma monocyte chemotactic protein-1 (MCP-1) levels were higher in HFD than NCD, and tended to be lower in HFD+EPA than HFD. The levels of intermediate metabolites in the glycolytic pathways were lower in HFD compared with NCD and HFD+EPA in both epi WAT and liver, while intermediate metabolites of the TCA cycles were elevated in HFD and HFD+EPA compared with NCD in epi WAT. Among the metabolites in epi WAT, the levels of thiaproline, phenaceturic acid, and pipecolic acid were specifically elevated in HFD+EPA, but not in HFD or NCD. Treatment of RAW264.7 cells with thiaproline significantly ameliorated LPS-induced iNOS expression, while pipecolic acid inhibited LPS-induced IL-1β expression. These results suggest that EPA normalizes glycolytic pathway intermediates in both epi WAT and liver, and induces metabolites with anti-inflammatory properties.