Miracle-dz/UniFAR-FTUs huggingface dataset:
Personalized switching from oral to long-acting injectable second-generation antipsychotics in schizophrenia treatment using pharmacokinetic considerations

ABSTRACT Introduction Long-acting injectable (LAI) formulations of second-generation antipsychotics (SGA) are a mainstay in the treatment of schizophrenia-spectrum patients, and their use improves adherence and reduces relapse risk. Personalizing LAI-based therapy involves tailoring the transition from oral to LAIs based on individual and drug-related pharmacokinetic peculiarities. Areas covered We discuss pharmacokinetic considerations as a cornerstone of a smooth transition from oral to LAI SGAs based on works identified using an updated search in PubMed and Embase in February 2023. Establishing the extent of antipsychotic exposure during oral SGA-treatment from the patient’s SGA levels is often a more appropriate orientation method to choose the equivalent LAI dose than population-based data. Oral dose adjustment during LAI transition can also be guided by checking SGA levels before the LAI injection. Expert opinion LAI SGAs may dominate the maintenance treatment of schizophrenia-spectrum disorders with increased use for other severe mental illnesses such as bipolar disorder. Spurring this trend is the development of newer formulations with longer injection intervals and increased administration ease, but transitioning from oral SGA remains a challenge. By understanding the pharmacokinetics of LAI formulations and measuring SGA levels during oral therapy, one can personalize/optimize the switch from oral SGAs to LAI counterparts.
The Cost-Effectiveness of a Novel Online Social Therapy to Maintain Treatment Effects From First-Episode Psychosis Services: Results From the Horyzons Randomized Controlled Trial

Abstract Background Digital interventions have potential applications in promoting long-term recovery and improving outcomes in first-episode psychosis (FEP). This study aimed to evaluate the cost-effectiveness of Horyzons, a novel online social therapy to support young people aged 16–27 years following discharge from FEP services, compared with treatment as usual (TAU) from a healthcare sector and a societal perspective. Study design A cost-effectiveness analysis (CEA), based on the change in social functioning, and a cost-utility analysis (CUA) using quality-adjusted life years were undertaken alongside a randomized controlled trial. Intervention costs were determined from study records; resources used by patients were collected from a resource-use questionnaire and administrative data. Mean costs and outcomes were compared at 18 months and incremental cost-effectiveness ratios were calculated. Uncertainty analysis using bootstrapping and sensitivity analyses was conducted. Study results The sample included 170 participants: Horyzons intervention group (n = 86) and TAU (n = 84). Total costs were significantly lower in the Horyzons group compared with TAU from both the healthcare sector (–AU$4789.59; P < .001) and the societal perspective (–AU$5131.14; P < .001). In the CEA, Horyzons was dominant, meaning it was less costly and resulted in better social functioning. In the CUA, the Horyzons intervention resulted in fewer costs but also yielded fewer QALYs. However, group differences in outcomes were not statistically significant. When young people engaged more with the platform, costs were shown to decrease and outcomes improved. Conclusions The Horyzons intervention offers a cost-effective approach for improving social functioning in young people with FEP after discharge from early intervention services.
Synergistic Antibacterial Effect of Phage pB3074 in Combination with Antibiotics Targeting Cell Wall against Multidrug-Resistant Acinetobacter baumannii In Vitro and Ex Vivo

Combined application of phages and antibiotics cannot only effectively inhibit the appearance of phage-resistant bacteria, but also reduce the effective use concentration of antibiotics, and even make some bacteria regain sensitivity to some resistant antibiotics. Therefore, phage-antibiotic combination (PAC) could improve the antibacterial activity of individual drug, providing a new choice for clinical treatment of multidrug-resistant bacterial infections. ABSTRACT Synergistic effects of phages in combination with antibiotics have received increasing attention. In this present study, we isolated a new phage pB3074 against clinically isolated multidrug-resistant Acinetobacter baumannii. Phage pB3074 combined with cell wall-targeting antibiotics could produce synergistic antibacterial effect in vitro bactericidal activities. Further research indicates that the bacteriophage dose is critical to synergistic antimicrobial effect of phage and antibiotic combination. Cefotaxime and meropenem were selected as the representative cell wall-targeting antibiotics for further synergistic antibacterial study. Results illustrated that phage pB3074 and cefotaxime or meropenem combination was very effective for the removal of mature biofilm and inhibition of biofilm formation. In a pig skin explant model, results also showed that phage pB3074 and cefotaxime or meropenem combination was very effective for the treatment of wound infection ex vivo. Subsequent studies showed that some extent recovery of drug sensitivity to cell wall-targeting antibiotics might be vital mechanism of synergistic antibacterial effect between bacteriophage pB3074 and these antibiotics. The existence of antibiotics could promote phage adsorption and proliferation, which might also be potential mechanism for synergistic antibacterial activities and have been observed in cefotaxime and meropenem application. In summary, results in the current study demonstrated that phage pB3074 has the potential to be developed as an antibacterial agent and combined application of phages and antibiotics might be a new choice for the treatment of current multidrug-resistant bacterial infections. IMPORTANCE Combined application of phages and antibiotics cannot only effectively inhibit the appearance of phage-resistant bacteria, but also reduce the effective use concentration of antibiotics, and even make some bacteria regain sensitivity to some resistant antibiotics. Therefore, phage-antibiotic combination (PAC) could improve the antibacterial activity of individual drug, providing a new choice for clinical treatment of multidrug-resistant bacterial infections.
SARS-CoV-2 Co-Infections and Recombinations Identified by Long-Read Single-Molecule Real-Time Sequencing

SARS-CoV-2 variants have been responsible for the successive waves of infection over the 3 years of pandemic. While co-infection followed by recombination is one driver of virus evolution, there have been few reports of co-infections, mainly between Delta and Omicron variants or between the first 2 Omicron variants 21K_BA. 1 and 21L_BA. 2. ABSTRACT Co-infection with at least 2 strains of virus is the prerequisite for recombination, one of the means of genetic diversification. Little is known about the prevalence of these events in SARS-CoV-2, partly because it is difficult to detect them. We used long-read PacBio single-molecule real-time (SMRT) sequencing technology to sequence whole genomes and targeted regions for haplotyping. We identified 17 co-infections with SARS-CoV-2 strains belonging to different clades in 6829 samples sequenced between January and October, 2022 (prevalence 0.25%). There were 3 Delta/Omicron co-infections and 14 Omicron/Omicron co-infections (4 cases of 21K/21L, 1 case of 21L/22A, 2 cases of 21L/22B, 4 cases of 22A/22B, 2 cases of 22B/22C and 1 case of 22B/22E). Four of these patients (24%) also harbored recombinant minor haplotypes, including one with a recombinant virus that was selected in the viral quasispecies over the course of his chronic infection. While co-infections remain rare among SARS-CoV-2-infected individuals, long-read SMRT sequencing is a useful tool for detecting them as well as recombinant events, providing the basis for assessing their clinical impact, and a precise indicator of epidemic evolution. IMPORTANCE SARS-CoV-2 variants have been responsible for the successive waves of infection over the 3 years of pandemic. While co-infection followed by recombination is one driver of virus evolution, there have been few reports of co-infections, mainly between Delta and Omicron variants or between the first 2 Omicron variants 21K_BA. 1 and 21L_BA. 2. The 17 co-infections we detected during 2022 included cases with the recent clades of Omicron 22A, 22B, 22C, and 22E; 24% harbored recombinant variants. This study shows that long-read SMRT sequencing is well suited to SARS-CoV-2 genomic surveillance.
Implementation of the injury prevention exercise programme Knee Control+: a cross-sectional study after dissemination efforts within a football district

Background The Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework can be used for evaluation of implementation initiatives in sports injury prevention. The aim was to evaluate the implementation of the injury prevention exercise programme Knee Control+ among amateur clubs and coaches in one regional football district using all five dimensions of the RE-AIM framework. Methods Dissemination of Knee Control+ during the 2021 season with information and webinars within one regional football district. This was followed by a cross-sectional study with questionnaires to club personnel and coaches after the season. Results The reach of Knee Control+ was fair to high, 83% of club personnel and 66% of coaches knew about the programme. 41% of club personnel and 51% of coaches had adopted it. Perceived programme effectiveness was high (6 on a 1–7 Likert scale) among coaches. Regarding implementation and maintenance, 27% of club personnel had informed coaches about Knee Control+ and 57% planned to inform coaches. The coaches had implemented the programme mainly as recommended, but half used the programme once per week or less. Intention to maintain use of the programme was high (7 on a 1–7 Likert scale) among coaches. Conclusion The reach of Knee Control+ was fair to high, and adoption was fair in clubs, but there was a lack of policies for preventive training. Active strategies probably need to accompany dissemination of programme material. Reach, perceived effectiveness, adoption, implementation and planned maintenance were positive among coaches, but further studies are needed to analyse long-term maintenance.
The insulin receptor regulates the persistence of mechanical nociceptive sensitization in flies and mice

ABSTRACT Early phase diabetes is often accompanied by pain sensitization. In Drosophila, the insulin receptor (InR) regulates the persistence of injury-induced thermal nociceptive sensitization. Whether Drosophila InR also regulates the persistence of mechanical nociceptive sensitization remains unclear. Mice with a sensory neuron deletion of the insulin receptor (Insr) show normal nociceptive baselines; however, it is uncertain whether deletion of Insr in nociceptive sensory neurons leads to persistent nociceptive hypersensitivity. In this study, we used fly and mouse nociceptive sensitization models to address these questions. In flies, InR mutants and larvae with sensory neuron-specific expression of RNAi transgenes targeting InR exhibited persistent mechanical hypersensitivity. Mice with a specific deletion of the Insr gene in Nav1.8+ nociceptive sensory neurons showed nociceptive thermal and mechanical baselines similar to controls. In an inflammatory paradigm, however, these mutant mice showed persistent mechanical (but not thermal) hypersensitivity, particularly in female mice. Mice with the Nav1.8+ sensory neuron-specific deletion of Insr did not show metabolic abnormalities typical of a defect in systemic insulin signaling. Our results show that some aspects of the regulation of nociceptive hypersensitivity by the insulin receptor are shared between flies and mice and that this regulation is likely independent of metabolic effects.
Alpha‐synuclein‐associated changes in PINK1‐PRKN‐mediated mitophagy are disease context dependent

Alpha‐synuclein (αsyn) aggregates are pathological features of several neurodegenerative conditions including Parkinson disease (PD), dementia with Lewy bodies, and multiple system atrophy (MSA). Accumulating evidence suggests that mitochondrial dysfunction and impairments of the autophagic‐lysosomal system can contribute to the deposition of αsyn, which in turn may interfere with health and function of these organelles in a potentially vicious cycle. Here we investigated a potential convergence of αsyn with the PINK1‐PRKN‐mediated mitochondrial autophagy pathway in cell models, αsyn transgenic mice, and human autopsy brain. PINK1 and PRKN identify and selectively label damaged mitochondria with phosphorylated ubiquitin (pS65‐Ub) to mark them for degradation (mitophagy). We found that disease‐causing multiplications of αsyn resulted in accumulation of the ubiquitin ligase PRKN in cells. This effect could be normalized by starvation‐induced autophagy activation and by CRISPR/Cas9‐mediated αsyn knockout. Upon acute mitochondrial damage, the increased levels of PRKN protein contributed to an enhanced pS65‐Ub response. We further confirmed increased pS65‐Ub‐immunopositive signals in mouse brain with αsyn overexpression and in postmortem human disease brain. Of note, increased pS65‐Ub was associated with neuronal Lewy body‐type αsyn pathology, but not glial cytoplasmic inclusions of αsyn as seen in MSA. While our results add another layer of complexity to the crosstalk between αsyn and the PINK1‐PRKN pathway, distinct mechanisms may underlie in cells and brain tissue despite similar outcomes. Notwithstanding, our finding suggests that pS65‐Ub may be useful as a biomarker to discriminate different synucleinopathies and may serve as a potential therapeutic target for Lewy body disease.
Efficient taxa identification using a pangenome index

Tools that classify sequencing reads against a database of reference sequences require efficient index data-structures. The r-index is a compressed full-text index that answers substring presence/absence, count, and locate queries in space proportional to the amount of distinct sequence in the database: O(r) space, where r is the number of Burrows–Wheeler runs. To date, the r-index has lacked the ability to quickly classify matches according to which reference sequences (or sequence groupings, i.e., taxa) a match overlaps. We present new algorithms and methods for solving this problem. Specifically, given a collection D of d documents, D={T1,T2,…,Td} over an alphabet of size σ, we extend the r-index with O(rd) additional words to support document listing queries for a pattern S[1.m] that occurs in ndoc documents in D in O(mloglogw(σ+n/ r)+ndoc) time and O(rd) space, where w is the machine word size. Applied in a bacterial mock community experiment, our method is up to three times faster than a comparable method that uses the standard r-index locate queries. We show that our method classifies both simulated and real nanopore reads at the strain level with higher accuracy compared with other approaches. Finally, we present strategies for compacting this structure in applications in which read lengths or match lengths can be bounded.
Predicting FDG-PET Images From Multi-Contrast MRI Using Deep Learning in Patients With Brain Neoplasms.

BACKGROUND 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is valuable for determining presence of viable tumor, but is limited by geographical restrictions, radiation exposure, and high cost. PURPOSE To generate diagnostic-quality PET equivalent imaging for patients with brain neoplasms by deep learning with multi-contrast MRI. STUDY TYPE Retrospective. SUBJECTS Patients (59 studies from 51 subjects; age 56 ± 13 years; 29 males) who underwent 18 F-FDG PET and MRI for determining recurrent brain tumor. FIELD STRENGTH/SEQUENCE 3T; 3D GRE T1, 3D GRE T1c, 3D FSE T2-FLAIR, and 3D FSE ASL, 18 F-FDG PET imaging. ASSESSMENT Convolutional neural networks were trained using four MRIs as inputs and acquired FDG PET images as output. The agreement between the acquired and synthesized PET was evaluated by quality metrics and Bland-Altman plots for standardized uptake value ratio. Three physicians scored image quality on a 5-point scale, with score ≥3 as high-quality. They assessed the lesions on a 5-point scale, which was binarized to analyze diagnostic consistency of the synthesized PET compared to the acquired PET. STATISTICAL TESTS The agreement in ratings between the acquired and synthesized PET were tested with Gwet's AC and exact Bowker test of symmetry. Agreement of the readers was assessed by Gwet's AC. P = 0.05 was used as the cutoff for statistical significance. RESULTS The synthesized PET visually resembled the acquired PET and showed significant improvement in quality metrics (+21.7% on PSNR, +22.2% on SSIM, -31.8% on RSME) compared with ASL. A total of 49.7% of the synthesized PET were considered as high-quality compared to 73.4% of the acquired PET which was statistically significant, but with distinct variability between readers. For the positive/negative lesion assessment, the synthesized PET had an accuracy of 87% but had a tendency to overcall. CONCLUSION The proposed deep learning model has the potential of synthesizing diagnostic quality FDG PET images without the use of radiotracers. EVIDENCE LEVEL 3 TECHNICAL EFFICACY: Stage 2.
Lazy Leak Resistant Exponentiation in RNS

In [1] the authors introduced the leak resistant arithmetic in RNS to randomize RSA modular exponentiation. This randomization is meant to protect implementations on embedded device from side channel analysis. We propose in this paper a lazy version of the approach of [1] in the case of right-to-left square-and-multiply exponentiation. We show that this saves roughly 30% of the computation when the randomization is done at each loop iteration. We also show that the level of randomization of the proposed approach is better than the one of [1] after a few number of loop iterations.
Escherichia coli ST2797 Is Abundant in Wastewater and Might Be a Novel Emerging Extended-Spectrum Beta-Lactamase E. coli

The incidence of drug-resistant bacteria found in the environment is increasing together with the levels of antibiotic-resistant bacteria that cause infections. The COVID-19 pandemic has shed new light on the importance of monitoring emerging threats and finding early warning systems. ABSTRACT The increasing prevalence of antibiotic-resistant bacteria is an emerging threat to global health. The analysis of antibiotic-resistant enterobacteria in wastewater can indicate the prevalence and spread of certain clonal groups of multiresistant bacteria. In a previous study of Escherichia coli that were isolated from a pump station in Norway over 15 months, we found a recurring E. coli clone that was resistant to trimethoprim, ampicillin, and tetracycline in 201 of 3,123 analyzed isolates (6.1%). 11 representative isolates were subjected to whole-genome sequencing and were found to belong to the MLST ST2797 E. coli clone with plasmids carrying resistance genes, including blaTEM-1B, sul2, dfrA7, and tetB. A phenotypic comparison of the ST2797 isolates with the uropathogenic ST131 and ST648 that were repeatedly identified in the same wastewater samples revealed that the ST2797 isolates exhibited a comparable capacity for temporal survival in wastewater, greater biofilm formation, and similar potential for the colonization of mammalian epithelial cells. ST2797 has been isolated from humans and has been found to carry extended spectrum β-lactamase (ESBL) genes in other studies, suggesting that this clonal type is an emerging ESBL E. coli. Collectively, these findings show that ST2797 was more ubiquitous in the studied wastewater than were the infamous ST131 and ST648 and that ST2797 may have similar abilities to survive in the environment and cause infections in humans. IMPORTANCE The incidence of drug-resistant bacteria found in the environment is increasing together with the levels of antibiotic-resistant bacteria that cause infections. The COVID-19 pandemic has shed new light on the importance of monitoring emerging threats and finding early warning systems. Therefore, to mitigate the antimicrobial resistance burden, the monitoring and early identification of antibiotic-resistant bacteria in hot spots, such as wastewater treatment plants, are required to combat the occurrence and spread of antibiotic-resistant bacteria. Here, we applied a PhenePlate system as a phenotypic screening method for genomic surveillance and discovered a dominant and persistent E. coli clone ST2797 with a multidrug resistance pattern and equivalent phenotypic characteristics to those of the major pandemic lineages, namely, ST131 and ST648, which frequently carry ESBL genes. This study highlights the continuous surveillance and report of multidrug resistant bacteria with the potential to spread in One Health settings.
First-Passage of a Brownian Particle - Escape from a Bounded Potential

Many different processes depend on the first crossing of a boundary. For example, the time it takes for a protein find its target site on DNA, and the waiting time until a neurone starts firing. Motivated by the lack of tools accessible for computing first passage time densities (FPDTs) for general potentials, we propose a new method based on the Independent Interval Approximation (IIA). We generalise the IIA framework to non–smooth Brownian processes and derive a closed form expression for the FPDT in Laplace space for arbitrary boundary and starting point in one dimension. We apply our results to a Brownian particle in a harmonic potential and we find good agreement with Langevin dynamics simulations for one and two boundaries. We anticipate that our results will have a wide applicability an a number of escape problems.
Fecal Biomarkers of Neutrophil and Eosinophil Origin Reflect the Response to Biological Therapy and Corticosteroids in Patients With Inflammatory Bowel Disease

INTRODUCTION: Fecal calprotectin (FC) is a noninvasive tool for examining response to biologics in inflammatory bowel disease (IBD), but its performance in relation to other novel fecal markers of various cellular origins is unknown. METHODS: We performed a prospective multicenter cohort study and included patients with active IBD who provided a fecal sample at initiation of biological therapy. Levels of FC, myeloperoxidase (MPO), human neutrophil lipocalin (HNL), and eosinophil-derived neurotoxin (EDN) were analyzed and related to clinical remission status at 3 months. Changes in levels of markers at 3 months were calculated, and the impact of concomitant use of corticosteroids at baseline was estimated. RESULTS: In patients achieving clinical remission (n = 27), a decrease in levels of FC (P = 0.005), MPO (P < 0.001), HNL (P < 0.001), and EDN (P < 0.001) was observed, whereas no significant decrease was seen in patients not achieving remission (n = 39). There was a significant difference in the change in the level of MPO (P = 0.01) and HNL (P = 0.02) between patients achieving clinical remission and those who did not, but changes in FC and EDN could not differentiate between these groups. Patients with concomitant systemic corticosteroids at inclusion had lower levels of HNL (P = 0.01) and EDN (P < 0.001) at baseline, compared with patients without corticosteroids. DISCUSSION: Fecal MPO, HNL, and EDN are all promising biomarkers for assessing the treatment outcome of biologics in patients with IBD. Fecal levels of EDN and HNL are significantly affected by corticosteroids indicating a greater sensitivity to the effects of corticosteroids compared with levels of FC and MPO.