bluuebunny/crossref_metadata_2025 huggingface dataset:
Pandemic, Primary Health Workers and work trajectories: A Memoing Representational Study
Authors: Nayar K Rajasekharan , Gupta Ujjwala , Vijayan Bindhya , SB Sunitha , VS Kapila , Sivanand Shringa , SH Krishna , Fazaludeen Koya Shaffi
Published: November 2021

More than 65 per cent of the population in India lives in rural areas with the highest overall burden of disease. The Indian rural health care system is composed of the three-tier system comprising Sub-Centres, Primary Health Centres, and Community Health Centres with a considerable shortfall in health facilities at different levels - 18 per cent at Sub centre level, 22 per cent at PHC level and 30 per cent at CHC level. The real facts and figures of the epidemic in rural areas are not known yet except for broad distribution patterns. The course of events with respect to preventive strategies to control COVID-19 especially the experiences in states like Kerala which has comparatively well-developed health infrastructure are important as a lesson for managing future emergencies. In the present study, the responses and experiences of the frontline health workers including ASHA workers toward the pandemic are documented. We followed a Memoing approach- largely similar to in-depth interviews- based on conversations with primary level health workers including ASHA workers and Junior Health Staff. The conversations which lasted for about one hour and in some cases more were presented by the respondents as experiential representations and memoranda on which reflective notes were prepared by the authors who conversed with the staff. The conversations mainly echoed the complaints, concerns and criticisms of the staff regarding the program and the severe limitations that they faced in COVID control. Based on the narratives as well as representations, we could identify interlinked dominant and minor specific-context related issues which are important for equity-based universal health coverage. Firstly, training of primary health workers in Primary Emergency Health care is important in order to counter unpleasant human interactions and also for maintaining security. The training is also important to counter misinformation which is hampering positive health actions. Secondly, it is important to reinvigorate the medical loop and preventive protocols in health programs to strengthen the health service system at the grassroots level especially enhance the trust between the workers and the people. COVID 19 pandemic is an opportunity to recognize and reinforce the role of primary care workers and formulate gender-sensitive and effective control strategies.
Transmission of B.1.617.2 Delta Variant between vaccinated healthcare workers
Authors: Kemp Steven A. , Cheng Mark TK , Hamilton Will , Kamelian Kimia ,   INSACOG Consortium, Singh Sujit , Rakshit Partha , Aggrawal Anurag , Illingworth Chris , Gupta Ravindra K.
Published: November 2021

Breakthrough infections with SARS-CoV-2 Delta variant have been reported in vaccine recipients and in individuals infected with previous variants. However the potential for fully vaccinated individuals (two doses) to transmit SARS-CoV-2 is unclear. We here analyse data from health care workers in two hospitals in India, constructing probable transmission networks from epidemiological and virus genome sequence data using a suite of computational approaches. Among known cases we identify a high probability that doubly vaccinated individuals transmitted SARS-CoV-2, and potential cases of virus transmission between individuals who had received two doses of vaccine. Our findings highlight the need for ongoing infection control measures even in highly vaccinated populations.
Epidemiological and microbiological investigation of the large increase of vibriosis in northern Europe in 2018
Authors: Amato Ettore , Riess Maximilian , Thomas-Lopez Daniel , Linkevicius Marius , Pitkänen Tarja , Wołkowicz Tomasz , Rjabinina Jelena , Jernberg Cecilia , Hjertqvist Marika , MacDonald Emily , Antony-Samy Jeevan Karloss , Bjerre Karsten Dalsgaard , Salmenlinna Saara , Fuursted Kurt , Hansen Anette , Naseer Umaer
Published: November 2021

Northern European countries and countries bordering the Baltic Sea have witnessed an increase of vibriosis cases during recent heatwaves. Here, we described the epidemiology of vibriosis cases and the genetic diversity of Vibrio isolates from Norway, Sweden, Denmark, Finland, Poland, Estonia, and Latvia in 2018, a year with an exceptionally warm summer. We conducted a retrospective study and analysed demographics, geographic distribution, seasonality, causative species, and severity of non-travel related vibriosis cases in 2018. Data sources included surveillance systems, national laboratory notification databases and/or nationwide surveys to public health microbiology laboratories. Moreover, we performed whole genome sequencing and multilocus sequence typing of available isolates from 2014-2018 to map their genetic diversity.

In 2018, we identified 445 non-travel related vibriosis cases in the study countries, which was considerably higher than the median of 126 cases between 2014-2017 (range: 87-272). The main reported mode of transmission was exposure to seawater. We observed a species-specific geographic disparity of vibriosis cases across the Nordic-Baltic region. Developing severe vibriosis was associated with infections of Vibrio vulnificus (adjOR: 17.2; 95% CI: 3.3-90.5) or Vibrio parahaemolyticus (adjOR: 2.1; 95% CI: 1.0-4.5), being ≥65 years of age (65-79 years, adjOR: 3.9; 95% CI: 1.7-8.7; 80+ years, adjOR: 15.5; 95% CI: 4.4-54.3) or acquiring infections during summer (adjOR: 5.1; 95% CI: 2.4-10.9). Although phylogenetic analysis revealed diversity between Vibrio isolates, two V. vulnificus clusters (<10 SNPs) were identified. A share sentinel surveillance system for vibriosis during summer months might be highly valuable to monitor this emerging public health issue.
Protective characteristics of COVID-19 convalescent and post-vaccination IgG antibodies
Authors: Klegerman Melvin E. , Peng Tao , Seferovich Ira , Rahbar Mohammad H. , Hessabi Manouchehr , Tahanan Amirali , Wanger Audrey , Grimes Carolyn Z. , Ostrosky-Zeichner Luis Z. , Koster Kent , Cirillo Jeffrey D. , Abeydeera Dinuka , De Lira Steve , McPherson David D.
Published: November 2021

Soon after commencement of the SARS-CoV-2 disease outbreak of 2019 (COVID-19), it became evident that the receptor-binding domain of the viral spike protein is the target of neutralizing antibodies that comprise a critical element of protective immunity to the virus. This study addresses the relative lack of information regarding actual antibody concentrations in convalescent plasma samples from COVID-19 patients and extends these analyses to post-vaccination samples to estimate protective IgG antibody (Ab) levels. Both sample populations were similar and a protective Ab level of 7.5 µg/ml was determined, based on 95% of the normal distribution of the post-vaccination population. The results of this study have implications for future vaccine development, projection of protective efficacy duration, and understanding of the immune response to SARS-CoV-2 infection.

One-Sentence Summary

Using two quantitative immunoassays, we have found similar IgG antibody responses to the SARS-CoV-2 spike protein in populations of COVID-19 survivors and vaccine recipients that indicate a protective antibody concentration.
A game theory based analysis of network connectivity reveals that state transition is crucial for epilepsy surgery outcome prediction
Authors: Ivankovic Karla , Principe Alessandro , Montoya Justo , Manubens-Gil Linus , Dierssen Mara , Rocamora Rodrigo
Published: November 2021

Seizures recur in half of patients who undergo epilepsy surgery. Presurgical workup mainly focuses on seizures, but only partially helps predicting outcomes, even after invasive electroencephalography. We conceived a generalizable model to detect epileptogenic networks through connectivity changes and identified the crucial role of the transition from pre-seizure to seizure, achieving the highest outcome prediction (93%) to date in a chronological cohort of 21 patients with 3-year follow-up or more.
Baseline hypocapnia is associated with intubation in COVID-19 diagnosed patients
Authors: Gounidis Athanasios , Evangeliou Alexandros P. , Kloura Christina , Manganari Evangelia , Parisi Christiana , Kourtidis Michalis , Kotronis Georgios , Apostolopoulou Martha , Apostolidou-Kiouti Fani
Published: November 2021

Introduction

Hypocapnia may be one of the several factors predefining the need for intubation of patients needing hospitalization for COVID-19 pneumonia.

Methods

A retrospective evaluation of patient files hospitalized for COVID-19 pneumonia from October 2020 until January 2021. Univariate and multivariate regression was used, as well as a multinomial regression to account for multiple endpoints (discharge, intubation, death).

Results

Hypocapnia was strongly associated with intubation (OR: 0.86, 95% CI: 0.76, 0.97). Additionally, last pCO2 (OR: 1.08, 95% CI: 1.01, 1.16), baseline FiO2 (OR: 1.05, 95% CI: 1.03, 1.07) as well as last FiO2 (OR: 1.21, 95% CI: 1.11, 1.46), total severity score on admission (OR: 1.18, 95% CI: 1.03, 1.37) and last pO2 (OR: 0.89, 95% CI: 0.85, 0.92) were found to have a significant impact on intubation. Incorporation of deceased patients withheld the negative association with pCO2 levels (OR: 0.88, 95% CI: 0.78, 0.98).

Conclusion

The dissociation between respiratory failure and a clinically comfortable patient is partly due to decreased carbon dioxide levels and clinicians should bare it in mind when handling patients with COVID-19 pneumonia. Hypocapnia seems to be a determinant factor of intubation in patients with COVID-19 pneumonia in this study.
Modelling optimal vaccination strategies against Covid-19 in a context of Gamma variant predominance in Brazil
Authors: Ferreira Leonardo Souto , de Almeida Gabriel Berg , Borges Marcelo Eduardo , Simon Lorena Mendes , Poloni Silas , Bagattini Ângela Maria , da Rosa Michelle Quarti Machado , Filho José Alexandre Felizola Diniz , de Souza Kuchenbecker Ricardo , Camey Suzi Alves , Kraenkel Roberto André , Coutinho Renato Mendes , Toscano Cristiana Maria
Published: November 2021

Brazil experienced moments of collapse in its health system throughout 2021, driven by a timid initial vaccination strategy against Covid-19, combined with the emergence of variants of interest (VOC). Mathematical modelling has been used to subsidize decision-makers in public health planning. Considering the vaccine products available, effectiveness estimates, the emergence of Gamma as the predominant VOC circulating in 2021, and national estimated doses available for the next several months, we developed a Markov-chain mathematical modelling approach to evaluate optimal strategies for Covid-19 vaccination in Brazil in terms of Covid deaths averted. Our main findings are that in order to reach higher vaccination impact in Brazil, Covid-19 immunization strategies should include recovering vaccination coverage rates in high-risk groups reaching higher coverage; expanding vaccination to younger age groups should be considered only after ensuring at least 80% coverage in older age groups; reducing the interval between doses of AZD1222 from 12 to 8 weeks. We also demonstrate that the latter is only feasible if accompanied by an increase in vaccine supply of at least 50% in the next six month period.
Deep Learning based Intraretinal Layer Segmentation using Cascaded Compressed U-Net
Authors: Yadav Sunil K. , Kafieh Rahele , Zimmermann Hanna G. , Kauer-Bonin Josef , Nouri-Mahdavi Kouros , Mohammadzadeh Vahid , Shi Lynn , Kadas Ella M. , Paul Friedemann , Motamedi Seyedamirhosein , Brandt Alexander U.
Published: November 2021

Abstract

Intraretinal layer segmentation on macular optical coherence tomography (OCT) images generates non invasive biomarkers querying neuronal structures with near cellular resolution. While first deep learning methods have delivered promising results with high computing power demands, a reliable, power efficient and reproducible intraretinal layer segmentation is still an unmet need. We propose a cascaded two-stage network for intraretinal layer segmentation, with both networks being compressed versions of U-Net (CCU-INSEG). The first network is responsible for retinal tissue segmentation from OCT B-scans. The second network segments 8 intraretinal layers with high fidelity. By compressing U-Net, we achieve 392- and 26-time reductions in model size and parameters in the first and second network, respectively. Still, our method delivers almost similar accuracy compared to U-Net without additional constraints of computation and memory resources. At the post-processing stage, we introduce Laplacian-based outlier detection with layer surface hole filling by adaptive non-linear interpolation. We trained our method using 17,458 B-scans from patients with autoimmune optic neuropathies, i.e. multiple sclerosis, and healthy controls. Voxel-wise comparison against manual segmentation produces a mean absolute error of 2.3μm, which is 2.5x better than the device’s own segmentation. Voxel-wise comparison against external multicenter data leads to a mean absolute error of 2.6μm for glaucoma data using the same gold standard segmentation approach, and 3.7μm mean absolute error compared against an externally segmented reference data set. In 20 macular volume scans from patients with severe disease, 3.5% of B-scan segmentation results were rejected by an experienced grader, whereas this was the case in 41.4% of B-scans segmented with a graph-based reference method.
Emergence and widespread circulation of a recombinant SARS-CoV-2 lineage in North America
Authors: Gutierrez Bernardo , Castelán Sánchez Hugo G. , da Silva Candido Darlan , Jackson Ben , Fleishon Shay , Ruis Christopher , Delaye Luis , Rambaut Andrew , Pybus Oliver G. , Escalera-Zamudio Marina
Published: November 2021

Genetic recombination is an important driving force of coronavirus evolution. While some degree of virus recombination has been reported during the COVID-19 pandemic, previously detected recombinant lineages of SARS-CoV-2 have shown limited circulation and been observed only in restricted areas. Prompted by reports of unusual genetic similarities among several Pango lineages detected mainly in North and Central America, we present a detailed phylogenetic analysis of four SARS-CoV-2 lineages (B.1.627, B.1.628, B.1.631 and B.1.634) in order to investigate the possibility of virus recombination among them. Two of these lineages, B.1.628 and B.1.631, are split into two distinct clusters (here named major and minor). Our phylogenetic and recombination analyses of these lineages find well-supported phylogenetic differences between the Orf1ab region and the rest of the genome (S protein and remaining reading frames). The lineages also contain several deletions in the NSP6, Orf3a and S proteins that can augment reconstruction of reliable evolutionary histories. By reconciling the deletions and phylogenetic data, we conclude that the B.1.628 major cluster originated from a recombination event between a B.1.631 major virus and a lineage B.1.634 virus. This scenario inferred from genetic data is supported by the spatial and temporal distribution of the three lineages, which all co-circulated in the USA and Mexico during 2021, suggesting this region is where the recombination event took place. We therefore support the designation of the B.1.628 major cluster as recombinant lineage XB in the Pango nomenclature. The widespread circulation of lineage XB across multiple countries over a longer timespan than the previously designated recombinant XA lineage raises important questions regarding the role and potential effects of recombination on the evolution of SARS-CoV-2 during the ongoing COVID-19 pandemic.
SARS-CoV2 serology assays: utility and limits of different antigen based tests through the evaluation and the comparison of four commercial tests
Authors: Gdoura Mariem , Halouani Habib , Mrad Mehdi , Donia Sahli , Chamsa Wafa , Mabrouk Manel , Salem Kamel Ben , Hogga Nahed , Triki Henda
Published: November 2021

Introduction

SARS-CoV2 serology testing is multipurpose provided to choose an efficient test. We evaluated and compared 4 different commercial serology tests, three of them had the Food and Drug Administration (FDA) approval. Our goal was to provide new data to help to guide the interpretation and the choice of the serological tests.

Methods

Four commercial tests were evaluated: Cobas®Roche®(total anti-N antibodies), VIDAS®Biomerieux®(IgM and IgG anti-RBD antibodies), Mindray®(IgM and IgG anti-N and anti-RBD antibodies) and Access®Beckman Coulter®(IgG anti-RBD antibodies). Were tested: a positive panel (n=72 sera) obtained from COVID-19 confirmed patients and a negative panel (n=119) of pre-pandemic sera. Were determined the analytical performances and was drawn the ROC curve to assess the manufacturer’s threshold.

Results

A large range of variability between the tests was found. Mindray®IgG and Cobas® tests showed the best overall sensitivity 79,2%CI95%[67,9-87,8]. Cobas® showed the best sensitivity after D14; 85,4%CI95%[72,2-93,9]. The best specificity was noted for Cobas®, VIDAS®IgG and Access® IgG(100%CI95%[96,9-100]). Access® had the lower sensitivity even after D14 (55,5% CI95%[43,4-67,3]). VIDAS®IgM and Mindray®IgM tests showed the lowest specificity and sensitivity rates. Overall, only 43 out of 72 sera gave concordant results (59,7%). Retained cut-offs for a significantly better sensitivity and accuracy, without altering significantly the specificity, were: 0,87 for Vidas®IgM(p=0,01), 0,55 for Vidas®IgG(p=0,05) and 0,14 for Access®(p<10−4).

Conclusion

Although FDA approved, each laboratory should realize its own evaluation for commercial tests. Tests variability may raise some concerns that seroprevalence studies may vary significantly based on the used serology test.
Doppler Slicing for Ultrasound Super-Resolution Without Contrast Agents
Authors: Bar-Zion Avinoam , Solomon Oren , Rabut Claire , Maresca David , Eldar Yonina C. , Shapiro Mikhail G.
Published: November 2021

Much of the information needed for diagnosis and treatment monitoring of diseases like cancer and cardiovascular disease is found at scales below the resolution limit of classic ultrasound imaging. Recently introduced vascular super-localization methods provide more than a ten-fold improvement in spatial resolution by precisely estimating the positions of microbubble contrast agents. However, most vascular ultrasound scans are currently performed without contrast agents due to the associated cost, training, and post-scan monitoring. Here we show that super-resolution ultrasound imaging of dense vascular structures can be achieved using the natural contrast of flowing blood cells. Instead of relying on separable targets, we used Fourier-based decomposition to separate signals arising from the different scales of vascular structures while removing speckle noise using multi-ensemble processing. This approach enabled the use of compressed sensing for super-resolution imaging of the underlying vascular structures, improving resolution by a factor of four. Reconstruction of ultrafast mouse brain scans revealed details that could not be resolved in regular Doppler images, agreeing closely with bubble-based super-localization microscopy of the same fields of view. By combining multi-ensemble Doppler acquisitions with narrowband Fourier decomposition and computational super-resolution imaging, this approach opens new opportunities for affordable and scalable super-resolution ultrasound imaging.
The rat frontal cortex encodes a value map for economic decisions under risk
Authors: Zhu Xiaoyue , Bao Chaofei , Moller-Mara Joshua , Li Jingjie , Dubroqua Sylvain , Erlich Jeffrey C.
Published: November 2021

Neurons in frontal and parietal cortex encode task variables during decision-making, but causal manipulations of the two regions produce strikingly different results. For example, silencing the posterior parietal cortex (PPC) in rats and monkeys produces minimal effects in perceptual decisions requiring integration of sensory evidence, but silencing frontal cortex profoundly impairs the same decisions. Here, we tested the causal roles of the rat frontal orienting field (FOF) and PPC in economic choice under risk. On each trial, rats chose between a lottery and a small but guaranteed surebet. The magnitude of the lottery was independently varied across trials and was indicated to the rat by the pitch of an auditory cue. As in perceptual decisions, both unilateral and bilateral PPC muscimol inactivations produced minimal effects. FOF inactivations produced substantial changes in behavior even though our task had no working memory component. We quantified control and bilateral inactivation behavior with a multi-agent model consisting of a mixture of a ‘rational’ utility-maximizing agent (U=Vρ) with two ‘habitual’ agents that either choose surebet or lottery. Effects of FOF silencing were best accounted for by a decrease inρ, the exponent of the utility function. The decrease inρcould be parsimoniously explained by a dynamical model where the FOF is part of a network that represents the value of the lottery to compare against a remembered boundary representing the value of the surebet. This dynamical model predicted that neurons in the FOF should increase their activity with increasing lottery values. In line with our predictions, single neurons recorded in the FOF encoded the value of the lottery even when controlling for choice. These results together demonstrate that FOF is a critical node in the neural circuit for decision under risk.
Neural population dynamics reveals disruption of spinal sensorimotor computations during electrical stimulation of sensory afferents
Authors: Secerovic Natalija Katic , Balaguer Josep-Maria , Gorskii Oleg , Pavlova Natalia , Liang Lucy , Ho Jonathan , Grigsby Erinn , Gerszten Peter C. , Karal-ogly Dzhina , Bulgin Dmitry , Orlov Sergei , Pirondini Elvira , Musienko Pavel , Raspopovic Stanisa , Capogrosso Marco
Published: November 2021

While neurostimulation technologies are rapidly approaching clinical applications for sensorimotor disorders, the impact of electrical stimulation on network dynamics is still unknown. Given the high degree of shared processing in neural structures, it is critical to understand if neurostimulation affects functions that are related to, but not targeted by the intervention. Here we approached this question by studying the effects of electrical stimulation of cutaneous afferents on unrelated processing of proprioceptive inputs. We recorded intra-spinal neural activity in four monkeys while generating proprioceptive inputs from the radial nerve. We then applied continuous stimulation to the radial nerve cutaneous branch and quantified the impact of the stimulation on spinal processing of proprioceptive inputs via neural population dynamics. Proprioceptive pulses consistently produced neural trajectories that were disrupted by concurrent cutaneous stimulation. This disruption propagated to the somatosensory cortex, suggesting that electrical stimulation can perturb natural information processing across the neural axis.
Oxygenated hemoglobin signal provides greater predictive performance of experimental condition than de-oxygenated
Authors: Luke Robert , Shader Maureen J , Gramfort Alexandre , Larson Eric , Lee Adrian KC , McAlpine David
Published: November 2021

Continuous-wave functional near-infrared spectroscopy (fNIRS) neuroimaging provides an estimate of relative changes in oxygenated and de-oxygenated hemoglobin content, from which regional neural activity is inferred. The relation between both signals is governed by neurovascular coupling mechanisms. However, the magnitude of concentration changes and the contribution of noise sources to each chromophore is unique. Subsequently, it is not apparent if either chromophore signal practically provides greater information about the underlying neural state and relation to an experimental condition. To assess this question objectively, we applied a machine-learning approach to four datasets and evaluated which hemoglobin signal best differentiated between experimental conditions. To further ensure the objective nature of the analysis, the algorithm utilized all samples from the epoched data rather than pre-selected features. Regardless of experimental task, brain region, or stimulus, the oxygenated hemoglobin signal was better able to differentiate between conditions than the de-oxygenated signal. Incorporating both signals into the analysis provided no additional improvement over oxygenated hemoglobin alone. These results indicate that oxyhemoglobin is the most informative fNIRS signal in relation to experimental condition.
A Comparison Study between Autism Spectrum Disorder and Typically Control in Graph Frequency Bands Using Graph and Triadic Interaction Metrics
Authors: Jafadideh Alireza Talesh , Mohammadzadeh Asl Babak
Published: November 2021

Many researchers using many different approaches have attempted to find features discriminating between autism spectrum disorder (ASD) and typically control (TC) subjects. In this study, this attempt has been continued by analyzing global metrics of functional graphs and metrics of functional triadic interactions of the brain in the low, middle, and high-frequency bands (LFB, MFB, and HFB) of the structural graph. The graph signal processing (GSP) provided the combinatorial usage of the functional graph of resting-state fMRI and structural graph of DTI. In comparison to TCs, ASDs had significantly higher clustering coefficients in the MFB, higher efficiencies and strengths in the MFB and HFB, and lower small-world propensity in the HFB. These results show over-connectivity, more global integration, and probably decreased local specialization in ASDs compared to TCs. Triadic analysis showed that the numbers of unbalanced triads were significantly lower for ASDs in the MFB. This finding may show the reason for restricted and repetitive behavior in ASDs. Also, in the MFB and HFB, the numbers of balanced triads and the energies of triadic interactions were significantly higher and lower for ASDs, respectively. These findings may reflect the disruption of the optimum balance between functional integration and specialization. All of these results demonstrated that the significant differences between ASDs and TCs existed in the MFB and HFB of the structural graph when analyzing the global metrics of the functional graph and triadic interaction metrics. In conclusion, the results demonstrate the promising perspective of GSP for attaining discriminative features and new knowledge, especially in the case of ASD.

Graphical Abstract
A Method for Computationally Constructing Eukaryotic Synthetic Signal Peptide Sequences
Authors: Daly Grant T. , Prakash Aishwarya , Benton Ryan G. , Johnsten Tom
Published: November 2021

We developed a computational method for constructing synthetic signal peptides from a base set of signal peptides (SPs) and non-SP sequences. A large number of structured “building blocks”, represented as m-step ordered pairs of amino acids, are extracted from the base. Using a straightforward procedure, the building blocks enable the construction of a diverse set of synthetic SPs that could be utilized for industrial and therapeutic purposes. We have validated the proposed methodology using existing sequence prediction platforms such as Signal-BLAST and MULocDeep. In one experiment, 9,555 protein sequences were generated from a large randomly selected set of “building blocks”. Signal-BLAST identified 8,444 (88%) of the sequences as signal peptides. In addition, the Signal-BLAST tool predicted that the generated synthetic sequences belonged to 854 distinct eukaryotic organisms. Here, we provide detailed descriptions and results from various experiments illustrating the potential usefulness of the methodology in generating signal peptide protein sequences.
Systematic in silico discovery of novel solute carrier-like proteins from proteomes
Authors: Gyimesi Gergely , Hediger Matthias A.
Published: November 2021

Solute carrier (SLC) proteins represent the largest superfamily of transmembrane transporters. While many of them play key biological roles, their systematic analysis has been hampered by their functional and structural heterogeneity. Based on available nomenclature systems, we hypothesized that many as yet unidentified SLC transporters exist in the human genome, which await further systematic analysis. Here, we present criteria for defining “SLC-likeness” to curate a set of “SLC-like” protein families from the Transporter Classification Database (TCDB) and Protein families (Pfam) databases. Computational sequence similarity searches surprisingly identified ∼120 more proteins in human with potential SLC-like properties compared to previous annotations. Interestingly, several of these have documented transport activity in the scientific literature. To complete the overview of the “SLC-ome”, we present an algorithm to classify SLC-like proteins into protein families, investigating their known functions and evolutionary relationships to similar proteins from 6 other clinically relevant experimental organisms, and pinpoint structural orphans. We envision that our work will serve as a stepping stone for future studies of the biological function and the identification of the natural substrates of the many under-explored SLC transporters, as well as for the development of new therapeutic applications, including strategies for personalized medicine and drug delivery.
Host exposure to symbionts and ecological drift generate divergence in parasite community assembly
Authors: Grunberg Rita L. , Joyner Brooklynn N. , Mitchell Charles E.
Published: November 2021

The initial colonization of a host by symbionts, ranging from parasites to mutualists, can generate priority effects that alter within-host interactions and the trajectory of parasite community assembly. At the same time, variation in parasite communities among hosts can also stem from stochastic processes. Community ecology theory posits that multiple processes (e.g. dispersal, selection and drift) interact to generate variation in community structure, but these processes are rarely considered simultaneously during community assembly. To test the role of these processes in a parasite community, we experimentally simulated dispersal of three symbionts by factorially inoculating individual plants of tall fescue with two foliar fungal parasites, Colletotrichum cereale and Rhizoctonia solani, and a hypothesized mutualist endophyte, Epichloë coenophiala. We then tracked parasite infections longitudinally in the field. After the initial inoculations, hosts were exposed to a common pool of parasites in the field, which we expected to cause parasite communities to converge towards a similar community state. To test for convergence, we analyzed individual hosts’ parasite community trajectories in multivariate space. In contrast to our expectation, there was no signal of convergence. Instead, parasite community trajectories generally diverged over time between treatment groups and the magnitude of divergence depended on the symbiont species inoculated. Parasite communities of hosts that were inoculated with only the mutualist, Epichloë, showed significant trends of divergence relative to all other symbiont inoculation treatments. In contrast, hosts inoculated with only Rhizoctonia did not exhibit clear trends of divergence when compared to other parasite inoculations. Further, co-inoculation with both parasite species resulted in faster rates of divergence and greater temporal change in parasite communities relative to hosts inoculated with only the parasite Colletotrichum. As predicted by existing theory, parasite communities showed evidence of drift during the beginning of the experiment, which contributed to among-host divergence in parasite community structure. Overall, these data provide evidence that initial dispersal of symbionts produced persistent changes in parasite community structure via ecological selection, that drift was important during the early stages of parasite community assembly, and together, dispersal, selection and drift resulted in parasite community divergence.

Open Research statement

The data and code that support the findings of this study are available through Zenodo at https://doi.org/10.5281/zenodo.5714452
Putting the theory into ‘burstlet theory’: A biophysical model of bursts and burstlets in the respiratory preBötzinger complex
Authors: Phillips Ryan S. , Rubin Jonathan E.
Published: November 2021

Inspiratory breathing rhythms arise from synchronized neuronal activity in a bilaterally distributed brainstem structure known as the preBötzinger complex (preBötC). In in vitro slice preparations containing the preBötC, extracellular potassium must be elevated above physiological levels (to 7 − 9 mM) to observe regular rhythmic respiratory motor output in the hypoglossal nerve to which the preBötC projects. Reexamination of how extracellular K+ affects preBötC neuronal activity has revealed that low amplitude oscillations persist at physiological levels. These oscillatory events are sub-threshold from the standpoint of transmission to motor output and are dubbed burstlets. Burstlets arise from synchronized neural activity in a rhythmogenic neuronal subpopulation within the preBötC that in some instances may fail to recruit the larger network events, or bursts, required to generate motor output. The fraction of subthreshold preBötC oscillatory events (burstlet fraction) decreases sigmoidally with increasing extracellular potassium. These observations underlie the burstlet theory of respiratory rhythm generation. Experimental and computational studies have suggested that recruitment of the non-rhythmogenic component of the preBötC population requires intracellular Ca2+ dynamics and activation of a calcium-activated non-selective cationic current. In this computational study, we show how intracellular calcium dynamics driven by synaptically triggered Ca2+ influx as well as Ca2+ release/uptake by the endoplasmic reticulum in conjunction with a calcium-activated non-selective cationic current can explain all of the key observations underlying the burstlet theory of respiratory rhythm generation. Thus, we provide a mechanistic basis to unify the experimental findings on rhythm generation and motor output recruitment in the preBötC.
Constructing threat probability, fear behaviour, and aversive prediction error in the brainstem
Authors: Strickland Jasmin A. , McDannald Michael A.
Published: November 2021

When faced with potential threat we must estimate its probability, respond advantageously, and leverage experience to update future estimates. Threat estimates are the proposed domain of the forebrain, while behaviour is elicited by the brainstem. Yet, the brainstem is also a source of prediction error, a learning signal to acquire and update threat estimates. Neuropixels probes allowed us to record single-unit activity across a 21-region brainstem axis during probabilistic fear discrimination with foot shock outcome. Against a backdrop of diffuse behaviour signaling, a brainstem network with a dorsal hub signaled threat probability. Neuronal function remapping during the outcome period gave rise to brainstem networks signaling prediction error and shock on multiple timescales. The results reveal construction of threat probability, behaviour, and prediction error along a single brainstem axis.

One-Sentence Summary

The brainstem constructs threat probability, behaviour, and prediction error from neuronal building blocks.
Short-Term Effects of Strengthening Exercises of Lower Limb Rehabilitation Protocol on Pain, Stiffness, Physical Function and Body Mass Index among Knee Osteoarthritis Participants Who Were Overweight or Obese: A Clinical Trial
Authors: Rafiq Muhammad Tariq , Abdul Hamid Mohamad Shariff , Hafiz Eliza
Published: November 2021

Background

Osteoarthritis (OA) of the knee is defined as a progressive disease of the synovial joints and is characterized by wear and tear of cartilage and underlying bone. This study aimed to determine the short-term effects of the lower limb rehabilitation protocol (LLRP) on pain, stiffness, physical function, and body mass index (BMI) among knee OA participants who were overweight or obese.

Methodology

Single blinded randomized controlled trial of one-month duration was conducted at Rehmatul-Lil-Alameen Postgraduate Institute, Lahore, Pakistan. Fifty overweight or obese participants with knee OA were randomly divided into two groups by a computer-generated number. Participants in the Rehabilitation Protocol Group (RPG) were provided with leaflets explaining the strengthening exercises of the LLRP and instruction of daily care (IDC), while the participants in the Control Group (CG) were provided with leaflets explaining IDC only for a duration of four weeks. The primary outcome measures were the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores for pain, stiffness, and physical function. The secondary outcome measures were BMI, exercise adherence, and patients’ satisfaction by the numeric rating scale ranging from 0 to 10. Paired Samples t-test was used to analyze the differences within groups from baseline to post-test evaluations. The analysis of variance 2 × 2 factor was used to analyze the difference of BMI, knee pain, stiffness, and physical function between the groups.

Results

Participants in the RPG and CG reported a statistically significant reduction in knee pain, and stiffness (p ≤ 0.05) within group. The reduction in the scores of knee pain was higher in participants of the RPG than the CG (p = 0.001). Additionally, participants in the RPG reported greater satisfaction (p = 0.001), higher self-reported exercise adherence (p = 0.010) and coordinator-reported exercise adherence (p = 0.046) compared to the participants in the CG.

Conclusion

Short-term effects of the LLRP appear to reduce knee pain and stiffness only, but not physical function and BMI.

TRIAL REGISTRATION

Name: Iranian Registry of Clinical Trials

Number: IRCT20191221045846N2

Date of registration: June 28, 2020

Registration timing: prospective
Turning green: the impact of changing to more eco-friendly respiratory healthcare. A carbon and cost analysis of Dutch prescription data
Authors: Have Pieter ten , van Hal Peter Th. W. , Wichers Iris , Kooistra Johan , Hagedoorn Paul , Brakema Evelyn , Chavannes Niels , de Heer Pauline , Ossebaard Hans C
Published: November 2021

Objectives

Dry powder inhalers (DPIs) and soft mist inhalers have a substantially lower global warming potential than pressurized metered-dose inhalers (pMDIs). To help mitigate climate change, we assessed the potential emission reduction in CO2-equivalents when replacing pMDIs by non-propellant inhalers in Dutch respiratory healthcare, and estimated the associated costs.

Design

We performed a four-step analysis based on data from two national databases of two independent governmental bodies (the Dutch National Healthcare Institute and the Dutch Healthcare Authority). First, we calculated the number of patients with chronic obstructive pulmonary disease and asthma that were using inhalation medication (2020). Second, we calculated the number and total of daily defined doses of pMDIs and non-propellant inhalers (NPIs) that include dry powder inhalers and soft mist inhalers, as well as the number of spacers per patient dispensed by non-hospital based pharmacies in 2020. Third, we estimated the potential reduction in greenhouse gas emission if 70% of patients would switch from using pMDIs to using NPIs as eco-friendly alternatives. Fourth, we performed a budget impact analysis.

Results

In 2020, 1.4 million patients used inhalers for COPD or asthma treatment. A total of 460 million defined daily doses (DDDs) from inhalers were dispensed, of which – after the exclusion of nebulizers – 50.4% through pMDIs. We estimated that this usage could be reduced by 70% which would lead to an annual reduction in greenhouse gas emission of 77 - 84 million kg. CO2-eq. saving at best EUR 49.8 million per year.

Conclusions

In the Netherlands, substitution of pMDIs to NPIs for eligible patients is theoretically safe and in accordance with medical guidelines, while reducing greenhouse gas emission by 80 million kg. CO2-eq. on average and saving at best EUR 49.8 million per year. This study confirms the potential climate and economic benefit of delivering a more eco-friendly respiratory care.

Strengths and limitations of this study

Given availability and reliability of the data, the present analysis can easily be replicated elsewhere which allows for international comparison and aggregation.

Implementation challenges remain underexposed.
Modelling of time-to-events in an ambispective study: illustration with the analysis ofABOblood groups on venous thrombosis recurrence
Authors: Munsch Gaëlle , Goumidi Louisa , van Hylckama Vlieg Astrid , Ibrahim-Kosta Manal , Bruzelius Maria , Deleuze Jean-François , Rosendaal Frits R. , Jacqmin-Gadda Hélène , Morange Pierre-Emmanuel , Trégouët David-Alexandre
Published: November 2021

In studies of time-to-events, it is common to collect information about events that occurred before the inclusion in a prospective cohort. In an ambispective design, when the risk factors studied are independent of time, including both pre- and post-inclusion events in the analyses increases the statistical power but may lead to a selection bias. To avoid such a bias, we propose a survival analysis weighted by the inverse of the survival probability at the time of data collection about the events.

This method is applied to the study of the association of ABO blood groups with the risk of venous thromboembolism (VT) recurrence in the MARTHA and MEGA cohorts. The former relying on an ambispective design and the latter on a standard prospective one. In the combined sample totalling 2,752 patients including 993 recurrences, compared with the O1 group, A1 has an increased risk (Hazard Ratio (HR) of 1.18, p=4.2×10−3), homogeneously in MARTHA and in MEGA. The same trend (HR=1.19, p=0.06) was observed for the less frequent A2 group.

In conclusion, this work clarified the association ofABOblood groups with the risk of VT recurrence. Besides, the methodology proposed here to analyse time-independent risk factors of events in an ambispective design has an immediate field of application in the context of genome wide association studies.
Meta-topologies define distinct anatomical classes of brain tumors linked to histology and survival
Authors: Kernbach Julius M. , Delev Daniel , Neuloh Georg , Clusmann Hans , Bzdok Danilo , Eickhoff Simon B. , Staartjes Victor E. , Vasella Flavio , Weller Michael , Regli Luca , Serra Carlo , Krayenbühl Niklaus , Akeret Kevin
Published: November 2021

Background

The current WHO classification integrates histological and molecular features of brain tumors. The aim of this study was to identify generalizable topological patterns with the potential to add an anatomical dimension to the classification of brain tumors.

Methods

We applied non-negative matrix factorization as an unsupervised pattern discovery strategy to the fine-grained topographic tumor profiles of 936 patients with primary and secondary brain tumors. From the anatomical features alone, this machine learning algorithm enabled the extraction of latent topological tumor patterns, termed meta-topologies. The optimal parts-based representation was automatically determined in 10,000 split-half iterations. We further characterized each meta-topology’s unique histopathologic profile and survival probability, thus linking important biological and clinical information to the underlying anatomical patterns

Results

In primary brain tumors, six meta-topologies were extracted, each detailing a transpallial pattern with distinct parenchymal and ventricular compositions. We identified one infratentorial, one allopallial, three neopallial (parieto-occipital, frontal, temporal) and one unisegmental meta-topology. Each meta-topology mapped to distinct histopathologic and molecular profiles. The unisegmental meta-topology showed the strongest anatomical-clinical link demonstrating a survival advantage in histologically identical tumors. Brain metastases separated to an infra- and supratentorial meta-topology with anatomical patterns highlighting their affinity to the cortico-subcortical boundary of arterial watershed areas.

Conclusions

Using a novel data-driven approach, we identified generalizable topological patterns in both primary and secondary brain tumors Differences in the histopathologic profiles and prognosis of these anatomical tumor classes provide insights into the heterogeneity of tumor biology and might add to personalized clinical decision making.
Efficacy of vasopressin, steroid, and epinephrine protocol for in-hospital cardiac arrest resuscitation: A systematic review and meta-analysis of randomized controlled trials with trial sequential analysis
Authors: Satti Danish Iltaf , Lee Yan Hiu Athena , Leung Keith Sai Kit , Hui Jeremy Man Ho , Kot Thompson Ka Ming , Babar Arslan , Wai Abraham KC , Liu Tong , Roever Leonardo , Tse Gary , Chan Jeffrey Shi Kai ,   International Health Informatics Study (IHIS) Network
Published: November 2021

Aim

To assess the effect of vasopressin, steroid and epinephrine (VSE) combination therapy on return of spontaneous circulation (ROSC) after in-hospital cardiac arrest (IHCA), and test the conclusiveness of evidence using trial sequential analysis (TSA).

Methods

The systematic search included PubMed, EMBASE, Scopus, and Cochrane Central Register of Controlled Trials. Randomized controlled trials that included adult patients with in-hospital cardiac arrest, with at least one group receiving combined vasopressin, epinephrine and steroid therapy were selected. Data was extracted independently by two reviewers. The main outcome of interest was ROSC. Other outcomes included survival to hospital discharge with good neurological outcomes and survival to 30 and 90 days with good neurological outcomes.

Results

We included a total of three randomized controlled trials (n=869 patients). Results showed that Vasopressin, steroid and epinephrine combination therapy increased return of spontaneous circulation (risk ratio, 1.32; 95% CI, 1.18-1.47) as compared to placebo. Trial sequential analysis demonstrated that the existing evidence is conclusive. This was also validated by the alpha-spending adjusted relative risk (1.32 [1.16, 1.49], p<0.0001). Other outcomes could not be meta-analysed due to differences in timeframe in the included studies.

Conclusions

VSE combination therapy administered in cardiopulmonary resuscitation led to improved rates of return of spontaneous circulation. Future trials of vasopressin, steroid and epinephrine combination therapy should evaluate survival to hospital discharge, neurological function and long-term survival.