bluuebunny/crossref_metadata_2025 huggingface dataset:
VGF as a biomarker and therapeutic target in neurodegenerative and psychiatric diseases
Authors: Quinn James P , Kandigian Savannah E , Trombetta Bianca A , Arnold Steven E , Carlyle Becky C
Published: October 2021

Neurosecretory protein VGF (non-acronymic) belongs to the granin family of neuropeptides. VGF and VGF-derived peptides have been repeatedly identified in well-powered and well-designed multi-omic studies as dysregulated in neurodegenerative and psychiatric diseases. New therapeutics is urgently needed for these devastating and costly diseases, as are new biomarkers to improve disease diagnosis and mechanistic understanding. From a list of 537 genes involved in Alzheimer’s disease pathogenesis, VGF was highlighted by the Accelerating Medicines Partnership in Alzheimer’s disease as the potential therapeutic target of greatest interest. VGF levels are consistently decreased in brain tissue and CSF samples from patients with Alzheimer’s disease compared to controls, and its levels correlate with disease severity and Alzheimer’s disease pathology. In the brain, VGF exists as multiple functional VGF-derived peptides. Full-length human VGF1–615 undergoes proteolytic processing by prohormone convertases and other proteases in the regulated secretory pathway to produce at least 12 active VGF-derived peptides. In cell and animal models, these VGF-derived peptides have been linked to energy balance regulation, neurogenesis, synaptogenesis, learning and memory, and depression-related behaviours throughout development and adulthood. The C-terminal VGF-derived peptides, TLQP-62 (VGF554–615) and TLQP-21 (VGF554–574) have differential effects on Alzheimer’s disease pathogenesis, neuronal and microglial activity, and learning and memory. TLQP-62 activates neuronal cell-surface receptors and regulates long-term hippocampal memory formation. TLQP-62 also prevents immune-mediated memory impairment, depression-like and anxiety-like behaviours in mice. TLQP-21 binds to microglial cell-surface receptors, triggering microglial chemotaxis and phagocytosis. These actions were reported to reduce amyloid-β plaques and decrease neuritic dystrophy in a transgenic mouse model of familial Alzheimer’s disease. Expression differences of VGF-derived peptides have also been associated with frontotemporal lobar dementias, amyotrophic lateral sclerosis, Lewy body diseases, Huntington’s disease, pain, schizophrenia, bipolar disorder, depression and antidepressant response. This review summarizes current knowledge and highlights questions for future investigation regarding the roles of VGF and its dysregulation in neurodegenerative and psychiatric disease. Finally, the potential of VGF and VGF-derived peptides as biomarkers and novel therapeutic targets for neurodegenerative and psychiatric diseases is highlighted.
Neutralizing Anti–Granulocyte-Macrophage Colony-Stimulating Factor Autoantibodies in Patients With Central Nervous System and Localized Cryptococcosis: Longitudinal Follow-up and Literature Review
Authors: Kuo Po Hsien , Wu Un In , Pan Yi Hua , Wang Jann Tay , Wang Yu Chen , Sun Hsin Yun , Sheng Wang Huei , Chen Yee Chun , Chang Shan Chwen
Published: October 2021

Background

Neutralizing anti–granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies (AAbs) have been increasingly recognized to predispose healthy individuals to disseminated cryptococcosis. However, studies have only considered patients with central nervous system (CNS) infection. No longitudinal study has captured the disease spectrum and clinical course.

Methods

We prospectively enrolled adults without human immunodeficiency virus infection who had disseminated or unusual cryptococcosis. We compared the demographics, clinical features, kinetics of serum cryptococcal antigen (CrAg) titers, anti–GM-CSF AAb concentrations, and treatment outcomes between patients with (case patients) and without (control patients) anti–GM-CSF AAbs. Additional reports from the literature were also reviewed.

Results

Twenty-three patients were enrolled, of whom 6 tested positive for anti–GM-CSF AAbs. All case patients with positive fungal cultures (5/5 [100%]) were infected with Cryptococcus gattii VGII. Among them, 3 had exclusively pulmonary involvement, and 1 had only musculoskeletal lesions. Patients with CNS cryptococcosis exhibited a higher serum concentration of anti–GM-CSF AAbs than those with extraneural cryptococcosis. Case patients had higher initial and peak levels of serum CrAg and longer duration of antigenemia compared with the control patients. All case patients who had completed antifungal therapy had favorable outcomes without recurrence.

Conclusions

Testing for anti–GM-CSF AAbs should be considered for not only previously healthy patients with disseminated cryptococcosis but also those with unexplained, localized cryptococcosis. Recurrence after completion of antifungal therapy was rare despite the persistence of anti–GM-CSF AAbs.
From Personalized Medicine to Personalized Aging Services
Authors: Glicksman Allen , Rodriguez Misha , Ring Lauren , Liebman Michael
Published: October 2021

As medical models become more ubiquitous in developing strategies to provide long-term care services and support (LTSS), we need to ask whether these models adequately account for sources of diversity and disadvantage that affect access to and use of services by older adults. Medical models typically focus on categorizing information about the individual in order to clearly define current health status and appropriate treatment. Any individual, however, reflects the sum of their life experiences. Therefore, this medicalization approach can miss key factors in determining health outcomes including social determinants of health. Just as importantly, this approach can miss issues of values, beliefs, and assumptions that older adults can bring into the encounter with service providers. This issue is especially important when dealing with older migrant communities. Beliefs and attitudes shaped in their place of origin, as well as the migration experience, can influence levels of trust and resulting decisions regarding the use of LTSS. We need to integrate an understanding of how these beliefs and attitudes affect decision making into any model designed to improve the lives of older persons.
The trade fair network in Apulia during the thirteenth and fourteenth centuries
Authors: Petracca Luciana
Published: October 2021

The article examines the places, times and spaces dedicated to the free market in Apulia during the thirteenth and fourteenth centuries. The primary documents consulted for this article indicate a significant increase in the regional fair circuit, starting from the reign of Frederick II. The increase in the number of fairs (divided between major and minor) inevitably favoured the development of the local and regional economy. Trade fairs, the focus of this article, represented the main opportunity for regular exchanges and the buying and selling of consumer goods. They allowed agricultural producers to sell their products, offering a variety of different goods from handicraft products to agricultural surplus.
An Invariant Protein That Colocalizes With VAR2CSA on Plasmodium falciparum-Infected Red Cells Binds to Chondroitin Sulfate A
Authors: Keitany Gladys J , Jenkins Bethany J , Obiakor Harold T , Daniel Shaji , Muehlenbachs Atis , Semblat Jean-Philippe , Gamain Benoit , Doritchamou Justin Y A , Desai Sanjay A , MacDonald Nicholas J , Narum David L , Morrison Robert , Saveria Tracy , Vignali Marissa , Oleinikov Andrew V , Fried Michal , Duffy Patrick E
Published: October 2021

Background

Plasmodium falciparum-infected red blood cells (iRBCs) bind and sequester in deep vascular beds, causing malaria-related disease and death. In pregnant women, VAR2CSA binds to chondroitin sulfate A (CSA) and mediates placental sequestration, making it the major placental malaria (PM) vaccine target.

Methods

In this study, we characterize an invariant protein associated with PM called P falciparum chondroitin sulfate A ligand (PfCSA-L).

Results

Recombinant PfCSA-L binds both placental CSA and VAR2CSA with nanomolar affinity, and it is coexpressed on the iRBC surface with VAR2CSA. Unlike VAR2CSA, which is anchored by a transmembrane domain, PfCSA-L is peripherally associated with the outer surface of knobs through high-affinity protein-protein interactions with VAR2CSA. This suggests that iRBC sequestration involves complexes of invariant and variant surface proteins, allowing parasites to maintain both diversity and function at the iRBC surface.

Conclusions

The PfCSA-L is a promising target for intervention because it is well conserved, exposed on infected cells, and expressed and localized with VAR2CSA.
Optimization and Validation of Limit Check Error-Detection Performance Using a Laboratory-Specific Data-Simulation Approach: A Prerequisite for an Evidence-Based Practice
Authors: van Rossum Huub H
Published: October 2021

Background

Autoverification procedures based on limit checks (LCs) provide important support to preanalytical, analytical, and postanalytical quality assurance in medical laboratories. A recently described method, based on laboratory-specific error-detection performances, was used to determine LCs for all chemistry analytes performed on random-access chemistry analyzers prior to application.

Methods

Using data sets of historical test results, error-detection simulations of limit checks were performed using the online MA Generator system (www.huvaros.com). Errors were introduced at various positions in the data set, and the number of tests required for an LC alarm to occur was plotted in bias detection curves. Random error detection was defined as an LC alarm occurring in 1 test result, whereas systematic error detection was defined as an LC alarm occurring within an analytical run, both with ≥97.5% probability. To enable the lower limit check (LLC) and the upper limit check (ULC) to be optimized, the simulation results and the LC alarm rates for specific LLCs and ULCs were presented in LC performance tables.

Results

Optimal LLCs and ULCs were obtained for 31 analytes based on their random and systematic error-detection performances and the alarm rate. Reliable detection of random errors greater than 60% was only possible for analytes known to have a rather small variation of results. Furthermore, differences for negative and positive errors were observed.

Conclusions

The used method brings objectivity to the error-detection performance of LCs, thereby enabling laboratory-specific LCs to be optimized and validated prior to application.
Containment logics: Algebraic Counterparts and Reduced Models
Authors: Bonzio Stefano , Pra Baldi Michele
Published: October 2021

The containment companion of a logic $\vdash $ consists of the consequence relation $\vdash ^{r}$ which satisfies all the inferences of $\vdash $, where the variables of the conclusion are contained into those of the set of premises, in case this is not inconsistent. Following the algebraic analysis started in Bonzio and Pra Baldi (2021, Studia Logica, 109, 969–994), this paper characterizes the algebraic counterpart of a finitary containment logic $\vdash ^{r}$ and investigates the structure of the Leibniz and Suszko reduced models. The analysis is carried within the framework of abstract algebraic logic.Mathematics Subject Classification: Primary: 03G27. Secondary: 03G25
The Excessive Regulation of Early Abortion Medication in the UK: The Case for Reform
Authors: Romanis Elizabeth Chloe , Mullock Alexandra , Parsons Jordan A
Published: October 2021

Early medical abortion (EMA) involves the administration of two medications—mifepristone and misoprostol—24–48 hours apart. These routinely used medications are recognised as safe and effective by the World Health Organization which recommends this combination of medications as a safe form of abortion until nine weeks’ gestation. Despite the safety and effectiveness of this drug regimen, there exists excessive regulation around EMA. This is despite new regulations introduced in Northern Ireland in 2020 and (temporary) changes made in 2020 to allow at-home administration of mifepristone in Great Britain (following earlier changes to permit home use of misoprostol). We argue that the excessive regulation of EMA is inappropriate because it fails to recognise that abortion is essential healthcare. Further, the regulation constitutes disproportionate interference with clinical discretion and service organisation because it is medically unnecessary and prevents abortion providers in the UK from adapting their service provision in line with emerging evidence of best practice.
The z–DM distribution of fast radio bursts
Authors: James C W , Prochaska J X , Macquart J-P , North-Hickey F O , Bannister K W , Dunning A
Published: October 2021

We develop a sophisticated model of fast radio burst (FRB) observations, accounting for the intrinsic cosmological gas distribution and host galaxy contributions, and give the most detailed account yet of observational biases due to burst width, dispersion measure, and the exact telescope beamshape. Our results offer a significant increase in both accuracy and precision beyond those previously obtained. Using results from ASKAP and Parkes, we present our best-fitting FRB population parameters in a companion paper. Here, we consider in detail the expected and fitted distributions in redshift, dispersion measure, and signal to noise. We estimate that the unlocalized ASKAP FRBs arise from z < 0.5, with between a third and a half within z < 0.1. Our predicted source-counts (‘logN–logS’) distribution confirms previous indications of a steepening index near the Parkes detection threshold of 1 Jy ms. We find no evidence for a minimum FRB energy, and rule out Emin > 1039.0 erg at 90 per cent C.L. Importantly, we find that above a certain DM, observational biases cause the Macquart (DM–z) relation to become inverted, implying that the highest-DM events detected in the unlocalized Parkes and ASKAP samples are unlikely to be the most distant. More localized FRBs will be required to quantitatively estimate this effect, though its cause is a well-understood observational bias. Works assuming a 1–1 DM–z relation may therefore derive erroneous results. Our analysis of errors suggests that limiting factors in our analysis are understanding of FRB spectral behaviour, sensitivity response of search experiments, and the treatment of the repeating population and luminosity function.
Deep searches for X-ray pulsations from Scorpius X-1 and Cygnus X-2 in support of continuous gravitational wave searches
Authors: Galaudage Shanika , Wette Karl , Galloway Duncan K , Messenger Chris
Published: October 2021

Neutron stars in low mass X-ray binaries (LMXBs) are hypothesised to emit continuous gravitational waves that may be detectable by ground-based observatories. The torque balance model predicts that a higher accretion rate produces larger-amplitude gravitational waves, hence LMXBs with high X-ray flux are promising targets for gravitational wave searches. The detection of X-ray pulsations would identify the spin frequency of these neutron stars, and thereby improve the sensitivity of continuous gravitational-wave searches by reducing the volume of the search parameter space. We perform a semi-coherent search for pulsations in the two LMXBs Scorpius X-1 (Sco X-1) and Cygnus X-2 (Cyg X-2) using X-ray data from the Rossi X-ray Timing Explorer Proportional Counter Array. We find no clear evidence for pulsations, and obtain upper limits (at 90 per cent confidence) on the fractional pulse amplitude, with the most stringent being 0.034 per cent for Sco X-1 and 0.23 per cent for Cyg X-2. These upper limits improve upon those in previous work by factors of ∼8.2 and ∼1.6, respectively.
Multiparametric radiomic tissue signature and machine learning for distinguishing radiation necrosis from tumor progression after stereotactic radiosurgery
Authors: Chen Xuguang , Parekh Vishwa S , Peng Luke , Chan Michael D , Redmond Kristin J , Soike Michael , McTyre Emory , Lin Doris , Jacobs Michael A , Kleinberg Lawrence R
Published: October 2021

Background

Stereotactic radiosurgery (SRS) may cause radiation necrosis (RN) that is difficult to distinguish from tumor progression (TP) by conventional MRI. We hypothesize that MRI-based multiparametric radiomics (mpRad) and machine learning (ML) can differentiate TP from RN in a multi-institutional cohort.

Methods

Patients with growing brain metastases after SRS at 2 institutions underwent surgery, and RN or TP were confirmed by histopathology. A radiomic tissue signature (RTS) was selected from mpRad, as well as single T1 post-contrast (T1c) and T2 fluid-attenuated inversion recovery (T2-FLAIR) radiomic features. Feature selection and supervised ML were performed in a randomly selected training cohort (N = 95) and validated in the remaining cases (N = 40) using surgical pathology as the gold standard.

Results

One hundred and thirty-five discrete lesions (37 RN, 98 TP) from 109 patients were included. Radiographic diagnoses by an experienced neuroradiologist were concordant with histopathology in 67% of cases (sensitivity 69%, specificity 59% for TP). Radiomic analysis indicated institutional origin as a significant confounding factor for diagnosis. A random forest model incorporating 1 mpRad, 4 T1c, and 4 T2-FLAIR features had an AUC of 0.77 (95% confidence interval [CI]: 0.66–0.88), sensitivity of 67% and specificity of 86% in the training cohort, and AUC of 0.71 (95% CI: 0.51–0.91), sensitivity of 52% and specificity of 90% in the validation cohort.

Conclusions

MRI-based mpRad and ML can distinguish TP from RN with high specificity, which may facilitate the triage of patients with growing brain metastases after SRS for repeat radiation versus surgical intervention.
Effect of dihydropyridine calcium channel blockers on blood pressure variability in the SPRINT trial: a treatment effects approach
Authors: de Havenon Adam , Petersen Nils , Wolcott Zoe , Goldstein Eric , Delic Alen , Sheibani Nazanin , Anadani Mohammad , Sheth Kevin N. , Lansberg Maarten , Turan Tanya , Prabhakaran Shyam
Published: October 2021

Objective:

Increased visit-to-visit blood pressure variability (vvBPV) has negative effects on multiple organ systems. Prior research has suggested that dihydropyridine calcium channel blockers (CCB) may reduce vvBPV, which we attempted to verify in a high-quality dataset with robust statistical methodology.

Methods:

We performed a post hoc analysis of the SPRINT trial and included participants who were on a dihydropyridine CCB either 0 or 100% of follow-up study visits. The primary outcome was vvBPV, defined as residual standard deviation (rSD) of SBP from month 6 until study completion. We estimated the average treatment effect of the treated (ATET) after augmented inverse-probability-weighting (AIPW) matching.

Results:

Of the 9361 participants enrolled in SPRINT, we included 5020, of whom 1959 were on a dihydropyridine CCB and 3061 were not; mean age was 67.4 ± 9.2 years, 34.5% were men, 65.9% were white, 49.4% were randomized to intensive blood pressure control, and the rSD was 10.1 ± 4.0 mmHg. Amlodipine represented greater than 95% of dihydropyridine CCB use. After AIPW matching of demographics and other antihypertensive medications, the ATET estimation for participants on a dihydropyridine CCB was an rSD that was 2.05 mmHg lower (95% CI −3.19 to −0.91). We did not find that other antihypertensive medications classes decreased vvBPV, and several increased it.

Conclusion:

In the SPRINT trial, consistent use of a dihydropyridine CCB was associated with a 2 mmHg reduction in vvBPV. The implication of this hypothesis-generating finding in a high-quality dataset is that future trials to reduce vvBPV could consider using dihydropyridine CCBs.
Primary Systemic Amyloidosis Presenting as Skin Vegetations: A Case Report
Authors: Li Meng-Hua , Wu Li-Ming
Published: October 2021

Introduction:

Primary systemic amyloidosis is characterized by clonal plasma cell disorder, and its signs and symptoms are various and complex, damage to the skin and mucous membrane is often more likely to attract attention.Here we reported a case of a 61-year-old male patient who presented with topical mucocutaneous lesion, as well unusual skin vegetations.

Case presentation:

A 61-year-old man was hospitalized due to repeated burning sensation on his back, multiple ecchymosis, and skin vegetations. Through a series of examinations (mainly including skin histopathology, bone marrow cytology, bone marrow flow cytometry, immunofixation electrophoresis), Primary systemic amyloidosis was diagnosed, but multiple myeloma could not be diagnosed. Subsequently, he received chemotherapy. In the half-year follow-up, there was no significant change in his symptoms and signs.

Discussion:

In this case, in addition to the typical skin damage of primary amyloidosis, the multiple skin vegetations in the buttocks, abdomen, and arms are particularly noteworthy. According to the histopathology and Immunohistochemistry of the skin vegetation, we infer that the formation mechanism of these skin vegetation is lymphatic obstruction caused by amyloid, which leads to lymphatic dilatation, lymph leakage, and dermal edema.

Conclusion:

Primary systemic amyloidosis is a rare disease, which is often difficult to diagnose. We should be alert to those atypical skin features so as not to delay diagnosis.
Many Moving Pieces: Virtual Preoperative Surgical Planning for Traumatic Occlusal Splints
Authors: Yoon Joshua , Lock Isabelle , Fan Caleb K. , Maduekwe Uma , Ha Michael , Rasko Yvonne , Grant Michael P. , Nam Arthur J. , Steinberg Jordan P. , Liang Fan
Published: October 2021

Introduction:

Achieving anatomic reduction and re-establishing premorbid occlusion in patients with complex maxillomandibular fractures is challenging even for seasoned surgeons. Historically, surgeons have utilized occlusal splints to help establish occlusal relationships before fracture reduction and fixation. These acrylic splints are fabricated from dental impressions and require manual repositioning of tooth bearing segments along the fracture line to reapproximate premorbid occlusion. The process is laborious, requires a dental lab, and is less efficacious in edentulous patients or those with significantly comminuted fractures; as such it has largely fallen out of practice. Recently, with advances in virtual 3D modeling and printing, we demonstrate that occlusal splints can be designed from computed tomography scans, manipulated virtually, and printed without obtaining impressions from the patient.

Methods/Results:

In our series of 3 patients with complex maxillomandibular fractures, occlusal splints were created by 1) obtaining maxillofacial computed tomography scans, 2) reducing the fractures virtually, and 3) using orthognathic virtual surgery software to create the splint. The time between planning and delivery of the splint was 4 to 7 days. These splints were successfully utilized to help establish premorbid occlusion in conjunction with maxillomandibular fixation and aided in expeditious intraoperative fracture reduction and fixation.

Conclusions:

In the treatment of complex facial fractures, occlusal splints can be a useful adjunct in the operative reduction and fixation of fractures. With the advent of virtual preoperative surgical planning via 3D modeling and 3D printing, these occlusal splints can be created of a sufficient fidelity to avoid the strict need for dental impressions.
Effect of Short-term-focused Training on a Phantom Model in Improving Operative Room Performance Among Surgical Residents: A Randomized Trial
Authors: Lingaraj Chaitra , Rai Sanjeet K. , Asuri Krishna , Prajapati Om P. , Kumar Subodh , Bhattacharjee Hemanga , Bansal Virinder K.
Published: October 2021

Background:

Meta-analysis has shown the effectiveness of various training methods for the acquisition of laparoscopic skills in surgical training. However, there is very limited literature focusing on the translation of skill acquisition on training models into improved operating room (OR) performance. This study was conducted to evaluate the effectiveness of the Tuebingen trainer with integrated Porcine tissue in improving OR the performance of surgical trainees using standard assessment tools.

Materials and Methods:

The study was a single-blinded double-armed randomized control study conducted between July 2016 and March 2018. Eighteen, fourth, and fifth semesters of surgery residents were included in the study. The baseline performance was assessed in OR by performing laparoscopic cholecystectomy using validated scores, that is, Global Operative Assessment of Laparoscopic Skills (GOALS), Additional Five Criteria, Task-specific Checklist, Error Checklist, Visual Analogue Scale. The residents were then randomized into trainee and nontrainee groups. The training group received 5 days of short-term-focused training on the Tuebingen trainer, and the improvement was reassessed in OR.

Results:

The demographic profile of residents was similar. The baseline scores were comparable. The training group showed statistically significant improvement in GOALS (9.88±1.76 to 12±0.66, P=0.05 vs. 10.33±1.5 to 11.4±2.24, P=0.28), task-specific checklist (42.22±10.92 to 53.33±14.14, P=0.027 vs. 45.55±10.13 to 50±17.32, P=0.51), and error checklist. The operating time significantly reduced (36.0±4.03 vs. 50.44±11.39, P=0.0025) following training.

Conclusions:

Our study concludes that the training on the Tuebingen trainer with integrated porcine organs results in a statistically significant improvement in the OR performance of surgical residents as compared with the nontrained residents, thereby indicating a transfer of skills from training to OR.
Epigenetic studies in suicidal ideation and behavior
Authors: Dada Oluwagbenga , Qian Jessica , Al-Chalabi Nzaar , Kolla Nathan J. , Graff Ariel , Zai Clement , Gerretsen Philip , De Luca Vincenzo
Published: October 2021

Most psychiatric disorders are associated with an elevated risk of suicide. Suicidal behavior is the product of the interaction of many risk factors, such as genetics and environmental factors. Hence, epigenetics research may help to understand the mechanisms leading to suicidal ideation and behavior. This review will discuss epigenetic studies in both suicidal ideation and behavior. Epigenetic modifications are likely to be important in both suicidal ideation and behavior. Most of the reviewed studies found significant epigenetic modifications linked with suicidal behavior rather than ideation. Although sizable research has been carried out on this topic, most studies have been done on small-scale samples, and future research is required in larger samples with better clinical characterization of suicide phenotypes to investigate these epigenetic modifications further.
Causality of cortical and cardiovascular activity during cyclic alternating pattern in non-rapid eye movement sleep
Authors: Hartmann Simon , Ferri Raffaele , Bruni Oliviero , Baumert Mathias
Published: October 2021

The dynamic interplay between central and autonomic nervous system activities plays a pivotal role in orchestrating sleep. Macrostructural changes such as sleep-stage transitions or phasic, brief cortical events elicit fluctuations in neural outflow to the cardiovascular system, but the causal relationships between cortical and cardiovascular activities underpinning the microstructure of sleep are largely unknown. Here, we investigate cortical–cardiovascular interactions during the cyclic alternating pattern (CAP) of non-rapid eye movement sleep in a diverse set of overnight polysomnograms. We determine the Granger causality in both 507 CAP and 507 matched non-CAP sequences to assess the causal relationships between electroencephalography (EEG) frequency bands and respiratory and cardiovascular variables (heart period, respiratory period, pulse arrival time and pulse wave amplitude) during CAP. We observe a significantly stronger influence of delta activity on vascular variables during CAP sequences where slow, low-amplitude EEG activation phases (A1) dominate than during non-CAP sequences. We also show that rapid, high-amplitude EEG activation phases (A3) provoke a more pronounced change in autonomic activity than A1 and A2 phases. Our analysis provides the first evidence on the causal interplay between cortical and cardiovascular activities during CAP. Granger causality analysis may also be useful for probing the level of decoupling in sleep disorders.

This article is part of the theme issue ‘Advanced computation in cardiovascular physiology: new challenges and opportunities’.
A novel artificial intelligence based intensive care unit monitoring system: using physiological waveforms to identify sepsis
Authors: Mollura Maximiliano , Lehman Li-Wei H. , Mark Roger G. , Barbieri Riccardo
Published: October 2021

A massive amount of multimodal data are continuously collected in the intensive care unit (ICU) along each patient stay, offering a great opportunity for the development of smart monitoring devices based on artificial intelligence (AI). The two main sources of relevant information collected in the ICU are the electronic health records (EHRs) and vital sign waveforms continuously recorded at the bedside. While EHRs are already widely processed by AI algorithms for prompt diagnosis and prognosis, AI-based assessments of the patients’ pathophysiological state using waveforms are less developed, and their use is still limited to real-time monitoring for basic visual vital sign feedback at the bedside. This study uses data from the MIMIC-III database (PhysioNet) to propose a novel AI approach in ICU patient monitoring that incorporates features estimated by a closed-loop cardiovascular model, with the specific goal of identifying sepsis within the first hour of admission. Our top benchmark results (AUROC = 0.92, AUPRC = 0.90) suggest that features derived by cardiovascular control models may play a key role in identifying sepsis, by continuous monitoring performed through advanced multivariate modelling of vital sign waveforms. This work lays foundations for a deeper data integration paradigm which will help clinicians in their decision-making processes.

This article is part of the theme issue ‘Advanced computation in cardiovascular physiology: new challenges and opportunities’.
Robustness of convolutional neural networks to physiological electrocardiogram noise
Authors: Venton J. , Harris P. M. , Sundar A. , Smith N. A. S. , Aston P. J.
Published: October 2021

The electrocardiogram (ECG) is a widespread diagnostic tool in healthcare and supports the diagnosis of cardiovascular disorders. Deep learning methods are a successful and popular technique to detect indications of disorders from an ECG signal. However, there are open questions around the robustness of these methods to various factors, including physiological ECG noise. In this study, we generate clean and noisy versions of an ECG dataset before applying symmetric projection attractor reconstruction (SPAR) and scalogram image transformations. A convolutional neural network is used to classify these image transforms. For the clean ECG dataset, F1 scores for SPAR attractor and scalogram transforms were 0.70 and 0.79, respectively. Scores decreased by less than 0.05 for the noisy ECG datasets. Notably, when the network trained on clean data was used to classify the noisy datasets, performance decreases of up to 0.18 in F1 scores were seen. However, when the network trained on the noisy data was used to classify the clean dataset, the decrease was less than 0.05. We conclude that physiological ECG noise impacts classification using deep learning methods and careful consideration should be given to the inclusion of noisy ECG signals in the training data when developing supervised networks for ECG classification.

This article is part of the theme issue ‘Advanced computation in cardiovascular physiology: new challenges and opportunities’.
A novel multi-branch architecture for state of the art robust detection of pathological phonocardiograms
Authors: Duggento Andrea , Conti Allegra , Guerrisi Maria , Toschi Nicola
Published: October 2021

Heart auscultation is an inexpensive and fundamental technique to effectively diagnose cardiovascular disease. However, due to relatively high human error rates even when auscultation is performed by an experienced physician, and due to the not universal availability of qualified personnel, e.g. in developing countries, many efforts are made worldwide to propose computational tools for detecting abnormalities in heart sounds. The large heterogeneity of achievable data quality and devices, the variety of possible heart pathologies, and a generally poor signal-to-noise ratio make this problem very challenging. We present an accurate classification strategy for diagnosing heart sounds based on (1) automatic heart phase segmentation, (2) state-of-the art filters drawn from the field of speech synthesis (mel-frequency cepstral representation) and (3) an ad hoc multi-branch, multi-instance artificial neural network based on convolutional layers and fully connected neuronal ensembles which separately learns from each heart phase hence implicitly leveraging their different physiological significance. We demonstrate that it is possible to train our architecture to reach very high performances, e.g. an area under the curve of 0.87 or a sensitivity of 0.97. Our machine-learning-based tool could be employed for heartsound classification, especially as a screening tool in a variety of situations including telemedicine applications.

This article is part of the theme issue ‘Advanced computation in cardiovascular physiology: new challenges and opportunities’.
Advanced computation in cardiovascular physiology: new challenges and opportunities
Authors: Valenza Gaetano , Faes Luca , Toschi Nicola , Barbieri Riccardo
Published: October 2021

Recent developments in computational physiology have successfully exploited advanced signal processing and artificial intelligence tools for predicting or uncovering characteristic features of physiological and pathological states in humans. While these advanced tools have demonstrated excellent diagnostic capabilities, the high complexity of these computational 'black boxes’ may severely limit scientific inference, especially in terms of biological insight about both physiology and pathological aberrations. This theme issue highlights current challenges and opportunities of advanced computational tools for processing dynamical data reflecting autonomic nervous system dynamics, with a specific focus on cardiovascular control physiology and pathology. This includes the development and adaptation of complex signal processing methods, multivariate cardiovascular models, multiscale and nonlinear models for central-peripheral dynamics, as well as deep and transfer learning algorithms applied to large datasets. The width of this perspective highlights the issues of specificity in heartbeat-related features and supports the need for an imminent transition from the black-box paradigm to explainable and personalized clinical models in cardiovascular research.

This article is part of the theme issue 'Advanced computation in cardiovascular physiology: new challenges and opportunities'.
Development of Permanent Artificial Bowel Replacement Substrates
Authors: Koysombat Kantida , Haneef Atikah
Published: October 2021

Short bowel syndrome (SDS) is a malabsorption disorder caused by loss of function of the small intestine, either by trauma or innately. Current treatment options include parenteral nutrition (PN) or allograft transplants. Long term PN dependence can lead to complications due to line infections and toxicity from the formula itself. A lack of healthy donors results in long waiting lists and high mortality rates. With allograft transplants, long-term graft and patient survival rates are poor (48% and 39% respectively at 5 years); graft loss occurs due to rejection (48%), thrombosis (28%), sepsis (12%); main causes of death are due to bacterial infection (94%) and rejection. Costs associated with PN annually per patient approximate to £40,000, whereas one allograft procedure costs approximately £80,000; not including intervention due to complications.

Interest in developing an off-the-shelf bioengineered alternative have been expressed. Autologous transplants could be a more beneficial route to improving survival rates, enabling the transplant of patients’ healthy cells back to them. We describe here the development of a synthetic poly(ethylene terephthalate) scaffold using electrospinning, which showed excellent physical and chemical characteristics; high surface area:volume ratio, high mechanical strength, high porosity, and the ability to be chemically/physically functionalised without losing integrity in structure and physical properties. The cost of electrospinning is far lower in comparison to the current available treatment options, potentially providing a stable, off-the-shelf, ready-to-culture product as the need arises for applications in tissue engineered small intestine (TESI), or 3D models for small bowel research.
Somatic mosaicism detected by genome-wide sequencing in 500 parent–child trios with suspected genetic disease: clinical and genetic counseling implications
Authors: Cook Courtney B. , Armstrong Linlea , Boerkoel Cornelius F. , Clarke Lorne A. , du Souich Christèle , Demos Michelle K. , Gibson William T. , Gill Harinder , Lopez Elena , Patel Millan S. , Selby Kathryn , Abu-Sharar Ziad ,   CAUSES Study, Elliott Alison M. , Friedman Jan M.
Published: October 2021

Identifying genetic mosaicism is important in establishing a diagnosis, assessing recurrence risk, and providing accurate genetic counseling. Next-generation sequencing has allowed for the identification of mosaicism at levels below those detectable by conventional Sanger sequencing or chromosomal microarray analysis. The CAUSES Clinic was a pediatric translational trio-based genome-wide (exome or genome) sequencing study of 500 families (531 children) with suspected genetic disease at BC Children's and Women's Hospitals. Here we present 12 cases of apparent mosaicism identified in the CAUSES cohort: nine cases of parental mosaicism for a disease-causing variant found in a child and three cases of mosaicism in the proband for a de novo variant. In six of these cases, there was no evidence of mosaicism on Sanger sequencing—the variant was not detected on Sanger sequencing in three cases, and it appeared to be heterozygous in three others. These cases are examples of six clinical manifestations of mosaicism: a proband with classical clinical features of mosaicism (e.g., segmental abnormalities of skin pigmentation or asymmetrical growth of bilateral body parts), a proband with unusually mild manifestations of a disease, a mosaic proband who is clinically indistinguishable from the constitutive phenotype, a mosaic parent with no clinical features of the disease, a mosaic parent with mild manifestations of the disease, and a family in which both parents are unaffected and two siblings have the same disease-causing constitutional mutation. Our data demonstrate the importance of considering the possibility of mosaicism whenever exome or genome sequencing is performed and that its detection via genome-wide sequencing can permit more accurate genetic counseling.
Ambiguities in and completeness of SAS data analysis of membrane proteins: the case of the sensory rhodopsin II–transducer complex
Authors: Ryzhykau Yury L. , Vlasov Alexey V. , Orekhov Philipp S. , Rulev Maksim I. , Rogachev Andrey V. , Vlasova Anastasia D. , Kazantsev Alexander S. , Verteletskiy Dmitry P. , Skoi Vadim V. , Brennich Martha E. , Pernot Petra , Murugova Tatiana N. , Gordeliy Valentin I. , Kuklin Alexander I.
Published: October 2021

Membrane proteins (MPs) play vital roles in the function of cells and are also major drug targets. Structural information on proteins is vital for understanding their mechanism of function and is critical for the development of drugs. However, obtaining high-resolution structures of membrane proteins, in particular, under native conditions is still a great challenge. In such cases, the low-resolution methods small-angle X-ray and neutron scattering (SAXS and SANS) might provide valuable structural information. However, in some cases small-angle scattering (SAS) provides ambiguous ab initio structural information if complementary measurements are not performed and/or a priori information on the protein is not taken into account. Understanding the nature of the limitations may help to overcome these problems. One of the main problems of SAS data analysis of solubilized membrane proteins is the contribution of the detergent belt surrounding the MP. Here, a comprehensive analysis of how the detergent belt contributes to the SAS data of a membrane-protein complex of sensory rhodopsin II with its cognate transducer from Natronomonas pharaonis (NpSRII–NpHtrII) was performed. The influence of the polydispersity of NpSRII–NpHtrII oligomerization is the second problem that is addressed here. It is shown that inhomogeneity in the scattering length density of the detergent belt surrounding a membrane part of the complex and oligomerization polydispersity significantly impacts on SAXS and SANS profiles, and therefore on 3D ab initio structures. It is described how both problems can be taken into account to improve the quality of SAS data treatment. Since SAS data for MPs are usually obtained from solubilized proteins, and their detergent belt and, to a certain extent, oligomerization polydispersity are sufficiently common phenomena, the approaches proposed in this work might be used in SAS studies of different MPs.
Structural insight into DNA recognition by bacterial transcriptional regulators of the SorC/DeoR family
Authors: Šoltysová Markéta , Sieglová Irena , Fábry Milan , Brynda Jiří , Škerlová Jana , Řezáčová Pavlína
Published: October 2021

The SorC/DeoR family is a large family of bacterial transcription regulators that are involved in the control of carbohydrate metabolism and quorum sensing. To understand the structural basis of DNA recognition, structural studies of two functionally characterized SorC/DeoR family members from Bacillus subtilis were performed: the deoxyribonucleoside regulator bsDeoR and the central glycolytic genes regulator bsCggR. Each selected protein represents one of the subgroups that are recognized within the family. Crystal structures were determined of the N-terminal DNA-binding domains of bsDeoR and bsCggR in complex with DNA duplexes representing the minimal operator sequence at resolutions of 2.3 and 2.1 Å, respectively. While bsDeoRDBD contains a homeodomain-like HTH-type domain, bsCggRDBD contains a winged helix–turn–helix-type motif. Both proteins form C2-symmetric dimers that recognize two consecutive major grooves, and the protein–DNA interactions have been analyzed in detail. The crystal structures were used to model the interactions of the proteins with the full DNA operators, and a common mode of DNA recognition is proposed that is most likely to be shared by other members of the SorC/DeoR family.
Financial literacy, financial distress and socioeconomic characteristics of individuals in Ghana
Authors: Karakara Alhassan Abdul-Wakeel , Sebu Joshua , Dasmani Isaac
Published: October 2021

Purpose

Personal financial stress-free living is desired by many, which dwells on sound financial literacy (including financial behaviour, financial knowledge and financial attitude). Many individuals do not make optimal savings and investment decisions. The realisation that these choices may well lead to low living standards has also increased economic anxiety, especially in Sub-Sahara African countries, including Ghana. Thus, this study underscores the link between financial literacy and financial distress in Ghana. It establishes whether persons that are financially literate escape financial distress in their life.

Design/methodology/approach

The paper engages nationally representative survey data and adopts a positivist research approach with logistic regression analysis to establish the likelihood of financial literate persons experiencing financial distress.

Findings

This study establishes that financially literate individuals are 2.4% less likely to experience financial distress. Socioeconomic characteristics greatly influence the probability of one experiencing financial hardship. It submits that policy can be directed towards improving financial habits (financial literacy) to enhance individuals' financial behaviour to lessen personal financial distress.

Originality/value

Not much attention has been paid to whether financial literacy has a nexus with financial distress. Few studies (not on Sub-Saharan Africa) that have looked at this are done, neglecting a sensitivity analysis of socioeconomic characteristics in establishing the relations. However, this current study dwells on econometric analysis to establish the margin or extend to which a financially literate person may or may not escape financial distress given his/her socioeconomic characteristics.
Hospital salutogenic public spaces: a conceptual framework of effective perceptional environment quality components on patients' satisfaction
Authors: Ghaffari Faezeh , Shabak Maryam , Norouzi Nima , Nayyeri Fallah Siyamak
Published: October 2021

Purpose

This study aimed at the identification of perceptional environment properties in hospital public spaces that can affect salutogenic components and patients' overall satisfaction and suggested a conceptual framework.

Design/methodology/approach

A systematic review focused on specific steps to clarify the impact of public spaces' environmental quality on patients' satisfaction through the salutogenic approach. Searches were conducted in five databases and four scientific journals.

Findings

Five perceptional environment components of hospital public spaces: physical–psychological comfort, visibility, accessibility, legibility and relationability can be related to three indicators of salutogenic approach: manageability, perception and meaning and can be evaluated in patients' overall satisfaction: desire to use hospital again, to recommend the hospital to others, to prefer hospital to other healthcare environments and to trust in the hospital.

Originality/value

Despite studies on healthcare environments, there is a lack of research on the salutogenic approach in hospital public spaces. Therefore, this paper focuses on the environmental quality in public spaces as an influence on patients' satisfaction with the salutogenic perspective to create a health-promoting environment.