Evidence-based rules from family practice to inform family practice; The learning healthcare system case study on urinary tract infections

Background: Analysis of encounter data relevant to the diagnostic process sourced from routine electronic medical record (EMR) databases represents a classic example of the concept of a learning healthcare system (LHS). By collecting International Classification of Primary Care (ICPC) coded EMR data as part of the Transition Project from Dutch and Maltese databases (using the EMR TransHIS), data mining algorithms can empirically quantify the relationships of all presenting reasons for encounter (RfEs) and recorded diagnostic outcomes. We have specifically looked at new episodes of care (EoC) for two urinary system infections: simple urinary tract infection (UTI, ICPC code: U71) and pyelonephritis (ICPC code: U70). Methods: Participating family doctors (FDs) recorded details of all their patient contacts in an EoC structure using the ICPC, including RfEs presented by the patient, and the FDs' diagnostic labels. The relationships between RfEs and episode titles were studied using probabilistic and data mining methods as part of the TRANSFoRm project. Results: The Dutch data indicated that the presence of RfE's "Cystitis/Urinary Tract Infection", "Dysuria", "Fear of UTI", "Urinary frequency/urgency", "Haematuria", "Urine symptom/complaint, other" are all strong, reliable, predictors for the diagnosis "Cystitis/Urinary Tract Infection". The Maltese data indicated that the presence of RfE's "Dysuria", "Urinary frequency/urgency", "Haematuria" are all strong, reliable, predictors for the diagnosis "Cystitis/Urinary Tract Infection". The Dutch data indicated that the presence of RfE's "Flank/axilla symptom/complaint", "Dysuria", "Fever", "Cystitis/Urinary Tract Infection", "Abdominal pain/cramps general" are all strong, reliable, predictors for the diagnosis "Pyelonephritis". The Maltese data set did not present any clinically and statistically significant predictors for pyelonephritis. Conclusions: We describe clinically and statistically significant diagnostic associations observed between UTIs and pyelonephritis presenting as a new problem in family practice, and all associated RfEs, and demonstrate that the significant diagnostic cues obtained are consistent with the literature. We conclude that it is possible to generate clinically meaningful diagnostic evidence from electronic sources of patient data

Experimental investigation of aminoacetonitrile formation through the Strecker synthesis in astrophysical-like conditions: reactivity of methanimine (CH2NH), ammonia (NH3), and hydrogen cyanide (HCN)

International audienceAstronomy & Astrophysics Experimental investigation of aminoacetonitrile formation through the Strecker synthesis in astrophysical-like conditions: reactivity of methanimine (CH 2 NH), ammonia (NH 3), and hydrogen cyanide (HCN) ABSTRACT Context. Studing chemical reactivity in astrophysical environments is an important means for improving our understanding of the origin of the organic matter in molecular clouds, in protoplanetary disks, and possibly, as a final destination, in our solar system. Laboratory simulations of the reactivity of ice analogs provide important insight into the reactivity in these environments. Here, we use these experimental simulations to investigate the Strecker synthesis leading to the formation of aminoacetonitrile in astrophysical-like conditions. The aminoacetonitrile is an interesting compound because it was detected in SgrB2, hence could be a precursor of the smallest amino acid molecule, glycine, in astrophysical environments. Aims. We present the first experimental investigation of the formation of aminoacetonitrile NH 2 CH 2 CN from the thermal processing of ices including methanimine (CH 2 NH), ammonia (NH 3), and hydrogen cyanide (HCN) in interstellar-like conditions without VUV photons or particules. Methods. We use Fourier Transform InfraRed (FTIR) spectroscopy to monitor the ice evolution during its warming. Infrared spec-troscopy and mass spectroscopy are then used to identify the aminoacetonitrile formation. Results. We demonstrate that methanimine can react with − CN during the warming of ice analogs containing at 20 K methanimine, ammonia, and [NH + 4 − CN] salt. During the ice warming, this reaction leads to the formation of poly(methylene-imine) polymers. The polymer length depend on the initial ratio of mass contained in methanimine to that in the [NH + 4 − CN] salt. In a methanimine excess, long polymers are formed. As the methanimine is progressively diluted in the [NH + 4 − CN] salt, the polymer length decreases until the aminoacetonitrile formation at 135 K. Therefore, these results demonstrate that aminoacetonitrile can be formed through the second step of the Strecker synthesis in astrophysical-like conditions

Phenotypic Variation in the Group A Streptococcus Due to Natural Mutation of the Accessory Protein-Encoding Gene rocA

Populations of a bacterial pathogen, whether recovered from a single patient or from a worldwide study, are often a heterogeneous mix of genetically and phenotypically divergent strains. Such heterogeneity is of value in changing environments and arises via mechanisms such as gene gain or gene mutation. Here, we identify an isolate of serotype M12 group A Streptococcus (GAS) (Streptococcus pyogenes) that has a natural mutation in rocA, which encodes an accessory protein to the virulence-regulating two-component system CovR/CovS (CovR/S). Disruption of RocA activity results in the differential expression of multiple GAS virulence factors, including the anti-phagocytic hyaluronic acid capsule and the chemokine protease SpyCEP. While some of our data regarding RocA-regulated genes overlaps with previous studies, which were performed with isolates of alternate GAS serotypes, some variability was also observed. Perhaps as a consequence of this alternate regulatory activity, we discovered that the contribution of RocA to the ability of the M12 isolate to survive and proliferate in human blood ex vivo is opposite that previously observed in M1, M3, and M18 GAS strains. Specifically, rocA mutation reduced, rather than enhanced, survival of the isolate. Finally, we also present data from an analysis of rocA transcription and show that rocA is transcribed in both mono- and polycistronic mRNAs. In aggregate, our data provide insight into the important regulatory role of RocA and into the mechanisms and consequences of GAS phenotypic heterogeneity. IMPORTANCE This study investigates the regulatory and phenotypic consequences of a naturally occurring mutation in a strain of the bacterial pathogen the group A Streptococcus (Streptococcus pyogenes). We show that this mutation, which occurs in a regulator-encoding gene, rocA, leads to altered virulence factor expression and reduces the ability of this isolate to survive in human blood. Critically, the blood survival phenotype and the assortment of genes regulated by RocA differ compared to previous studies into RocA activity. The data are consistent with there being strain-or serotype-specific variability in RocA function. Given that phenotypic variants can lead to treatment failures and escape from preventative regimes, our data provide information with regard to a mechanism of phenotypic variation in a prevalent Gram-positive pathogen

Moonraker: Enceladus Multiple Flyby Mission

Enceladus, an icy moon of Saturn, possesses an internal water ocean and jets expelling ocean material into space. Cassini investigations indicated that the subsurface ocean could be a habitable environment having a complex interaction with the rocky core. Further investigation of the composition of the plume formed by the jets is necessary to fully understand the ocean, its potential habitability, and what it tells us about Enceladus’s origin. Moonraker has been proposed as an ESA M-class mission designed to orbit Saturn and perform multiple flybys of Enceladus, focusing on traversals of the plume. The proposed Moonraker mission consists of an ESA-provided platform with strong heritage from JUICE and Mars Sample Return and carrying a suite of instruments dedicated to plume and surface analysis. The nominal Moonraker mission has a duration of ∼13.5 yr. It includes a 23-flyby segment with 189 days allocated for the science phase and can be expanded with additional segments if resources allow. The mission concept consists of investigating (i) the habitability conditions of present-day Enceladus and its internal ocean, (ii) the mechanisms at play for the communication between the internal ocean and the surface of the South Polar Terrain, and (iii) the formation conditions of the moon. Moonraker, thanks to state-of-the-art instruments representing a significant improvement over Cassini's payload, would quantify the abundance of key species in the plume, isotopic ratios, and the physical parameters of the plume and the surface. Such a mission would pave the way for a possible future landed mission

Moonraker -- Enceladus Multiple Flyby Mission

Enceladus, an icy moon of Saturn, possesses an internal water ocean and jets expelling ocean material into space. Cassini investigations indicated that the subsurface ocean could be a habitable environment having a complex interaction with the rocky core. Further investigation of the composition of the plume formed by the jets is necessary to fully understand the ocean, its potential habitability, and what it tells us about Enceladus' origin. Moonraker has been proposed as an ESA M-class mission designed to orbit Saturn and perform multiple flybys of Enceladus, focusing on traversals of the plume. The proposed Moonraker mission consists of an ESA-provided platform, with strong heritage from JUICE and Mars Sample Return, and carrying a suite of instruments dedicated to plume and surface analysis. The nominal Moonraker mission has a duration of 13.5 years. It includes a 23-flyby segment with 189 days allocated for the science phase, and can be expanded with additional segments if resources allow. The mission concept consists in investigating: i) the habitability conditions of present-day Enceladus and its internal ocean, ii) the mechanisms at play for the communication between the internal ocean and the surface of the South Polar Terrain, and iii) the formation conditions of the moon. Moonraker, thanks to state-of-the-art instruments representing a significant improvement over Cassini's payload, would quantify the abundance of key species in the plume, isotopic ratios, and physical parameters of the plume and the surface. Such a mission would pave the way for a possible future landed mission.Comment: Accepted for publication in The Planetary Science Journa

The Involvement of SMILE/TMTC3 in Endoplasmic Reticulum Stress Response

The state of operational tolerance has been detected sporadically in some renal transplanted patients that stopped immunosuppressive drugs, demonstrating that allograft tolerance might exist in humans. Several years ago, a study by Brouard et al. identified a molecular signature of several genes that were significantly differentially expressed in the blood of such patients compared with patients with other clinical situations. The aim of the present study is to analyze the role of one of these molecules over-expressed in the blood of operationally tolerant patients, SMILE or TMTC3, a protein whose function is still unknown.We first confirmed that SMILE mRNA is differentially expressed in the blood of operationally tolerant patients with drug-free long term graft function compared to stable and rejecting patients. Using a yeast two-hybrid approach and a colocalization study by confocal microscopy we furthermore report an interaction of SMILE with PDIA3, a molecule resident in the endoplasmic reticulum (ER). In accordance with this observation, SMILE silencing in HeLa cells correlated with the modulation of several transcripts involved in proteolysis and a decrease in proteasome activity. Finally, SMILE silencing increased HeLa cell sensitivity to the proteasome inhibitor Bortezomib, a drug that induces ER stress via protein overload, and increased transcript expression of a stress response protein, XBP-1, in HeLa cells and keratinocytes.In this study we showed that SMILE is involved in the endoplasmic reticulum stress response, by modulating proteasome activity and XBP-1 transcript expression. This function of SMILE may influence immune cell behavior in the context of transplantation, and the analysis of endoplasmic reticulum stress in transplantation may reveal new pathways of regulation in long-term graft acceptance thereby increasing our understanding of tolerance