Abstract
Introduction
Clostridioides difficile infection is an urgent public health threat, and the incidence has been increasing over the last decades. Knowledge of the prevalence of C. difficile in ...acutely admitted patients and risk factors for colonization with C. difficile assists emergency departments (EDs) in prioritizing preventive initiatives. This national study aimed to describe prevalence and risk factors for C. difficile carriers acutely admitted to EDs, focusing on the impact of earlier antibiotic prescription.
Methods
We conducted a nationwide analytic cross-sectional study with prospective data collection combined with a nested case–control study with retrospective data collection. All adults visiting one of eight Danish EDs were interviewed and examined for C. difficile. Using a national register, we collected the antibiotic history within the 2 years prior to enrolment. The primary outcome was the prevalence of C. difficile colonization, and secondary outcomes were related to risk factors and prior antibiotic prescription. Multivariate analyses examined the association between earlier antibiotic prescription and C. difficile colonization.
Results
Of 5019 participants, 89 were colonized with C. difficile (prevalence of 1.8%). A significant and exposure-dependent association was found for penicillins DDD/person-year(PY) > 20; OR 4.93 (95% CI 2.22–10.97) and fluoroquinolones DDD/PY > 20; OR 8.81 (95% CI 2.54–30.55), but not macrolides. Timing of the prescription did not affect the association.
Conclusions
One out of 55 patients visiting a Danish ED were colonized with C. difficile. Risk factors for colonization included high age, comorbidity and prior prescription of fluoroquinolones and penicillins.
Amyloid fibril formation plays a role in more than 20 diseases including Alzheimer’s disease.
In vitro detection of these fibrils is often performed using Thioflavin T (ThT), though the ThT binding ...mode is largely unknown. In the present study, spectral properties of ThT in binding environments representing β-sheet-rich and non-β-sheet cavities were examined. Acetylcholinesterase and γ-cyclodextrin induced a characteristic ThT fluorescence similar to that with amyloid fibrils, whereas β-cyclodextrin and the β-sheet-rich transthyretin did not. The cavities of acetylcholinesterase and γ-cyclodextrin were of similar diameter and only these cavities could accommodate two ThT ions according to molecular modelling. Binding stoichiometry studies also showed a possible binding of two ThT ions. Thus, the characteristic ThT fluorescence is induced in cavities with a diameter of 8–9
Å and a length able to accommodate the entire length of the ThT ion. The importance of a cavity diameter capable of binding two ThT ions, among others, indicates that an excimer formation is a plausible mechanism for the characteristic fluorescence. We propose a similar ThT binding mode in amyloid fibrils, where cavities of an appropriate size running parallel to the fibril axis have previously been proposed in several amyloid fibril models.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background
The novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has escalated rapidly to a global pandemic stretching healthcare ...systems worldwide to their limits. Surgeons have had to immediately react to this unprecedented clinical challenge by systematically repurposing surgical wards.
Purpose
To provide a detailed set of guidelines developed in a surgical ward at University Hospital Wuerzburg to safely accommodate the exponentially rising cases of SARS-CoV-2 infected patients without compromising the care of emergency surgery and oncological patients or jeopardizing the well-being of hospital staff.
Conclusions
The dynamic prioritization of SARS-CoV-2 infected and surgical patient groups is key to preserving life while maintaining high surgical standards. Strictly segregating patient groups in emergency rooms, non-intensive care wards and operating areas prevents viral spread while adequately training and carefully selecting hospital staff allow them to confidently and successfully undertake their respective clinical duties.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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The immunogenicity risk of therapeutic protein aggregates has been extensively investigated over the past decades. While it is established that not all aggregates are equally ...immunogenic, the specific aggregate characteristics, which are most likely to induce an immune response, remain ambiguous. The aim of this study was to perform comprehensive in vitro and in vivo immunogenicity assessment of human insulin aggregates varying in size, structure and chemical modifications, while keeping other morphological characteristics constant. We found that flexible aggregates with highly altered secondary structure were most immunogenic in all setups, while compact aggregates with native-like structure were found to be immunogenic primarily in vivo. Moreover, sub-visible (1–100 µm) aggregates were found to be more immunogenic than sub-micron (0.1–1 µm) aggregates, while chemical modifications (deamidation, ethylation and covalent dimers) were not found to have any measurable impact on immunogenicity. The findings highlight the importance of utilizing aggregates varying in few characteristics for assessment of immunogenicity risk of specific morphological features and may provide a workflow for reliable particle analysis in biotherapeutics.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The serotonin transporter (SERT) regulates extracellular levels of the neurotransmitter serotonin (5-hydroxytryptamine) in the brain by facilitating uptake of released 5-hydroxytryptamine into ...neuronal cells. SERT is the target for widely used antidepressant drugs, including imipramine, fluoxetine, and (S)-citalopram, which are competitive inhibitors of the transport function. Knowledge of the molecular details of the antidepressant binding sites in SERT has been limited due to lack of structural data on SERT. Here, we present a characterization of the (S)-citalopram binding pocket in human SERT (hSERT) using mutational and computational approaches. Comparative modeling and ligand docking reveal that (S)-citalopram fits into the hSERT substrate binding pocket, where (S)-citalopram can adopt a number of different binding orientations. We find, however, that only one of these binding modes is functionally relevant from studying the effects of 64 point mutations around the putative substrate binding site. The mutational mapping also identify novel hSERT residues that are crucial for (S)-citalopram binding. The model defines the molecular determinants for (S)-citalopram binding to hSERT and demonstrates that the antidepressant binding site overlaps with the substrate binding site.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Delayed recognition of acute disease among older adults hinders timely management and increases the risk of hospital admission. Point-of-Care testing, including Focused Lung Ultrasound (FLUS) and ...in-home analysis of biological material, may support clinical decision-making in suspected acute respiratory disease. The aim of this study was to pilot test the study design for a planned randomised trial, investigate whether in-home extended use of point-of-care testing is feasible, and explore its' potential clinical impact.
A non-randomised pilot and feasibility study was conducted during September-November 2021 in Kolding Municipality, Denmark. A FLUS-trained physician accompanied an acute community nurse on home-visits to citizens aged 65 + y with signs of acute respiratory disease. The acute community nurses did a clinical assessment (vital signs, capillary C-reactive protein and haemoglobin) and gave a presumptive diagnosis. Subsequently, the physician performed FLUS, venipuncture with bedside analysis (electrolytes, creatinine, white blood cell differential count), nasopharyngeal swab (PCR for upper respiratory pathogens), and urine samples (flow-cytometry). Primary outcomes were feasibility of study design and extended point-of-care testing; secondary outcome was the potential clinical impact of extended point-of-care testing.
One hundred consecutive individuals were included. Average age was 81.6 (SD ± 8.4). Feasibility of study design was acceptable, FLUS 100%, blood-analyses 81%, PCR for upper respiratory pathogens 79%, and urine flow-cytometry 4%. In addition to the acute community nurse's presumptive diagnosis, extended point-of-care testing identified 34 individuals with a condition in need of further evaluation by a physician.
Overall, in-home assessments with extended point-of-care testing are feasible and may aid to identify and handle acute diseases in older adults.
Proton-coupled oligopeptide transporters (POTs) couple the inward transport of di- or tripeptides with an inwardly directed transport of protons. Evidence from several studies of different POTs has ...pointed toward involvement of a highly conserved sequence motif, E1XXE2RFXYY (from here on referred to as E1XXE2R), located on Helix I, in interactions with the proton. In this study, we investigated the intracellular substrate accumulation by motif variants with all possible combinations of glutamate residues changed to glutamine and arginine changed to a tyrosine, the latter being a natural variant found in the Escherichia coli POT YjdL. We found that YjdL motif variants with E1XXE2R, E1XXE2Y, E1XXQ2Y, or Q1XXE2Y were able to accumulate peptide, whereas those with E1XXQ2R, Q1XXE2R, or Q1XXQ2Y were unable to accumulate peptide, and Q1XXQ2R abolished uptake. These results suggest a mechanism that involves swapping of an intramotif salt bridge, i.e. R-E2 to R-E1, which is consistent with previous structural studies. Molecular dynamics simulations of the motif variants E1XXE2R and E1XXQ2R support this mechanism. The simulations showed that upon changing conformation arginine pushes Helix V, through interactions with the highly conserved FYING motif, further away from the central cavity in what could be a stabilization of an inward facing conformation. As E2 has been suggested to be the primary site for protonation, these novel findings show how protonation may drive conformational changes through interactions of two highly conserved motifs.
Background: Proton-coupled oligopeptide transporters (POTs) facilitate di- and tripeptide uptake.
Results: Both glutamates of the highly conserved POT motif EXXERFXYY are required simultaneously for substrate accumulation. Arginine swaps interaction between the glutamates and interacts with another conserved motif, FYING, to facilitate larger structural change.
Conclusion: Two conserved motifs interact to facilitate structural changes upon substrate and proton binding.
Significance: Our results have contributed to understanding the mechanism of POTs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Due to ageing-related physiological changes, diagnosing older adults is challenging. Delayed disease recognition may lead to adverse health outcomes and increased hospitalisation, necessitating the ...development of new initiatives for timely diagnosis and treatment of older adults. Point-of-care technology, such as focused lung ultrasound scan and bedside analysis of blood samples (leucocytes with differential count, electrolytes, and creatinine) conducted in the patients' home, may support clinical decision-making, and potentially reduce acute hospital admissions. We present the protocol for a randomized controlled trial, which aims at assessing the effect of focused lung ultrasound scan and bedside blood analysis during in-home assessments among older adults with signs of potential acute respiratory disease on hospital admissions.
We will use a parallel open-label, individually randomised controlled trial design in an acute community healthcare setting. The trial will initiate on October 2022 and is expected to end one year later. The study population will include older adults (65 + year), with at least one of the following inclusion criteria: Cough, dyspnoea, fever, fall, or rapid functional decline. Expected study sample will comprise 632 participants. Participants in the control group will receive usual care, while the intervention group will undergo extended point-of-care technology (focused lung ultrasound scan and bedside venous blood analysis), in addition to usual care. The primary outcome is acute hospital admission within 30 days follow-up. Secondary outcomes include readmissions, mortality, length of hospital stay, hospital-free days, complications during hospital admission, treatment initiations or changes, functional level, re-referrals to the acute community healthcare service, and contacts to the primary care physician. A tertiary outcome is the diagnostic accuracy of Acute Community Nurses for conducting focused lung ultrasound compared with a specialist. Outcomes will be analysed as intention-to-treat.
To our knowledge, this is the first randomised controlled trial examining the effect of extended use of point-of-care technology conducted in an in-home setting. We expect that the results may contribute to the development of new interventions aiming to improve timely diagnostics, treatment decisions, and reduce acute hospital admissions.
www.
org NCT05546073 (Date of registration: September 19th, 2022).
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