Background We used data from a prospective cohort to explore two-year trajectories of “long COVID” (persistent symptoms after SARS-CoV-2 infection) and their association with illness perception. Methods RECoVERED participants (adults; prospectively enrolled following laboratory-confirmed SARS-CoV-2 infection, May 2020-June 2021) completed symptom questionnaires at months 2-12, 18 and 24, and the Brief Illness Perception Questionnaire (B-IPQ) at months 1, 6, and 12. Using group-based trajectory models (GBTM), we modelled symptoms (mean total numbers and proportion with 4 specific complaints), including age, sex, BMI and timing of infection as covariates. In a multivariable linear mixed-effects model, we assessed the association between symptom trajectories and repeated B-IPQ scores. Results Among 292 participants (42% female; median age 51 [IQR=36-62]), four trajectories were identified, ranging from Trajectory 4 (8.9%; 6+ symptoms) to Trajectory 1 (24.8%; no symptoms). The occurrence of fatigue and myalgia increased among 23% and 12% of participants, respectively. Individuals in Trajectory 4 experienced more negative adjusted B-IPQ scores over time than those in Trajectories 1-3. Conclusions We observed little fluctuation in the total number of symptoms but individual symptoms may develop as others resolve. Reporting a greater number of symptoms was congruent with more negative illness perception over time.

Background: Pathogenic variants in the mismatch repair (MMR) genes are the drivers of Lynch Syndrome; optimal variant interpretation is required for the management of suspected and confirmed cases. Given the onerous nature of extracting information related to genetic variants, literature searching tools which harness artificial intelligence may aid in retrieving information to allow optimum variant classification. Methods: In this study, we described the nature of discordance in a sample of 80 variants from a list of variants requiring updating by InSiGHT for ClinGen by comparing their existing InSiGHT classifications on ClinVar. Variants were searched for using a traditional method (Google Scholar) and literature searching tool (Mastermind Genomenon) independently. Descriptive statistics were used to compare: the number of articles before and after screening for relevance and the number of relevant articles unique to either method. Results: 916 articles were returned by both methods. Mastermind averaged four relevant articles per search, Google Scholar, three. Of relevant Mastermind articles, 193/308 (62.7%) were unique to it, compared to 87/202, (43.0%) for Google Scholar. All 6/80 (20%) variants with pathogenic or likely pathogenic InSiGHT classifications have newer VUS assertions on ClinVar. Conclusion: Mastermind on average returned a more relevant literature search. Google Scholar still found unique information, suggesting that Mastermind could play a complementary role.

The cell culture is the central piece of a biotechnological industrial process. It includes upstream (e.g. media preparation, fixed costs, etc.) and downstream steps (e.g. product purification, waste disposal, etc.). In the continuous mode of cell culture, a constant flow of fresh media replaces culture fluid until the system reaches a steady state. This steady state is the standard operation mode which, under very general conditions, is a function of the ratio between the cell density and the dilution rate and depends on the media supplied to the culture. To optimize the production process it is widely accepted that the concentration of the metabolites in this media should be careful tuned. A poor media may not provide enough nutrients to the culture, while a media too rich in nutrients may be a waste of resources because, either the cells do not use all of the available nutrients, or worse, they over-consume them producing toxic byproducts. In this work we show how an in-silico study of a genome scale metabolic network coupled to the dynamics of a chemostat could guide the strategy to optimize the media to be used in a continuous process. Given a known media we model the concentrations of the cells in a chemostat as a function of the dilution rate. Then, we cast the problem of optimizing the production process within a linear programming framework in which the goal is to minimize the cost of the media keeping fixed the cell concentration for a given dilution rate in the chemostat. We evaluate our results in two metabolic models: first a simplified model of mammalian cell metabolism, and then in a realistic genome-scale metabolic networks of mammalian cells, the Chinese Hamster Ovary (CHO) cell line. We explore the latter in more detail given specific meaning to the predictions of the concentrations of several metabolites.

The deployment of artesunate for severe malaria and the artemisinin combination therapies (ACTs) for uncomplicated malaria has been a major advance in antimalarial therapeutics. These drugs have reduced treated mortality, accelerated recovery, and reduced treatment failure rates and transmission from the treated infection. These drugs remain highly effective against falciparum malaria in most malaria endemic areas but significant resistance has emerged in the Greater Mekong subregion of Southeast Asia. Resistance to artemisinin was followed by resistance in the ACT partner drugs, and fit multidrug resistant parasite lineages have now spread widely across the region. ACTs are highly effective against P. vivax and the other malaria species. Recent studies show that radical curative regimens of primaquine (to prevent relapse) can be shortened to seven days, and that the newly introduced single dose tafenoquine is an alternative, although the currently recommended dose is insufficient in Southeast Asia and Oceania. Targeted malaria elimination using focal mass treatments with dihydroartemisinin-piperaquine have proved safe and effective malaria elimination accelerators, but progress overall towards malaria elimination is very slow. Indeed since 2015 overall malaria case numbers globally have risen.

This paper introduces version one of an assessment tool developed to address the challenges posed by the assessment of data thickness and richness in primary qualitative studies for Qualitative Evidence Syntheses (QES). The tool has been in development since 2014. Three pilot versions from three review teams have been used in six Cochrane reviews. Key members from the original three review teams came together to create a consensus-based definitive version 1 of the tool for publication. Four review authors piloted the version 1 tool. The definitive version 1 assessment tool consists of two components: assessing the thickness of contextual data and assessing the richness of conceptual data. A sliding scale with four points is used to rate these aspects, offering nuanced and qualitative judgments. The accompanying guidance emphasizes the importance of assessing data that addresses the review question. Paragraph locked by Heather Melanie R Ames The paper provides guidance on how to apply the tool, emphasizing the importance of reaching a consensus among review authors, and fostering a shared understanding of what constitutes rich and thick data in the context of the review. The potential challenges related to the time and resource constraints of this additional review process are acknowledged. Version 1 of the data thickness/richness assessment tool represents a significant development in QES methodology, filling a critical gap in tools for evaluating the richness of conceptual data and the level of contextual detail in primary qualitative studies. It enhances the transparency and rigor of the sampling process and offers valuable insights for assessing the thickness and richness of data in primary qualitative studies that addresses the review requestion, objectives and context as specified in the review protocol. The authors invite feedback from the research community to further test, refine and improve this tool based on wider user experiences.

Guillain-Barre syndrome (GBS) is a rare autoimmune disease that often manifests as a post-viral complication. However, its association with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is unclear. We present a rare case of GBS secondary to COVID-19 infection complicated by rapidly progressive sensorimotor deterioration resistant to plasma exchange therapy.

Peptides play a key role in controlling many physiological and neurobiological pathways. Many bioactive peptides require a C-terminal α-amide for full activity. The bifunctional enzyme catalyzing α-amidation, peptidylglycine α-amidating monooxygenase (PAM), is the sole enzyme responsible for amidated peptide biosynthesis, from Chlamydomonas reinhardtii to Homo sapiens. Many neuronal and endocrine functions are dependent upon amidated peptides; additional amidated peptides are growth promoters in tumors. The amidation reaction occurs in two steps, glycine α-hydroxylation followed by dealkylation to generate the α-amide product. Currently, most potentially useful inhibitors target the first reaction, which is rate-limiting. PAM is a membrane-bound enzyme that visits the cell surface during peptide secretion. PAM is then used again in the biosynthetic pathway, meaning that cell-impermeable inhibitors or inactivators could have therapeutic value for the treatment of cancer or psychiatric abnormalities. To date, inhibitor design has not fully exploited the structures and mechanistic details of PAM.

Introduction: Although the presence of left atrial low-voltage areas (LVAs) is strongly associated with the recurrence of atrial fibrillation (AF) after ablation, few methods are available to classify the prevalence of LVAs. The purpose of this study was to establish a risk score for predicting the prevalence of LVAs in patients undergoing ablation for AF. Methods: We enrolled 1004 consecutive patients who underwent initial ablation for AF (age, 68 ± 10 years old; female, 346 (34%); persistent atrial fibrillation, 513 (51%)). LVAs were deemed present when the voltage map after pulmonary vein isolation demonstrated low-voltage areas with a peak-to-peak bipolar voltage of <0.5 mV covering ≥5 cm2 of the left atrium. Results: LVAs were present in 206 (21%) patients. The SPEED score was obtained as the total number of independent predictors as identified on multivariate analysis, namely female sex (odds ratio (OR) 3.4 [95% confidence interval (CI) 2.2-5.2], p <0.01), persistent AF (OR 1.8 [95% CI 1.1-3.0], p=0.02), age ≥70 years (OR 2.3 [95% CI 1.5-3.4], p <0.01), elevated brain natriuretic peptide ≥100 pg/ml or N-terminal pro-brain natriuretic peptide ≥400 pg/ml (OR 1.7 [95% CI 1.02-2.8], p=0.04), and diabetes mellitus (OR 1.8 [95% CI 1.1-2.8], p=0.02). LVAs were more frequent in patients with a higher SPEED score, and prevalence increased with each additional SPEED score point (OR 2.4 [95% CI 2.0-2.8], p <0.01). Conclusion: The SPEED score accurately predicts the prevalence of LVAs in patients undergoing ablation for AF.

First described in 1965 by Johnson and Wilcox, partial absence of the tricuspid valve (TV) associated with a ventricular septal defect(VSD) is a very rare malformation.(1) Heart failure secondary to severe TV regurgitation results in-utero fetal compromise. (2) We present here a fetus with partial absence of the tricuspid valve with conoventricular septal defect.

1. Animal abundance estimation is increasingly based on drone or aerial survey photography. Manual post-processing has been used extensively, however volumes of such data are increasing, necessitating some level of automation, either for complete counting, or as a labour-saving tool. Any automated processing can be challenging when using the tools on species that nest in close formation such as Pygoscelid penguins. 2. We present here an adaptation of state-of-the-art crowd-counting methodologies for counting of penguins from aerial photography. 3. The crowd-counting model performed significantly better in terms of model performance and computational efficiency than standard Faster RCNN deep-learning approaches and gave an error rate of only 0.8 percent. 4. Crowd-counting techniques as demonstrated here have the ability to vastly improve our ability to count animals in tight aggregations, which will demonstrably improve monitoring efforts from aerial imagery.

A proper benchmarking on the properties of HF and its dimer inside C60 using density functional theory (DFT) based approaches is presented. For this purpose, 10 different DFT functionals following Jacob’s Ladder have been chosen. Geometrical parameters, viz., bond length, bond angle, etc., and dipole moment have been computed. Two types of orientations, viz., L-shaped and anti-parallel of (HF)2 inside C60 are considered, the latter with an extremely short hydrogen bond. HF bond lengths are elongated upon encapsulation in comparison to its free state analogue. The calculated stability of HF@C60 is functional dependent whereas, (HF)2C60 is thermodynamically unstable for all the functionals. The kinetic stability of (HF)2@C60 is observed through ADMP simulation at 300K temperature. The red shift in HF stretching frequencies is noticed in all cases. NCI analysis exhibits a non-covalent type interaction between HF dimer and the C60 cage. The total interaction energy is found to be negative for HF@C60. EDA analysis showed a high value of repulsive ΔEpauli which makes the (HF)2@C60 system unstable except for the functional BP86-D3 of GGA family. Furthermore, QTAIM analysis is performed and confirmed the presence of (3, -1) bond critical point along the hydrogen bond region for L-shaped (HF)2C60.

NMR studies can provide unique information about protein conformations in solution. In CASP14, three reference structures provided by solution NMR methods were available (T1027, T1029, and T1055), as well as a fourth data set of NMR-derived contacts for a integral membrane protein (T1088). For the three targets with NMR-based structures, the best prediction results ranged from very good (GDT_TS = 0.90, for T1055) to poor (GDT_TS = 0.47, for T1029). We explored the basis of these results by comparing all CASP14 prediction models against experimental NMR data. For T1027, the NMR data reveal extensive internal dynamics, presenting a unique challenge for protein structure prediction. The analysis of T1029 motivated exploration of a novel method of “inverse structure determination”, in which an AF2 model was used to guide NMR data analysis. NMR data provided to CASP predictor groups for target T1088, a 238-residue integral membrane porin, was also used to assess several NMR-assisted prediction methods. Most groups involved in this exercise generated similar beta-barrel models, with good agreement with the experimental data. However, as was also observed in CASP13, some pure prediction groups that did not use the NMR data generated structures for T1088 that better fit the NMR data than the models generated using these experimental data. These results demonstrate the remarkable power of modern methods to predict structures of proteins with accuracies rivaling solution NMR structures, and that it is now possible to reliably use prediction models to guide and complement experimental NMR data analysis.

Reproductive character displacement is a pattern whereby sympatric lineages diverge more in reproductive character morphology than allopatric lineages. This pattern has been observed in many plant species, but comparably few have sought to disentangle underlying mechanisms. Here, in a hyperdiverse lineage of Neotropical plants (Ruellia; Acanthaceae), we present evidence of reproductive character displacement in a macroevolutionary framework (i.e., among species) and document mechanistic underpinnings. In a series of inter-specific hand pollinations in a controlled glasshouse environment, we found that crosses between species that differed more in overall flower size, particularly in style length, were significantly less likely to produce viable seeds. Further, species pairs that failed to set seed were more likely to have sympatric distributions in nature. While these findings could result from competition for pollinators or differential fusion of sympatric populations based on variable crossability, our results instead lend support for a role of reinforcement whereby selection has acted to increase reproductive barriers between sympatric species, especially given divergence in floral traits less likely to be under selection by pollinators (i.e., style length). Our results add to growing evidence that character displacement contributes to exceptional floral diversity of angiosperms.

Background: The paracondylar process is of clinical interest due to its proximity to anatomical structures involved in vital functions. There are limited reports describing abnormalities affecting the paracondylar process (PCP), with traumatic fractures being the most prevalent pathology. Affected horses can present with a variety of signs including headshaking, facial paralysis and/or poor performance. In almost all cases reported in the literature to date, computed tomography has been used to diagnose a PCP fracture. Objectives: The aim of this study was to develop a radiographic technique for imaging the PCP, to determine the optimum radiographic projection angle and trial its use in standing sedated horses. Study design: Pilot study conducted in 10 standing sedated horses. Methods: Three tangential radiographs of the left and right paracondylar processes at 5º, 15º and 20º to the transverse plane were obtained in 10 standing sedated horses. Three blinded observers independently ranked each of the three images for clarity of viewing the PCP. The radiographic projection allowed imaging of the ventral portion of the PCP while avoiding superimposition of other osseous structures. Results: The highest grades were obtained for radiographs with a 5º angle from the transverse plane, and the lowest grades were obtained for a 20º angle. Main limitations: Complex anatomy of the PCP with superimposition of osseous and soft tissue structures. Conclusions: The radiographic technique for the PCP can be safely performed in standing, sedated horses. It is suitable for implementation in general veterinary practice before considering referral for advanced imaging techniques in horses presenting with headshaking or facial paralysis.

Identifying candidate drugs effective in the new coronavirus disease 2019 (Covid-19) is crucial, pending a vaccine against SARS-CoV2. We suggest the hypothesis that Cannabidiol (CBD), a non-psychotropic phytocannabinoid, has the potential to limit the severity and progression of the disease for several reasons: 1) High-CBD Cannabis Sativa extracts are able to downregulate the expression of the two key receptors for SARS-CoV2 in several models of human epithelia 2) CBD exerts a wide range of immunomodulatory and anti-inflammatory effects and it can mitigate the uncontrolled cytokine production featuring Acute Lung Injury 3) Being a PPARΥ agonist, it can display a direct antiviral activity 4) PPARΥ agonists are regulators of fibroblast/myofibroblast activation and can inhibit the development of pulmonary fibrosis, thus ameliorating lung function in recovered patients. We hope our hypothesis, corroborated by several preclinical evidence, will inspire further targeted studies to test CBD as a support drug against the COVID-19 pandemic.

This case highlights an atypical presentation of a patient with no history of mental illness who has been diagnosed with a bipolar disorder associated with severe COVID-19 symptoms. Neuroimaging was only positive for subtle white matter changes; he was treated with antipsychotics and mood-stabilizing agents until he reached partial remission.

We introduce a new pattern of population genetic structure in a host-parasite system that can arise after secondary contact of previously isolated populations. Due to different generation time and therefore different tempo of molecular evolution the host and parasite populations reach different degrees of genetic differentiation during their separation (e.g. in refugia). Consequently, during the secondary contact the host populations are able to re-establish a single panmictic population across the area of contact, while the parasite populations stop their dispersal at the secondary contact zone and create a narrow hybrid zone. From the host’s perspective, the parasite’s hybrid zone functions on a microevolutionary scale as a “parasite turnover zone”: while the hosts are passing from area A to area B, their parasites turn genetically from the area A genotypes to the area B genotypes. We demonstrate this novel pattern on a model composed of Apodemus mice and Polyplax lice by comparing maternally inherited markers (complete mitochondrial genomes, and complete genomes of vertically transmitted symbiont Legionella polyplacis) with SNPs derived from the louse genomic data. We discuss circumstances that may lead to this pattern and possible reasons why it has been overlooked in the studies on host-parasite population genetics.

Models of surface enhancement of molecular electronic response properties are challenging for two reasons: (1) molecule-surface interactions require the simultaneous solution of the molecular and the surface dynamic response (a daunting task); (2) when solving for the electronic structure of the combined molecule+surface system, it is not trivial to single out the particular physical effects responsible for enhancement. To attack this problem, in this work we apply a formally exact decomposition of the system’s response function into subsystem contributions by employing subsystem DFT which grants access to dynamic polarizabilities and optical spectra. In order to access information about the interactions between the subsystems, we extend a previously developed subsystem-based adiabatic connection fluctuation-dissipation theorem of DFT to separate the additive from the nonadditive correlation energy and identify the nonadditive correlation as the van der Waals interactions. As an example, we choose benzene adsorbed on monolayer MoS2. We isolate the contributions to the benzene’s dynamic response arising from the interaction with the surface and for the first time, we evaluate the enhancements to the effective C6 coefficients as a function of benzene-MoS2 distance and adsorption site. We also quantify the spectral broadening of the benzene’s electronic excited states due to their interaction with the surface. We find that the broadening has a similar decay law with the molecule-surface distance as the leading van der Waals interactions (i.e., R-6) and that the surface enhancement of dispersion interactions between benzene molecules is less than 5\%, but still large enough (0.5 kcal/mol) to likely play a role in the prediction of interface morphologies.