Revolutionizing Clinical Microbiology Laboratory Organization in Hospitals with In Situ Point-of-Care

BACKGROUND: Clinical microbiology may direct decisions regarding hospitalization, isolation and anti-infective therapy, but it is not effective at the time of early care. Point-of-care (POC) tests have been developed for this purpose. METHODS AND FINDINGS: One pilot POC-lab was located close to the core laboratory and emergency ward to test the proof of concept. A second POC-lab was located inside the emergency ward of a distant hospital without a microbiology laboratory. Twenty-three molecular and immuno-detection tests, which were technically undemanding, were progressively implemented, with results obtained in less than four hours. From 2008 to 2010, 51,179 tests yielded 6,244 diagnoses. The second POC-lab detected contagious pathogens in 982 patients who benefited from targeted isolation measures, including those undertaken during the influenza outbreak. POC tests prevented unnecessary treatment of patients with non-streptococcal tonsillitis (n = 1,844) and pregnant women negative for Streptococcus agalactiae carriage (n = 763). The cerebrospinal fluid culture remained sterile in 50% of the 49 patients with bacterial meningitis, therefore antibiotic treatment was guided by the molecular tests performed in the POC-labs. With regard to enterovirus meningitis, the mean length-of-stay of infected patients over 15 years old significantly decreased from 2008 to 2010 compared with 2005 when the POC was not in place (1.43±1.09 versus 2.91±2.31 days; p = 0.0009). Altogether, patients who received POC tests were immediately discharged nearly thrice as often as patients who underwent a conventional diagnostic procedure. CONCLUSIONS: The on-site POC-lab met physicians' needs and influenced the management of 8% of the patients that presented to emergency wards. This strategy might represent a major evolution of decision-making regarding the management of infectious diseases and patient care

Latin Americans show wide-spread Converso ancestry and imprint of local Native ancestry on physical appearance

Historical records and genetic analyses indicate that Latin Americans trace their ancestry mainly to the intermixing (admixture) of Native Americans, Europeans and Sub-Saharan Africans. Using novel haplotype-based methods, here we infer sub-continental ancestry in over 6,500 Latin Americans and evaluate the impact of regional ancestry variation on physical appearance. We find that Native American ancestry components in Latin Americans correspond geographically to the present-day genetic structure of Native groups, and that sources of non-Native ancestry, and admixture timings, match documented migratory flows. We also detect South/East Mediterranean ancestry across Latin America, probably stemming mostly from the clandestine colonial migration of Christian converts of non-European origin (Conversos). Furthermore, we find that ancestry related to highland (Central Andean) versus lowland (Mapuche) Natives is associated with variation in facial features, particularly nose morphology, and detect significant differences in allele frequencies between these groups at loci previously associated with nose morphology in this sample

Quantifying the Effects of Elastic Collisions and Non-Covalent Binding on Glutamate Receptor Trafficking in the Post-Synaptic Density

One mechanism of information storage in neurons is believed to be determined by the strength of synaptic contacts. The strength of an excitatory synapse is partially due to the concentration of a particular type of ionotropic glutamate receptor (AMPAR) in the post-synaptic density (PSD). AMPAR concentration in the PSD has to be plastic, to allow the storage of new memories; but it also has to be stable to preserve important information. Although much is known about the molecular identity of synapses, the biophysical mechanisms by which AMPAR can enter, leave and remain in the synapse are unclear. We used Monte Carlo simulations to determine the influence of PSD structure and activity in maintaining homeostatic concentrations of AMPARs in the synapse. We found that, the high concentration and excluded volume caused by PSD molecules result in molecular crowding. Diffusion of AMPAR in the PSD under such conditions is anomalous. Anomalous diffusion of AMPAR results in retention of these receptors inside the PSD for periods ranging from minutes to several hours in the absence of strong binding of receptors to PSD molecules. Trapping of receptors in the PSD by crowding effects was very sensitive to the concentration of PSD molecules, showing a switch-like behavior for retention of receptors. Non-covalent binding of AMPAR to anchored PSD molecules allowed the synapse to become well-mixed, resulting in normal diffusion of AMPAR. Binding also allowed the exchange of receptors in and out of the PSD. We propose that molecular crowding is an important biophysical mechanism to maintain homeostatic synaptic concentrations of AMPARs in the PSD without the need of energetically expensive biochemical reactions. In this context, binding of AMPAR with PSD molecules could collaborate with crowding to maintain synaptic homeostasis but could also allow synaptic plasticity by increasing the exchange of these receptors with the surrounding extra-synaptic membrane

Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.

Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection

Near-future CO2 levels impair the olfactory system of a marine fish

This is the author accepted manuscript. The final version is available from Springer Nature via the DOI in this recordData availability: All raw sequence data are accessible at the NCBI Sequence Read Archive through accession number SRP097118. Water chemistry, behaviour and electrophysiology data are available through Pangaea (https://doi.pangaea.de/10.1594/PANGAEA.884674).Survival of marine fishes that are exposed to elevated near-future CO2levels is threatened by their altered responses to sensory cues. Here we demonstrate a physiological and molecular mechanism in the olfactory system that helps to explain altered behaviour under elevated CO2. We combine electrophysiology measurements and transcriptomics with behavioural experiments to investigate how elevated CO2affects the olfactory system of European sea bass (Dicentrarchus labrax). When exposed to elevated CO2(approximately 1,000 µatm), fish must be up to 42% closer to an odour source for detection, compared with current CO2levels (around 400 µatm), decreasing their chances of detecting food or predators. Compromised olfaction correlated with the suppression of the transcription of genes involved in synaptic strength, cell excitability and wiring of the olfactory system in response to sustained exposure to elevated CO2levels. Our findings complement the previously proposed impairment of γ-aminobutyric acid receptors, and indicate that both the olfactory system and central brain function are compromised by elevated CO2levels.This study was supported by grants from Association of European Marine Biology Laboratories (227799), the Natural Environment Research Council (R.W.W.; NE/H017402/1), the Biotechnology and Biological Sciences Research Council (R.W.W.; BB/D005108/1), Fundação para a Ciência e Tecnologia (Portuguese Science Ministry) (UID/Multi/04326/2013) and a Royal Society Newton International Fellowship to C.S.P. C.S.P. is also a beneficiary of a Starting Grant from AXA

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Evaluation of vitamin D biosynthesis and pathway target genes reveals UGT2A1/2 and EGFR polymorphisms associated with epithelial ovarian cancer in African American Women

An association between genetic variants in the vitamin D receptor (VDR) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets (EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5, CYP2R1, CYP27B1, CYP24A1, CYP11A1, and GC). Genotyping was performed using the custom-designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high-grade serous (HGSOC), and 1,235 controls. All subjects are of African ancestry (AA). Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI). We further evaluated statistical significance of selected SNPs using the Bayesian False Discovery Probability (BFDP). A significant association with EOC was identified in the UGT2A1/2 region for the SNP rs10017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 1.2 × 10-6 , BFDP = 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele OR = 2.3, 95% CI = 1.6-3.4, P = 1.6 × 10-5 , BFDP = 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 2.3 × 10-5 , BFDP = 0.23). Genetic variants in the EGFR and UGT2A1/2 may increase susceptibility of EOC in AA women. Future studies to validate these findings are warranted. Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC