Miracle-dz/UniFAR-FTUs huggingface dataset:
Real-world implementation of diabetes management by pharmacists: The RXING Practice Tool

Introduction The incidence and prevalence of diabetes are increasing in Canada. Currently, one-third of the Canadian population is living with diabetes or prediabetes. Moreover, Canadian adults are now at 50% risk of developing diabetes during their lifetime. Despite its serious complications and the advancement in diabetes care, optimal community-based care for patients with diabetes remains elusive. Indeed, it has been reported that only 13% of the Canadian community-dwelling patients met the triple target of glycemic control, lipids and blood pressure. Furthermore, Al Hamarneh and colleagues found that around half of community-dwelling patients with diabetes are not achieving their glycemic control target. Such sobering statistics indicate the need for new and innovative ways to tackle one of Canada’s largest public health issues. Pharmacists are highly accessible primary care professionals who see patients with diabetes frequently and have strong interest in diabetes management. Their interventions in patients with diabetes are well supported by high-level evidence in the literature. In fact, in their systematic review, Wubben and Vivian reported great improvement when a pharmacist provides direct care to patients with diabetes. More recently, our group published the RxING and the RxEACH studies, where we reported large reduction in A1C (between 0.9% and 1.8%) in a short period of time (3-6 months) with independent pharmacist prescribing interventions. While there is strong evidence for the impact of pharmacist care in diabetes, implementation of this evidence is lacking. Perhaps practical implementation tools are needed. As such, we designed this registry to evaluate the impact of an implementation strategy (an online practice tool) for pharmacists (based upon the RxING study ) on estimated cardiovascular (CV) risk in patients with diabetes.
American College of Rheumatology, American Academy of Dermatology, Rheumatologic Dermatology Society, and American Academy of Ophthalmology 2020 Joint Statement on Hydroxychloroquine Use With Respect to Retinal Toxicity

Four major medical societies involved with hydroxychloroquine (HCQ) therapy concur on the need for common principles and cooperation to minimize the risk of ocular toxicity. At a daily dosage of ≤5 mg/kg/day actual body weight, the risk of retinal toxicity from HCQ is <2% for usage up to 10 years. Widespread adoption of more sensitive testing techniques, such as optical coherence tomography and automated visual fields, by eye care providers will allow the detection of early toxicity and thus preserve the patient’s visual function. Baseline testing is advised to rule out confounding disease when a patient is started on HCQ. Annual screening with sensitive tests should begin no more than 5 years after treatment initiation. Providers should be sensitive to the medical value of HCQ, and not stop the drug for uncertain indications. It is important to note that effective communication among prescribing physicians, patients, and eye care providers will optimize the utility and safety of HCQ.
On the Applicability of Machine Learning Fairness Notions

Machine Learning (ML) based predictive systems are increasingly used to support decisions with a critical impact on individuals' lives such as college admission, job hiring, child custody, criminal risk assessment, etc. As a result, fairness emerged as an important requirement to guarantee that ML predictive systems do not discriminate against specific individuals or entire sub-populations, in particular, minorities. Given the inherent subjectivity of viewing the concept of fairness, several notions of fairness have been introduced in the literature. This paper is a survey of fairness notions that, unlike other surveys in the literature, addresses the question of "which notion of fairness is most suited to a given real-world scenario and why? ". Our attempt to answer this question consists in (1) identifying the set of fairness-related characteristics of the real-world scenario at hand, (2) analyzing the behavior of each fairness notion, and then (3) fitting these two elements to recommend the most suitable fairness notion in every specific setup. The results are summarized in a decision diagram that can be used by practitioners and policy makers to navigate the relatively large catalogue of ML fairness notions.
The type 3 secretion system requires actin polymerization to open translocon pores

Many bacterial pathogens require a type 3 secretion system (T3SS) to establish a niche. Host contact activates bacterial T3SS assembly of a translocon pore in the host plasma membrane. Following pore formation, the T3SS docks onto the translocon pore. Docking establishes a continuous passage that enables the translocation of virulence proteins, effectors, into the host cytosol. Here we investigate the contribution of actin polymerization to T3SS-mediated translocation. Using the T3SS model organism Shigella flexneri, we show that actin polymerization is required for assembling the translocon pore in an open conformation, thereby enabling effector translocation. Opening of the pore channel is associated with a conformational change to the pore, which is dependent upon actin polymerization and a coiled-coil domain in the pore protein IpaC. An IpaC mutant is identified that shows actin polymerization-dependent pore opening is distinct from the previously described actin polymerization-dependent ruffles that are required for bacterial internalization. Moreover, actin polymerization is not required for other pore functions, including docking or pore protein insertion into the plasma membrane. Thus, activation of the T3SS is a multilayered process in which host signals are sensed by the translocon pore leading to the activation of effector translocation. Significance Statement The type 3 secretion system (T3SS) is required for the virulence of a variety of bacteria that infect humans. The T3SS forms in the host cell membrane a pore that is the conduit for delivering virulence proteins into the cell. Here, we demonstrate that actin polymerization is necessary to convert pores into an open conformation that is competent for virulence protein delivery. We find that activation of type 3 secretion proceeds in a multistep process whereby bacteria dock onto the translocon pore and then activate secretion and delivery of virulence proteins.
Spatial Variability of Soil Physical Properties Affecting Florida Citrus Production

Spatial variability of citrus yield is very common in Florida, but very little has been done to identify the responsible soil factors. Our objective was to characterize variations in soil physical properties in sandy soils where citrus is produced in Florida. A citrus grove was divided into five productivity zones defined as "very poor," "poor," "medium," "good," and "very good" based on tree canopy volume. Six random soil samples were collected from each zone at depths of 0 to 15, 15 to 30, 30 to 45, and 45 to 60 cm. Samples were analyzed for soil color, particle size and sand size distribution, and water retention parameters. Although the coefficients of variation (1%-60%) were large for color, texture, and water retention, the values were generally higher in areas with large trees and vice versa. The trend was opposite for soil lightness and sand content, which were lower in areas of greater growth. Most of the soil properties had a large spatial variation with semivariogram range of 100 to 250 m and varied greatly with increased productivity. Differences between the productivity zones were even more prominent at greater soil depth. Characterization and quantification of spatial soil variability in citrus groves would assist in planning future soil sampling in new fields showing soil and/or tree growth variability. The selection of soil sampling sites should be based on the sampling interval suggested by the variogram range (<75 m) and include the depth (45-60 cm) influencing productivity.
Actin Dynamics as a Multiscale Integrator of Cellular Guidance Cues

Cells are able to integrate multiple, and potentially competing, cues to determine a migration direction. For instance, in wound healing, cells follow chemical signals or electric fields to reach the wound edge, regardless of any local guidance cues. To investigate this integration of guidance cues, we monitor the actin-polymerization dynamics of immune cells in response to cues on a subcellular scale (nanotopography) and on the cellular scale (electric fields, EFs). In the fast, amoeboid-type migration, commonly observed in immune cells, actin polymerization at the cell’s leading edge is the driver of motion. The excitable systems character of actin polymerization leads to self-propagating, two-dimensional wavefronts that enable persistent cell motion. We show that EFs guide these wavefronts, leading to turning of cells when the direction of the EF changes. When nanoridges promote one-dimensional (1D) waves of actin polymerization that move along the ridges (esotaxis), EF guidance along that direction is amplified. 1D actin waves cannot turn or change direction, so cells respond to a change in EF direction by generating new 1D actin waves. At the cellular scale, the emergent response is a turning of the cell. For nanoridges perpendicular to the direction of the EF, the 1D actin waves are guided by the nanotopography, but both the average location of new actin waves and the whole cell motion are guided by the EF. Thus, actin waves respond to each cue on its intrinsic length scale, allowing cells to exhibit versatile responses to the physical microenvironment. Significance Statement Effective cell migration requires the integration of multiple, and sometimes competing, guidance cues. For instance, in wound healing, immune cells are guided towards a wound edge by long-range electrical and chemical cues that may conflict with guidance cues from the local environment. How cells combine and respond to such cues is not well understood. We demonstrate that multiple guidance mechanisms can act simultaneously, but on different scales. Nanotopography, a local mechanical cue, guides individual waves of actin polymerization, thereby biasing the direction cell motion on the time scale of these waves. An external electric field applied at the same time biases the locations of new waves of actin polymerization, leading to overall directed migration over long distance scales.
Effective interferon (IFN)-λ treatment regimen to control lethal MERS-CoV infection in mice

Effective broad-spectrum antivirals are critical to prevent and control emerging human coronavirus (hCoV) infections. Despite considerable progress made towards identifying and evaluating several synthetic broad-spectrum antivirals against hCoV infections, a narrow therapeutic window has limited their success. Enhancing the endogenous interferon (IFN) and interferon-stimulated gene (ISG) response is another antiviral strategy known for decades. However, the side effects of pegylated type-I IFNs (IFN-Is) and the pro-inflammatory response detected after delayed IFN-I therapy have discouraged their clinical use. In contrast to IFN-Is, IFN-λ, a dominant IFN at the epithelial surface, is shown to be less pro-inflammatory. Consequently, we evaluated the prophylactic and therapeutic efficacy of IFN-λ in hCoV infected airway epithelial cells and mice. Human primary airway epithelial cells treated with a single dose of IFN-I (IFN-α) and IFN-λ showed similar ISG expression, whereas cells treated with two doses of IFN-λ expressed elevated levels of ISG compared to IFN-a treated cells. Similarly, mice treated with two dose IFN-λ were better protected compared to mice receiving a single dose, and a combination of prophylactic and delayed therapeutic regimens completely protected mice from lethal MERS-CoV-infection. A two dose IFN-λ regimen significantly reduced lung viral RNA and inflammatory cytokine levels with marked improvement in lung inflammation. Collectively, we identify an ideal regimen for IFN-λ use and demonstrate the protective efficacy of IFN-λ in MERS-CoV infected mice.
Reduced sensitivity of infectious SARS-CoV-2 variant B.1.617.2 to monoclonal antibodies and sera from convalescent and vaccinated individuals

The SARS-CoV-2 B.1. 617 lineage emerged in October 2020 in India1–6. It has since then become dominant in some indian regions and further spread to many countries. The lineage includes three main subtypes (B1.617.1, B.1617.2 and B.1.617.3), which harbour diverse Spike mutations in the N-terminal domain (NTD) and the receptor binding domain (RBD) which may increase their immune evasion potential. B.1. 617.2 is believed to spread faster than the other versions. Here, we isolated infectious B.1. 617.2 from a traveller returning from India. We examined its sensitivity to monoclonal antibodies (mAbs) and to antibodies present in sera from COVID-19 convalescent individuals or vaccine recipients, in comparison to other viral lineages. B.1. 617.2 was resistant to neutralization by some anti-NTD and anti-RBD mAbs, including Bamlanivimab, which were impaired in binding to the B.1. 617.2 Spike. Sera from convalescent patients collected up to 12 months post symptoms and from Pfizer Comirnaty vaccine recipients were 3 to 6 fold less potent against B.1. 617.2, relative to B.1. 1.7. Sera from individuals having received one dose of AstraZeneca Vaxzevria barely inhibited B.1. 617.2. Thus, B.1. 617.2 spread is associated with an escape to antibodies targeting non-RBD and RBD Spike epitopes.
The P5-ATPase ATP13A1 modulates MR1-mediated antigen presentation

The monomorphic antigen presenting molecule MHC-I-related protein 1 (MR1) presents small molecule metabolites to mucosal-associated invariant T (MAIT) cells. The MR1-MAIT cell axis has been implicated in a variety of infectious and non-communicable diseases and recent studies have begun to develop an understanding of the molecular mechanisms underlying this specialised antigen presentation pathway. Yet, the proteins regulating MR1 folding, loading, stability, and surface expression remain to be identified. Here, we performed a gene trap screen to discover novel modulators of MR1 surface expression through insertional mutagenesis of an MR1-overexpressing clone derived from the near-haploid human cell line HAP1 (HAP1.MR1). The most significant positive regulators identified included β2-microglobulin, a known regulator of MR1 surface expression, and ATP13A1, a P5-ATPase in the endoplasmic reticulum (ER) with putative transporter function not previously associated with MR1-mediated antigen presentation. CRISPR/Cas9-mediated knock-out of ATP13A1 in both HAP1.MR1 and THP-1 cell lines revealed a profound reduction in MR1 protein levels and a concomitant functional defect specific to MR1-mediated antigen presentation. Collectively, these data are consistent with the ER-resident ATP13A1 as a key post-transcriptional determinant of MR1 surface expression.
The 3-phosphoinositide–dependent protein kinase 1 is an essential upstream activator of protein kinase A in malaria parasites

Cyclic AMP (cAMP) signalling is crucial for the propagation of asexual malaria blood stage parasites. Recent work on Plasmodium falciparum demonstrated that phosphorylation of the invasion ligand AMA1 by the catalytic subunit of cAMP-dependent protein kinase A (PfPKAc) is an essential step during parasite invasion into red blood cells. However, the exact mechanisms regulating PfPKAc activity are only partially understood and PfPKAc function has not been extensively studied in gametocytes, the sexual blood stage forms that are essential for malaria transmission. By studying a conditional PfPKAc knockdown mutant, we confirm the essential role for PfPKAc in erythrocyte invasion and demonstrate that PfPKAc is involved in regulating gametocyte deformability. Interestingly, we observed that the conditional overexpression of PfPKAc also caused a profound lethal phenotype by preventing intra-erythrocytic parasite multiplication. Whole genome sequencing of parasites selected to tolerate increased PfPKAc expression levels identified missense mutations exclusively in the gene encoding the putative parasite orthologue of 3-phosphoinositide-dependent protein kinase-1 (PfPDK1). Using targeted mutagenesis, we show that PfPDK1 is essential for PfPKAc activation, most likely by phosphorylating T189 in the PfPKAc activation loop. In summary, our results corroborate the importance of tight regulation of PfPKA signalling for parasite survival and identify PfPDK1 as a crucial upstream regulator in this pathway and potential new drug target.
Polyelectrolyte Coating of Ferumoxytol Differentially Impacts the Labeling of Inflammatory and Steady-State Dendritic Cell Subtypes

Engineered magnetic nanoparticles (MNPs) are emerging as advanced tools for medical applications. The coating of MNPs using polyelectrolytes (PEs) is a versatile means to tailor MNP properties and is used to optimize MNP functionality. Dendritic cells (DCs) are critical regulators of adaptive immune responses. Functional distinct DC subsets exist either under steady-state or inflammatory conditions, which are explored for the specific treatment of various diseases, such as cancer, autoimmunity or transplant rejection. Here, the impact of PE coating of ferumoxytol for uptake into both inflammatory and steady-state DCs and cellular responses to the MNP labeling is addressed. Labeling efficiency by uncoated and PE-coated ferumoxytol is highly variable in different DC subsets, and PE coating significantly improves the labeling of steady-state DCs. Uncoated ferumoxytol results in increased cytotoxicity of steady-state DCs after labeling that is abolished by the PE coating, while no increased cell death is observed in inflammatory DCs. Furthermore, uncoated and PE-coated ferumoxytol appears immunologically inert in inflammatory DCs but induces activation of steady-state DCs. These results show that PE coating of MNPs can be applied to endow particles with desired properties for enhanced uptake and cell type-specific responses in distinct target DC populations.
DeepNull: Modeling non-linear covariate effects improves phenotype prediction and association power

Genome-wide association studies (GWAS) examine the association between genotype and phenotype while adjusting for a set of covariates. Although the covariates may have non-linear or interactive effects, due to the challenge of specifying the model, GWAS often neglect such terms. Here we introduce DeepNull, a method that identifies and adjusts for non-linear and interactive covariate effects using a deep neural network. In analyses of simulated and real data, we demonstrate that DeepNull maintains tight control of the type I error while increasing statistical power by up to 20% in the presence of non-linear and interactive effects. Moreover, in the absence of such effects, DeepNull incurs no loss of power. When applied to 10 phenotypes from the UK Biobank (n=370K), DeepNull discovered more hits (+6%) and loci (+7%), on average, than conventional association analyses, many of which are biologically plausible or have previously been reported. Finally, DeepNull improves upon linear modeling for phenotypic prediction (+23% on average).
Population Genomics of Wall Lizards Reflects the Dynamic History of the Mediterranean Basin

The Mediterranean Basin has experienced extensive change in geology and climate over the past six million years. Yet, the relative importance of key geological events for the distribution and genetic structure of the Mediterranean fauna remains poorly understood. Here, we use population genomic and phylogenomic analyses to establish the evolutionary history and genetic structure of common wall lizards (Podarcis muralis). This species is particularly informative because, in contrast to other Mediterranean lizards, it is widespread across the Iberian, Italian, and Balkan peninsulas, and in extra-Mediterranean regions. We found strong support for six major lineages within P. muralis, which were largely discordant with the phylogenetic relationship of mitochondrial DNA. The most recent common ancestor of extant P. muralis was likely distributed in the Italian Peninsula, and experienced an “Out-of-Italy” expansion following the Messinian salinity crisis (~5 Mya), resulting in the differentiation into the extant lineages on the Iberian, Italian and Balkan peninsulas. Introgression analysis revealed that both inter- and intraspecific gene flow have been pervasive throughout the evolutionary history of P. muralis. For example, the Southern Italy lineage has a hybrid origin, formed through admixture between the Central Italy lineage and an ancient lineage that was the sister to all other P. muralis. More recent genetic differentiation is associated with the onset of the Quaternary glaciations, which influenced population dynamics and genetic diversity of contemporary lineages. These results demonstrate the pervasive role of Mediterranean geology and climate for the evolutionary history and population genetic structure of extant species.
Plasmodium falciparum and Helminth Coinfections Increase IgE and Parasite-Specific IgG Responses

Coinfection with Plasmodium falciparum and helminths may impact the immune response to these parasites because they induce different immune profiles. We compared the antibody profile between groups of Mozambican individuals defined by P. falciparum and helminth previous exposure and/or current infection. ABSTRACT Coinfection with Plasmodium falciparum and helminths may impact the immune response to these parasites because they induce different immune profiles. We studied the effects of coinfections on the antibody profile in a cohort of 715 Mozambican children and adults using the Luminex technology with a panel of 16 antigens from P. falciparum and 11 antigens from helminths (Ascaris lumbricoides, hookworm, Trichuris trichiura, Strongyloides stercoralis, and Schistosoma spp.) and measured antigen-specific IgG and total IgE responses. We compared the antibody profile between groups defined by P. falciparum and helminth previous exposure (based on serology) and/or current infection (determined by microscopy and/or qPCR). In multivariable regression models adjusted by demographic, socioeconomic, water, and sanitation variables, individuals exposed/infected with P. falciparum and helminths had significantly higher total IgE and antigen-specific IgG levels, magnitude (sum of all levels) and breadth of response to both types of parasites compared to individuals exposed/infected with only one type of parasite (P ≤ 0.05). There was a positive association between exposure/infection with P. falciparum and exposure/infection with helminths or the number of helminth species, and vice versa (P ≤ 0.001). In addition, children coexposed/coinfected tended (P = 0.062) to have higher P. falciparum parasitemia than those single exposed/infected. Our results suggest that an increase in the antibody responses in coexposed/coinfected individuals may reflect higher exposure and be due to a more permissive immune environment to infection in the host. IMPORTANCE Coinfection with Plasmodium falciparum and helminths may impact the immune response to these parasites because they induce different immune profiles. We compared the antibody profile between groups of Mozambican individuals defined by P. falciparum and helminth previous exposure and/or current infection. Our results show a significant increase in antibody responses in individuals coexposed/coinfected with P. falciparum and helminths in comparison with individuals exposed/infected with only one of these parasites, and suggest that this increase is due to a more permissive immune environment to infection in the host. Importantly, this study takes previous exposure into account, which is particularly relevant in endemic areas where continuous infections imprint and shape the immune system. Deciphering the implications of coinfections deserves attention because accounting for the real interactions that occur in nature could improve the design of integrated disease control strategies.