bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeted proteomic quantitation of NRF2 signaling and predictive biomarkers in HNSCC
Authors: Wamsley Nathan T. , Wilkerson Emily M. , Guan Li , LaPak Kyle M. , Schrank Travis P. , Holmes Brittany J. , Sprung Robert W. , Gilmore Petra Erdmann , Gerndt Sophie P. , Jackson Ryan S. , Paniello Randal , Pipkorn Patrik , Puram Sidarth V. , Rich Jason T. , Townsend Reid R. , Zevallos José P. , Zolkind Paul , Le Quynh-Thu , Goldfarb Dennis , Major M. Ben
Published: March 2023

The NFE2L2/NRF2 oncogene and transcription factor drives a gene expression program that promotes cancer progression, metabolic reprogramming, immune evasion and chemoradiation resistance. Patient stratification by NRF2 activity may guide treatment decisions to improve outcome. Here, we developed a mass spectrometry (MS)-based targeted proteomics assay based on internal standard triggered parallel reaction monitoring (IS-PRM) to quantify 69 NRF2 pathway components and targets as well as 21 proteins of broad clinical significance in head and neck squamous cell carcinoma (HNSCC). We improved the existing IS-PRM acquisition algorithm, called SureQuant™, to increase throughput, sensitivity, and precision. Testing the optimized platform on 27 lung and upper aerodigestive cancer cell models revealed 35 NRF2 responsive proteins. In formalin-fixed paraffin-embedded (FFPE) HNSCCs, NRF2 signaling intensity positively correlated with NRF2 activating mutations and with SOX2 protein expression. PD-L2/CD273 and protein markers of T-cell infiltration correlated positively with one another and with human papilloma virus (HPV) infection status. p16/CDKN2A protein expression positively correlated with the HPV oncogenic E7 protein, and confirmed the presence of translationally active virus. This work establishes a clinically actionable HNSCC protein biomarker assay capable of quantifying over 600 peptides from frozen or FFPE archived tissues in under 90 minutes.
Inequities in hypertension management: an observational cross-sectional study in North-East London using electronic health records
Authors: Rison Stuart , Redfern Oliver , Dostal Isabel , Carvalho Chris , Mathur Rohini , Raisi-Estabragh Zahra , Robson John
Published: March 2023

Background

Hypertension is a key potentially modifiable risk factor for cardiovascular disease-the leading cause of death in the UK. Good blood pressure (BP) control reduces mortality; however, health inequalities may lead to variability in hypertension management.

Aim

To investigate health inequities related to ethnicity, sex, age, and socio-economic status in the treatment and control of BP in a large cohort of adult patients with hypertension.

Design and Setting

A cross-sectional cohort study of adults with hypertension registered with general practices in North East London on 1stApril 2019.

Method

Multivariable logistic regression was used to estimate associations of demographics and treatment intensity on the following hypertension management indicators: 1) BP recording in last 12 months, 2) BP on age-adjusted target, 3) BP on age-adjusted target and BP recorded in last 12 months.

Results

In total, 156,296 adults were included. Black/Black British ethnic groups were less likely to have controlled BP than White ethnic groups (OR 0.89, 95% CI = 0.86-0.92). Asian/Asian British ethnic groups were more likely to have controlled blood pressure (OR 1.29, 95% CI = 1.25-1.34). Ethnic differences in control could not be explained by the likelihood of having a recent blood pressure recording, nor by treatment intensity differences. Older adults were more likely to have controlled hypertension than younger patients.

Conclusion

Black/Black British and younger people are less likely to have controlled hypertension and may warrant targeted interventions. Possible explanations for these findings are presented and further research is needed on reasons for ethnic differences.

HOW THIS FITS IN

Health inequities in the management of long-term conditions are widely recognised. This study identifies ethnic, age, gender and deprivation inequities in the control of blood pressure in a large unselected cohort of adults with hypertension in an ethnically diverse and nationally disadvantaged area of London. It confirms previous findings that blood pressure control in Black ethnic groups with hypertension is worse than in White or Asian ethnic groups. These differences were not related to access to blood pressure recording or treatment intensity. Younger adults were less likely to have controlled hypertension than older adults.
Evaluation of polygenic score for hypertrophic cardiomyopathy in the general population and across clinical settings
Authors: Zheng Sean L , Jurgens Sean J , McGurk Kathryn A , Xu Xiao , Grace Chris , Theotokis Pantazis I , Buchan Rachel J , Francis Catherine , Marvao Antonio de , Curran Lara , Bai Wenjia , Pua Chee Jian , Chiaw Tang Hak , Jorda Paloma , Slegtenhorst Marjon A van , Verhagen Judith MA , Harper Andrew R , Ormondroyd Elizabeth , Chin Calvin WL ,   Genomics England Research Consortium,   HCM GWAS Collaborators, Pantazis Antonis , Baksi John , Halliday Brian P , Matthews Paul , Pinto Yigal M , Walsh Roddy , Amin Ahmad S , Wilde Arthur AM , Cook Stuart A , Prasad Sanjay K , Barton Paul JR , O’Regan Declan P , Lumbers RT , Goel Anuj , Tadros Rafik , Michels Michelle , Watkins Hugh , Bezzina Connie R , Ware James S
Published: March 2023

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality, with rare pathogenic variants found in about a third of cases (sarcomere-positive). Large-scale genome-wide association studies (GWAS) demonstrate that common genetic variation contributes substantially to HCM risk. Here, we derive polygenic scores (PGS) from HCM GWAS, and multi-trait analysis of GWAS incorporating genetically-correlated traits, and test their performance in the UK Biobank, 100,000 Genomes Project, and across clinical cohorts. Higher PGS substantially increases population risk of HCM, particularly amongst sarcomere-positive carriers where HCM penetrance differs 10-fold between those in the highest and lowest PGS quintiles. In relatives of HCM patients, PGS stratifies risks of developing HCM and adverse outcomes. Finally, PGS strongly predicts risk of adverse outcomes in HCM, with a 4 to 6-fold increase in death between cases in the highest and lowest PGS quintiles. These findings promise broad clinical utility of PGS in the general population, in cases, and in families with HCM, enabling tailored screening and surveillance, and stratification of risk of adverse outcomes.
Multisensory Flicker Modulates Widespread Brain Networks and Reduces Interictal Epileptiform Discharges in Humans
Authors: Blanpain Lou T. , Chen Emily. , Park James , Walelign Michael Y. , Gross Robert E. , Cabaniss Brian T. , Willie Jon T. , Singer Annabelle C.
Published: March 2023

Modulating brain oscillations has strong therapeutic potential. However, commonly used non-invasive interventions such as transcranial magnetic or direct current stimulation have limited effects on deeper cortical structures like the medial temporal lobe. Repetitive audio- visual stimulation, or sensory flicker, modulates such structures in mice but little is known about its effects in humans. Using high spatiotemporal resolution, we mapped and quantified the neurophysiological effects of sensory flicker in human subjects undergoing presurgical intracranial seizure monitoring. We found that flicker modulates both local field potential and single neurons in higher cognitive regions, including the medial temporal lobe and prefrontal cortex, and that local field potential modulation is likely mediated via resonance of involved circuits. We then assessed how flicker affects pathological neural activity, specifically interictal epileptiform discharges, a biomarker of epilepsy also implicated in Alzheimer’s and other diseases. In our patient population with focal seizure onsets, sensory flicker decreased the rate interictal epileptiform discharges. Our findings support the use of sensory flicker to modulate deeper cortical structures and mitigate pathological activity in humans.
Neonatal apnea and hypopnea prediction in infants with Robin sequence with neural additive models for time series
Authors: Vetter Julius , Lim Kathleen , Dijkstra Tjeerd M. H. , Dargaville Peter A. , Kohlbacher Oliver , Macke Jakob H. , Poets Christian F.
Published: March 2023

Neonatal apneas and hypopneas present a serious risk for healthy infant development. Treating these adverse events requires frequent manual stimulation by skilled personnel, which can lead to alert fatigue. Automatically predicting these adverse events before they occur would enable the use of methods for automatic intervention. In this work, we propose a neural additive model to predict individual events of neonatal apnea and hypopnea and apply it to a physiological dataset from infants with Robin sequence at risk of upper airway obstruction. The dataset will be made publicly available together with this study. Our model achieved an average area under the receiver operating characteristic curve of 0.80 by additively combining information from different modalities of the respiratory polygraphy recording. This permits the prediction of individual apneas and hypopneas up to 15 seconds before they occur. Its additive nature makes the model inherently interpretable, which allowed insights into how important a given signal modality is for prediction and which patterns in the signal are discriminative. For our problem of predicting apneas and hyponeas in infants with Robin sequence, prior irregularities in breathing-related modalities as well as decreases in SpO2levels were especially discriminative.
The role of Late Presenters on HIV-1 transmission clusters in Europe
Authors: Miranda Mafalda N. S. , Pingarilho Marta , Pimentel Victor , Gomes Perpétua , O. Martins Maria do Rosário , Seabra Sofia G. , Kaiser Rolf , Böhm Michael , Seguin-Devaux Carole , Paredes Roger , Bobkova Marina , Zazzi Maurizio , Incardona Francesca , Abecasis Ana B.
Published: March 2023

Background

Investigating the role of late presenters (LP) on HIV-1 transmission is important, as they can contribute to the onward spread of HIV-1 virus in the long period before diagnosis, when they are not aware of their HIV status

Objective

To describe the clinical and socio-demographic characteristics of HIV-1 infected individuals followed in Europe, to characterize patients in clusters and to compare transmission clusters (TC) in LP vs non-late presenters (NLP) populations.

Methods

Clinical, socio-demographic and genotypic information from 38531 HIV-1 infected patients was collected from the EuResist Integrated Database (EIDB) between 1981 and 2019. Sequences were aligned using VIRULIGN. Maximum likelihood (ML) phylogenies were constructed using FastTree. Putative transmission clusters were identified using ClusterPicker v1.332. Statistical analyses were performed using R.

Results

32652 (84·7%) sequences were from subtype B, 3603 (9·4%) were from subtype G, and 2276 (5·9%) were from subtype A. The median age was 33 (IQR: 26·0-41·0) years old and 75·5% of patients were males. The main transmission route was through homosexual (MSM) contact (36·9%) and 86·4% were originated from Western Europe. Most patients were native (84·2%), 59·6% had a chronic infection, and 73·4% had acquired drug resistance (ADR). CD4 count and viral load at diagnosis (log10) presented a median of 341 cells/mm3, and of log10 4·3 copies/mL, respectively. 51·4% of patients were classified as LP and 21·6% patients were inside TCs. Most patients from subtype B (85·6%) were in clusters, compared to subtypes A (5·2%) and G (9·2%). Phylogenetic analyses showed consistent clustering of MSM individuals. In subtype A, patients in TCs were more frequently MSM patients and with a recent infection. For subtype B, patients in TCs were more frequently those with older age (≥ 56), MSM transmission route, originating from Western Europe, migrants, and with a recent infection. For subtype G, patients in TC were more frequently patients with recent infection and migrants. When analysing cluster size, we found that NLP more frequently belonged to large clusters (>8 patients) when compared to LP.

Conclusion

While late presentation is still a threat to HIV-1 transmission, LP individuals are more present either outside or in small clusters, indicating a limited role of late presentation to HIV-1 transmission.
LymphoML: An interpretable artificial intelligence-based method identifies morphologic features that correlate with lymphoma subtype
Authors: Shankar Vivek , Yang Xiaoli , Krishna Vrishab , Tan Brent T. , Silva Oscar , Rojansky Rebecca , Ng Andrew Y. , Valvert Fabiola , Briercheck Edward L. , Weinstock David M. , Natkunam Yasodha , Fernandez-Pol Sebastian , Rajpurkar Pranav
Published: March 2023

Lymphomas vary in terms of clinical behavior, morphology, and response to therapies and thus accurate classification is essential for appropriate management of patients. In this study, using a set of 670 cases of lymphoma obtained from a center in Guatemala City, we propose an interpretable machine learning method, LymphoML, for lymphoma subtyping into eight diagnostic categories. LymphoML sequentially applies steps of (1) object segmentation to extract nuclei, cells, and cytoplasm from hematoxylin and eosin (H&E)-stained tissue microarray (TMA) cores, (2) feature extraction of morphological, textural, and architectural features, and (3) aggregation of per-object features to create patch-level feature vectors for lymphoma classification. LymphoML achieves a diagnostic accuracy of 64.3% (AUROC: 85.9%, specificity: 88.7%, sensitivity: 66.9%) among 8 lymphoma subtypes using only H&E-stained TMA core sections, at a level similar to experienced hematopathologists. We find that the best model’s set of nuclear and cytoplasmic morphological, textural, and architectural features are most discriminative for diffuse large B-cell lymphoma (F1: 78.7%), classic Hodgkin lymphoma (F1 score: 74.5%), and mantle cell lymphoma (F1: 71.0%). Nuclear shape features provide the highest diagnostic yield, with nuclear texture, cytoplasmic, and architectural features providing smaller gains in accuracy. Finally, combining information from the H&E-based model together with the results of a limited set of immunohistochemical (IHC) stains resulted in a similar diagnostic accuracy (accuracy: 85.3%, AUROC: 95.7%, sensitivity: 84.5%, specificity: 93.5%) as with a much larger set of IHC stains (accuracy: 86.1%, AUROC: 96.7%, specificity: 93.2%, sensitivity: 86.0%). Our work suggests a potential way to incorporate machine learning tools into clinical practice to reduce the number of expensive IHC stains while achieving a similar level of diagnostic accuracy.
Detecting post-stroke aphasia using EEG-based neural envelope tracking of natural speech
Authors: De Clercq Pieter , Kries Jill , Mehraram Ramtin , Vanthornhout Jonas , Francart Tom , Vandermosten Maaike
Published: March 2023

After a stroke, approximately one-third of patients suffer from aphasia, a language disorder that impairs communication ability. The standard behavioral tests used to diagnose aphasia are time-consuming, require subjective interpretation, and have low ecological validity. As a consequence, comorbid cognitive problems present in individuals with aphasia (IWA) can bias test results, generating a discrepancy between test outcomes and everyday-life language abilities. Neural tracking of the speech envelope is a promising tool for investigating brain responses to natural speech. The envelope of speech is crucial for speech understanding, encompassing cues for detecting and segmenting linguistic units, e.g., phrases, words and phonemes. In this study, we aimed to test the potential of the neural envelope tracking technique for detecting language impairments in IWA.

We recorded EEG from 27 IWA in the chronic phase after stroke and 22 healthy controls while they listened to a 25-minute story. We quantified neural envelope tracking in a broadband frequency range as well as in the delta, theta, alpha, beta, and gamma frequency bands using mutual information analysis. Besides group differences in neural tracking measures, we also tested its suitability for detecting aphasia at the individual level using a Support Vector Machine (SVM) classifier. We further investigated the required recording length for the SVM to detect aphasia and to obtain reliable outcomes.

IWA displayed decreased neural envelope tracking compared to healthy controls in the broad, delta, theta, and gamma band, which is in line with the assumed role of these bands in auditory and linguistic pro-cessing of speech. Neural tracking in these frequency bands effectively captured aphasia at the individual level, with an SVM accuracy of 84% and an area under the curve of 88%. Moreover, we demonstrated that high-accuracy detection of aphasia can be achieved in a time-efficient (5 minutes) and highly reliable manner (split-half reliability correlations between R=0.62 and R=0.96 across frequency bands).

Our study shows that neural envelope tracking of natural speech is an effective biomarker for language impairments in post-stroke aphasia. We demonstrated its potential as a diagnostic tool with high reliability, individual-level detection of aphasia, and time-efficient assessment. This work represents a significant step towards more automatic, objective, and ecologically valid assessments of language impairments in aphasia.
Ethnic differences in receipt of psychological interventions in Early Intervention in Psychosis services in England: a cross-sectional study
Authors: Schlief Merle , Rich Nathalie , Rains Luke Sheridan , Baldwin Helen , Rojas-Garcia Antonio , Nyikavaranda Patrick , Persaud Karen , Dare Ceri , French Paul , Lloyd-Evans Brynmor , Crawford Mike , Smith Jo , Kirkbride James B. , Johnson Sonia
Published: March 2023

Background

There is some evidence of inequitable psychosis care provision by ethnicity. We investigated variations in the receipt of CBTp and family intervention across ethnic groups in Early Intervention in Psychosis (EIP) teams throughout England, where national policy mandates offering these interventions to all.

Methods

We included data on 29,610 service users from the National Clinical Audit of Psychosis (NCAP), collected between 2018 and 2021. We conducted mixed effects logistic regression to examine odds ratios of receiving an intervention (CBTp, family intervention, or either intervention) across 17 ethnic groups while accounting for the effect of years and variance between teams and adjusting for individual- (age, gender, occupational status) and team-level covariates (care-coordinator caseload and mental health inequalities strategies).

Findings

Compared with White British people, every minoritized ethnic group, except those of mixed Asian-White and mixed Black African-White ethnicities, had lower adjusted odds of receiving CBTp (aOR 0·39, 95%CI 0·32-0·47 to 0·80, 0·64-1·00). People of Black African (0·61, 0·53-0·69), Black Caribbean (0·67, 0·56-0·81), non-African/Caribbean Black (0·63, 0·51-0·79), non-British/Irish White (0·73, 0·64-0·84), and of “any other” (0·66, 0·54-0·81) ethnicity also experienced lower adjusted odds of receiving family intervention.

Interpretation

Pervasive inequalities in receiving CBTp for first episode psychosis exist for almost all minoritized ethnic groups, and family intervention for many groups. Investigating how these inequalities arise should be a research priority, allowing co-produced development and testing of approaches to address them.

Funding

Independent research commissioned and funded by the National Institute for Health Research Policy Research Programme.
A genomic perspective on the near-term impact of doxycycline post-exposure prophylaxis onNeisseria gonorrhoeaeantimicrobial resistance
Authors: Mortimer Tatum D. , Grad Yonatan H.
Published: March 2023

Post-exposure prophylaxis with doxycycline (doxyPEP) is being introduced to prevent bacterial sexually transmitted infections (STIs). Pre-existing tetracycline resistance inNeisseria gonorrhoeaelimits doxyPEP effectiveness against gonorrhea, and selection for tetracycline resistant lineages may influence prevalence of resistance to other antimicrobials via selection for multi-drug resistant strains. Using genomic and antimicrobial susceptibility data from 5,644 clinical isolates ofN. gonorrhoeae, we assessed the near-term impact of doxyPEP onN. gonorrhoeaeantimicrobial resistance. We found that the impact on antimicrobial resistance is likely to be influenced by the strength of selection for plasmid-encoded and chromosomally-encoded tetracycline resistance, as isolates with high-level, plasmid-encoded resistance had lower minimum inhibitory concentrations to other antimicrobials compared to isolates with low-level tetracycline resistance. The impact of doxyPEP may differ across demographic groups and geographic regions within the United States due to variation in pre-existing tetracycline resistance.
Transcriptomic profiling of lymphocytic colitis highlights distinct diarrhoeal pathomechanisms
Authors: Bhardwaj Archana , Münch Andreas , Montague Julia , Koch Stefan , Rosenstiel Philip , Escudero-Hernández Celia
Published: March 2023

Background and Aims

The pathobiology of the non-destructive inflammatory bowel disease (IBD) lymphocytic colitis (LC) is poorly understood. Our aim was to define a LC-specific transcriptome to gain insight into LC pathology, identify genetic signatures uniquely linked to LC, and uncover potentially druggable disease pathways.

Methods

We performed whole mucosa bulk RNA-sequencing of LC and CC samples from patients with active disease, and healthy controls (n=4-10 per cohort). Differential gene expression was analyzed by gene-set enrichment and deconvolution analyses to identify pathologically relevant pathways and cells, respectively, altered in LC. Key findings were validated using reverse transcription quantitative PCR and/or immunohistochemistry. Finally, we compared our sequencing data to a previous cohort of ulcerative colitis and Crohn’s disease patients (n=4 per group) to distinguish non-destructive from classic IBD.

Results

The LC-specific transcriptome was defined by a limited mucosal immune response against microbiota compared to CC and classic IBD samples. In contrast, we noted a distinct induction of regulatory non-coding RNA species in LC samples. Moreover, compared to CC, we observed decreased water channel and cell adhesion molecule gene expression, which was associated with reduced intestinal epithelial cell proliferation.

Conclusions

We conclude that LC is a pathomechanistically distinct disease that is characterized by a dampened immune response despite massive mucosal immune cell infiltration. Our results point to regulatory micro-RNAs as a potential disease-specific feature that may be amenable to therapeutic intervention.
The effect ofM. tuberculosislineage on clinical phenotype
Authors: Du Duc Hong , Geskus Ronald B , Zhao Yanlin , Codecasa Luigi Ruffo , Cirillo Daniela Maria , van Crevel Reinout , Pascapurnama Dyshelly Nurkartika , Chaidir Lidya , Niemann Stefan , Diel Roland , Omar Shaheed Vally , Grandjean Louis , Rokadiya Sakib , Ortitz Arturo Torres , Lân Nguyễn Hữu , Minh Hà Đặng Thị , Smith E. Grace , Robinson Esther , Dedicoat Martin , Hoang Nhat Le Thanh , Thwaites Guy E , Van Le Hong , Thuong Thuong Nguyen Thuy , Walker Timothy M
Published: March 2023

Eight lineages ofMycobacterium tuberculosis sensu strictoare described. Single-country or small observational data suggest differences in clinical phenotype between lineages. We present strain lineage and clinical phenotype data from 12,246 patients from 3 low-incidence and 5 high-incidence countries. We used multivariable logistic regression to explore the effect of lineage on site of disease and on cavities on chest radiography, given pulmonary TB; multivariable multinomial logistic regression to investigate types of extra-pulmonary TB, given lineage; and accelerated failure time and Cox proportional-hazards models to explore the effect of lineage on time to smear and culture-conversion. Mediation analyses quantified the direct effects of lineage on outcomes. Pulmonary disease was more likely among patients with lineage(L) 2, L3 or L4, than L1 (adjusted odds ratio (aOR) 1.79, (95% confidence interval 1.49-2.15), p<0.001; aOR=1.40(1.09-1.79), p=0.007; aOR=2.04(1.65-2.53), p<0.001, respectively). Among patients with pulmonary TB, those with L1 had greater risk of cavities on chest radiography versus those with L2 (aOR=0.69(0.57-0.83), p<0.001) and L4 strains (aOR=0.73(0.59-0.90), p=0.002). L1 strains were more likely to cause osteomyelitis among patients with extra-pulmonary TB, versus L2-4 (p=0.033, p=0.008 and p=0.049 respectively). Patients with L1 strains showed shorter time-to-sputum smear conversion than for L2. Causal mediation analysis showed the effect of lineage in each case was largely direct. The pattern of clinical phenotypes seen with L1 strains differed from modern lineages (L2-4). This has implications for clinical management and could influence clinical trial selection strategies.
Novel kinetoplastid-specific cAMP binding proteins identified by RNAi screening for cAMP resistance inT. brucei
Authors: Bachmaier Sabine , Gould Matthew K. , Polatoglou Eleni , Omelianczyk Radoslaw , Brennand Ana E. , Aloraini Maha A. , Munday Jane C. , Horn David , Boshart Michael , de Koning Harry P.
Published: March 2023

Cyclic AMP signalling in trypanosomes differs from most eukaryotes due to absence of known cAMP effectors and cAMP independence of PKA. We have previously identified four genes from a genome-wide RNAi screen for resistance to the cAMP phosphodiesterase (PDE) inhibitor NPD-001. The genes were named cAMP Response Protein (CARP) 1 through 4. Here, we report an additional six CARP candidate genes from the original sample, after deep sequencing of the RNA interference target pool retrieved after NPD-001 selection (RIT-seq). The resistance phenotypes were confirmed by targeted RNAi knockdown and highest level of resistance to NPD-001, approximately 17-fold, was seen for knockdown of CARP7 (Tb927.7.4510). CARP1 and CARP11 contain predicted cyclic AMP binding domains and bind cAMP as evidenced by capture and competition on immobilised cAMP. CARP orthologues are strongly enriched in kinetoplastid species, and CARP3 and CARP11 are unique toTrypanosoma. Localization data and/or domain architecture of all CARPs predict association with theT. bruceiflagellum. This suggests a crucial role of cAMP in flagellar function, in line with the cell division phenotype caused by high cAMP and the known role of the flagellum for cytokinesis. The CARP collection is a resource for discovery of unusual cAMP pathways and flagellar biology.

Importance

Trypanosomes are major pathogens of humans and livestock. In addition they have been invaluable as a model system to investigate new biological systems, and not just of protozoa. Equally, they are known to have a lot of unique biology and biochemistry. One example of this is signal transduction by cyclic nucleotides. Some elements, including phosphodiesterases and the catalytic domains of its dozens of adenylate cyclase isoforms, are highly conserved, while the absence of G-proteins, a cAMP-responsive protein kinase A and other known effector types suggests a unique cAMP-dependent pathway, which as yet is mostly uncharacterised. Here, we identify a set of tenTrypanosoma bruceiproteins, all localised to its flagellum, that appear to be involved in the production of cAMP, or in mediating its cellular effects. These cAMP Response Proteins (CARPs) were mostly unique to trypanosomes, suggesting a completely novel pathway. Two of the CARPs were shown to bind cAMP and were found to possess structurally conserved cyclic nucleotide binding domains.
Changes in morbimortality patterns due to heart failure in patients of the Unified Health System and their economic impacts: a challenge for Public Health management
Authors: Lins Matheus Manoel Diogo , Borges Vivian Fernandes Alves
Published: March 2023

A descriptive ecological study was conducted to form a profile of morbimortality due to cardiac care in the Brazilian population based on patients registered in the Department of Informatics of the Unified Health System (DATASUS). The results of the article show that, during the studied period, 2,984,424 patients were hospitalized due to cardiac care, predominantly represented by males, with the age group predominating in elderly individuals between 70 and 79 years old, of white ethnicity, and with a character of emergency care. The average hospitalization cost was estimated at R$ 1,371.67, generating an annual cost to the Brazilian economy of R$ 341,137,000.

Background

Heart failure (HF) is a complex syndrome considered the common endpoint of various cardiovascular diseases, and due to its high prevalence, it is necessary to understand its morbidity and mortality profile.

Objective

To describe the morbidity and mortality profile of HF among patients registered in the Department of Informatics of the Unified Health System (DATASUS) and its impact on public health between 2008 and 2020.

Materials and Methods

A descriptive epidemiological study was conducted using data obtained from the TABNET application developed by DATASUS. Patients of both sexes, without age restrictions, who were hospitalized with a confirmed diagnosis of HF in Brazil, from January 2008 to December 2020 were included. Data were stratified by sex, age group, self-reported ethnicity/race, type of healthcare plan, and nature of care.

Results

During the study period, 2,984,424 patients were hospitalized due to HF in the SUS. The majority were male: 1,533,469 (51.38%); elderly with the predominant age group between 70 and 79 years: 788,367 (26.41%); of white ethnicity: 1,102,860 (36.95%); private healthcare plan: 1,196,559 (46.10%), and with emergency care character: 2,827,354 (94.73%). The average hospitalization cost was estimated at R$ 1,371.67, generating an annual cost to the Brazilian economy of R$ 341,137,000.

Conclusions

Heart failure is an important public health problem, causing not only high morbidity in affected individuals but also a significant financial burden on the Unified Health System (SUS).
Pre-pandemic inequalities in the burden of disease: a Scottish Burden of Disease study
Authors: Grant Ian , Chalmers Neil , Fletcher Eilidh , Lakha Fatim , McCartney Gerry , Stockton Diane , Wyper Grant
Published: March 2023

Background

Health inequalities in Scotland are well documented, including the contribution of different causes to inequalities in mortality. Our aim was to estimate inequalities within a burden of disease framework, accounting for both premature mortality and the effects of morbidity, to understand the contribution of specific diseases to health inequalities prior to the COVID-19 pandemic.

Methods

Disability Adjusted Life Years (DALYs) for 70 individual causes of disease and injury were sourced from the Scottish Burden of Disease Study. Area-level deprivation was measured using the Scottish Index of Multiple Deprivation. Inequalities were measured by the range, Relative Index of Inequality, Slope Index of Inequality, and attributable DALYs were estimated by using the least deprived decile as a reference.

Results

The overall disease burden was double that in the most deprived areas (50,305 vs 20,955 DALYS per 100, 000), largely driven by inequalities in premature mortality. The rate in the most deprived decile was around 48% higher than the mean population rate (RII = 0.96), with 35% of DALYs attributed to differences in area-based deprivation. Many leading causes of disease burden in 2019 – heart disease, drug use disorders, lung cancer and COPD – were also the leading drivers of absolute and relative inequalities in the disease burden.

Conclusion

Our study evidences the extent of the stark levels of absolute and relative inequality prior to the COVID-19 pandemic. Given pre-pandemic stalling of mortality trend improvements and widening health inequalities, and the exacerbation of these caused by COVID-19, urgent policy attention is required to address this.
Alpha globin gene copy number and incident ischemic stroke risk among Black Americans
Authors: Ruhl A. Parker , Jeffries Neal , Yang Yu , Brooks Steven D. , Naik Rakhi P. , Pecker Lydia H. , Mott Bryan T. , Winkler Cheryl A. , Armstrong Nicole D. , Zakai Neil A. , Gutierrez Orlando M. , Judd Suzanne E. , Howard Virginia J. , Howard George , Irvin Marguerite R. , Cushman Mary , Ackerman Hans C.
Published: March 2023

Introduction

People with African ancestry have greater stroke risk and greater heritability of stroke risk than people of other ancestries. Given the importance of nitric oxide (NO) in stroke, and recent evidence that alpha globin restricts nitric oxide release from vascular endothelial cells, we hypothesized that alpha globin gene (HBA)deletion would be associated with reduced risk of incident ischemic stroke.

Methods

We evaluated 8,947 participants self-reporting African ancestry in the national, prospective Reasons for Geographic And Racial Differences in Stroke (REGARDS) cohort. Incident ischemic stroke was defined as non-hemorrhagic stroke with focal neurological deficit lasting ≥ 24 hours confirmed by the medical record or focal or non-focal neurological deficit with positive imaging confirmed with medical records. Genomic DNA was analyzed using droplet digital PCR to determineHBAcopy number. Multivariable Cox proportional hazards regression was used to estimate the hazard ratio (HR) ofHBAcopy number on time to first ischemic stroke.

Results

Four-hundred seventy-nine (5.3%) participants had an incident ischemic stroke over a median (IQR) of 11.0 (5.7, 14.0) years’ follow-up.HBAcopy number ranged from 2 to 6: 368 (4%) -α/-α, 2,480 (28%) -α/αα, 6,014 (67%) αα/αα, 83 (1%) ααα/αα and 2 (<1%) ααα/ααα. The adjusted HR of ischemic stroke withHBAcopy number was 1.04; 95%CI 0.89, 1.21; p = 0.66.

Conclusions

Although a reduction inHBAcopy number is expected to increase endothelial nitric oxide signaling in the human vascular endothelium,HBAcopy number was not associated with incident ischemic stroke in this large cohort of Black Americans.
Impact of COVID-19 and effects of booster vaccination with BNT162b2 on six-month long COVID symptoms, quality of life, work productivity and activity impairment during Omicron
Authors: Di Fusco Manuela , Sun Xiaowu , Moran Mary M. , Coetzer Henriette , Zamparo Joann M. , Alvarez Mary B. , Puzniak Laura , Tabak Ying P. , Cappelleri Joseph C.
Published: March 2023

Background

Longitudinal estimates of long COVID burden during Omicron remain limited. This study characterized long-term impacts of COVID-19 and booster vaccination on symptoms, Health-Related Quality of Life (HRQoL), and Work Productivity Activity Impairment (WPAI).

Methods

Outpatients with ≥1 self-reported symptom and positive SARS-CoV-2 test at CVS Health United States test sites were recruited between 01/31-04/30/2022. Symptoms, EQ-5D and WPAI were collected via online surveys until 6 months following infection. Both observed and model-based estimates were analyzed. Effect sizes based on Cohen’s d quantified the magnitude of outcome changes over time, within and between vaccination groups. Mixed models for repeated measures were conducted for multivariable analyses, adjusting for covariates. Logistic regression assessed odds ratio (OR) of long COVID between vaccination groups.

Results

At long COVID start (Week 4), 328 participants included 87 (27%) Boosted with BNT162b2, 86 (26%) with a BNT162b2 primary series (Primed), and 155 (47%) Unvaccinated. Mean age was 42.0 years, 73.8% were female, 26.5% had ≥1 comorbidity, 36.9% prior infection, and 39.6% reported ≥3 symptoms (mean: 3.1 symptoms). At Month 6, among 260 participants, Boosted reported a mean of 1.1 symptoms versus 3.4 and 2.8 in Unvaccinated and Primed, respectively (p<0.001). Boosted had reduced risks of ≥3 symptoms versus Unvaccinated (observed: OR 0.22, 95% CI, 0.10-0.47, p<0.001; model-based: OR: 0.36, 95% CI, 0.15-0.87, p=0.019) and Primed (observed: OR 0.29, 95% CI, 0.13-0.67, p=0.003; model-based: OR 0.59, 95% CI, 0.21-1.65, p=0.459). Results were consistent using ≥2 symptoms. Regarding HRQoL, among those with long COVID, Boosted had higher EQ-5D Utility Index (UI) than Unvaccinated (observed: 0.922 versus 0.731, p=0.014; model-based: 0.910 versus 0.758, p-value=0.038) and Primed (0.922 versus 0.648, p=0.014; model-based: 0.910 versus 0.708, p-value=0.008). Observed and model-based estimates for EQ-VAS and UI among Boosted were comparable with pre-COVID since Month 3. Subjects vaccinated generally reported better WPAI scores.

Conclusions

Long COVID negatively impacted HRQoL and WPAI. The BNT162b2 booster could have a beneficial effect in reducing the risk and burden of long COVID. Boosted participants reported fewer and less durable symptoms, which contributed to improve HRQoL and maintain WPAI levels. Limitations included self-reported data and small sample size for WPAI.
The Extra-Islet Pancreas Supports Autoimmunity in Human Type 1 Diabetes
Authors: Barlow G.L. , Schürch C.M , Bhate S.S. , Phillips D. , Young A. , Dong S. , Martinez HA. , Kaber G. , Nagy N. , Ramachandran S. , Meng J. , Korpos E. , Bluestone J.A. , Nolan G.P. , Bollyky P.L.
Published: March 2023

In autoimmune Type 1 diabetes (T1D), immune cells infiltrate and destroy the islets of Langerhans — islands of endocrine tissue dispersed throughout the pancreas. However, the contribution of cellular programs outside islets to insulitis is unclear. Here, using CO-Detection by indEXing (CODEX) tissue imaging and cadaveric pancreas samples, we simultaneously examine islet and extra-islet inflammation in human T1D. We identify four sub-states of inflamed islets characterized by the activation profiles of CD8+T cells enriched in islets relative to the surrounding tissue. We further find that the extra-islet space of lobules with extensive islet-infiltration differs from the extra-islet space of less infiltrated areas within the same tissue section. Finally, we identify lymphoid structures away from islets enriched in CD45RA+T cells — a population also enriched in one of the inflamed islet sub-states. Together, these data help define the coordination between islets and the extra-islet pancreas in the pathogenesis of human T1D.
Acute pharmacodynamic responses to exenatide: Drug-induced increases in insulin secretion and glucose effectiveness
Authors: Taylor Simeon I. , Montasser May E. , Yuen Ashley H. , Fan Hubert , Yazdi Zhinoosossadat Shahidzadeh , Whitlatch Hilary B. , Mitchell Braxton D. , Shuldiner Alan R. , Muniyappa Ranganath , Streeten Elizabeth A. , Beitelshees Amber L.
Published: March 2023

Background

GLP1R agonists provide multiple benefits to patients with type 2 diabetes – including improved glycemic control, weight loss, and decreased risk of major adverse cardiovascular events. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses.

Methods

Exenatide (5 µg, sc) or saline (0.2 mL, sc) was administered to 62 healthy volunteers. Frequently sampled intravenous glucose tolerance tests were conducted to assess the impact of exenatide on insulin secretion and insulin action. This pilot study was designed as a crossover study in which participants received exenatide and saline in random order.

Results

Exenatide increased first phase insulin secretion 1.9-fold (p=1.9×10-9) and accelerated the rate of glucose disappearance 2.4-fold (p=2×10-10). Minimal model analysis demonstrated that exenatide increased glucose effectiveness (Sg) by 32% (p=0.0008) but did not significantly affect insulin sensitivity (Si). The exenatide-induced increase in insulin secretion made the largest contribution to inter-individual variation in exenatide-induced acceleration of glucose disappearance while inter-individual variation in the drug effect on Sgcontributed to a lesser extent (β=0.58 or 0.27, respectively).

Conclusions

This pilot study provides validation for the value of an FSIGT (including minimal model analysis) to provide primary data for our ongoing pharmacogenomic study of pharmacodynamic effects of semaglutide (NCT05071898). Three endpoints provide quantitative assessments of GLP1R agonists’ effects on glucose metabolism: first phase insulin secretion, glucose disappearance rates, and glucose effectiveness.

Registration

NCT02462421 (clinicaltrials.gov)

Funding

American Diabetes Association (1-16-ICTS-112); National Institute of Diabetes and Digestive and Kidney Disease (R01DK130238, T32DK098107, P30DK072488)
Sex-and-gender differences in cardiovascular risk factors and their correlates among adults in Freetown, Sierra Leone: A population-based health-screening survey
Authors: Russell James Baligeh Walter , Koroma Theresa Ruba , Sesay Santigie , Samura Sallieu K , Lakoh Sulaiman , Bockarie Ansu , Abiri Onomeh Thomas , Kanu Joseph Sam , Appiah Lambert Tetteh , Coker Joshua , Jalloh Abdul , Conteh Victor , Conteh Sorie , Smith Mohamed , Lisk Durodami. R.
Published: March 2023

Objectives

to evaluate the association of sex-and-gender-specific cardiovascular disease risk factors, their prevalence, and correlates among adults in Sierra Leone.

Study design

This community-based cross-sectional study used a stratified multistage random sampling.

Methods

the survey was conducted in eight (8) selected randomized sub-zonal communities across the western urban area in Sierra Leone, with an included sampling of 2394 adults. The WHO stepwise approach for non-communicable diseases was utilized. Multivariable logistic regression was done to determine associations between demographic characteristics and cardiovascular risk factors.

Results

The prevalence of hypertension (33.4% vs 37.4%, p=0.068), diabetes mellitus (7.4% vs 9.2%, p=0.101), overweight (32.3% vs 34.2%, p=0.323) and obesity (9.9% vs 10.2%, p=0.818) were higher among males in comparison to females. Body Mass Index (BMI) (25.0 ± 5.0 vs 24.6 ± 4.4, p = 0.029), waist circumference (WC) (93.6 ± 4.5 vs 80.0 ± 5.0, p < 0.001), triglyceride (1.7±0.35 vs 1.6±0.32, p=0.013), total cholesterol (5.1±0.77 vs 4.9±0.66, p < 0.001) and low HDL-C (1.28 ± 0.29 vs 1.3±0.24, p = 0.016) were significantly higher among females as compared to males. The odds of having dyslipidemia [OR = 1.339; 95% C.I: (1.101-1.629), p=0.003] and consuming alcohol [OR = 1.229; 95% C.I: (1.026-1.472),p=0.025] were higher among females. Women had 1.8 times greater odds [AOR=1.849; 95% C.I: (0.713 - 1.010),p=0.030] of being hypertensive, 1.4 times greater odds [AOR=1.441; 95% C.I: (1.176 - 1.765),p=<0.001] of being dyslipidemic and 1.2 times greater odds [AOR = 1.225, 95% C.I: (1.0123-1.481),p=0.037] of consuming alcohol compared to men. BMI, WC, and raised blood sugar had a strong correlation among women than men.

Conclusion

Being female was associated with a high prevalence of cardiovascular health risks in Sierra Leone. This study emphasizes the importance of reducing the CVD burden among females through policies related to public health education and screening strategies.
Effect ofAndrographis paniculatatreatment for patients with early-stage COVID-19 on the prevention of pneumonia: A retrospective cohort study
Authors: Benjaponpitak Amporn , Sawaengtham Thiti , Thaneerat Tewan , Wanaratna Kulthanit , Chotsiri Palang , Rungsawang Chalermquan , Bhubhanil Sakkarin , Charoensuk Sataporn , Benjaponpitak Suwat , Lapmanee Sarawut , Sirinavin Sayomporn
Published: March 2023

There is a need for safe and cost-effective treatments for COVID-19.Andrographis paniculata(AP) is an herbal plant that has been used for centuries to treat upper respiratory tract infections. Andrographolide is the major active component of AP that inhibits intracellular SARS-CoV-2 replication and has anti-inflammatory action. We performed a retrospective cohort study to evaluate the therapeutic and adverse effects of oral AP-products on COVID-19 by using the risk of pneumonia diagnosed by chest radiography as an indicator. This study included patients 15 to 60 years of age with laboratory-confirmed early-stage (asymptomatic or mild) COVID-19 without comorbidities at seven hospitals in three adjacent provinces in Thailand, between December 2020 and March 2021. Patients were treated for five days with either AP-extract (60 mg andrographolide, 3 times daily) or crude-AP (48 mg andrographolide, 3 times daily), when available. Patient information was prospectively recorded in the structured medical records and retrospectively reviewed. All eligible patients who received AP-treatment were included and control patients who did not receive AP-treatment were randomly selected using a ratio of approximately 1:1. Pneumonia occurred in 1/243 AP-treatment patients and 69/285 control patients. The risks of pneumonia after adjusting for confounding effects were 0.3% (95%CI, 0%-0.9%) and 24.3% (95%CI, 19.0%-29.7%) in the AP-treatment and control groups, respectively. The number needed to treat to avoid pneumonia development in one patient was four (95% CI, 3-5). Eight patients developed mild adverse events. AP-treatment regimens are acceptably safe and associated with highly reduced rates of pneumonia for patients with early-stage COVID-19.
Users’ perception of the OH-EpiCap evaluation tool based on its application to nine national antimicrobial resistance surveillance systems
Authors: Moura Pedro , Collineau Lucie , Sandberg Marianne , Tomassone Laura , De Meneghi Daniele , Norström Madelaine , Bennani Houda , Häsler Barbara , Colomb-Cotinat Mélanie , Bourély Clémence , Filippitzi Maria-Eleni , Mediouni Sarah , Boriani Elena , Asaduzzaman Muhammad , Caniça Manuela , Aenishaenslin Cécile , Alban Lis
Published: March 2023

Antimicrobial resistance (AMR) surveillance systems involve multiple stakeholders and multilevel standard operating procedures, which increase in complexity with further integration of the One Health (OH) concept. AMR is a OH challenge. It is crucial for the success of an AMR surveillance system to evaluate its performance in meeting the proposed objectives, while complying with resource restrictions. The OH-EpiCap tool was created to evaluate the degree of compliance of hazard surveillance activities with essential OH concepts across there dimensions: organization, operational activities, and impact of the OH surveillance system.

To present feedback on the application of the OH-EpiCap from a user’s perspective, the tool was used to evaluate nine national AMR surveillance systems, each with different monitoring contexts and objectives. The OH-EpiCap tool was assessed using the updated CoEvalAMR methodology. This methodology evaluates the content themes and functional aspects of the tool in a standardized way, while it also captures the user’s subjective experiences in using the tool via a strengths, weaknesses, opportunities, and threats (SWOT) approach.

The results of the evaluation of the OH-EpiCap are presented and discussed. The OH-EpiCap is an easy-to-use tool, which can facilitate a fast macro-overview of the application of the OH concept to a surveillance activity, when used by specialists in the matter, serving as a basis for the discussion of possible adaptations of AMR surveillance activities, or targeting areas that may be further investigated using other pre-established tools.