bluuebunny/crossref_metadata_2025 huggingface dataset:
Midbrain structure volume, estimated myelin and functional connectivity in idiopathic generalised epilepsy
Authors: McKavanagh Andrea , Ridzuan-Allen Adam , Kreilkamp Barbara A.K. , Chen Yachin , Manjón José V. , Coupé Pierrick , Bracewell Martyn , Das Kumar , Taylor Peter N. , Marson Anthony G. , Keller Simon S.
Published: August 2022

Background

Previous neuroimaging studies reported functional and structural impairments of the upper basal ganglia (specifically, the striatum) in idiopathic generalised epilepsy (IGE). However, these studies often overlook lower basal ganglia structures located in and adjacent to the midbrain due to poor contrast on clinically acquired volumetric T1-weighted scans. Here, we acquired 3D isotropic T1-weighted, T2-weighted and resting state functional MR images to investigate differences in volume, estimated myelin content and functional connectivity in three midbrain and midbrain-adjacent structures in patients with IGE: the substantia nigra (SN), subthalamic nuclei (SubTN) and red nuclei (RN).

Methods

A total of 33 patients with IGE (23 refractory, 10 non-refractory) and 39 age and sex matched healthy controls underwent MR imaging. The SN, SubTN and RN were automatically segmented from T2-weighted images. Estimated median myelin content for each structure was determined using a previously described T1-weighted/T2-weighted ratio method. Functional connectivity analysis between midbrain structures and the rest of the brain was performed using seed-based resting state fMRI analysis and compared between participant groups using the CONN toolbox running in SPM12 (pFDR<0.05, cluster corrected).

Results

An increased volume of the right RN was found in patients with IGE relative to healthy controls. Structural volumes of the right SubTN differed between patients with non-refractory and refractory IGE. No myelin alterations of midbrain structures were found in patients with IGE or between treatment outcome groups. Functional connectivity alterations were found for all midbrain regions in patients with IGE, including significantly decreased functional connectivity between the left SN and the thalamus compared to controls, and significantly increased functional connectivity observed between the right SubTN and the left superior frontal gyrus in patients with IGE relative to controls. Connectivity alterations specific to patients with non-refractory IGE were also found.

Conclusion

We report volumetric and functional connectivity alterations of midbrain and lower basal ganglia structures in patients with IGE. We postulate that an increased structural volume of the RN in patients is due to increased iron deposition that impacts on T2-weighted contrast. These findings are consistent with previous experiential work demonstrating pathophysiological abnormalities of the lower basal ganglia in animal models of generalised epilepsy.
Transcriptome analyses of the cortex and white matter of focal cortical dysplasia type II: insights into disease mechanisms and tissue characterization
Authors: Assis-Mendonça Guilherme Rossi , Pedro Athié Maria Carolina , Gerdulli Tamanini João Vitor , de Souza Arethusa , Zanetti Gabriel Gerardini , de Aguiar Araújo Patrícia Aline Oliveira Ribeiro , Ghizoni Enrico , Tedeschi Helder , Machado Alvim Marina Koutsodontis , de Almeida Vanessa Simão , de Souza Welliton , Coras Roland , Yasuda Clarissa Lin , Blümcke Ingmar , Vieira André Schwambach , Cendes Fernando , Lopes-Cendes Iscia , Rogerio Fabio
Published: August 2022

Focal cortical dysplasia (FCD) is a common cause of pharmacoresistant epilepsy. According to the 2022 International League Against Epilepsy classification, FCD type II is characterized by dysmorphic neurons (IIa and IIb) and may be associated with balloon cells (IIb). We present a multicentric study to evaluate the transcriptomes of the gray and white matters of surgical FCD type II specimens. We aimed to contribute to pathophysiology and tissue characterization. We investigated FCD II (a and b) and control samples by performing RNA-sequencing followed by immunohistochemical validation employing digital analyses. We found 342 and 399 transcripts differentially expressed in the gray matter of IIa and IIb lesions compared to controls, respectively. The top enriched cellular pathway in IIa and IIb gray matter was cholesterol biosynthesis, the genes HMGCS1, HMGCR, and SQLE being upregulated in both type II groups. We also found 12 differentially expressed genes when comparing transcriptomes of IIa and IIb lesions. Only 1 transcript (MTRNR2L12) was significantly upregulated in FCD IIa. The white matter in IIa and IIb lesions showed 2 and 24 transcripts differentially expressed, respectively, compared to controls. No enriched cellular pathways were detected. GPNMB, not previously described in FCD samples, was upregulated in IIb compared to IIa and control groups. Upregulations of cholesterol biosynthesis enzymes and GPNMB genes in FCD groups were immunohistochemically validated. Such enzymes were mainly detected in both dysmorphic and normal neurons, whereas GPNMB was observed only in balloon cells. Overall, our study contributed to identifying cortical enrichment of cholesterol biosynthesis in FCD type II, which may correspond to a neuroprotective response to seizures. Moreover, specific analyses in either the gay or the white matter revealed upregulations of MTRNR2L12 and GPNMB, which might be potential neuropathological biomarkers of a cortex chronically exposed to seizures and of balloon cells, respectively.
Knowledge, attitude, and practice of ward attendant and housekeeping staffs towards dead body care of COVID-19 patient at tertiary care hospital : A cross sectional study
Authors: Saini Giriraj , Panda Prasan K , Sharma Maneesh , Singh Mahendra , Meshram Ravi
Published: August 2022

Background

Healthcare workers worked untiringly during entire pandemic period and taken efforts to protect individuals, families and communities in adverse situations with stretched resources. Among health care workers role of ward attendant and housekeeping staffs have been very significant particularly in infection control practices and dead body management. Present study’s aim is to gain an understanding of the knowledge, attitudes, and practices (KAP) of ward attendant and housekeeping staffs towards dead body management.

Methods

Hospital-based cross-sectional study design was conducted among ward attendant and housekeeping staffs working in COVID units. A total of 62 participants were selected using simple random sampling technique. Self-administered questionnaire was used to collect data. Binary logistic regression model was used to see association between outcome and independent variables.

Result

Present study found mean knowledge, attitude and practice score of participants were 6.1, 49.9 and 12.28 indicates good knowledge, positive attitude and inappropriate practice towards dead body care. Study result also shows that odds of good knowledge were not significantly associated with demographic variables. However, the participants who didn’t receive any training on dead body care were found to have positive attitude towards dead body care(AOR=3.90,95%CI=1.092-13.92), whereas gender (AOR=1.85,95%CI=.430-7.96), working experience in COVID units (AOR=99.5,95%CI=.913-98.8) and educational qualification (AOR=30.33,95%CI=1.5-577) were significantly associated with practice of dead body care of COVID-19 patients.

Conclusion

The study found that majority of participants were having good knowledge, positive attitude and inappropriate practice towards dead body care of COVID-19 patients. Hospital administration should conduct regular training of dead body care of COVID-19 patients for all the housekeeping staffs and ward attendant to minimise the risk of exposure to infections and better management of dead bodies.
Hierarchical machine learning predicts geographical origin of Salmonella within four minutes of sequencing
Authors: Bayliss Sion C. , Locke Rebecca K. , Jenkins Claire , Chattaway Marie Anne , Dallman Timothy J. , Cowley Lauren A.
Published: August 2022

Salmonella enterica serovar Enteritidis is one of the most frequent causes of Salmonellosis globally and is commonly transmitted from animals to humans by the consumption of contaminated foodstuffs. Herein, we detail the development and application of a hierarchical machine learning model to rapidly identify and trace the geographical source of S. Enteritidis infections from whole genome sequencing data. 2,313 S. Enteritidis genomes collected by the UKHSA between 2014-2019 were used to train a ‘local classifier per node’ hierarchical classifier to attribute isolates to 4 continents, 11 sub-regions and 38 countries (53 classes). Highest classification accuracy was achieved at the continental level followed by the sub-regional and country levels (macro F1: 0.954, 0.718, 0.661 respectively). A number of countries commonly visited by UK travellers were predicted with high accuracy (hF1: >0.9). Longitudinal analysis and validation with publicly accessible international samples indicated that predictions were robust to prospective external datasets. The hierarchical machine learning framework provides granular geographical source prediction directly from sequencing reads in <4 minutes per sample, facilitating rapid outbreak resolution and real-time genomic epidemiology.
Understanding Waiting Lists Pressures
Authors: Fong Kevin , Mushtaq Yasser , House Thomas , Gordon Dan , Chen Yingrae , Griffths Darren , Ahmad Shazaad , Walton Neil
Published: August 2022

NHS waiting lists currently sit at record lengths due to a combination of the immediate impact of the pandemic and, as well as, long-run pressures requiring investment on NHS resources. These factors have left managers and clinicians with increasingly complex decisions when scheduling elective operations. It is imperative that managers understand the basic dynamics, tradeoffs, and pressures when managing waiting lists.

Queueing theory is a key part of operational research, extensively used throughout manufacturing, retail, information technology and other sectors. This article provides an exposition of the theory of queues within the context of the current NHS backlog. With this information a manager will be able understand the demand, queue size, waiting times, capacity requirements and trade-offs for different waiting lists. We describe the metrics and a reporting system developed to understand waiting list pressures in a large NHS trust. Our aim is to enable managers to better understand their waiting lists, to achieve targets and improve health outcomes.
Sleep Instability in Paradoxical Insomnia is Associated with Perception of Sleep
Authors: Lo Evelyn , Tsai Hsin-Jung , Yang Albert C.
Published: August 2022

Objective

The main clinical characteristics that diversify paradoxical insomniacs from objective insomnia patients remain unclear. The current study systematically examined the difference in sleep-related, subjective-and objective parameters between insomnia patients with or without misperception.

Methods

Patients who reported having poor sleep quality (subjective sleep efficiency; SE ≤ 85%) on both weekends and weekdays and difficulty falling asleep in the Sleep Heart Health Study were examined in this study. Patients with objective SE ≤ 85% and > 85% were then classified as objective insomnia (n = 58) and paradoxical insomnia (n = 61), respectively. The differences in demographic data, subjective sleep quality, daytime function, and objective sleep architecture measured by polysomnography, were assessed between the groups.

Results

Though there were no significant group differences in the demographics between objective insomniacs and paradoxical insomniacs, paradoxical insomniacs reported significantly poorer daytime function than patients with objective insomnia. Moreover, paradoxical insomniacs’ subjective sleep evaluation on recording day was significantly higher than habitual reports. The main finding from this research was that the transition indices from stage N3 to stage N2 or N1 was significantly different between the two groups, which could indicate that sleep instability may be a factor in leading paradoxical insomnia patients to underestimate their sleep efficiency.

Conclusions

Our findings indicated a possible link between sleep misperception and the microstructure of sleep, specifically the sleep-state instability. The interplay between the neurobiology of sleep instability and perception of sleep needs further investigation.
The Role of Modelling and Analytics in South African COVID-19 Planning and Budgeting
Authors: Meyer-Rath Gesine , Hounsell Rachel A , Pulliam Juliet RC , Jamieson Lise , Nichols Brooke E , Moultrie Harry , Silal Sheetal P
Published: August 2022

Background

The South African COVID-19 Modelling Consortium (SACMC) was established in late March 2020 to support planning and budgeting for COVID-19 related healthcare in South Africa. We developed several tools in response to the needs of decision makers in the different stages of the epidemic, allowing the South African government to plan several months ahead of time.

Methods

Our tools included epidemic projection models, several cost and budget impact models, and online dashboards to help government and the public visualise our projections, track case development and forecast hospital admissions. Information on new variants, including Delta and Omicron, were incorporated in real time to allow the shifting of scarce resources when necessary.

Results

Given the rapidly changing nature of the outbreak globally and in South Africa, the model projections were updated regularly. The updates reflected 1) the changing policy priorities over the course of the epidemic; 2) the availability of new data from South African data systems; and 3) the evolving response to COVID-19 in South Africa such as changes in lockdown levels and ensuing mobility and contact rates, testing and contact tracing strategies, and hospitalisation criteria. Insights into population behaviour required updates by incorporating notions of behavioural heterogeneity and behavioural responses to observed changes in mortality. We incorporated these aspects into developing scenarios for the third wave and developed additional methodology that allowed us to forecast required inpatient capacity. Finally, real-time analyses of the most important characteristics of the Omicron variant first identified in South Africa in November 2021 allowed us to advise policymakers early in the fourth wave that a relatively lower admission rate was likely.

Conclusion

The SACMC’s models, developed rapidly in an emergency setting and regularly updated with local data, supported national and provincial government to plan several months ahead of time, expand hospital capacity when needed, allocate budgets, and procure additional resources where possible. Across four waves of COVID-19 cases, the SACMC continued to serve the planning needs of the government, tracking waves and supporting the national vaccine rollout.
Exploring the KISS principle (Keep It Simple) for decision support systems
Authors: Eduardo Anderson Aires , Sousa Roberto Alves de , Loureiro Rafael Maffei , Tachibana Adriano , dos Santos André Pires
Published: August 2022

The current existence of massive data has not proved to be sufficient, by itself, for the quality of decision-making in organizations that provide health services. Thus, decision support systems (DSS) have a high strategic potential. However, initiatives focusing on the implementation of such systems commonly frustrate the involved professionals, precisely because of the challenges at data-collection stage. In this context, here we propose a conceptual model of DSS, prioritizing pipelines composed of simple algorithms, presenting low resource consumption for implementation. Our experimental implementation confirmed the computational characteristics preconized by the conceptual model, presenting the potential to mitigate a series of critical points reported by other authors and that negatively impact the real-world implementation of DSSs. Future work should empirically quantify the gains that the implementation of our model can yield, as well as experimentally explore its implementation for more complex organizational scenarios.
EMERGE: Evaluating the value of measuring random plasma glucose values for managing hyperglycemia in the inpatient setting
Authors: Manzoor Saba , Colacci Mike , Moggridge Jason , Gyenes Michelle , Biering-Sørensen Tor , Højbjerg Lassen Mats C. , Razak Fahad , Verma Amol , Sarma Shohinee , Fralick Michael
Published: August 2022

Importance

A diagnosis of diabetes is considered when a patient has hyperglycemia with a random plasma glucose ≥200 mg/dL. However, in the inpatient setting, hyperglycemia is frequently non-specific, especially among patients who are acutely unwell. As a result, patients with transient hyperglycemia may be incorrectly labeled as having diabetes, leading to unnecessary treatment, and potential harm.

Design, Setting, and Participants

We conducted a multicentre cohort study of patients hospitalized at seven hospitals in Ontario, Canada and identified those with a glucose value ≥200 mg/dL. We validated a definition for diabetes using manual chart review that included physician notes, pharmacy notes, home medications, and hemoglobin A1C. Among patients with a glucose value ≥200 mg/dL, we identified patients without diabetes who received a diabetes medication, and the number who experienced hypoglycaemia during the same admission.

Main Outcomes and Measures

To determine the diagnostic value of using random blood glucose to diagnose diabetes in the inpatient setting, and its impact on patient outcomes.

Results

We identified 328,786 hospitalizations from hospital between 2010 and 2020. A blood glucose value of ≥200 mg/dL had a positive predictive value of 68% and a negative predictive value of 90% for a diagnosis of diabetes. Of the 76,967 patients with an elevated glucose value reported, 16,787 (21.8%) did not have diabetes, and of these, 5,375 (32%) received a diabetes medication. Hypoglycemia was frequently reported among the 5,375 patients that received a diabetes medication, with 1,406 (26.2%) experiencing hypoglycemia and 405 (7.5%) experiencing severe hypoglycemia.

Conclusions and Relevance

Elevated plasma glucose in hospital is common but does not necessarily indicate a patient has diabetes. Furthermore, it can lead to treatment with diabetes medications with potential harm. Our findings highlight that clinicians should be cautious when responding to elevated random plasma glucose tests in the inpatient setting.
Plumage color evolves as distinct dorsal and ventral modules in Australasian honeyeaters
Authors: Friedman Nicholas R. , Remeš Vladimír
Published: August 2022

Many animals exhibit contrast between their dorsal and ventral coloration. If selection acts differently on dorsal versus ventral coloration, these body parts should evolve as independent modules of trait evolution, irrespective of ancestral covariance. Here, we compare the evolution of feather color across 11 body regions for a clade of Australasian songbirds (Meliphagoidea). We find evidence for three modules of covarying color regions: dorsal, ventral, and flight feathers. Among these modules, ventral feathers had color that was highly labile, evolving at 3 times the rate for dorsal plumage and 20 times the rate for flight feathers. While both dorsal and ventral plumage tend to be correlated with precipitation or the degree of vegetation, we find that dorsal plumage is twice as similar to colors of background substrates in satellite photos. This finding, which a direct effect of climate in Gloger’s rule does not predict, adds support for background matching as an explanation for geographic gradients in animal color. Furthermore, it suggests that selection for background matching has had a greater effect on dorsal plumage than ventral plumage color. Overall, differential selection on ventral and dorsal colors likely maintains these as distinct modules over evolutionary time scales – a novel explanation for dorsoventral contrast in pigmentation.
Pinging the brain to reveal the hidden attentional priority map using encephalography
Authors: Duncan Dock , van Moorselaar Dirk , Theeuwes Jan
Published: August 2022

Attention has been usefully thought of as organized in priority maps – putative maps of space where attentional priority is weighted across spatial regions in a winner-take-all competition for attentional deployment. Recent work has highlighted the influence of past experiences on the weighting of spatial priority – called selection history. Aside from being distinct from more well-studied, top-down forms of attentional enhancement, little is known about the neural substrates of history-mediated attentional priority. Using a task known to induce statistical learning of target distributions, in an EEG study we demonstrate that this otherwise invisible, latent attentional priority map can be visualized during the intertrial period using a ‘pinging’ technique in conjunction with multivariate pattern analyses. Our findings not only offer a novel method of visualizing the history-mediated attentional priority map, but also shed light on the underlying mechanisms allowing our past experiences to influence future behaviour.
Interpretable prognostic modeling of endometrial cancer
Authors: Zagidullin Bulat , Pasanen Annukka , Loukovaara Mikko , Bützow Ralf , Tang Jing
Published: August 2022

Endometrial carcinoma (EC) is one of the most common gynecological cancers in the world. In this work we apply Cox proportional hazards (CPH) and optimal survival tree (OST) algorithms to the retrospective prognostic modeling of disease-specific survival in 842 EC patients. We demonstrate that the linear CPH models are preferred for the EC risk assessment based on clinical features alone, while the interpretable, non-linear OST models are favored when patient profiles are enriched with tumor molecular data. By studying the OST decision path structure, we show how explainable tree models recapitulate existing clinical knowledge prioritizing L1 cell-adhesion molecule and estrogen receptor status indicators as key risk factors in the p53 abnormal EC subgroup. We believe that visually interpretable tree algorithms are a promising method to explore feature interactions and generate novel research hypotheses. To aid further clinical adoption of advanced machine learning techniques, we stress the importance of quantifying model discrimination and calibration performance in the development of explainable clinical prediction models.
Age-related decrease in appetitive associative memory in fruit flies
Authors: König Christian , Gerber Bertram
Published: August 2022

Memory scores are dynamic across developmental stages. In particular, memory scores typically decrease from late adolescence into old age, reflecting complex changes in mnemonic and sensory-motor faculties, metabolic and motivational changes, and changes in cognitive strategy as well. In Drosophila melanogaster, such age-related decreases in memory scores have been studied intensely for the association of odours with electric shock punishment. We report that odour-sucrose reward memory scores likewise decrease as the flies age. This was observed after one-trial and after two-trial conditioning, and for both immediate testing and for recall tests one day later. This decrease was already particularly pronounced in relatively young animals, in the first 2-3 weeks after adult hatching, and was more pronounced in female than in male flies.
Differences in the inflammatory proteome of East African and Western European adults and associations with environmental and dietary factors
Authors: Temba Godfrey S. , Vadaq Nadira , Kullaya Vesla , Pecht Tal , Lionetti Paolo , Cavalieri Duccio , Schultze Joachim L. , Kavishe Reginald , Joosten Leo A.B. , van der Ven Andre J. , Mmbaga Blandina T. , Netea Mihai G. , de Mast Quirijn
Published: August 2022

Non-communicable diseases (NCDs) are rising rapidly in urbanizing populations in sub-Saharan Africa. Assessment of inflammatory and metabolic characterstics of an urbanizing African population and the comparison with populations outside Africa could provide insight in the pathophysiology of the rapidly increasing epidemic of NCDs, including the role of environmental and dietary changes. Using a proteomic plasma profiling approach comprising 92 inflammation-related molecules, we examined differences in the inflammatory proteome in healthy Tanzanian and healthy Dutch adults. We show that healthy Tanzanians display a pro-inflammatory phenotype compared to Dutch subjects, with enhanced activity of the Wnt/β-catenin signalling pathway and higher concentrations of different metabolic regulators such as 4E-BP1 and fibroblast growth factor 21. Among the Tanzanian volunteers, food-derived metabolites were identified as an important driver of variation in inflammation-related molecules, emphasizing the potential importance of lifestyle changes. These findings endorse the importance of the current dietary transition in the NCDs epidemic in sub-Saharan Africa and the inclusion of underrepresented populations in systems immunology studies.
Liraglutide protects against diastolic dysfunction and improves ventricular protein translation
Authors: Rutledge Cody , Enriquez Angela , Redding Kevin , Lopez Mabel , Mullett Steven , Wendell Stacy , Jurczak Michael , Goetzman Eric , Kaufman Brett A.
Published: August 2022

Purpose

Diastolic dysfunction is an increasingly common cardiac pathology linked to heart failure with preserved ejection fraction. Previous studies have implicated glucagon-like peptide 1 (GLP-1) receptor agonists as potential therapies for improving diastolic dysfunction. In this study, we investigate the physiologic and metabolic changes in a mouse model of angiotensin II (AngII) mediated diastolic dysfunction with and without the GLP-1 receptor agonist liraglutide (Lira).

Methods

Mice were divided into sham, AngII, or AngII + Lira therapy for 4 weeks. Mice were monitored for cardiac function, weight change, and blood pressure at baseline and after 4 weeks of treatment. After 4 weeks of treatment, tissue was collected for histology, protein analysis, targeted metabolomics, and protein synthesis assays.

Results

AngII treatment causes diastolic dysfunction when compared to sham mice. Lira partially prevents this dysfunction. The improvement in function in Lira mice is associated with dramatic changes in amino acid accumulation in the heart. Lira mice also have improved markers of protein translation by Western blot and increased protein synthesis by puromycin assay, suggesting that increased protein turnover protects against fibrotic remodeling and diastolic dysfunction seen in the AngII cohort. Lira mice also lost lean muscle mass compared to the AngII cohort, raising concerns about peripheral muscle scavenging as a source of the increased amino acids in the heart.

Conclusions

Lira therapy protects against AngII-mediated diastolic dysfunction, at least in part by promoting amino acid uptake and protein turnover in the heart. Liraglutide therapy is associated with loss of mean muscle mass, and long-term studies are warranted to investigate sarcopenia and frailty with liraglutide therapy in the setting of diastolic disease.
Mechanisms of Dominant Electrophysiological Features of Four Subtypes of Layer 1 Interneurons
Authors: Meng John Hongyu , Schuman Benjamin , Rudy Bernardo , Wang Xiao-Jing
Published: August 2022

Neocortical Layer 1 (L1) consists of the distal dendrites of pyramidal cells and GABAergic interneurons (INs) and receives extensive long-range “top-down” projections, but L1 INs remain poorly understood. In this work, we systematically examined the distinct dominant electrophysiological features for four unique IN subtypes in L1 that were previously identified from mice of either gender: Canopy cells show an irregular firing pattern near rheobase; Neurogliaform cells (NGFCs) are late-spiking, and their firing rate accelerates during current injections; cells with strong expression of theα7 nicotinic receptor (α7 cells), display onset (rebound) bursting; vasoactive intestinal peptide (VIP) expressing cells exhibit high input resistance, strong adaptation, and irregular firing. Computational modeling revealed that these diverse neurophysiological features could be explained by an extended exponential-integrate-and-fire neuron model with varying contributions of a slowly inactivatingK+channel (SIK), a T-typeCa2+channel, and a spike-triggeredCa2+-dependentK+channel. In particular, we show that irregular firing results from square-wave bursting through a fast-slow analysis. Furthermore, we demonstrate that irregular firing is frequently observed in VIP cells due to the interaction between strong adaptation and a SIK channel. At last, we reveal that the VIP andα7 cell models resonant with Alpha/Theta band input through a dynamic gain analysis.

Significance Statement

In the neocortex, about 25% of neurons are interneurons. Interestingly, only somas of interneurons reside within Layer 1 (L1) of the neocortex, but not of excitatory pyramidal cells. L1 interneurons are diverse and believed to be important in the cortical-cortex interactions, especially top-down signaling in the cortical hierarchy. However, the electrophysiological features of L1 interneurons are poorly understood. Here, we systematically studied the electrophysiological features within each L1 interneuron subtype. Furthermore, we build computational models for each subtype and study the mechanisms behind these features. These electrophysiological features within each subtype should be incorporated to elucidate how different L1 interneuron subtypes contribute to communication between cortexes.
RTNet neural network exhibits the signatures of human perceptual decision making
Authors: Rafiei Farshad , Shekhar Medha , Rahnev Dobromir
Published: August 2022

Convolutional neural networks show promise as models of biological vision. However, their decision behavior, including the facts that they are deterministic and use equal number of computations for easy and difficult stimuli, differs markedly from human decision-making, thus limiting their applicability as models of human perceptual behavior. Here we develop a new neural network, RTNet, that generates stochastic decisions and human-like response time (RT) distributions. We further performed comprehensive tests that showed RTNet reproduces all foundational features of human accuracy, RT, and confidence and does so better than all current alternatives. To test RTNet’s ability to predict human behavior on novel images, we collected accuracy, RT, and confidence data from 60 human subjects performing a digit discrimination task. We found that the accuracy, RT, and confidence produced by RTNet for individual novel images correlated with the same quantities produced by human subjects. Critically, human subjects who were more similar to the average human performance were also found to be closer to RTNet’s predictions, suggesting that RTNet successfully captured average human behavior. Overall, RTNet is a promising model of human response times that exhibits the critical signatures of perceptual decision making.
Identification of DOT1L Inhibitor in a Screen for Factors that Promote Dopaminergic Neuron Survival
Authors: Cui Jun , Carey Joseph , Pera Renee A. Reijo
Published: August 2022

Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra region of the midbrain. Diagnostic criteria for PD require that at least two of three motor signs are observed: tremor, rigidity, and/or bradykinesia. The most common and effective treatment for PD is Levodopa (L-DOPA) which is readily converted to DA and has been the primary treatment since the 1960’s. Dopamine agonists have also been developed but are less effective than L-DOPA. Although the lack of a model system to study PD has hampered efforts to identify treatments, diverse screening strategies have been proposed for identification of new pharmaceutical candidates. Here, we describe a pilot screen to identify candidate molecules from a bioactive compound library, that might increase formation, maintenance and/or survival of DA neurons in vitro. The screen used a previously characterized reporter construct consisting of the luciferase gene inserted downstream of the endogenous tyrosine hydroxylase (TH) gene and neurons differentiated from human pluripotent stem cells for 18 days. The reporter mimics expression of TH and includes a secreted luciferase whose activity can be measured non-invasively over multiple timepoints. Screening of the bioactive compound library resulted in the identification of a single molecule, SGC0946, that is an inhibitor of DOT1L (Disruptor Of Telomeric silencing 1-Like) which encodes a widely-conserved histone H3K79 methyltransferase that is able to both activate and repress gene transcription. Our results indicate that SGC0946 increased reporter luciferase activity with a single treatment at 8-hours post-plating being equivalent to continuous treatment. Moreover, data suggested that the total number of neurons differentiated in the assays was comparable from experiment to experiment under different SGC0946 treatments over time. In contrast, data suggested that the survival and/or maintenance of DA neurons might be specifically enhanced by SGC0946 treatment. These results confirm other reports that indicate inhibition of DOT1L may play an important role in maintenance and survival of neural progenitor cells (NPCs) and their lineage-specific differentiation.
Individual differences in information processing during sleep and wake predict sleep-based memory consolidation of complex rules
Authors: Richter Madison , Cross Zachariah R. , Bornkessel-Schlesewsky Ina
Published: August 2022

Memory is critical for many cognitive functions, from remembering facts, to learning complex environmental rules. While memory encoding occurs during wake, memory consolidation is associated with sleep-related neural activity. Further, research suggests that individual differences in alpha frequency during wake (∼ 7 – 13 Hz) modulate memory processes, with higher individual alpha frequency (IAF) associated with greater memory performance. However, the relationship between wake-related EEG individual differences, such as IAF, and sleep-related neural correlates of memory consolidation has been largely unexplored, particularly in a complex rule-based memory context. Here, we aimed to investigate whether wake-derived IAF and sleep neurophysiology interact to influence rule learning in a sample of 35 healthy adults (16 males; mean age = 25.4, range: 18 – 40). Participants learned rules of a modified miniature language prior to either 8hrs of sleep or wake, after which they were tested on their knowledge of the rules in a grammaticality judgement task. Results indicate that sleep neurophysiology and wake-derived IAF do not interact but modulate memory for complex linguistic rules separately. Phase-amplitude coupling between slow oscillations and spindles during non-rapid eye-movement (NREM) sleep also promoted memory for rules that were analogous to the canonical English word order. As an exploratory analysis, we found that rapid eye-movement (REM) sleep theta power at posterior regions interacts with IAF to predict rule learning and proportion of time in REM sleep predicts rule learning differentially depending on grammatical rule type. Taken together, the current study provides behavioural and electrophysiological evidence for a complex role of NREM and REM sleep neurophysiology and wake-derived IAF in the consolidation of rule-based information.
A Rigid Parallel-Plate Artificial Placenta Oxygenator with a Hemocompatible Blood Flow Path
Authors: Blauvelt David G. , Higgins Nicholas C. , De Bianca , Goodin Mark S. , Wright Nathan , Blaha Charles , Moyer Jarrett , Chui Benjamin W. , Baltazar Francisco J. , Oishi Peter , Roy Shuvo
Published: August 2022

Extremely preterm infants have poor clinical outcomes due to lung immaturity. An artificial placenta could provide extracorporeal gas exchange, allowing normal lung growth outside of the uterus, thus improving outcomes. However, current devices in development use hollow-fiber membrane oxygenators, which have a high rate of bleeding and clotting complications. Here, we present a novel style of oxygenator composed of a stacked array of rigid and flat silicon semi-permeable membranes. Using computational fluid dynamic (CFD) modeling, we demonstrated favorable hemocompatibility properties, including laminar blood flow, low pressure drop, and minimal cumulative shear stress. We then constructed and tested prototype devices on the benchtop and in an extracorporeal pig model. At 20 mL/min of blood flow, the oxygenators exhibited an average oxygen flux of 0.081 ± 0.020 mL (mean ± standard error) and a pressure drop of 2.25 ± 0.25 mmHg. This study demonstrates the feasibility of a building a stacked flat-plate oxygenator with a blood flow path informed by CFD.
Common genetic variations in telomere length genes and lung cancer
Authors: Penha Ricardo Cortez Cardoso , Smith-Byrne Karl , Atkins Joshua R , Haycock Philip , Kar Siddhartha , Codd Veryan , Samani Nilesh J , Nelson Christopher P , Milojevic Maja , Gabriel Aurélie AG , Amos Christopher , Brennan Paul , Hung Rayjean J , Kachuri Linda , McKay James D
Published: August 2022

Background

Genome-wide association studies (GWAS) have identified genetic susceptibility variants for both leukocyte telomere length (LTL) and lung cancer susceptibility. Recently, 108 novel genetic loci within genes involved in telomere biology and DNA repair have been linked to LTL in UK Biobank. In the current work, we investigated the relationship between genetically predicted LTL and lung cancer.

Methods

To explore the shared genetic basis between LTL and lung cancer, we performed genetic correlation, Mendelian Randomization (MR), and colocalisation analyses using the largest available GWASs of LTL (N=464,716) and lung cancer (29,239 cases; 56,450 controls). To further characterize the molecular mechanisms underlying this relationship, principal component analysis (PCA) was used to summarize gene expression profiles in lung adenocarcinoma tumours from The Cancer Genome Atlas.

Results

Although there was no genome-wide genetic correlation between LTL and lung cancer risk (rg=-0.01, p=0.88), MR analyses using 144 instruments identified a putatively causal association. Longer LTL conferred an increased risk of lung cancer (OR=1.62, 95%CI=1.44-1.83, p=9.9×10−15), lung cancer in never smokers (OR=2.02, 95%CI=1.45-2.83, p=3.78×10−05), and lung adenocarcinoma (OR=2.43, 95%CI=2.02-2.92, p=3.8×10−21). Of these 144 LTL genetic instruments, 12 showed evidence of colocalisation with lung adenocarcinoma risk and revealed novel susceptibility loci, including MPHOSPH6 (rs2303262), PRPF6 (rs80150989), and POLI (rs2276182). A polygenic risk score for LTL was associated with the second principal component (PC2) of gene expression (Beta=0.17, p=1.0×10−3). The aspect of PC2 associated with longer LTL was also associated with being female (p=0.005), never smokers (p=0.04), and earlier tumour stage (p=0.002). PC2 was strongly associated with cell proliferation score (p=3.6×10−30) and genomic features related to genome stability, including copy number changes (p=1.6×10−5) and telomerase activity (p=1.3×10−5) in the multivariate regression analyses.

Conclusions

This study identified an association between longer genetically predicted LTL and lung cancer and sheds light on the potential molecular mechanisms related to LTL in lung adenocarcinomas.
Post-COVID syndrome prevalence and risk factors in children and adolescents: A population-based serological study
Authors: Dumont Roxane , Richard Viviane , Lorthe Elsa , Loizeau Andrea , Pennacchio Francesco , Zaballa María-Eugenia , Baysson Hélène , Nehme Mayssam , Perrin Anne , L’Huillier Arnaud G. , Kaiser Laurent , Barbe Rémy P. , Posfay-Barbe Klara M. , Stringhini Silvia , Guessous Idris
Published: August 2022

Abstract

Objectives

Post-COVID syndrome remain poorly studied in children and adolescents. In this study, we aimed to investigate the prevalence and risk factors of pediatric post-COVID in a population-based sample, stratifying by serological status.

Study design

We used data from the SEROCoV-KIDS cohort study (State of Geneva, Switzerland), which included children (aged 6 months to 17 years) selected from random samples drawn from state registries or who had a household member participating in a COVID-19 seroprevalence study conducted by our group. Children were tested for anti-SARS-CoV-2 N antibodies. Parents filled in a questionnaire on persistent symptoms in their children (lasting over 12 weeks) compatible with post-COVID syndrome.

Results

From December 1st, 2021 to February 16th, 2022, 1034 children were included, among whom 570 (55.1%) were seropositive. The sex- and age-adjusted prevalence of persistent symptoms among seropositive children was 9.1% (95%CI: 6.7;11.8) and 5.0% (95%CI: 3.0;7.1) among seronegatives, with an adjusted prevalence difference (ΔaPrev) of 4.1% (95%CI: 1.1;7.3). After stratification by age group, the prevalence was higher among adolescents aged 12-17 years (ΔaPrev=8.3%, 95%CI: 3.5;13.5) than among younger children (0.0%, 95%CI: −5.2;5.2 among 6-11 years old and 4.2%; 95%CI: −4.4;13.3 among 0-5 years old). The most frequently declared persistent symptoms among seropositives were smell loss, trouble concentrating and abdominal pain. Older age, having a chronic condition and lower socioeconomic conditions were identified as risk factors.

Conclusion

A significant proportion of seropositive children, particularly adolescents, experienced persistent symptoms. While there is a need for further investigation, growing evidence of pediatric post-COVID syndrome urges early screening and primary care management.
Adherence to methotrexate and associated factors considering social desirability in patients with rheumatoid arthritis: a multicenter cross-sectional study
Authors: Yajima Nobuyuki , Kawaguchi Takashi , Takahashi Ryo , Nishiwaki Hiroki , Toyoshima Yoichi , Oh Koei , Odai Tsuyoshi , Kanai Takayuki , Morisky Donald E. , Yamaguchi Takuhiro , Kasama Tsuyoshi
Published: August 2022

Background

Assessing medication adherence in rheumatoid arthritis (RA) is clinically significant as low adherence is associated with high disease activity. Self-reported medication adherence surveys have been shown to have problems with overestimation of adherence due to social desirability bias. However, no MTX adherence studies adjusted for social desirability have been conducted to date. This study aimed to evaluate adherence to MTX and perform an investigatory search for factors associated with MTX adherence including social desirability.

Methods

This cross-sectional multicenter study was conducted among adult RA patients consuming oral MTX for ≥3 months. We examined the distribution of MTX adherence, according to the eight-item Morisky Medication Adherence Scale (MMAS-8). Social desirability was using the Social Desirability Scale (SDS). Furthermore, an exploratory factor analysis involving social desirability was examined to identify factors associated with MTX adherence using linear regression analysis. To deal with missing values, we used multiple imputations with chained equations methods.

Results

A total of 165 RA patients were enrolled. The median age was 64 years, and 86.1% were women. Based on the MMAS-8, low, medium, and high adherences were noted in 12.1%, 60.0%, and 27.9% of participants, respectively. High social desirability (coefficient, 0.14; 95% confidence interval [CI], 0.05–0.23; p<0.05) and high age (coefficient per 10 years, 0.16; 95% CI, 0.01–0.03; p<0.05) were associated with high MTX adherence, whereas full-time work was negatively associated with high MTX adherence (coefficient, -0.50; 95% CI, -0.95–-0.05; p<0.05).

Conclusions

A large proportion of patients with RA do not take MTX as prescribed. High social desirability, high educational level, and non-full-time work may be associated with high MTX adherence. Physicians should confirm MTX adherence before switching or adding disease-modifying anti-rheumatic drugs in cases of uncontrolled disease activity.
The necessity of pyloric drainage in esophagectomies: protocol of a meta-analysis and a systematic review of randomized controlled trials
Authors: Csontos Armand , Németh Dávid , Szakó Lajos , Berke Gergő , Lili Sindler Dóra , Hegyi Péter , Papp András
Published: August 2022

Background

Esophageal carcinoma is the 8th most common malignant tumour in the world with more than 600 000 cases (3.1% of all), while being the 6th most common reason of tumour mortality, causing more than 500 000 deaths (5.5% of all) annually. The 1, 3 and 5 year-prevalence are 2.4%, 1.6% and 1.3% respectively. The question of this meta-analysis is whether pyloric drainage is preferable over the lack of pyloric drainage during elective esophagectomies in patients suffering from esophageal cancer, regarding mortality, anastomosis leakage, respiratory morbidity, vomiting, gastric emptying time.

Methods

We plan to identify randomized controlled trials to investigate the question by performing extensive search in multiple databases. Based on of predefined criteria, two independent authors will perform the steps of selection, after which appropriate statistical analysis will be performed to identify potential significant differences. Cochrane Risk of Bias Tool 2, and GRADE approach will be used to estimate the risk of bias and quality of results.

Dissemination plans

We plan to distribute our results in peer-reviewed journal.
Cost-effectiveness of testing for Mycoplasma genitalium among men who have sex with men in Australia
Authors: Ong Jason J. , Lim Aaron G. , Bradshaw Catriona S. , Taylor-Robinson David , Unemo Magnus , Horner Patrick J. , Vickerman Peter , Zhang Lei
Published: August 2022

Objectives

Mycoplasma genitalium (MG) disproportionately affects men who have sex with men (MSM). We determined the cost-effectiveness of testing strategies for MG using a healthcare provider perspective.

Methods

We used inputs from a dynamic transmission model of MG among MSM living in Australia in a decision tree model to evaluate the impact of four testing scenarios on MG incidence: 1) no one tested; 2) symptomatic MSM; 3) symptomatic and high-risk asymptomatic MSM; 4) all MSM. We calculated the incremental cost-effectiveness ratios (ICERs) using a willingness to pay threshold of $30,000 AUD per QALY gained. We explored the impact of adding an AMR tax (i.e. additional cost per antibiotic consumed) to identify the threshold whereby any testing for MG is no longer cost-effective.

Results

Testing only symptomatic MSM is the most cost-effective (ICER $3,677 per QALY gained) approach. Offering testing to all men is dominated (i.e. not recommended because of higher costs and lower QALYs gained compared to other strategies). When the AMR tax was above $150, any testing for MG was no longer cost-effective.

Conclusion

Testing only symptomatic MSM is the most cost-effective option even when the potential costs associated with AMR are accounted for (up to $150 additional cost per antibiotic consumed). For pathogens like MG where there are anticipated future costs related to AMR, we recommend models to test the impact of incorporating these costs as they can change the conclusions of cost-effectiveness studies.

KEY MESSAGES

What is already known on this topic - Mycoplasma genitalium (MG) is a sexually transmitted pathogen with rising antimicrobial resistance.

What this study adds - This economic evaluation found that testing only symptomatic men who have sex with men (MSM) is the most cost-effective option. When the costs per antibiotic consumed is greater than $150, any testing for MG is no longer cost-effective.

How this study might affect research, practice or policy - Among testing strategies for MSM, testing for MG should be restricted to symptomatic men only.