bluuebunny/crossref_metadata_2025 huggingface dataset:
TEXT MINING OF THE PEOPLE’S PHARMACY RADIO SHOW TRANSCRIPTS CAN IDENTIFY NOVEL DRUG REPURPOSING HYPOTHESES
Authors: Yedida Rahul , Beasley Jon-Michael , Korn Daniel , Abrar Saad Mohammad , Melo-Filho Cleber C. , Muratov Eugene , Graedon Joe , Graedon Terry , Chirkova Rada , Tropsha Alexander
Published: February 2022

Objective

Social media mining may provide surprising information about unknown effects of drugs. We endeavored to uncover such unknown drug-disease relationships by text mining of audio record transcripts from the popular NPR show, The People’s Pharmacy.

Materials and Methods

We used Google Cloud to transcribe episodes of the NPR podcast into textual documents. We then built a pipeline for systematically pre-processing the text to ensure quality input to the core classification model. Finally, results of the model were filtered by a series of post-processing steps. Our classification model itself uses the FLAIR language model pre-trained on PubMed abstracts. The modular nature of our pipeline allows for ease of future developments in this area by substituting higher quality components at each stage of the pipeline. To validate the drug-disease relating assertions extracted from the podcast, we utilized the DrugCentral database and ROBOKOP biomedical knowledge graph, which capture drug-disease relationships for FDA approved medications.

Results

Our model identified 128 drug-disease pairs that were found in DrugCentral and 112 novel candidate pairs requiring expert review. To demonstrate the expert review process, we found literature evidence supporting the assertions for novel drug-disease pairs.

Discussion and Conclusion

Text mining of social media is increasingly used to uncover novel relationships between semantic concepts corresponding to biomedical concepts. However, mining audio transcripts of specialized podcast shows has not been explored previously for this purpose. Using this approach, we have identified several unknown drug-disease relationships with support in biomedical literature. The proposed approach can extend beyond radio podcasts and could be applied to any source of audio and textual data.
Liability-scale heritability estimation for biobank studies of low prevalence disease
Authors: Ojavee Sven E. , Kutalik Zoltan , Robinson Matthew R.
Published: February 2022

Theory for liability-scale models of the underlying genetic basis of complex disease provides an important way to interpret, compare and understand results generated from biological studies. In particular, liability models facilitate an understanding and comparison of the relative importance of genetic and environmental risk factors that shape different clinically important disease outcomes, through estimation of the liability-scale heritability (LSH). Increasingly, large-scale biobank studies that link genetic information to electronic health records are becoming available, containing hundreds of disease diagnosis indicators that mostly occur infrequently within the sample. Here, we propose an extension of the existing liability-scale model theory suitable for estimating LSH in biobank studies of low-prevalence disease. In a simulation study, we find that our derived expression yields lower MSE and is less sensitive to prevalence misspecification as compared to previous transformations, for diseases with ≤ 2% population prevalence and LSH of ≤ 0.45, especially if the biobank sample prevalence is less than that of the wider population. Applying our expression to 13 diagnostic outcomes of ≤ 3% prevalence in the UK Biobank study, revealed important differences in LSH obtained from the different theoretical expressions, that impact the conclusions made when comparing LSH across disease outcomes. This demonstrates the importance of careful consideration for estimation and prediction of low prevalence disease outcomes, and facilitates improved inference of the underlying genetic basis of ≤ 2% population prevalence diseases, especially where biobanking sample ascertainment results in a healthier sample population.
Choice of Intraoperative Ultrasound adjuncts for Brain Tumor Surgery
Authors: Kumar Manoj , Noronha Santosh , Rangaraj Narayan , Moiyadi Aliasgar , Shetty Prakash , Singh Vikas Kumar
Published: February 2022

Background

Gliomas are among the most typical brain tumors tackled by neurosurgeons. During navigation for surgery of glioma brain tumors, preoperatively acquired static images may not be accurate due to shifts. Surgeons use intraoperative imaging technologies (2-Dimensional and navigated 3 Dimensional ultrasound) to assess and guide resections. This paper aims to precisely capture the importance of preoperative parameters to decide which type of ultrasound to be used for a particular surgery.

Methods

This paper proposes two bagging algorithms considering base classifier logistic regression and random forest. These algorithms are trained on different subsets of the original data set. The goodness of fit of Logistic regression-based bagging algorithms is established using hypothesis testing. Furthermore, the performance measures for random-forest-based bagging algorithms used are AUC under ROC and AUC under the precision-recall curve. We also present a composite model without compromising the explainability of the models.

Results

These models were trained on the data of 350 patients who have undergone brain surgery from 2015 to 2020. The hypothesis test shows that a single parameter is sufficient instead of all three dimensions related to the tumor (p < 0.05). We observed that the choice of intraoperative ultrasound depends on the surgeon making a choice, and years of experience of the surgeon could be a surrogate for this dependence.

Conclusion

This study suggests that neurosurgeons may not need to focus on a large set of preoperative parameters in order to decide on ultrasound. Moreover, it personalizes the use of a particular ultrasound option in surgery. This approach could potentially lead to better resource management and help healthcare institutions improve their decisions to make the surgery more effective.
Trend and Weightage of Problem-based Questions in Undergraduate Pharmacology Written Question Papers of Bangladesh
Authors: Johora Fatema , Abbasy Asma Akter , Mahboob Sabiha , Jeenia Fatiha Tasmin , Ferdoush Jannatul , Rahman Md. Sayedur
Published: February 2022

Background

The key objective of pharmacology education is to make graduates competent enough to prescribe safely and effectively. There is worldwide speculation of inadequacy of pharmacology education to achieve the expected learning outcomes. Problem-based pharmacotherapy is considered as one of the crucial way to prepare future physicians as rational prescribers. As assessment drives learning priorities, adequate weightage on problem-based questions in undergraduate pharmacology examination might be helpful.

Materials and Methods

This descriptive cross-sectional study was conducted to analyze the undergraduate pharmacology written question papers (SAQ) of MBBS curriculum of 07 different universities (Bangladesh University of Professionals, University of Dhaka, University of Chittagong, University of Rajshahi, Shahjalal University of Science and Technology, University of Science and Technology, Chittagong and Gono Bishwabidyalay) of Bangladesh in last 10 years (January 2010 to November 2019). Total 131 question papers were collected, and trend and weightage of problem-based questions were evaluated.

Results

Problem-based questions have been reduced dramatically over the decade and Mean percentage of marks allocated for problem-based questions was 1.2±1.3 over last years. There was significant difference (<0.00001) of weightage of problem-based questions among different universities of Bangladesh. Highest presence of problem-based question was observed in Gono Bishwabidyalay (GB), followed by Shahjalal University of Science and Technology (SUST), University of Rajshahi (RU) and Bangladesh University of Professionals (BUP) but there was not a single problem-based question in University of Dhaka (DU), University of Chittagong (CU) and University of Science and Technology (USTC) over 10 years period.

Conclusion

Current study revealed negligible presence of problem-based questions in undergraduate pharmacology written question papers of Bangladesh over 10 years period.
Characterization of the adult zebrafish electrocardiogram
Authors: Arel E. , Rolland L. , Thireau J. , Torrente AG. , Bechard E. , Bride J. , Jopling C. , Demion M. , Le Guennec J-Y.
Published: February 2022

Background

The use of zebrafish to explore cardiac physiology has been widely adopted within the scientific community. Whether this animal model can be used to determine drug cardiac toxicity via electrocardiogram (ECG) analysis, is still an ongoing question. Several reports indicate that the recording configuration severely affects the ECG waveforms and its derived-parameters, emphasizing the need for improved characterization.

Methods

ECGs were recorded from adult zebrafish hearts in 3 different configurations (unexposed heart, exposed heart and extracted heart) to identify the most reliable method to explore ECG recordings at baseline and in response to commonly used clinical therapies.

Results

We found that the exposed heart configuration provided the most reliable and reproducible ECG recordings of waveforms and intervals. We were unable to determine T-wave morphology in unexposed hearts. In extracted hearts, ECG intervals were lengthened and P-waves were unstable. However, in the exposed heart configuration, we were able to reliably record ECGs and subsequently establish the QT-RR relationship (Holzgrefe correction) in response to changes in heart rate.

Conclusions

The exposed heart configuration appears to be the most reliable technique to record ECGs in adult zebrafish. In this configuration, the QT-RR relationship, an important parameter in cardiac toxicity evaluation, can be determined using the Holzgrefe correction.
Emergence of time persistence in a data-driven neural network model
Authors: Wolf Sebastien , Le Goc Guillaume , Debrégeas Georges , Cocco Simona , Monasson Rémi
Published: February 2022

Establishing accurate as well as interpretable models of network activity is an open challenge in systems neuroscience. Here we infer an energy-based model of the ARTR, a circuit that controls zebrafish swimming statistics, using functional recordings of the spontaneous activity of hundreds of neurons. Although our model is trained to reproduce the low-order statistics of the network activity at short time-scales, its simulated dynamics quantitatively captures the slowly alternating activity of the ARTR. It further reproduces the modulation of this persistent dynamics by the water temperature and visual stimulation. Mathematical analysis of the model unveils a low-dimensional landscape-based representation of the ARTR activity, where the slow network dynamics reflects Arrhenius-like barriers crossings between metastable states. Our work thus shows how data-driven models built from large neural populations recordings can be reduced to low-dimensional functional models in order to reveal the fundamental mechanisms controlling the collective neuronal dynamics.
Corticospinal suppression underlying intact movement preparation fades in late Parkinson’s disease
Authors: Wilhelm Emmanuelle , Quoilin Caroline , Derosiere Gerard , Paço Susana , Jeanjean Anne , Duque Julie
Published: February 2022

In Parkinson’s disease, neurophysiological abnormalities within the primary motor cortex have been shown to contribute to cardinal symptoms such as bradykinesia, but the exact modalities are still uncertain. Here, we propose that such impairment could involve alterations of mechanisms shaping motor activity specifically during voluntary movement preparation. Indeed, several past studies in healthy populations have suggested that a strong suppression of corticospinal excitability called “preparatory suppression” – propels movement execution by increasing motor neural gain. Thus, we hypothesized that a gradual alteration to this mechanism may contribute to progressive motor slowness in Parkinson’s disease. We also predicted a benefit of dopamine medication in restoring correct motor neural activity during action preparation.

To test these hypotheses, we investigated preparatory suppression on two consecutive days in 29 Parkinson’s disease patients (ON and OFF medication) and 29 matched healthy controls. Single-pulse transcranial magnetic stimulation was applied over both primary motor cortices, eliciting concurrent motor-evoked potentials in the two hands, while subjects were either at rest or prepared a left- or right-hand response in an instructed-delay choice reaction time task. Preparatory suppression was assessed by expressing the amplitude of motor potentials evoked during movement preparation relative to those obtained at rest. These neurophysiological measures were cross-analysed with task behaviour and clinical data.

Contrary to healthy controls, Parkinson’s disease patients showed a lack of preparatory suppression, which appeared to depend on disease progression, but not on dopamine medication. Indeed, in relatively early disease stages, patients still exhibited partial preparatory suppression, while in later stages, they lacked it completely and even exhibited a tendency for corticospinal facilitation in the hand selected for movement execution. As expected, patients also showed increasing motor handicap with disease progression as well as a decreased movement velocity during the task, but such findings did not directly correlate with levels of preparatory suppression in our cohort. While dopamine medication had no effect on the latter, it did however globally reduce raw corticospinal excitability in the dominant hand.

Taken together, our results are in line with the idea that a lack of corticospinal suppression during movement preparation in Parkinson’s disease slows down response execution and illustrate the importance of considering disease stages in such investigations; they also suggest differential roles of dopamine in shaping corticospinal output in those patients. Our findings thus support the use of task-related functional markers such as preparatory suppression in future studies on motor impairment in Parkinson’s disease.
Effectiveness of a Text Message Intervention Promoting Seat Belt Use Among Targeted Young Adults: A Randomized Clinical Trial
Authors: Suffoletto Brian , Pacella-LaBarabara Maria L. , Huber James , Bocage Claire , Delgado M. Kit , McDonald Catherine
Published: February 2022

Background

Seat belt use is an effective way to reduce the morbidity and mortality of motor vehicle crashes. However, 1 in 10 adults do not always wear a seat belt, with the lowest use rates of seat belt use among young adults. Digital behavioral interventions could be useful to increase seat belt use, but remain under-developed. This randomized clinical trial tested the efficacy of a 6-week behavioral text message program promoting seat belt use among young adults.

Methods

A parallel, 2-group, single-blind, individually randomized clinical trial. Eligible individuals recruited from 4 Emergency Departments were aged 18 to 25 years who reported driving or being a passenger without always using a seat belt in the past 2-weeks. Two hundred eighteen participants completed the 2-week trial run-in phase were randomly assigned 1:1 to intervention: self-monitoring control. The intervention arm (n = 110) received SaVE, a 6-week automated interactive text message program including weekly seat belt use queries with feedback and goal support to promote consistent use of a seat belt. The control arm (n = 108) received identical weekly seat belt use queries but no additional feedback. The primary and secondary outcomes were the proportion of young adults reporting always wearing a seat belt at 6- and 12-weeks, collected via web-based self-assessments and analyzed under intent-to-treat models.

Results

The mean (SD) age was 21.5 (2.2) years, 137 (63%) were female, 110 (50%) were White, and 33 (15%) were Hispanic. The 6-week follow-up rate was 86.2% (n = 187), with no differential attrition. At 6-weeks, 39.1% (95% CI, 30.0%-48.9%) of intervention participants always wore a seat belt vs. 23.1% (95% CI, 15.6%-32.2%) of control participants (odds ratio, 2.13; 95% CI, 1.18-3.84; P = .01). The 12-week follow-up rate was 64.2% (n = 140), with no differential attrition. At 12 weeks, 42.7% (95% CI, 15.6%-32.2%) of intervention participants always wore a seatbelt vs. 32.3% (95% CI, 20.6%-44.0%) of control participants (odds ratio, 1.25; 95% CI, 0.67-2.31; P=.48).

Conclusions

Results of this randomized clinical trial demonstrated that an interactive text message intervention using goal support was more effective at promoting seat belt use among targeted young adults than self-monitoring at 6-weeks. These findings, if replicated, suggest a scalable approach to help improve seat belt use and reduce crash-related morbidity and mortality.

Trial registration

ClinicalTrials.gov Identifier: NCT03833713
Evaluating the Association and Predictability of Complex Medication Regimen Scores with Clinical Outcomes Among the Critically Ill
Authors: Al-Mamun Mohamamd , Strock Jacob , Sharker Yushuf , Schmidt Rebecca , Shawwa Khaled , Slain Douglas , Sakhuja Ankit , Brothers Todd
Published: February 2022

Introduction

Medication Regimen Complexity (MRC) refers to the combination of medication classes, dosages, and frequencies. The relationship between MRC and clinical outcomes in the intensive care unit (ICU) has not been examined. The objective of this study is to examine the association between MRC scoring tools and their utility in predicting clinical outcomes.

Methods

We conducted a retrospective cohort study that includes 322 adult patients admitted and stayed (>24 hours) to the ICU between February 1, 2020, and August 30, 2020 in a community-based, teaching hospital in Rhode Island. Medication complexity was assessed using two MRC scoring tools: MRC Index (MRCI) and the MRC in ICU (MRCICU). We used a multivariable logistic regression model to identify the association between MRC scores and clinical outcomes and to predict the clinical outcomes.

RESULTS

Among the 317 patients included in the study (55.2% men with a median age of 62 [IQR: 51-75] years). Higher MRC scores (i.e., > 63 MRCI or > 6 MRCICU) were associated with increased mortality (14% and 15%), longer ICU length of stay (LOS)(30% and 34%), and need for MV (24% and 28%). MRCICU scores at 24 hours were found to be a significant risk factor in all clinical outcomes (ICU mortality, LOS, and MV) with Odds Ratio (ORs) of 1.12 (95% CI: 1.06-1.19), 1.17 (1.1-1.24), and 1.21 (1.14-1.29), respectively. In the prediction models, both MRCI and MRCICU models performed similarly (AUC: 0.88 [0.75-0.97] and 0.88 [0.76-0.97] in predicting mortality. The Medication Model included 15 medication classes outperformed others (AUC: 0.82 [0.71-0.93] in predicting ICU LOS and the MRCICU model outperformed others (AUC: 0.87 [0.77-0.96]) in predicting the need for MV.

CONCLUSION

MRC scores are associated with poorer clinical outcomes and improves the prediction of poorer clinical outcomes which will support clinicians to prescribe safer therapies.
RISK STRATIFICATION OF PATIENTS WITH COVID-19 DISEASE THROUGH THE USE OF CLINICAL SCORES IN AN EMERGENCY DEPARTMENT. A review of the literature
Authors: Zanella Simone , Alena Mancosu , Anna Brugnolli , Alessandro Carrara , Anita Bevilacqua , Elisa Marinelli , Nicola Ricci , Buccelletti Francesco
Published: February 2022

DISCLAIMER STATEMENT

The authors have withdrawn the manuscript because there are some errors in the Area Under the Curve values regarding to intensive care unit admission and mortality for some scores analyzed. The article must be revised in its conclusions in order to affirm that NEWS and NEWS2 are the best clinical scores to be used in Emergency to evaluate patients with Covid-19 disease.

Therefore, the authors do not wish this work to be cited as reference for one project. If you have any questions, please contact the corresponding author.
VE607 Stabilizes SARS-CoV-2 Spike In the “RBD-up” Conformation and Inhibits Viral Entry
Authors: Ding Shilei , Gong Shang Yu , Grover Jonathan , Mohammadi Mohammadjavad , Chen Yaozong , Vézina Dani , Beaudoin-Bussières Guillaume , Verma Vijay Tailor , Goyette Guillaume , Richard Jonathan , Yang Derek , Smith Amos B. , Pazgier Marzena , Côté Marceline , Abrams Cameron , Mothes Walther , Finzi Andrés , Baron Christian
Published: February 2022

SARS-CoV-2 infection of host cells starts by binding of the Spike glycoprotein (S) to the ACE2 receptor. The S-ACE2 interaction is a potential target for therapies against COVID-19 as demonstrated by the development of immunotherapies blocking this interaction. Here, we present the commercially available VE607, comprised of three stereoisomers, that was originally described as an inhibitor of SARS-CoV-1. We show that VE607 specifically inhibits infection of SARS-CoV-1 and SARS-CoV-2 S-expressing pseudoviral particles as well as authentic SARS-CoV-2. VE607 stabilizes the receptor binding domain (RBD) in its “up” conformation. In silico docking and mutational analysis map the VE607 binding site at the RBD-ACE2 interface. The IC50 values are in the low micromolar range for pseudoparticles derived from SARS-CoV-2 Wuhan/D614G as well as from variants of concern (Alpha, Beta, Gamma, Delta and Omicron), suggesting that VE607 has potential for the development of drugs against SARS-CoV-2 infections.
Intrinsic Capacity of Rural Elderly in Thar Desert using WHO ICOPE (Integrated Care for Older Persons) Screening Tool: A Pilot Study
Authors: Mathur Arvind , Bhardwaj Pankaj , Joshi Nitin Kumar , Jain Yogesh Kumar , Singh Kuldeep
Published: February 2022

Introduction

ICOPE (Integrated Care for Older Persons) screening tool helps to address declines in physical and mental capacities in older people. In India majority of the older population resides in rural areas and there is a paucity of studies that demonstrates the utility of the ICOPE screening tool in India. Thus, this study was conducted to demonstrate the feasibility of using WHO ICOPE screening tool in a rural population.

Methods

A cross-sectional study was conducted in the two villages of Jodhpur. WHO ICOPE screening was done for a comprehensive geriatric assessment of intrinsic capacity by determining cognitive decline, the decline in mobility, malnutrition, sensory loss, depressive symptoms, health risks, social care, and support. Additionally, demographic details and information about health conditions were gathered.

Result

A total 451 participants (Male=54.5% and Female= 45.5%) surveyed. The mean age was 68.36 (SD=7.73) years and the majority of participants (68.3%) were illiterate. Most of the elderly have good families and lived with their children. Cognitive decline was found to be prevalent in 31.5% (n=142) of the participants, while mobility was diminished in 52.1% (n=235) participants. Eye problems were observed in 49.4% (n=223) participants, while 68.3% (n=308) were observed to be suffering from hearing loss. Limitation in mobility observed with the chair rise test and feeling of pain was found to be significantly associated with gender difference, with more limitation in females than males (p = 0.005; χ2 = 7.95) and more pain felt by females than males (p = 0.001; χ2 = 15.64).

Conclusion

This tool seems suitable in identifying the intrinsic capacity of the rural elderly.
KMT2C deficiency promotes APOBEC mutagenesis and genomic instability in multiple cancers
Authors: Hu Xiaoju , Biswas Antara , De Subhajyoti
Published: February 2022

Histone methyltransferase KMT2C is among the frequently mutated epigenetic modifier genes in cancer. It has additional roles in DNA replication, but the effects of KMT2C deficiency on genomic instability during tumorigenesis are unclear. Analyzing 9,663 tumors from 30 cohorts, we report that KMT2C mutant tumors have a significant excess of APOBEC mutational signatures in several cancer types. We show that KMT2C deficiency promotes APOBEC expression and deaminase activity, and compromises DNA replication speed and delays fork restart, facilitating APOBEC mutagenesis targeting ssDNA near stalled forks. APOBEC-mediated mutations primarily accumulate during early replication, and tend to cluster along the genome and also in 3D nuclear contexts. Excessive APOBEC mutational signatures in KMT2C mutant tumors correlate with elevated genomic instability and signatures of homologous recombination deficiency. We propose that in multiple cancer types KMT2C deficiency is a likely driver of APOBEC mutagenesis, which promotes further genomic instability during cancer progression.
Trends in pregnancy-associated cervical cancer in Japan between 2012 and 2017: A multicenter survey
Authors: Enomoto Sayako , Yoshihara Kosuke , Kondo Eiji , Iwata Akiko , Tanaka Mamoru , Tabata Tsutomu , Kudo Yoshiki , Kondoh Eiji , Mandai Masaki , Sugiyama Takashi , Okamoto Aikou , Saito Tsuyoshi , Enomoto Takayuki , Ikeda Tomoaki
Published: February 2022

Large-scale data on maternal and neonatal outcomes of pregnancy-associated cervical cancer in Japan are scarce, and treatment strategies have not been established. We conducted this multicenter retrospective observational study at 523 secondary/tertiary care hospitals in Japan to investigate the clinical features and trends in pregnancy-related cervical cancer treatments. We collected data for 290 patients with pregnancy-associated cervical cancer (during pregnancy, n=203; postpartum, n=87) diagnosed between January 1, 2012, and December 31, 2017. Of the 40 patients diagnosed at ≥22 gestational weeks, 34 (85.0%) were carefully followed until delivery without intervention. Of the 163 patients diagnosed at <22 gestational weeks, 111 and 52 patients continued and terminated their pregnancies, respectively. Although the termination rate increased with cervical cancer stage, 90 patients with stage IB1 disease had a variety of treatment options, including termination of pregnancy. When we divided the 59 stage IB1 patients who continued their pregnancy into four groups based on the primary treatment (strict follow-up, conization, trachelectomy, and neoadjuvant chemotherapy), there were no significant differences in progression-free or overall survival. The percentile of birth weight at delivery was smaller in the neoadjuvant chemotherapy group than in the strict follow-up group (P =.02). The full-term delivery rate was relatively higher in the trachelectomy group (35%) than in the other groups. In conclusion, treatment decisions, including pregnancy termination for pregnancy-associated cervical cancer, should be made after estimating the stage, with careful consideration of both maternal and fetal benefits. These findings will help in developing treatment guidelines for pregnancy-associated cervical cancer.
SARS-CoV-2 mRNA vaccination fails to elicit humoral and cellular immune responses in multiple sclerosis patients receiving fingolimod
Authors: Meyer-Arndt Lil , Braun Julian , Fauchere Florent , Vanshylla Kanika , Loyal Lucie , Henze Larissa , Kruse Beate , Dingeldey Manuela , Jürchott Karsten , Mangold Maike , Maraj Ardit , Braginets Andre , Böttcher Chotima , Nitsche Andreas , de la Rosa Kathrin , Ratswohl Christoph , Sawitzki Birgit , Holenya Pavlo , Reimer Ulf , Sander Leif E. , Klein Florian , Paul Friedemann , Bellmann-Strobl Judith , Thiel Andreas , Giesecke-Thiel Claudia
Published: February 2022

SARS-CoV-2 mRNA vaccination of healthy individuals is highly immunogenic and protective against severe COVID-19. However, there are limited data on how disease-modifying therapies (DMTs) alter SARS-CoV-2 mRNA vaccine immunogenicity in patients with autoimmune diseases. Here we investigated the induction and stability of vaccine-specific antibodies, B cells, and T cells in multiple sclerosis (MS) patients on different DMTs in a prospective cohort study up to 6 months after homologous prime-boost mRNA vaccination. We analysed 103 MS patients of which 86 received anti-CD20-based B cell depletion (aCD20-BCD), fingolimod, interferon-β, dimethyl fumarate, glatiramer acetate, teriflunomide or natalizumab, and compared them to 17 untreated MS patients. In contrast to all other DMTs and untreated patients, treatment with aCD20-BCD or fingolimod significantly reduced anti-S1 IgG, serum neutralizing activity, and RBD- and S2-specific B cells. MS patients receiving fingolimod additionally lacked S1- and S2-reactive CD4+ T cell responses. The duration of fingolimod treatment, rather than peripheral blood B and T cell counts prior to vaccination, determined whether patients successfully developed humoral immune responses. Fingolimod blocks the ability of immune cells to recirculate and migrate within secondary lymphoid organs demonstrating that functional immune responses require not only immune cells themselves but also access of these cells to the site of inoculation and their unimpeded movement. The absence of humoral and T cell responses in fingolimod-treated MS patients suggests that these patients are at risk for severe SARS-CoV-2 infections despite vaccination, which is highly relevant for clinical decision-making and adapted protective measures, particularly in light of additional recently approved S1P receptor antagonists for MS treatment.
Preclinical Efficacy in Investigator’s Brochures: Stakeholders’ views on measures to improve Completeness and Robustness
Authors: Haslberger Martin , Schorr Susanne Gabriele , Strech Daniel , Haven Tamarinde
Published: February 2022

Research ethics committees (RECs) and regulatory agencies assess whether the benefits of a proposed early-stage clinical trial outweigh the risks based on preclinical studies reported in investigator’s brochures (IBs). Recent studies have indicated that preclinical evidence presented in IBs is reported in a way that does not enable proper risk-benefit assessment. We interviewed different stakeholders (regulators, REC members, industry representatives, preclinical and clinical researchers, ethicists, and metaresearchers) about their views on measures to increase the completeness and robustness of preclinical evidence reporting in IBs.

This study was preregistered (https://osf.io/nvzwy/). We used purposive sampling and invited stakeholders to participate in an online semistructured interview between March and June 2021. The themes were derived using inductive content analysis. We used a strengths, weaknesses, opportunities, and threats (SWOT) matrix to categorize our findings.

Twenty-seven international stakeholders participated. The interviewees pointed to several strengths and opportunities to improve completeness and robustness, mainly more transparent and systematic justifications of the inclusion of studies. However, weaknesses and threats were mentioned that could undermine efforts to enable more thorough assessment: The interviewees stressed that current review practices are sufficient to ensure the safe conduct of first-in-human trials. They feared that changes to the IB structure or review process could overburden stakeholders and slow drug development.

In principle, having more robust decision-making processes in place aligns with the interests of all stakeholders and with many current initiatives to increase the translatability of preclinical research and limit uninformative or ill-justified trials early in the development process. Further research should investigate measures that could be implemented to benefit all stakeholders.
Interscapular fat is associated with impaired glucose tolerance and insulin resistance independent of visceral fat mass
Authors: Vosseler Andreas , Machann Jürgen , Fritsche Louise , Kübler Christian , Häring Hans-Ulrich , Birkenfeld Andreas L. , Stefan Norbert , Peter Andreas , Fritsche Andreas , Wagner Robert , Heni Martin
Published: February 2022

Dysregulated body fat distribution is a major determinant of various diseases. Adipose tissue in different localizations of the body appear to have protective or detrimental properties. Particularly increased visceral fat mass and ectopic lipids in the liver are linked to metabolic disorders such as insulin resistance and type 2 diabetes. Furthermore, interscapular fat is considered to be a non-classical, but metabolically active, fat compartment.

In this study, we measured interscapular fat mass and investigated its relationship with glucose tolerance, insulin sensitivity and insulin secretion in 822 subjects with a wide range of body mass index (BMI) and different glucose tolerance status. Magnetic resonance imaging was used to quantify body fat depots and an oral glucose tolerance test (OGTT) was performed to determine glucose metabolism.

Elevated interscapular fat mass was positively associated with age, BMI, total body, visceral and subcutaneous adipose tissue mass. High interscapular fat mass associated with elevated fasting glucose levels, glucose levels at 2 hours during the OGTT, glycated hemoglobin, as well as with insulin resistance, independently of sex, age, total body and visceral fat mass.

In conclusion, interscapular fat might be a highly specific fat compartment with potential impact on glucose metabolism and the pathogenesis of diabetes mellitus. Since this depot is assessible by ultrasound, it could represent a feasible target to quantify metabolic risk in the future.
OCTA observation of changes in macular vessel density in diabetic patients and its correlation with diabetic retinopathy staging : A cross-sectional study
Authors: Yu Deng , Chuanhong Jie , Jianwei Wang , Ziqiang Liu , Yuanyuan Li
Published: February 2022

Objective

To investigate the association between disease progression and OCTA vessel density and other indices in patients with diabetic retinopathy.

Methods

Participants were selected with the following criteria: 63 patients (100 eyes) diagnosed with type 2 diabetes mellitus, which included 44 patients (72 eyes) with diabetic retinopathy and 19 patients (28 eyes) with type 2 diabetes mellitus and non-diabetic retinopathy (NDR), who were seen at the Eye Hospital China Academy of Chinese Medical Sciences from September 2020 to July 2021. All patients underwent OCTA examination, and FAZ, PERIM, AI, FD, SVD, DVD and other indices were counted.

Results

(1) The correlation coefficients of SVD, paracentric SVD, DVD, paracentric DVD and DR processes were: -0.525, -0.586, -0.323, and -0.424 (P< 0.05), respectively, and all were moderately negatively correlated. (2) The correlation coefficients of FAZ and PERIM with DR process were: -0.031, 0.084 (P>0.05), respectively, and not correlated. The correlation coefficients of AI and FD with DR process were: 0.307, −0.459 (P<0.05), and with moderate positive and negative correlations, respectively. (3) The correlation coefficients of FAZ, PERIM, AI and FD with age were: -0.124, -0.052, 0.113, -0.170 (P>0.05), and no correlation, respectively.

Conclusion

The disease progression of DR was moderately correlated with OCTA superficial vessel density and deep vessel density; and moderately correlated with AI and FD. OCTA could assist in the assessment of DR disease progression.
Industry 4.0 oriented predictive analytics of cardiovascular diseases using machine learning, hyperparameter tuning and ensemble techniques
Authors: Ahamed Jameel , Mir Roohie Naaz , Chishti Mohammad Ahsan
Published: February 2022

Purpose

The world is shifting towards the fourth industrial revolution (Industry 4.0), symbolising the move to digital, fully automated habitats and cyber-physical systems. Industry 4.0 consists of innovative ideas and techniques in almost all sectors, including Smart health care, which recommends technologies and mechanisms for early prediction of life-threatening diseases. Cardiovascular disease (CVD), which includes stroke, is one of the world’s leading causes of sickness and deaths. As per the American Heart Association, CVDs are a leading cause of death globally, and it is believed that COVID-19 also influenced the health of cardiovascular and the number of patients increases as a result. Early detection of such diseases is one of the solutions for a lower mortality rate. In this work, early prediction models for CVDs are developed with the help of machine learning (ML), a form of artificial intelligence that allows computers to learn and improve on their own without requiring to be explicitly programmed.

Design/methodology/approach

The proposed CVD prediction models are implemented with the help of ML techniques, namely, decision tree, random forest, k-nearest neighbours, support vector machine, logistic regression, AdaBoost and gradient boosting. To mitigate the effect of over-fitting and under-fitting problems, hyperparameter optimisation techniques are used to develop efficient disease prediction models. Furthermore, the ensemble technique using soft voting is also used to gain more insight into the data set and accurate prediction models.

Findings

The models were developed to help the health-care providers with the early diagnosis and prediction of heart disease patients, reducing the risk of developing severe diseases. The created heart disease risk evaluation model is built on the Jupyter Notebook Web application, and its performance is calculated using unbiased indicators such as true positive rate, true negative rate, accuracy, precision, misclassification rate, area under the ROC curve and cross-validation approach. The results revealed that the ensemble heart disease model outperforms the other proposed and implemented models.

Originality/value

The proposed and developed CVD prediction models aims at predicting CVDs at an early stage, thereby taking prevention and precautionary measures at a very early stage of the disease to abate the predictive maintenance as recommended in Industry 4.0. Prediction models are developed on algorithms’ default values, hyperparameter optimisations and ensemble techniques.
Assessing community awareness for participatory conservation of cultural heritage: the case of Tepebağ Tumulus and its surroundings in Adana Turkey
Authors: Umar Nur , Yüceer Hülya , Aydın Rozelin
Published: February 2022

Purpose

The purpose of this paper is to identify the levels of awareness of locals about conservation and cultural heritage, in order to develop suggestions and methods for them to participate in these processes.

Design/methodology/approach

The method of research is based on face-to-face surveys, mainly questionnaires that were conducted with 1,200 local people. The data obtained was evaluated using the SPSS 25.0.0 V program.

Findings

The results show that locals mainly find appropriate the assets that reflect their culture but disregard archaeological remains. The participation of locals in the conservation process will end up benefiting them economically.

Social implications

It is currently accepted that effective conservation cannot be achieved unless its technical considerations are considered together with social and cultural aspects. Ensuring the participation of local people in the conservation process has proved to be important in the development of holistic and sustainable outcomes. In places, where multilayered cultural heritage exists and local residents are from different cultural backgrounds, a detailed assessment of cultural heritage perception that involves local people gains significance.

Originality/value

It is project-based in the sense of adding the dimension of community awareness to the practice of cultural heritage conservation in the multilayered and multicultural places.
Enhanced water dispersibility and Caco‐2 cell monolayer permeability of quercetin by complexation with casein hydrolysate
Authors: Inada Asuka , Sawao Ayane , Takahashi Koki , Oshima Tatsuya
Published: February 2022

Although quercetin (Que) has many beneficial therapeutic effects on the human body, its oral bioavailability is poor because of its low water solubility. Herein, we describe the preparation of casein hydrolysate (Pepcas) and its use as a dispersant to enhance the water dispersibility of Que resulting in an improvement of its bioavailability. By complexation with Pepcas, the apparent solubility of Que in the complex (Que@Pepcas) was significantly increased under acidic and neutral conditions. Que@Pepcas was pre‐digested in vitro using a simulated digestive juice, and a Caco‐2 cell monolayer permeation assay was performed to evaluate the oral bioavailability of Que. The cumulative amount of Que that permeated the monolayer using Que@Pepcas after 8, 16, and 24 h was increased compared with a blank sample (Que@Blank), and the apparent permeation coefficient Papp of Que@Pepcas was approximately 2.6‐fold better than that of Que@Blank.

Practical Application

Pepcas can be used as a high absorption supplement and food additive, and our Pepcas complexation technique should be widely applicable to not only Que but also to other poorly water‐soluble substances.
Perceptions, concerns and reported behaviours in response to the first wave of the coronavirus disease 2019 pandemic across metropolitan, regional, rural and remote Australian communities
Authors: Argus Geoff , Walker Clara , Baratiny Genevieve , Cotter Nicola , Fallon Tony
Published: February 2022

Objective

To investigate coronavirus disease 2019 community transmission concerns and adherence to social distancing and hygiene practices across metropolitan, regional, rural and remote areas in Australia.

Design

Cross‐sectional online survey of Australian adults conducted between April and May 2020 through convenience snowball sampling.

Setting

A range of locations across all states and territories of Australia.

Participants

Six hundred and seventy‐seven Australian adults, of which 78.8% lived outside of a metropolitan area.

Main outcome measures

Perceived threat of coronavirus disease 2019; social distancing guidelines and adherence; infection concerns; hygiene practices; frequency of leaving the house; impact of coronavirus disease 2019 on day‐to‐day life.

Results

Almost all respondents perceived the threat of the coronavirus disease 2019 pandemic was serious. There were high levels of support for the Australian Government's social distancing guidelines, although the perception that social distancing guidelines in participants’ communities were ‘too strict’ increased with remoteness area classification. Most respondents reported adherence with Australian Government social distancing guidelines. There was an association between remoteness and risk perception, with non‐metropolitan respondents more likely to feel safe when leaving the house. However, there was no association between geographical remoteness and self‐reported adherence with Australian Government social distancing guidelines.

Conclusions

This study provides an important initial insight into Australian perceptions and behaviours relating to the coronavirus disease 2019 pandemic, and how perceptions and behaviours varied by geographical remoteness. The geographical remoteness of communities should be considered by policy makers to ensure effective communication with the Australian public regarding coronavirus disease 2019 and ongoing adherence with preventative health behaviours.
Delayed presentation of a post‐traumatic large right diaphragmatic hernia displacing liver and gallbladder – A case report
Authors: Jain Nikunj , Raju Bhanu Prakash , Dhanda Sourabh , Johri Vishwas , Reddy Prasanna Kumar , Jameel Jainudeen Khalander Abdul
Published: February 2022

Blunt or penetrating trauma resulting in injury or rupture of the diaphragm is rare and constitutes about 1% to 3.9% of all thoraco‐abdominal injuries. It is often regarded as a marker of severe trauma. Unfortunately about half of these injuries can be missed during the index admission. Contrast‐enhanced computed tomography is the best modality to assess the extent, size of diaphragmatic defect and nature of hernial contents. Surgery is mandatory once the diagnosis is made to prevent future strangulation of hernial contents. Although technically challenging, laparoscopic reduction and mesh repair is feasible in expert hands. We report our experience with laparoscopic repair and mesh re‐enforcement in a patient who had a large right diaphragmatic hernia with part of liver, gallbladder, small bowel and omentum within the right hemithorax secondary to a penetrating trauma he had incurred 29 years earlier.
Payment is a benefit and why it matters for pediatric trials
Authors: Steel Robert
Published: February 2022

Alan Wertheimer has argued persuasively that research ethics committees should be willing to count payment as a benefit when evaluating studies' risk–benefit ratios. In this paper, I begin by first recapitulating his argument and adding my own, complementary one. I then do two further things. First, I explain why the practical implications of these arguments for studies enrolling competent adults are less than fully clear. Second, I explain why the practical implication for trials enrolling children are clear and significant. I argue that we should be comfortable paying children to compensate them for undergoing research risks. I propose we do so by putting money into accounts that the child gains access to upon attaining majority.
Limonene and linalool hydroperoxides review: Pros and cons for routine patch testing
Authors: Ogueta Isabel A , Brared Christensson Johanna , Giménez‐Arnau Elena , Brans Richard , Wilkinson Mark , Stingeni Luca , Foti Caterina , Aerts Olivier , Svedman Cecilia , Gonçalo Margarida , Giménez‐Arnau Ana
Published: February 2022

Limonene and linalool are among the most common fragrance terpenes used in everyday products. They are pre‐haptens, forming hydroperoxides (Lim‐OOHs, Lin‐OOHs) upon oxidation and inducing frequent positive patch test reactions in patients with dermatitis, and yet they are not routinely tested in Europe. This review evaluates current patch testing with Lim‐OOHs and Lin‐OOHs by asking whether hydroperoxide patch testing is warranted, examining the difficulties or challenges related to reading and interpreting hydroperoxide patch test results with currently available material, and assessing their relevance. Studies are increasingly pointing to high percentages of positive reactions in patients consecutively patch tested with these oxidized products. An association between a positive clinical history and a strong patch test reaction has been described, but problems with doubtful/irritant reactions have also been reported. Considering the high frequency of relevant positive reactions, the incorporation of Lim‐OOHs 0.3% and Lin‐OOHs 1% in the baseline series may be justified. Since exposure, sensitization, and elicitation limits of Lim‐OOHs and Lin‐OOHs in the products still need to be better determined, an assessment of previous exposure, possible sensitizations, and reactions may help to improve the clinical assessment.