bluuebunny/crossref_metadata_2025 huggingface dataset:
Representation of evidence-based clinical practice guideline recommendations on FHIR
Authors: Lichtner Gregor , Jurth Carlo , Alper Brian S , Spies Claudia , Boeker Martin , Meerpohl Joerg J , von Dincklage Falk
Published: May 2022

Background

Various formalisms have been developed to represent clinical practice guideline recommendations in a computer-interpretable way. However, none of the existing formalisms leverage the structured and computable information that emerge from the evidence-based guideline development process. Thus, we here propose a FHIR-based guideline representation format that is structurally aligned to the knowledge artifacts emerging during the process of evidence-based guideline development.

Methods

We identified the information required to represent evidence-based clinical practice guideline recommendations and reviewed the knowledge artifacts emerging during the evidence-based guideline development process. Then we conducted a consensus-based design process with domain experts to develop an information model for guideline recommendation representation that is structurally aligned to the evidence-based guideline recommendation development process and a corresponding representation based on evidence-based medicine (EBM)-on-FHIR resources.

Results

The information model of clinical practice guideline recommendations and its EBMonFHIR-based representation contain the clinical contents of individual guideline recommendations, a set of metadata for the recommendations, the ratings for the recommendations (e.g., strength of recommendation, certainty of overall evidence), the ratings of certainty of evidence for individual outcomes (e.g., risk of bias) and links to the underlying evidence (systematic reviews based on primary studies). We created profiles and an implementation guide for all FHIR resources required to represent a complete clinical practice guideline and used the profiles to implement an exemplary clinical guideline recommendation.

Conclusions

Our EBMonFHIR-based representation of clinical practice guideline recommendations allows to directly link the evidence assessment process through systematic reviews and evidence grading, and the underlying evidence from primary studies to the resulting guideline recommendations. This not only allows to evaluate the evidence on which recommendations are based on transparently and critically, but also allows for a more direct and in future automatable way to generate computer-interpretable guideline recommendations based on computable evidence.
E-cigarettes With Varenicline Versus Varenicline for Smoking Cessation: A Pragmatic Randomised Controlled Trial
Authors: Tattan-Birch Harry , Kock Loren , Brown Jamie , Beard Emma , Bauld Linda , West Robert , Shahab Lion
Published: May 2022

Background

We examined whether, in adults receiving behavioural support, offering e-cigarettes together with varenicline helps more people stop smoking cigarettes than varenicline alone.

Methods

A two-group, parallel-arm, pragmatic randomised controlled trial was conducted in six English stop smoking services from 2019-2020. Adults enrolled onto a 12-week programme of in-person one-to-one behavioural smoking cessation support (N=92) were randomised to receive either (i) a nicotine e-cigarette starter-kit alongside varenicline or (ii) varenicline alone. The primary outcome was biochemically-verified abstinence from cigarette smoking between weeks nine-to-12 post quit-date, with those lost to follow-up considered not abstinent. The trial was stopped early due to COVID-19 restrictions and a varenicline recall (92/1266 participants recruited).

Results

Nine-to-12-week smoking abstinence rates were 47.9% (23/48) in the e-cigarette-varenicline group compared with 31.8% (14/44) in the varenicline-only group, a 51% increase in abstinence among those offered e-cigarettes; however, the confidence interval (CI) was wide, including the possibility of no difference (risk ratio [RR]=1.51, 95%CI=0.91-2.64). The e-cigarette-varenicline group had 43% lower hazards of relapse from continuous abstinence than the varenicline-only group (hazards ratio [HR]=0.57, 95%CI=0.34-0.96). Attendance for 12 weeks was higher in the e-cigarette-varenicline than varenicline-only group (54.2% versus 36.4%; RR=1.49, 95%CI=0.95-2.47), but similar proportions of participants in both groups used varenicline daily for ≥8 weeks after quitting (22.9% versus 22.7%; RR=1.01, 95%CI=0.47-2.20). Estimates were too imprecise to determine how adverse events differed by group.

Conclusion

Preliminary evidence suggests offering e-cigarettes alongside varenicline to people receiving behavioural support may be more effective for smoking cessation than varenicline alone.

Implications

Offering e-cigarettes to people quitting smoking with varenicline may help them remain abstinent from cigarettes, but the evidence is preliminary because our sample size was smaller than planned — caused by COVID-19 restrictions and a manufacturing recall. This meant our effect estimates were imprecise, and additional evidence is needed to confirm that providing e-cigarettes and varenicline together helps more people remain abstinent than varenicline alone.
The health effects of 14 weeks of physical activity in a real-life setting for adults with intellectual disabilities
Authors: Højberg Laurits Munk , Helge Eva Wulff , Pingel Jessica , Wienecke Jacob
Published: May 2022

Background

Individuals with intellectual disabilities (ID) have a reduced physical health compared to the general population, and one of the main contributors is inactivity.

Aim

To investigate how 14 weeks of physical activity (PA) in a real-life setting affects cardiovascular fitness, body composition and bone health of adults with ID.

Methods

Adults with ID were recruited into a PA-group or a control group (CON). The PA-group participated in 14 weeks of PA. Body composition, cardiovascular fitness and bone health were assessed before and after the intervention.

Outcomes & results

Cardiovascular fitness and body composition improved from pre to post within the PA-group: Heart rates (HR) during the last 30 seconds of two increments of a treadmill test, were reduced (3.2 km/h: -4.4 bpm, p<0.05; 4.8 km/h: -7.5 bpm, p<0.001) and fat mass was reduced (−1.02 kg, p<0.05). Between-group differences in favour of the PA-group, were observed in whole body bone mineral density (BMD) (0.024 g/cm2, p<0.05) and in BMD of the left femur neck (0.043 g/cm2, p<0.05).

Conclusions & Implications

Fourteen weeks of PA increase cardiovascular fitness, reduced fat mass and improved BMD in the weight-bearing skeleton in the PA-group. Increased and regular PA seems to be a promising tool to promote physical health in adults with ID.

What this paper adds

This paper underlines the importance of including physical activity in the everyday lives of individuals with intellectual disabilities. The health impact of physical activity performed outside controlled research laboratories needs further investigation, and therefore this paper sheds light on physical activity performed in a real-life setting. Our results indicate a positive impact of physical activity on the cardiovascular system and body composition, as well as bone health. The question of how of bone health of adults with intellectual disabilities responds to physical activity is largely understudied in intervention designs, and this paper includes state-of-the art investigation of development in bone mineral density after participation in varied physical activities. These results give promise and indicate a positive impact of the intervention on the bone health of the participants.
Analytical performance of rapid antigen tests for the detection of SARS-CoV-2 during widespread circulation of the Omicron variant
Authors: Suzuki Hiromichi , Akashi Yusaku , Kato Daisuke , Takeuchi Yuto , Kiyasu Yoshihiko , Terada Norihiko , Kurihara Yoko , Kuwahara Miwa , Muramatsu Shino , Ueda Atsuo , Notake Shigeyuki , Nakamura Koji
Published: May 2022

Introduction

Antigen testing is essential in the clinical management of COVID-19. However, most evaluations of antigen tests have been performed before the emergence of the Omicron variant. Thus, an assessment of the diagnostic performance of antigen tests for the detection of SARS-CoV-2 during the circulation of Omicron variant is required.

Methods

This prospective observational study evaluated QuickNavi-COVID19 Ag, a rapid antigen detection test between December 2021 and February 2022 in Japan, using real-time reverse transcription (RT)-PCR as a reference. Two nasopharyngeal samples were simultaneously collected for antigen testing and for RT-PCR. Variant analysis of the SARS-CoV-2 genomic sequencing was also performed.

Results

In total, nasopharyngeal samples were collected from 1,073 participants (417 positive; 919 symptomatic; 154 asymptomatic) for analysis. Compared with those of RT-PCR, the sensitivity, specificity, positive predictive value, and negative predictive value were 94.2% (95% CI: 91.6%–96.3%), 99.5% (95% CI: 98.7%–99.9%), 99.2% (95% CI: 97.8%–99.8%), and 96.5% (95% CI: 94.8%–97.7%), respectively. The sensitivity among symptomatic individuals was 94.3% (95% CI: 91.5%–96.4%). Overall, 85.9% of sequences were classified as Omicron sublineage BA.1, 12.4% were Omicron sublineage BA.2, and 1.6% were Delta B.1.617.2. (Delta variant). Most of the samples (87.1%) had Ct values <25.

Conclusions

The QuickNavi-COVID19 Ag test showed high diagnostic performance for the detection of the SARS-CoV-2 Omicron sublineages BA.1 and BA.2 from nasopharyngeal samples.
Cannabinoids For Fibromyalgia: An Updated Systematic Review
Authors: Scicluna Jean Claude , Di Giovanni Giuseppe
Published: May 2022

Fibromyalgia is an increasingly prevalent condition resulting in high morbidity and economic burden for sufferers. Minimal to modest benefit has been achieved by pharmacotherapies, creating a strong rationale for novel therapies. Substantial evidence has implicated the endocannabinoid system in the modulation of fibromyalgia symptoms. However, the therapeutic potential and potential adverse effects of cannabis-based therapy in fibromyalgia are still under-reported, leading to clinicians’ hesitation to opt for such therapy. This systematic review examined the literature and provided a critical review of the safety and efficacy of cannabis-based therapy in fibromyalgia. It resulted that medical cannabis is a safe and effective treatment option for fibromyalgia, whilst further research in this area is needed.
LEGAL AGE OF CONSENT FOR HIV TESTING AMONG ADOLESCENTS IN SUB SAHARAN AFRICA, A SYSTEMATIC REVIEW
Authors: Mollel Getrud Joseph , Katende Andrew , Shahmanesh Maryam
Published: May 2022

Sub Saharan Africa (SSA) harbours more than 80% of adolescents living with HIV. High age of consent for HIV testing has been identified as one of the key barriers to adolescents’ access to HIV testing. We conducted a systematic literature review to demonstrate the status of age of consent policies in SSA and evidence of relationship between age of consent policies and adolescent’s uptake of HIV testing. We obtained peer reviewed literature from Medline, Embase, Scopus and Web of Science databases and policy review from national HIV testing guidelines and UNAIDS data reports. Age of consent for HIV testing in the region ranged between 12 and 18 years. Among 33 included countries, 14 (42.4%) had age of consent between 12 – 14 years, 9 (27.3%) had age of consent between 15 – 17 years and 10 countries (30.3%) still have the highest age of consent at 18 years as of 2019. Lowering age of consent has been associated with increased access to HIV testing among adolescents.
Enhanced flavour profiles through radicicol induced genomic variation in S. pastorianus lager yeast
Authors: de la Cerda Garcia-Caro Roberto , Thompson Georgia , Zhang Penghan , Hokamp Karsten , Roche Fiona , Carlin Silvia , Vrhovsek Urska , Bond Ursula
Published: May 2022

The yeasts, Saccharomyces pastorianus, are hybrids of Saccharomyces cerevisiae and Saccharomyces eubayanus and have acquired traits from the combined parental genomes such as ability to ferment a range of sugars at low temperatures and to produce aromatic flavour compounds, allowing for the production of lager beers with crisp, clean flavours. The polyploid strains are sterile and have reached an evolutionary bottleneck for genetic variation. Here we describe an accelerated evolution approach to obtain lager yeasts with enhanced flavour profiles. As the relative expression of orthologous alleles is a significant contributor to the transcriptome during fermentation, we aimed to induce genetic variation by altering the S. cerevisiae to S. eubayanus chromosome ratio. Aneuploidy was induced through the temporary inhibition of the cell’s stress response and strains with increased production of aromatic amino acids via the Shikimate pathway were selected by resistance to amino acid analogues. Genomic changes such as gross chromosomal rearrangements, chromosome loss and chromosome gain were detected in the characterised mutants, as were Single Nucleotide Polymorphisms in ARO4, encoding for DAHP synthase, the catalytic enzyme in the first step of the Shikimate pathway. Transcriptome analysis confirmed the upregulation of genes encoding enzymes in the Ehrlich pathway and the concomitant increase in the production of higher alcohols and esters such as 2-phenylethanol, 2-phenylethyl acetate, tryptophol, and tyrosol. We propose that the plasticity of polyploid S. pastorianus genomes is an advantageous trait supporting opportunities for genetic diversity in otherwise sterile strains.

Significance Statement

Lager beer is the product of fermentations conducted with Saccharomyces pastorianus, which are hybrids of Saccharomyces cerevisiae and Saccharomyces eubayanus. A quintessential property of lager beers is the distinctive flavours produced during fermentation. Hybrids are sterile and have reached an evolutionary bottleneck. Finding ways to introduce genetic variation as a means of enhancing the flavour profiles is a challenge. Here, we describe an approach to introduce genetic variation by inducing aneuploidy through the temporary inhibition of the cell’s stress response. Strains with an enhanced flavour production were selected by resistance to amino acid analogues. We identified genomic changes and transcriptome analysis confirmed the upregulation of genes in the Ehrlich pathway which is responsible for the production of flavour compounds.
Zidovudine multi-combos with last-line fosfomycin, ceftazidime-avibactam, colistin and tigecycline against Multi-Drug Resistant Klebsiella pneumoniae
Authors: Gómara-Lomero Marta , López-Calleja Ana Isabel , Rezusta Antonio , Aínsa José Antonio , Ramón-García Santiago
Published: May 2022

Drug repurposing is a novel strategy for the development of new therapies against antibiotic-resistant bacteria. Zidovudine, an antiviral largely used in the HIV-therapy, exerts antibacterial activity against Gram-negative bacteria. Zidovudine was identified in a previous drug repurposing synergy screening as fosfomycin enhancer against Klebsiella pneumoniae ATCC 13883. Our aim was to evaluate the antibacterial in vitro activity of zidovudine-based combinations with last-line antibiotics against MDR/XDR K. pneumoniae isolates. We validated the zidovudine/fosfomycin combination against a collection of 12 MDR K. pneumoniae isolates by the checkerboard assay (CBA). In addition, we performed time-kill assays (TKA) to analyze synergistic and bactericidal activities of zidovudine paired combinations with fosfomycin, ceftazidime-avibactam, colistin and tigecycline. These were compared with frequent clinical combinations in the treatment of MDR Enterobacteriaceae. The potential of the triple zidovudine/fosfomycin/colistin was also assessed by TKA. CBA synergy confirmation rate between zidovudine/fosfomycin was 83.33%. TKA yielded synergy confirmation rates of 83.3% for zidovudine/ceftazidime-avibactam, 75% for zidovudine/fosfomycin, 75% for zidovudine/colistin and 66.6% for zidovudine/tigecycline with potent killing activities. Frequent clinical combinations displayed synergy rates of 41.6% for meropenem/ertapenem, 33.33% for meropenem/colistin, 75% for fosfomycin/colistin and 66.6% for fosfomycin/tigecycline with lower bactericidal efficacy than zidovudine-based combinations. The triple zidovudine/fosfomycin/colistin combination exhibited activities similar to fosfomycin/colistin and fosfomycin/zidovudine. As conclusion, zidovudine is an effective partner in in vitro combinations with existing antibiotics against MDR K. pneumoniae, especially with ceftazidime-avibactam, fosfomycin or colistin. Further studies are needed to elucidate the clinical potential of zidovudine as a repurposed drug in the antibacterial therapy.
Host and pathogen drivers of infection-induced changes in social aggregation behavior
Authors: Romano Valéria , Lussiana Amy , Monteith Katy M. , MacIntosh Andrew J.J. , Vale Pedro F.
Published: May 2022

Identifying how infection modifies host behaviours that determine social contact networks is important for understanding heterogeneity in infectious disease dynamics. Here, we investigate whether group social behaviour is modified during bacterial infection in Drosophila melanogaster, an established system for behavioural genetics, according to pathogen species, infectious dose, host genetic background and sex. We find that systemic infection with four different bacterial species results in a reduction in the mean pairwise distance within infected flies, and that the extent of this change depends on the infectious dose in a pathogen-specific way. In the presence of infected conspecifics, susceptible flies also tended to aggregate throughout time, but did not show any evidence of avoiding infected flies. We also observed genetic- and sex-based variation in social aggregation, with infected female flies aggregating more closely than infected males. In general, our results confirm that bacterial infection induces changes in fruit fly behaviour across a range of pathogen species, but also highlight that these effects vary between fly genetic backgrounds and can be sex-specific. We discuss possible explanations for sex differences in social aggregation and their consequences for individual variation in pathogen transmission.
A Systematic review of ‘Fair’ AI model development for image classification and prediction
Authors: Correa Ramon , Shaan Mahtab , Trivedi Hari , Patel Bhavik , Celi Leo Anthony G. , Gichoya Judy W. , Banerjee Imon
Published: May 2022

Background

Artificial Intelligence (AI) models have demonstrated expert-level performance in image-based recognition and diagnostic tasks, resulting in increased adoption and FDA approvals for clinical applications. The new challenge in AI is to understand the limitations of models to reduce potential harm. Particularly, unknown disparities based on demographic factors could encrypt currently existing inequalities worsening patient care for some groups.

Method

Following PRISMA guidelines, we present a systematic review of ‘fair’ deep learning modeling techniques for natural and medical image applications which were published between year 2011 to 2021. Our search used Covidence review management software and incorporates articles from PubMed, IEEE, and ACM search engines and three reviewers independently review the manuscripts.

Results

Inter-rater agreement was 0.89 and conflicts were resolved by obtaining consensus between three reviewers. Our search initially retrieved 692 studies but after careful screening, our review included 22 manuscripts that carried four prevailing themes; ‘fair’ training dataset generation (4/22), representation learning (10/22), model disparity across institutions (5/22) and model fairness with respect to patient demographics (3/22). However, we observe that often discussion regarding fairness are also limited to analyzing existing bias without further establishing methodologies to overcome model disparities. Particularly for medical imaging, most papers lack the use of a standardized set of metrics to measure fairness/bias in algorithms.

Discussion

We benchmark the current literature regarding fairness in AI-based image analysis and highlighted the existing challenges. Based on the current research trends, exploration of adversarial learning for demographic/camera/institution agnostic models is an important direction to minimize disparity gaps for imaging. Privacy preserving approaches also present encouraging performance for both natural and medical image domain.
Prodromal manifestations of Parkinson’s disease in adults with 22q11.2 microdeletion syndrome
Authors: Juri Carlos , Chaná-Cuevas Pedro , Kramer Vasko , Fritsch Rosemarie , Ornstein Claudia , Cuiza Analía , Hernández Carlos , Villanueva Katiuska , Cordova Teresa , Mauro Jorge , Ocampo Adrian , Rebolledo-Jaramillo Boris , Encina Gonzalo , Calleja Andrea , Dinator Javiera , Alcayaga Juan Pablo , Crossley Nicolas A. , Repetto Gabriela M.
Published: May 2022

22q11.2 microdeletion syndrome (22qDS) was recently identified as a risk factor for development of early-onset Parkinson’s disease (PD). The classical motor manifestations of this disease are preceded by early signs and symptoms of neurodegeneration. The progression of 22qDS-associated PD is unknown. We aimed to evaluate the presence of prodromal PD in a group of adults with 22qDS using the Movement Disorders Society (MDS) Criteria for Prodromal PD. Thirty-eight persons with 22qDS and 13 age-matched controls participated in the study, and their results were compared using the Mann-Whitney U test. Persons with 22qDS had lower scores on olfaction testing (p=7.42E×10−5), higher scores on the COMPASS 31 scale for dysautonomia (p=2.28×10−3) and on the motor evaluation using Movement Disorder Society (MDS)-sponsored revision of Unified Parkinson’s Disease Rating Scale motor subscore (UPDRS-III) (p=1.84×10−4), compared with healthy controls. Home polysomnogram did not find participants with REM-sleep behavior disorder. Integrity of nigrostriatal dopaminergic system was evaluated by PET-CT imaging of presynaptic dopamine with 18F-PR04.MZ. Patients showed significantly higher specific binding ratios in the striatum, compared to controls (p=9.57×10−3 at the caudate nuclei). Two patients with 22qDS (5.2%) had decreased uptake in the posterior putamen (less than 60% of controls) and one fulfilled MDS criteria for prodromal PD. These results show that patients with 22qDS manifest some signs and symptoms of prodromal PD such as hyposmia, dysautonomia and mild movement alterations. In the majority, this was associated with elevated dopaminergic signaling, suggesting that loss of dopaminergic neurons may not be the cause. A smaller subgroup did show evidence of a decrease in nigrostriatal dopaminergic signaling, as seen in classical prodromal PD. Longitudinal studies are necessary to understand the progression to and risk of PD in persons with 22qDS.
PRIMEtime: an epidemiological model for informing diet and obesity policy
Authors: Cobiac Linda J , Law Cherry , Scarborough Peter
Published: May 2022

Background

Mathematical modelling can play a vital role in guiding public health action. In this paper, we provide an overview of the revised and updated PRIMEtime model, a tool for evaluating health and economic impacts of policies impacting on diet and obesity. We provide guidance on populating PRIMEtime with country-specific data; and illustrate its validation and implementation in evaluating a combination of interventions in the UK: a sugar-sweetened beverage (SSB) tax; a ban on television advertising of unhealthy foods; and a weight loss program.

Methods

PRIMEtime uses routinely available epidemiological data to simulate the effects of changes in diet and obesity on 19 non-communicable diseases, in open- or closed-population cohorts, over time horizons from 1 year to a lifetime. From these simulations, the model can estimate impact of a policy on population health (obesity prevalence, cases of disease averted, quality-adjusted life years), health and social care costs, and economic measures (net monetary benefit, cost-effectiveness ratios). We populated PRIMEtime with UK data and validated epidemiological predictions against two published data collections. We then evaluated three current obesity intervention policies based on estimates of effectiveness from published evaluation studies.

Results

There was considerable variation in the modelled impact of interventions on prevalence of obesity and subsequent changes in health and the need for health care: restrictions on TV advertising of unhealthy foods to children led to the largest reductions in obesity prevalence; but the SSB tax, which also targeted adults, had the biggest benefits in reducing obesity-related disease; and the weight loss program, while having very small impact on obesity prevalence at the population scale, had large and immediate benefits in improving health and reducing health sector spending. From a health sector perspective, the combination of interventions produced a favourable net monetary benefit of £31,400 (12,200 to 50,700) million. But the combined effect in reducing prevalence of overweight and obesity, was not estimated to reach more than 0.81 percentage points (95% uncertainty interval: 0.21 to 1.4) for males and 0.95 percentage points (0.24 to 1.7) for females by 2050.

Conclusions

Diet and obesity interventions have the potential to improve population health and reduce health sector spending both immediately and in the long-term. Models such as PRIMEtime can be used to evaluate the economic merits of intervention strategies and determine how best to combine interventions to achieve maximum population benefit. But with almost a third of children and two-thirds of adults currently overweight or obese, we need to broaden the application of public health models to evaluating the structural and systemic changes that are needed in our society to address the underlying drivers of the obesity epidemic.
Differences in Dietary Intake Exist Among U.S. Adults by Diabetic Status Using NHANES 2009-2016
Authors: Lin Luotao , Zhu Fengqing , Delp Edward J. , Eicher-Miller Heather A.
Published: May 2022

Objectives

Insulin takers’ diets have rarely been described although insulin dosing is highly dependent on dietary intake. The objective of this paper was to determine the most frequently consumed food or beverage items, food subcategories, and food categories, and those that contributed most to total energy intake among U.S. insulin takers, those with type 2 diabetes (T2D) not taking insulin and those without diabetes; the groups were also compared at the broad food category level.

Methods

The Laboratory tests and questionnaires of the NHANES 2009–2016 classified 774 insulin takers, 2,758 T2D not taking insulin, and 17,796 participants without diabetes. USDA assigned 8-digit food codes identifying each food item and its membership to a category and subcategory of foods were used to categorize foods based on the WWEIA categories. Raw and weighted frequency and energy contributions of each food item, food subcategory, and food category were calculated and ranked. Comparisons among groups by broad food category used the Rao–Scott modified chi-square test.

Results

Diet soft drinks ranked as the 4th and 7th most consumed food subcategory in insulin takers and T2D not taking insulin, respectively. Soft drinks ranked as the 8th and 6th most consumed food subcategory in T2D not taking insulin and those without diabetes, and contributed 5th and 2nd most to energy, respectively. Protein foods represented 4 of the top 10 highest energy contributing food subcategories among insulin takers, 3 of the top 10 food subcategories among those with T2D not taking insulin, and only 1 subcategory among those without diabetes. Insulin takers had higher consumption frequency of grains, and lower consumption frequency of sweets and alcohol, and a larger share of energy comprising protein, vegetables, and grains, and a smaller share of energy comprising beverages and alcohol compared to participants without diabetes.

Conclusions

Differences in dietary intake exist among U.S. adults by diabetic status. Insulin takers are likely to consume more protein foods and less regular soft drinks compared to other 2 groups. Lists of the most frequently reported foods and foods contributing most to energy may be helpful for nutrition education, prescribing diets, and digital-based dietary assessment for insulin takers.
Molecular Phylogenetics of HIV-1 Subtypes in African Populations: A Case Study of Sub-Saharan African Countries
Authors: Obura Hesborn Omwandho , Mlay Clement Dastan , Moyo Lindani , Karumbo Brenda Muthoni , Omar Kauthar Mwanamkuu , Sinza Erick Masunge , Rotich Gladys Jerono , Mudaki Wilson , Kamau Brenda Muthoni , Awe Olaitan I. , Dillman Allissa
Published: May 2022

Despite advances in antiretroviral therapy that have revolutionized HIV-1 disease management, effective control of the HIV-1 infection pandemic remains elusive. Increased HIV-1 infection rates and genetic diversity in Sub-Saharan African countries pose a challenge in HIV-1 clinical management. This study provides a picture of HIV-1 genetic diversity and its implications for HIV-1 disease spread and the effectiveness of therapies in Africa. Whole-genome sequences of HIV-1 were obtained from Genbank using the accession numbers from 10 African countries with high HIV-1 prevalence. Alignment composed of the query and reference sequences retrieved from the Los Alamos database. The alignment file was viewed and curated in Aliview. Phylogenetic analysis was done by constructing a phylogenetic tree using the maximum likelihood method implemented in IQ-TREE. The clustering pattern of the studied countries showed both homogeneous clustering and heterogeneous clustering with all Zambia sequences clustering with HIV-1 subtype-C indicating local distribution of only subtype-C. Sequences from nine countries showed heterogeneous clustering along with different subtypes as well as individual clustering of the sequences away from references suggesting cross border genetic exchange. Sequences from Kenya and Nigeria clustered with almost all the HIV-1 subtypes suggesting high HIV-1 genetic diversity in Kenya and Nigeria as compared to other African countries. Our results indicate that there is the presence of subtype-specific HIV-1 polymorphisms and interactions during border movements.
Spatial Transcriptomics-correlated Electron Microscopy
Authors: Androvic Peter , Schifferer Martina , Anderson Katrin Perez , Cantuti-Castelvetri Ludovico , Ji Hao , Liu Lu , Besson-Girard Simon , Knoferle Johanna , Simons Mikael , Gokce Ozgun
Published: May 2022

Current spatial transcriptomics methods identify cell states in a spatial context but lack morphological information. Scanning electron microscopy, in contrast, provides structural details at nanometer resolution but lacks molecular decoding of the diverse cellular states. To address this, we correlated MERFISH spatial transcriptomics with large area volume electron microscopy using adjacent tissue sections. We applied our technology to characterize the damage-associated microglial identities in mouse brain, allowing us, for the first time, to link the morphology of foamy microglia and interferon-response microglia with their transcriptional signatures.
Aiolos modulates the TFH and CD4-CTL differentiation programs via reciprocal regulation of the Zfp831/TCF-1/Bcl-6 axis and CD25
Authors: Read Kaitlin A. , Jones Devin M. , Pokhrel Srijana , Hales Emily D.S. , Varkey Aditi , Tuazon Jasmine A. , Eisele Caprice D. , Abdouni Omar , Saadey Abbey , Warren Robert T. , Powell Michael D. , Boss Jeremy M. , Hemann Emily A. , Yount Jacob S. , Ghoneim Hazem E. , Lio Chan-Wang J. , Freud Aharon G. , Collins Patrick L. , Oestreich Kenneth J.
Published: May 2022

Effective immunity to influenza virus and other respiratory viruses requires the generation of CD4+ T cell subsets that coordinate multiple aspects of the immune response. These subsets include T follicular helper (TFH) and T helper 1 (TH1) cells, which promote humoral and cell-mediated responses, respectively. A third population, CD4+ cytotoxic T lymphocytes (CD4-CTLs) facilitates clearance of infection via mechanisms normally associated with CD8+ T cells. Here, we identify the transcription factor Aiolos as a regulator of TFH and CD4-CTL responses. We demonstrate that Aiolos deficiency compromises TFH differentiation and antibody production during influenza virus infection. Conversely, we find that CD4+ T cells acquire a cytotoxic-like program in the absence of Aiolos, including increased expression of the CTL-associated transcription factors Eomes and Blimp-1. We further show that while Aiolos positively regulates the TFH transcriptional regulators Zfp831, TCF-1 and Bcl-6, it also directly represses expression of IL-2Rα and IL-2/STAT5-driven expression of the cytotoxic gene program. Thus, our findings identify Aiolos as a pivotal regulator of TFH and CD4-CTL differentiation and highlight its potential as a target for manipulating CD4+ T cell humoral and cytotoxic responses.
The TERT promoter is polycomb-repressed in neuroblastoma cells with long telomeres
Authors: Graham Mindy Kim , Xu Beisi , Davis Christine , Meeker Alan K. , Heaphy Christopher M. , Yegnasubramaian Srinivasan , Dyer Michael A. , Zeineldin Maged
Published: May 2022

Acquiring a telomere maintenance mechanism is one of the hallmarks of high-risk neuroblastoma and commonly occurs by expressing telomerase (TERT). Telomerase-negative neuroblastoma has, characteristically, long telomeres and most utilize the telomerase-independent alternative lengthening of telomeres (ALT) mechanism. Conversely, no discernable telomere maintenance mechanism is detected in a fraction of neuroblastoma with long telomeres, representing a phenomenon referred to as ever-shorter telomeres. Here, we show that, unlike most cancers, DNA of the TERT promoter is broadly hypomethylated in neuroblastoma. In telomerase-positive neuroblastoma cells, the hypomethylated DNA promoter is approximately 1.5-kb in length and is bound by hypermethylated TERT gene body and upstream intergenic sequences. The TERT locus shows active chromatin marks including H3K4me3, H3K27Ac, H3K14Ac, RNA PolII and BRD4 with low enrichment for the repressive mark, H3K27me3. Strikingly, in neuroblastoma with long telomeres, the hypomethylated region spans the entire TERT locus, including multiple nearby genes with enrichment for the repressive H3K27me3 chromatin mark. Furthermore, subtelomeric regions showed enrichment of repressive chromatin marks in neuroblastomas with long telomeres relative to those with short telomeres. These repressive marks were even more evident at the genic loci, suggesting a telomere position effect. Inhibiting H3K27 methylation by the EZH2 inhibitor, Tazemetostat, induced the expression of TERT, particularly in cell lines with long telomeres and H3K27me3 marks in the promoter region. Taken together, these data suggest that epigenetic regulation of TERT expression differs in neuroblastoma depending on the telomere maintenance status, and H3K27 methylation is important in repressing TERT expression in neuroblastoma with long telomeres.
Ter-Seq: A high-throughput method to stabilize transient ternary complexes and measure associated kinetics
Authors: Chattopadhyay Gopinath , Ahmed Shahbaz , Srilatha Nonavinakere Seetharam , Ashok Apana , Varadarajan Raghavan
Published: May 2022

Regulation of biological processes by proteins often involves the formation of transient, multimeric complexes whose characterisation is mechanistically important but challenging. The bacterial toxin CcdB binds and poisons DNA Gyrase. The corresponding antitoxin CcdA extracts CcdB from its complex with Gyrase through formation of a transient ternary complex, thus rejuvenating Gyrase. We describe a high throughput methodology called Ter-Seq to stabilize probable ternary complexes and measure associated kinetics using the CcdA-CcdB-GyrA14 ternary complex as a model system. The method involves screening a YSD saturation mutagenesis library of one partner (CcdB) for mutants that show enhanced ternary complex formation. We also isolated CcdB mutants that were either resistant or sensitive to rejuvenation, and used SPR with purified proteins to validate the kinetics measured using surface display. Positions where CcdB mutations lead to slower rejuvenation rates are largely involved in CcdA-binding, though there were several notable exceptions. Mutations at these positions reduce the affinity towards CcdA, thereby slowing down the rejuvenation process. Mutations at GyrA14-interacting positions significantly enhanced rejuvenation rates, either due to reduced affinity or complete loss of CcdB binding to GyrA14. We examined the effect of different parameters (CcdA affinity, GyrA14 affinity, surface accessibilities, evolutionary conservation) on the rate of rejuvenation. Finally, we further validated the Ter-Seq results by monitoring kinetics of ternary complex formation for individual CcdB mutants in solution by FRET studies.
Evaluating the impact on health outcomes of an event that resulted in a delay in contact tracing of COVID-19 cases
Authors: Findlater Lucy , Pierotti Livia , Turner Charlie , Wensley Adrian , Chen Cong , Seaman Shaun , Samartsidis Pantelis , Charlett Andre , Anderson Charlotte , Hughes Gareth , Hickman Matt , Edeghere Obaghe , Oliver Isabel
Published: May 2022

Objective

In September 2020, records of 15,861 SARS-CoV-2 cases failed to upload from the Second Generation Laboratory Surveillance System (SGSS) to the Contact Tracing Advisory Service (CTAS) tool, resulting in a delay in the contact tracing of these cases. This study used CTAS data to determine the impact of this delay on health outcomes: transmission events, hospitalisations, and mortality. Previously, a modelling study had suggested a substantial impact.

Design

Observational study

Setting

England.

Population

Individuals testing positive for SARS-CoV-2 and their reported contacts.

Main outcome measures

Secondary attack rates (SARs), hospitalisations, and deaths amongst primary and secondary contacts were calculated, compared to all other concurrent, unaffected cases. SGSS records affected by the event were matched to CTAS records and successive contacts and cases were identified.

Results

The initiation of contact tracing was delayed by 3 days on average in the primary cases in the delay group (6 days) compared to the control group (3 days). This was associated with lower completion of contact tracing of primary cases in the delay group: 80% (95%CI: 79-81%) in the delay group and 83% (95%CI: 83-84%) in the control group. There was some evidence to suggest an increase in transmission to non-household contacts amongst those affected by the delay. The SAR for non-household contacts was higher amongst secondary contacts in the delay group than the control group (delay group: 7.9%, 95%CI:6.4% to 9.2%; control group: 5.9%, 95%CI: 5.3% to 6.6%). There was no evidence of a difference between the delay and control groups in the odds of hospitalisation (crude odds ratio: 1.1 (95%CI: 0.9 to 1.2) or death (crude odds ratio: 0.7 (0.1 to 4.0)) amongst secondary contacts.

Conclusions

The delay in contact tracing had a limited impact on population health outcomes.

Strengths and limitations of the study

Shows empirical data on the health impact of an event leading to a delay in contact tracing so can test hypotheses generated by models of the potential impact of a delay in contact tracing

Estimates the extent of further transmission and odds of increased mortality or hospitalisation in up to the third generation of cases affected by the event

The event acts as a natural experiment to describe the possible impact of contact tracing, comparing a group affected by chance by delayed contact tracing to a control group who experienced no delay

Contact tracing was not completed for all individuals, so the study might not capture all affected contacts or transmissions
SARS-CoV-2 Variants of Concern (VOC) Alpha, Beta, Gamma, Delta, and Omicron coincident with consecutive pandemic waves in Pakistan
Authors: Nasir Asghar , Aamir Uzma Bashir , Kanji Akbar , Samreen Azra , Ansar Zeeshan , Ghanchi Najia K. , Bukhari Ali Raza , Masood Kiran Iqbal , Islam Nazneen , Ghani Samina , Syed M. Asif , Wassan Mansoor , Mahmood Syed Faisal , Hasan Zahra
Published: May 2022

Identification and monitoring of SARS-CoV-2 Variants of Concern/Interest (VOC/VOIs) is essential to guide public health measures. We report the surveillance of VOCs circulating in Karachi during the pandemic between April 2021 and February 2022. We screened 2150 SARS-CoV-2 PCR positive samples received at the AKUH Clinical Laboratories. VOC was identified using a PCR-based approach targeting lineage-specific mutations using commercially available assays. Of the SARS-CoV-2 PCR positive samples, 81.7% had VOC/VOI, while 18.3% were undetermined. Alpha variants were predominant at 82.5% and 40.3% of the cases in April and May 2021. Beta variants increased in May (29%) and June (42%) and then reduced to 6% by July. Gamma variant cases were at 14.5% and 9% in May and June, respectively. Delta variants first detected in May, increased to comprise 66% of all variants by July, remaining dominant in August, September, October, and November 2021 at 88%, 91%, 91% and 85% respectively. Omicron (BA.1) variants emerged in December, rising to 42% of cases with an increase to 81% by January 2022 and then reducing to 45% in February 2022. Delta variant prevalence was coincident with increased hospital admissions and mortality. The Omicron variant surge was associated with increased daily infections but limited COVID-19 severity. We highlight the predominance of the VOCs identified through a rapid PCR based approach. As this is important to inform a public health response, we propose that a mutation targeted approach can be a rapid, lower cost solution to aid tracking of known VOCs during pandemic waves.
Predicting Age-Related Macular Degeneration Progression with Contrastive Attention and Time-Aware LSTM
Authors: Yin Changchang , Moroi Sayoko E. , Zhang Ping
Published: May 2022

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in developed countries. Identifying patients at high risk of progression to late AMD, the sight-threatening stage, is critical for clinical actions, including medical interventions and timely monitoring. Recently, deep-learning-based models have been developed and achieved superior performance for late AMD prediction. However, most existing methods are limited to the color fundus photography (CFP) from the last ophthalmic visit and do not include the longitudinal CFP history and AMD progression during the previous years’ visits. Patients in different AMD subphenotypes might have various speeds of progression in different stages of AMD disease. Capturing the progression information during the previous years’ visits might be useful for the prediction of AMD progression. In this work, we propose a Contrastive-Attention-based Time-aware Long Short-Term Memory network (CAT-LSTM) to predict AMD progression. First, we adopt a convolutional neural network (CNN) model with a contrastive attention module (CA) to extract abnormal features from CFPs. Then we utilize a time-aware LSTM (T-LSTM) to model the patients’ history and consider the AMD progression information. The combination of disease progression, genotype information, demographics, and CFP features are sent to T-LSTM. Moreover, we leverage an auto-encoder to represent temporal CFP sequences as fixed-size vectors and adopt k-means to cluster them into subphenotypes. We evaluate the proposed model based on real-world datasets, and the results show that the proposed model could achieve 0.925 on area under the receiver operating characteristic (AUROC) for 5-year late-AMD prediction and outperforms the state-of-the-art methods by more than 3%, which demonstrates the effectiveness of the proposed CAT-LSTM. After analyzing patient representation learned by an auto-encoder, we identify 3 novel subphenotypes of AMD patients with different characteristics and progression rates to late AMD, paving the way for improved personalization of AMD management. The code of CAT-LSTM can be found at GitHub1.

CCS CONCEPTS

• Applied computing → Health informatics; • Computing methodologies → Neural networks.

ACM Reference Format

Changchang Yin, Sayoko E. Moroi, and Ping Zhang. 2018. Predicting Age-Related Macular Degeneration Progression with Contrastive Attention and Time-Aware LSTM. In Proceedings of SIGKDD 2022. ACM, New York, NY, USA, 11 pages. https://doi.org/10.1145/1122445.1122456
Nerve pathology is prevented by linker proteins in mouse models for LAMA2-related muscular dystrophy
Authors: Reinhard Judith R. , Porrello Emanuela , Lin Shuo , Pelczar Pawel , Previtali Stefano C. , Rüegg Markus A.
Published: May 2022

LAMA2-related muscular dystrophy (LAMA2 MD or MDC1A) is caused by mutations in the LAMA2 gene encoding laminin-α2, the long chain of several heterotrimeric laminins. Laminins are essential components of the extracellular matrix that interface with underlying cells. The pathology of LAMA2 MD patients is dominated by the severe muscular dystrophy but also involves other tissues. In the dyW/dyW mouse model for LAMA2 MD, amelioration of muscle function by skeletal muscle-specific expression of the two linker proteins, mini-agrin and αLNNd, is sufficient to greatly increase survival. In such survivors, the phenotype is dominated by the hindlimb paralysis. We now show that ubiquitous expression of the two linker proteins in dyW/dyW mice improves muscle function and prevents hindlimb paralysis. The same ameliorating effect of the linker proteins was seen in dy3K/dy3K mice, which represent the most severe mouse model of LAMA2 MD. In summary, these data show that the two linker proteins can compensate the loss of laminin-α2 in many, if not all tissues affected in LAMA2 MD.
Study of the glycome of synovial mast cells in normal tissues, osteoarthritis and rheumatoid arthritis reveals MGAT5 activity in these and endochondral cells
Authors: McClure Sheena F , McClure John
Published: May 2022

Mast cells and angiogenesis play roles in the synovium of both osteoarthritis and rheumatoid disease but precise mechanisms are unclear. In a study of the glycome of human synovial biopsies from normal, osteoarthritic and rheumatoid disease cases mast cell numbers were increased in both osteoarthritic and rheumatoid disease synovial samples (the latter more than the former). Both mast cells and endothelial cells expressed receptors for the lectinPhaseolus vulgarisleukagglutinin (lPHA). Endothelial cells only expressed receptors forPsophocarpus tetragonolobus(PTL-II). Mast cells and angiogenesis are, therefore, likely to have a common pathogenetic mechanism in osteoarthritis and rheumatoid synovitis, the difference being one of degree. lPHA receptor expression in both mast cells and endothelial cells indicates βl,6N–acetylglucosaminyl (GlcNAc) – transferase V (GnTaseV/MGAT5) activity. This provides a linkage between mast cells and endothelial cell proliferation. Endothelial cells show core 1 O-glycosylation (positive PTL-II staining) which is probably necessary for the formation of competent tubular structures and for continuing vascular integrity.
A Microfluidic Chip for LAMP-based Multiplex Detection of Pathogen
Authors: Guan Jingyi , Wang Yunhua , Jin Jing , Zheng Guoxia
Published: May 2022

Early diagnosis of bacterial causing the disease is important for treatment of patent and preventing the spread of pathogen. Utilizing of POCT devices to detect the pathogens on-site will accelerate the diagnosis of infectious disease. By using loop-mediated-amplification, we developed a microfluidic chip for multiplex detection of three bacterial, where the samples were driven by negative pressure were loaded quickly. The performance of the device was preliminarily evaluated. The specificities of the detections were demonstrated. And the LOD for Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa were measured as 17.15, 5.67 and 16.47 ng/μL, respectively. The results demonstrated the feasibility of the method.