bluuebunny/crossref_metadata_2025 huggingface dataset:
The assessment of hypertension in kidney transplant patients: time to change our approach?
Authors: Demiray Atalay , Kanbay Mehmet
Published: September 2021

Kidney transplantation (KT) is an increasingly utilized treatment for end-stage kidney disease. Hypertension either as a cause of kidney disease or as a complication of chronic kidney disease is the most frequently encountered comorbidity of KT patients. Hence, the management of hypertension in KT patients is crucial to prolong patient and graft survival. Ambulatory blood pressure monitoring (ABPM) appeared as a promising technique that has superiority over office and home blood pressure (BP) monitoring to correctly diagnose and manage hypertension. A recent meta-analysis by Pisano et al. including 42 studies with 4115 participants provided strong data for the comparison of ABPM with office BP monitoring in KT patients. In addition to the current literature knowledge, the findings of Pisano et al. filled the long-awaited evidence gap to suggest ABPM as a first-line BP monitoring technique for KT patients. Despite its disadvantages, such as patient discomfort, cost–effectiveness and limited availability, ABPM has crucial advantages in the management of hypertension including the detection of abnormal circadian BP patterns, the assessment of effects of physical activity and short-term variability of BP, and the exclusion of masked and white-coat hypertension.
Patterns of chronic and transient hyperkalaemia and clinically important outcomes in patients with chronic kidney disease
Authors: Trevisan Marco , Clase Catherine M , Evans Marie , Popov Tamara , Ludvigsson Jonas F , Sjölander Arvid , Carrero Juan Jesus
Published: September 2021

Background

Whether hyperkalaemia in CKD is chronic or transient, and whether this has different outcome implications, is not known.

Methods

This was an observational study of adults with CKD G3–5 from Stockholm, Sweden 2006–11. We examined individual trajectories of potassium from all measurements obtained through routine outpatient care. For each month of follow-up, we created a rolling assessment of the proportion of time in which potassium was abnormal during the previous 12 months. We defined patterns of hyperkalaemia as transient (≤50% of time during the previous year with potassium >5.0 mmol/L) and chronic (>50% of time with potassium >5.0 mmol/L), and examined whether previous hyperkalaemia pattern offers additional predictive value beyond that provided by the most recent (current) potassium value.

Results

We included 36 511 participants (56% women) with CKD G3–5 and median estimated glomerular filtration rate 46 mL/min/1.73 m2. Transient and chronic hyperkalaemia, respectively, were observed in 15% and 4% of patients with CKD G3a, and in 50% and 17% of patients with CKD G5. In fully adjusted models, transient (hazard ratio 1.36, 95% confidence interval 1.29–1.46) or chronic (1.16, 1.04–1.32) hyperkalaemia patterns, but not current hyperkalaemia, were associated with major adverse cardiovascular events (MACE), compared with normokalaemia. Transient hyperkalaemia (1.43, 1.35–1.52) and current potassium values, but not chronic hyperkalaemia, were associated with the risk of death.

Conclusions

Between 4% and 17% of patients with CKD G3–5 develop chronic hyperkalaemia. In general, hyperkalaemia predicted MACE and death; however, the lack of effect of current potassium on MACE when adjusted for the previous pattern, and the stronger effects on death than on MACE, lead us to question whether hyperkalaemia is causal in these relationships.
Pre-emptive BioGlue priming of the branched Evita Open NEO hybrid prosthesis: tackling excessive oozing
Authors: Ho Jacky Y K , Lim Kevin , Fujikawa Takuya , Wong Randolph H L
Published: September 2021

Excessive oozing after total arch replacement with the frozen elephant trunk technique through the fabric of the E-vita Open NEO raised concern about its early adaptation. The mechanism is speculated to be multifactorial. Our goal was to report our approach using pre-emptive BioGlue priming on the fabric against the oozing phenomenon.
A review: antimicrobial properties of several medicinal plants widely used in Traditional Chinese Medicine
Authors: Chen Kun , Wu Wei , Hou Xiudan , Yang Qingli , Li Zhaojie
Published: September 2021

Due to the dramatic increase in the use of antibiotics and growing health threat of bacterial resistance to many commonly used antibiotics, many studies have been directed at developing new and effective antibacterial compounds, among which many new, natural, and effective antibacterial compounds discovered from medicinal plants have drawn great interest and raised new hope for treating the challenges of antibiotic resistance. This review aimed to summarize the most important and widely used medicinal plants that were reported to have antibacterial activities. A general literature search from 2010 to 2020 was conducted using different databases, including Science Direct, Web of Science, and PubMed. According to the literature, three medicinal plants with outstanding antibacterial activities, Taraxacum officinale, Coptis Rhizome, and Scutellaria baicalensis, were screened and reviewed by prioritization. The extraction methods, antibacterial activities of different parts of plants or the plant-derived compounds, spectra of antibacterial activities, and toxicity were described, respectively. However, the antibacterial activities of the extracts or pure compounds as reported in the reviewed literature were mostly based on in vitro assays, and moreover, the deeper antibacterial mechanisms have not been elucidated clearly. Therefore, further studies are required in the fields of purification and identification of the antibacterial compounds, its mechanisms of action, and synergistic effects in combination with other antibacterial drugs, which may be helpful in the development of new antibacterial drugs.
Projecting Ancient Ancestry in Modern-Day Arabians and Iranians: A Key Role of the Past Exposed Arabo-Persian Gulf on Human Migrations
Authors: Ferreira Joana C , Alshamali Farida , Montinaro Francesco , Cavadas Bruno , Torroni Antonio , Pereira Luisa , Raveane Alessandro , Fernandes Veronica
Published: September 2021

The Arabian Peninsula is strategic for investigations centered on the early structuring of modern humans in the wake of the out-of-Africa migration. Despite its poor climatic conditions for the recovery of ancient human DNA evidence, the availability of both genomic data from neighboring ancient specimens and informative statistical tools allow modeling the ancestry of local modern populations. We applied this approach to a data set of 741,000 variants screened in 291 Arabians and 78 Iranians, and obtained insightful evidence. The west-east axis was a strong forcer of population structure in the Peninsula, and, more importantly, there were clear continuums throughout time linking western Arabia with the Levant, and eastern Arabia with Iran and the Caucasus. Eastern Arabians also displayed the highest levels of the basal Eurasian lineage of all tested modern-day populations, a signal that was maintained even after correcting for a possible bias due to a recent sub-Saharan African input in their genomes. Not surprisingly, eastern Arabians were also the ones with highest similarity with Iberomaurusians, who were, so far, the best proxy for the basal Eurasians amongst the known ancient specimens. The basal Eurasian lineage is the signature of ancient non-Africans who diverged from the common European-eastern Asian pool before 50,000 years ago, prior to the later interbred with Neanderthals. Our results appear to indicate that the exposed basin of the Arabo-Persian Gulf was the possible home of basal Eurasians, a scenario to be further investigated by searching ancient Arabian human specimens.
Pension Policy Literacy and Retirement Expectations: A Cross-Country Survey Experiment
Authors: Radl Jonas , Fernández Juan J
Published: September 2021

Objectives

This study reports the findings of the first cross-national survey experiment on the effects of information on the expected retirement age. Given the drawbacks of unrealistic retirement expectations, the study examines the impacts of nonpartisan information about future demographic aging and forecasted pension benefit levels.

Methods

An online survey experiment was conducted in the United States, Germany, and Spain in 2018 using an internet access panel. We assigned respondents to 2 random treatments: one citing the change in the projected share of the population older than 65 years (demographic treatment) and another citing the projected change in pension replacement rates (benefits treatment), both for 2015–2040. Treatment effects on the expected retirement age are reported.

Results

The benefits treatment has a strong influence on retirement expectations. In the United States, respondents informed of the expected decline in pension replacement rates expect to retire 2 years later than respondents not informed of the decline. In Spain, this treatment leads to an approximately 9-month postponement of expected retirement, while no significant effect is found in Germany. In addition, the demographic treatment does not affect retirement expectations in the countries studied. Respondents in all countries informed of future population aging do not show different expected retirement ages than respondents not given this information.

Discussion

People’s retirement expectations are sensitive to information on future changes in pension generosity but not to information on population aging. The results suggest information campaigns focused on declining pension replacement rates may help extend working lives.
Early Diagnosis, Early Stratification, and Early Intervention to Deliver Precision Medicine in IBD
Authors: Noor Nurulamin M , Sousa Paula , Paul Stéphane , Roblin Xavier
Published: September 2021

Despite huge advances in understanding the molecular basis of IBD, clinical management has continued to rely on a “trial and error” approach. In addition, a therapeutic ceiling has emerged whereby even the most effective interventions are only beneficial for approximately 30% of patients. Consequently, several tools have been developed to aid stratification and guide treatment-decisions.

We review the potential application for many of these precision medicine approaches, which are now almost within reach. We highlight the importance of early action (and avoiding inaction) to ensure the best outcomes for patients and how combining early action with precision tools will likely ensure the right treatment is delivered at the right time and place for each individual person living with IBD.

The lack of clinical impact to date from precision medicine, despite much hype and investment, should be tempered with the knowledge that clinical translation can take a long time, and many promising breakthroughs might be ready for clinical implementation in the near future. We discuss some of the remaining challenges and barriers to overcome for clinical adoption. We also highlight that early recognition, early diagnosis, early stratification, and early intervention go hand in hand with precision medicine tools. It is the combination of these approaches that offer the greatest opportunity to finally deliver on the promise of precision medicine in IBD.
Learning curve for two-port video-assisted thoracoscopic surgery lung segmentectomy
Authors: Dimitrovska Natasha Toleska , Bao Feichao , Yuan Ping , Hu Shoujun , Chu Xiao , Li Wentao
Published: September 2021

OBJECTIVES

When lung cancer evolves from a large, centrally located mass to small, peripherally located pulmonary nodules, such as ground glass nodules, segmentectomy offers a reasonable method by which to save lung parenchyma without eliciting compromising oncological effects. To master these techniques, it is important to analyse the learning curve of surgeons. Therefore, the aim of the present study was to analyse the learning curve for two-port video-assisted thoracoscopic surgery (VATS) segmentectomy in our institution.

METHODS

We retrospectively collected data from 86 consecutive patients who underwent two-port VATS segmentectomy between June 2019 and November 2019. The operative time (OT) and estimated blood loss and other complications were analysed. The learning curve was evaluated using the OT and the cumulative sum (CUSUM) value of OTs across all cases.

RESULTS

We generated a graph of the CUSUM of OTs and found that the learning curve could be differentiated into 3 phases: phase 1, the initial learning phase (1st to 27th operation); phase 2, the increased competence phase (28th to 54th operation); and phase 3, the experienced phase (55th to 86th operation). The CUSUM value inflected at patient number 47. There were significant reductions in the OT and bleeding in phase 3 relative to phases 1 and 2. There were also significant differences in OT and estimated blood loss between the simple and complex segmentectomy procedures.

CONCLUSIONS

In conclusion, the 3 phases identified using CUSUM analysis of the OT represented characteristic stages of the learning curve for two-port VATS segmentectomy. The data indicate that, in our institution, the inflection point for the learning curve was achieved after operating on 47 cases.
Practice Theory and Postsocialist Civil Society: Toward a New Analytical Framework
Authors: Baća Bojan
Published: September 2021

When discussing postsocialist civil societies in Central and Eastern Europe (CEE), scholars have predominantly focused on the nonparticipatory and advocacy-oriented activities of nongovernmental organizations (NGOs), effectively narrowing the concept of “civil society” to that of the “civic sector.” This actor-focused and normative approach has resulted in a systematic obfuscation of less structured forms of everyday resistance, civic engagement, active citizenship, contentious politics, and social movements, giving only a partial view of civil societies in the region. Through a critical dialogue between state-of-the-art research on postsocialist civil society and the practice turn in international political sociology (IPS), this article postulates an analytical distinction between contentious and compliant practices in order to arrive at a more comprehensive and nuanced understanding of the ways in which postsocialist civil societies are manifested, enacted, and actualized. On the one hand, the proposed practice turn moves the research agenda away from abstract, universalist, and normative assumptions of what civil society should be in favor of an embedded, contextual, and critical understanding of what it actually is; on the other hand, this shift opens venues for theorizing not only about, but also from the “postsocialist condition” of civil societies in the transnational space of CEE.
Interactive, on-line visualization tools to measure and drive equity in COVID-19 vaccine administrations
Authors: Shaheen Amy W , Ciesco Eileen , Johnson Kevin , Kuhnen Greg , Paolini Christopher , Gartner Gary
Published: September 2021

Equitable distribution of vaccines is necessary to ensure those at highest risk of illness are protected from COVID-19 (coronavirus disease 2019). Unfortunately, there is significant evidence that vaccines have not been reaching the most vulnerable. At our large hospital system, we created interactive online tools to measure and visualize equitability of vaccine administrations and to help stakeholders identify populations at highest risk within state-designated eligible vaccine groups. Using race, ethnicity, gender, and social vulnerability, we are able to measure and reflect our vaccine administration performance against the communities that we serve. With our visualization tools, stakeholders have been able to target interventions to improve equity in vaccine administrations, including improvements in race, ethnicity, and social vulnerability. We plan to use the data elements incorporated in our electronic health record and data warehouse due to the COVID-19 pandemic to guide further population health efforts at decreasing disparities.
Community Foundations as Network Conveners: Structuring Collective Agency for Child Education and Development System Impact
Authors: Sedgwick Donna , Lemaire Robin H , Wirgau Jessica , McKeague Lauren K
Published: September 2021

The resource investment and flexibility necessary to support the development of collective agency among autonomous organizational actors can be substantial. Public agencies, with their rigid budget cycles and regulatory burdens, often struggle with providing the resources needed to forge this type of system building to address complex community issues. Community foundations, as anchor institutions in communities, exhibit financial and social power, flexibility, and a reputation for broad community interests that position them to be such conveners. Framing our examination with structuration theory, we conducted a longitudinal mixed methods action research project from Fall 2015 to Spring 2019 to document how a community foundation dislodged schemas and convened a purpose-oriented network to forge collective agency. Data collection included surveying 40 system providers before the launching of the network and 49 providers 3 yr later, interviews with 10 network participants, and field observations of 21 network meetings. Network analysis was employed to examine the changes to the system while qualitative methods were used to analyze the processes behind those changes. The implications of this study are that emphasizing the resources and processes that contribute to building collective action broadens perspectives about which organizations may be well suited to convening networks in the public sphere.
Edge influence on herbaceous plant species, diversity and soil properties in sparse oak forest fragments in Iran
Authors: Valadi Gelareh , Eshaghi Rad Javad , Khodakarami Yahia , Nemati Peykani Mostafa , Harper Karen A
Published: September 2021

Forest edges have been well studied in temperate and tropical forests, but less so in open canopy forests. We investigated edge influence on plant species diversity and soil properties in sparse oak forest fragments. Data were collected along three transects from the edge to the interior of three small (under 10 ha) and three large (over 10 ha) oak forest fragments in Kermanshah Province, Iran. We measured herbaceous plants (<0.5 m in height) and soil attributes at 0 (forest edge), 25, 50, 100 and 150 m. We quantified species diversity using the Shannon index, used rarefaction to compare species richness between two different sizes of fragments and applied non-metric multidimensional scaling ordination to investigate the variation in species composition. We estimated the distance of edge influence using randomization tests. Generalized linear mixed models with post-hoc Tukey’s HSD tests were used to assess the effects of distance from edge and fragment size on diversity and soil properties. We found greater species richness, diversity and evenness at the edge of both small and large fragments and lower nitrogen and organic carbon at the edge compared to the interior of large fragments, with most changes within 50 m of the edge. Species composition, organic carbon and total nitrogen were significantly different between small and large fragments. Our findings of significant edge influence on herbaceous plants and soil properties in these sparse forests provide a significant contribution to the literature on edges, especially in relation to herbaceous plants.
Mental well-being promotion by Australian community pharmacists: what’s happening and what needs to be done?
Authors: Suppiah Vijayaprakash , Kelly Fiona , Watt Oliver , Wheeler Amanda J , Hotham Elizabeth , McMillan Sara
Published: September 2021

Objectives

This study aimed to explore the range of activities provided by community pharmacists for promoting mental well-being in Australia.

Methods

An online survey was developed and piloted by 2 community pharmacists, 1 representative from the Pharmaceutical Society of Australia and 11 pharmacy students for content and face validity. Community pharmacists were recruited via direct emails to pharmacy groups and social media between November 2019 and January 2020. Descriptive statistics and chi-squared analyses were conducted.

Key findings

Data were analysed from 85 pharmacists (of 115 total pharmacy staff respondents). Although 40% reported working in a pharmacy that promoted mental well-being, most (88.2%) were not involved in such activities. However, most respondents (88.0%) identified community pharmacy as a suitable setting to promote mental well-being. Barriers to mental well-being promotion included busy pharmacy environment with competing priorities, a lack of staff training and confidence in discussing mental well-being and stigma associated with mental illness.

Conclusions

Community pharmacy presents a suitable setting to promote mental well-being. However, pharmacists may not be utilizing their full range of skills and knowledge in promoting a national health priority. This study identified opportunities for increased pharmacist-led promotion of mental well-being, particularly given the emerging mental health impacts of the COVID-19 pandemic. The pandemic has highlighted the growing urgency for mental health-friendly health workers across the sector including the community pharmacy workforce to engage consumers about their mental well-being.
A cluster of cutaneous larva migrans in travellers returning from Zanzibar
Authors: Korzeniewski Krzysztof
Published: September 2021

Beaches of East Africa are the place to relax, but when contaminated with animal faeces, they are a likely source of health problems, such as cutaneous larva migrans. Cases of CLM were diagnosed in Polish travellers returned from holidays in Zanzibar.
A case of C-ANCA-positive systematic lupus erythematous and ANCA-associated vasculitis overlap syndrome superimposed by COVID-19: a fatal trio
Authors: Mashinchi Baharnaz , Aryannejad Armin , Namazi Mansoor , Moradi Soroush , Masoumi Zahra , Parsaei Amirhossein , Masoumi Maryam
Published: September 2021

Coronavirus disease 2019 (COVID-19) poses a substantial challenge for rheumatologists and rheumatologic patients. They are concerned about the reciprocal interaction between connective tissue diseases, such as systemic lupus erythematosus (SLE), and the virus. Here, we report a 21-year-old female SLE patient presented to the emergency department with gastrointestinal symptoms and kidney involvement evidence. Based on the pathology and laboratory assessments, she was suspected of C-antineutrophil cytoplasmic antibody (ANCA) positive SLE and ANCA-associated vasculitis overlap syndrome (SLE/AAV OS), and plasmapheresis was performed every other day due to this diagnosis alongside the high titer of C-ANCA. We also administered methylprednisolone [1 g/day, intravenous (IV)] for 3 days, followed by dexamethasone with the maintenance dosage (1 mg/kg/day, IV). Although the patient’s general condition improved the next days, her condition deteriorated suddenly on the 7th day of hospitalisation. She got intubated and went to the intensive care unit. Despite taking possible measures to manage the patient’s condition, she eventually passed away due to severe acute respiratory distress syndrome, triggered by COVID-19. The distinct role of C-ANCA in SLE/AAV vascular damage and activating neutrophil cytokine release accompanied by the impaired immune system while facing COVID-19 seems to lead to increased morbidity and mortality in such patients. This report is presented to bring into consideration the possible role of C-ANCA in the prognosis of COVID-19 in SLE/AAV OS patients.
Considering opportunistic parasitic infections in COVID-19 policies and recommendations
Authors: Mewara Abhishek , Sahni Neeru , Jain Amit
Published: September 2021

The COVID-19 pandemic has led to a significant increase in the immunosuppressed population worldwide due to the disease pathology and extensive use of corticosteroids. This has subsequently increased the risk of opportunistic parasitic infections such as Toxoplasma gondii, Strongyloides stercoralis and other parasites in these patients. The reactivation of such parasites may remain unnoticed due to overlapping symptoms, the difficulty of diagnosis and lack of guidelines for opportunistic parasitic infections in COVID-19 management. Therefore, recommendations for systematic screening of high-risk patients in endemic regions and active research and surveillance to estimate the impact of these infections are required in COVID-19 policy guidelines.
GENOME-WIDE ASSOCIATIONS OF AORTIC DISTENSIBILITY SUGGEST CAUSAL RELATIONSHIPS WITH AORTIC ANEURYSMS AND BRAIN WHITE MATTER HYPERINTENSITIES
Authors: Francis Catherine M , Futschik Matthias E , Huang Jian , Bai Wenjia , Sargurupremraj Muralidharan , Petretto Enrico , Ho Amanda SR , Amouyel Philippe , Engelter Stefan T , Ware James S , Debette Stephanie , Elliott Paul , Dehghan Abbas , Matthews Paul M
Published: September 2021

Aortic dimensions and distensibility are key risk factors for aortic aneurysms and dissections, as well as for other cardiovascular and cerebrovascular diseases. We tested genome-wide associations of ascending and descending aortic distensibility and area derived from cardiac magnetic resonance imaging (MRI) data of up to 32,590 Caucasian individuals in UK Biobank. We identified 102 loci (including 31 novel associations) tagging genes related to cardiovascular development, extracellular matrix production, smooth muscle cell contraction and heritable aortic diseases. Functional analyses highlighted four signalling pathways associated with aortic distensibility (TGF-β, IGF, VEGF and PDGF). We identified distinct sex-specific associations with aortic traits. We developed co-expression networks associated with aortic traits and applied phenome-wide Mendelian randomization (MR-PheWAS), generating evidence for a causal role for aortic distensibility in development of aortic aneurysms. Multivariable MR suggested a causal relationship between aortic distensibility and cerebral white matter hyperintensities, mechanistically linking aortic traits and brain small vessel disease.
Lack of benefit of temozolomide forMGMTmethylated patients with high vascular glioblastoma: a confirmatory study
Authors: Álvarez-Torres María del Mar , Fuster-García Elies , Balaña Carmen , Puig Josep , García-Gómez Juan Miguel
Published: September 2021

In this study we evaluated the benefit on survival of the combination ofMGMTmethylation and moderate vascularity in glioblastoma using a retrospective dataset of 123 patients from a multicenter cohort. MRI processing and calculation of relative cerebral blood volume (rCBV), used to define moderate- and high-vascular groups, were performed with the automatic ONCOhabitats method. We assessed the previously proposed rCBV threshold (10.7) and the new calculated ones (9.1 and 9.8) to analyze the association with survival for different populations according to vascularity andMGMTmethylation status. We found that patients included at the moderate-vascular group had longer survival whenMGMTis methylated (significant median survival difference of 174 days, p = 0.0129*). However, we did not find significant differences depending on theMGMTmethylation status for the high-vascular group (p = 0.9119). In addition, we investigated the combined correlation ofMGMTmethylation status and rCBV with the prognostic effect of the number of temozolomide cycles, and only significant results were found for the moderate-vascular group. In conclusion, there is a lack of benefit of temozolomide forMGMTmethylated patients with high vascular glioblastomas. Preliminary results suggest that patients with moderate vascularity and methylatedMGMTwould benefit more from prolonged adjuvant chemotherapy.

Simple Summary

Despite the complete treatment with surgery, chemotherapy and radiotherapy, patients with glioblastoma have a devasting prognosis. Although the role of extending temozolomide treatment has been explored, the results are inconclusive. Recent evidence suggested that tumor vascularity may be a modulating factor in combination withMGMTmethylation on the effect of temozolomide-based therapies, opening new possibilities for personalized treatments. Before proposing a prospective interventional clinical study, it is necessary to confirm the beneficial effect of the combined effect ofMGMTmethylation and moderate tumor vascularity. As well as the lack of benefit of temozolomide in patients with a highly vascular tumor.
Transcriptomics of acute DENV-specific CD8+ T cells does not support qualitative differences as drivers of disease severity
Authors: Grifoni Alba , Voic Hannah , Mateus Jose , Fung Kai Mei Yan , Wang Alice , Seumois Grégory , De Silva Aruna D. , Tennekon Rashika , Premawansa Sunil , Premawansa Gayani , Tippalgama Rashmi , Wijewickrama Ananda , Chawla Ashu , Greenbaum Jason , Peters Bjoern , Pandagrundan Vijayanand , Weiskopf Daniela , Sette Alessandro
Published: September 2021

While several lines of evidence suggest a protective role of T cells against disease associated with Dengue virus (DENV) infection, their potential contribution to immunopathology in the acute phase of DENV infection remains controversial, and it has been hypothesized that the more severe form of the disease (dengue hemorrhagic fever, DHF) is associated with altered T cell responses. To address this question, we determined the transcriptomic profiles of DENV-specific CD8+T cells in a cohort of 40 hospitalized DENV donors with either a milder form of the disease (dengue fever, DF) or a more severe disease form (dengue hemorrhagic fever, DHF). We found multiple transcriptomic signatures, one associated with DENV-specific Interferon-gamma responding cells, and two other gene signatures, one specifically associated with the acute phase, and the other with the early convalescent phase. Additionally, we found no differences in quantity and quality of DENV-specific CD8+T cells based on disease severity. Taken together with previous findings that did not detect altered DENV-specific CD4 T cell responses, the current analysis argues against alteration in DENV-specific T cell responses as being a correlate of immunopathology.
Microbiota development in early life mediates association between mode of delivery and vaccine responses
Authors: de Koff E.M. , van Baarle D. , van Houten M.A. , Reyman M. , Berbers G.A.M. , de Heij F. , Chu M.L.J.N. , Sanders E.A.M. , Bogaert D. , Fuentes S.
Published: September 2021

The gut microbiota in early life, when critical immune maturation takes place, may influence the immunogenicity of childhood vaccinations. We assessed the association between mode of delivery, gut microbiota development in the first year of life, and mucosal antigen-specific immunoglobulin G (IgG) responses against pneumococcal and meningococcal conjugate vaccination at ages 12 and 18 months, respectively, in a prospective birth cohort of 120 infants. Birth by natural delivery was associated with higher IgG responses against both vaccines, which for the anti-pneumococcal IgG response could be explained by a gut microbial community composition with high abundances of Bifidobacterium and Escherichia coli in the first weeks of life. High E. coli abundance in the same period was also associated with higher anti-meningococcal IgG responses. Our results suggest that associations between mode of delivery and antibody responses to routine childhood vaccines are mediated by gut microbiota development.
Physical activity specifically evokes release of cell-free DNA from granulocytes thereby affecting liquid biopsy
Authors: Neuberger Elmo W.I. , Sontag Stephanie , Brahmer Alexandra , Philippi Keito F.A. , Radsak Markus P. , Wagner Wolfgang , Simon Perikles
Published: September 2021

Cell-free DNA (cfDNA) methylation-based diagnostics is a promising approach in oncology and hematooncology. Exercise impacts immune homeostasis and leads to a rapid and marked increase of cfDNA levels in blood. Since the origin of cfDNA during exercise remains elusive, the implications for liquid biopsy are unknown. In this study, we identified the source of cfDNA in 10 healthy untrained individuals before, immediately after, and 30 min after exercise, and in 6 patients with myeloid neoplasms or acute leukemia under resting conditions. A pyrosequencing assay was used to analyze the methylation levels of four CpGs, representing DNA from granulocytes, lymphocytes, monocytes, and non-hematopoietic cells. After exercise, cfDNA was almost exclusively released from granulocytes, with cell type specific proportions increasing significantly from 54.1% to 90.2%. Exercise did not trigger the release of cfDNA from lymphocytes or other analyzed cell types, whereas a small amount of cfDNA was released from monocytes. Compared to healthy people, patients with hematological malignancies show significantly higher cfDNA levels at rest with 48.1 (19.1; 78) vs. 8.5 (8.2; 9.5) ng/ml, data expressed as median (25th; 75th percentiles), and considerably higher levels of lymphocyte specific hypomethylated cg17587997 (P<.001). Hence, exercise-induced cfDNA elevations can compromise diagnostic accuracy.

Key Points

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cfDNA is a robust sample source for targeted bisulfite sequencing, enabling reliable mapping of the source cells.

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cfDNA methylation signatures differ between healthy people and patients with hematological malignancies.

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During intense exercise, cfDNA is almost exclusively derived from granulocytes, which can affect results of liquid biopsy.
DNA methylation profiling of immune cells from tuberculosis-exposed individuals overlaps with BCG-induced epigenetic changes and correlates with the emergence of anti-mycobacterial ‘corralling cells’
Authors: Pehrson Isabelle , Braian Clara , Karlsson Lovisa , Idh Nina , Danielsson Eva Kristin , Andersson Blanka , Paues Jakob , Das Jyotirmoy , Lerm Maria
Published: September 2021

The mechanism of protection of the only approved tuberculosis (TB) vaccine, Bacillus Calmette Guérin (BCG) is poorly understood. In recent years, epigenetic modifications induced by BCG have been demonstrated to reflect a state of trained immunity. The concept of trained immunity is now explored as a potential prevention strategy for a variety of infections. Studies on human TB immunity are dominated by those using peripheral blood as surrogate markers for immunity. Here, we instead studied the lung compartment by obtaining induced sputum from subjects included in a TB contact tracing. CD3- and HLA-DR-positive cells were isolated from the collected sputum and DNA methylome analyses performed. Unsupervised cluster analysis revealed that DNA methylomes of cells from TB-exposed individuals and controls appeared as separate clusters, and the numerous genes that were differentially methylated were functionally connected. The enriched pathways were strongly correlated to previously reported epigenetic changes and trained immunity in immune cells exposed to the BCG vaccine in human and animal studies. We further demonstrated that similar pathways were epigenetically modified in human macrophages trained with BCG in vitro. Finally, we found evidence of an M. tuberculosis-triggered emergence of a non-macrophage cell population from BCG-trained macrophage cultures. These cells did not phagocytose M. tuberculosis, but ‘corralled’ the bacteria into focal points, resulting in limitation of bacterial growth. Altogether, our study demonstrates that similar epigenetic changes are induced by M. tuberculosis and BCG and suggests that the modifications promote transformation of macrophages (or an unknown progenitor) to establish a yet undescribed cellular defense mechanism which we term ‘corralling’, based on the metaphorical resemblance to sheepdog herding.
Investigating Presence of Ethnoracial Bias in Clinical Data using Machine Learning
Authors: Velichkovska Bojana , Gjoreski Hristijan , Denkovski Daniel , Kalendar Marija , Celi Leo Anthnoy , Osmani Venet
Published: September 2021

An important target for machine learning research is obtaining unbiased results, which require addressing bias that might be present in the data as well as the methodology. This is of utmost importance in medical applications of machine learning, where trained models should be unbiased so as to result in systems that are widely applicable, reliable and fair. Since bias can sometimes be introduced through the data itself, in this paper we investigate the presence of ethnoracial bias in patients’ clinical data. We focus primarily on vital signs and demographic information and classify patient ethnoraces in subsets of two from the three ethnoracial groups (African Americans, Caucasians, and Hispanics). Our results show that ethnorace can be identified in two out of three patients, setting the initial base for further investigation of the complex issue of ehtnoracial bias.
Severe COVID-19 is characterised by inflammation and immature myeloid cells early in disease progression
Authors: Townsend Liam , Dyer Adam H , Naughton Aifric , Imangaliyev Sultan , Dunne Jean , Kiersey Rachel , Holden Dean , Mooney Aoife , Leavy Deirdre , Ridge Katie , Sugrue Jamie , Aldoseri Mubarak , Kelliher Jo Hannah , Hennessy Martina , Byrne Declan , Browne Paul , Bacon Christopher L , Doyle Catriona , O’Riordan Ruth , McLaughlin Anne-Marie , Bannan Ciaran , Martin-Loeches Ignacio , White Arthur , McLoughlin Rachel M , Bergin Colm , Bourke Nollaig M , O’Farrelly Cliona , Conlon Niall , Ní Cheallaigh Clíona
Published: September 2021

SARS-CoV-2 infection causes a wide spectrum of disease severity. Immune changes associated with severe disease include pro-inflammatory cytokine production and expansion of immature myeloid populations. The relative importance of the immunological changes in driving progression to severe disease remain poorly understood.

We aimed to identify and rank clinical and immunological features associated with progression to severe COVID-19. We sought to use tests available in an on-site diagnostic hospital laboratory to identify an immunological signature for severe disease development which could be detected prior to peak severity thereby allowing initiation of therapeutic interventions. We used univariate and multivariate analysis, including unbiased machine learning, to investigate the relationships between clinical and demographic characteristics, inflammatory markers, and leukocyte immunophenotypes with progression to severe disease in 108 patients and to rank these in importance. A combination of four features (elevated levels of interleukin-6 and C-reactive protein, coupled with reduced monocyte HLA-DR expression and reduced neutrophil CD10 expression), were strongly predictive of severe disease with an average prediction score of 0.925.

Highlights

Severe COVID-19 can be predicted by a combination of emergency myelopoiesis (CD10-neutrophils and HLA DR-monocytes) and inflammation (raised IL-6 and CRP)

These changes can be identified from tests carried out prior to peak illness severity in a diagnostic laboratory

This predictive model was derived from a cohort of patients with a wide range of ages, frailty and COVID-19 severity

Graphical Abstract
Consequences of coupled barriers to gene flow for the build-up of genomic differentiation
Authors: Kunerth Henry D. , Bogdanowicz Steven M. , Searle Jeremy B. , Harrison Richard G. , Coates Brad S. , Kozak Genevieve M. , Dopman Erik B.
Published: September 2021

Theory predicts that when different barriers to gene flow become coincident, their joint effects enhance reproductive isolation and genomic divergence beyond their individual effects, but empirical tests of this ‘coupling’ hypothesis are rare. Here, we analyze patterns of gene exchange among populations of European corn borer moths that vary in the number of acting barriers, allowing for comparisons of genomic variation when barrier traits or loci are in coincident or independent states. We find that divergence is mainly restricted to barrier loci when populations differ by a single barrier, whereas the coincidence of temporal and behavioral barriers is associated with divergence of two chromosomes harboring barrier loci. Furthermore, differentiation at temporal barrier loci increases in the presence of behavioral divergence and differentiation at behavioral barrier loci increases in the presence of temporal divergence. Our results demonstrate how the joint action of coincident barrier effects leads to levels of genomic differentiation that far exceed those of single barriers acting alone, consistent with theory arguing that coupling allows indirect selection to combine with direct selection and thereby lead to a stronger overall barrier to gene flow. Thus, the state of barriers – independent or coupled – strongly influences the accumulation of genomic differentiation.
Viral Phrenology
Authors: Wilson David , Roof Danielle
Published: September 2021

We introduce Viral Phrenology, a new scheme for understanding the genomic composition of spherical viruses base on the locations of their structural protrusions. We used icosahedral point arrays to classify 135 distinct viral capsids collected from over 600 capsids available in the VIPERdb. Using gauge points of point arrays, we found 149 unique structural protrusions. We then show how to use the locations of these protrusions to determine the genetic composition of the virus. We then show that ssDNA, dsDNA, dsRNA and ssRNA viruses use different arrangements for distributing their protrusions. We also found that Triangulation number is also partially dependent on the structural protrusions. This analysis begins to tie together Baltimore classification and Triangulation number using point arrays.
Multi-landmark alignment of genomic signals reveals conserved expression patterns across transcription start sites
Authors: Vilar Jose M. G. , Saiz Leonor
Published: September 2021

The prevalent one-dimensional alignment of genomic signals to a reference landmark is a cornerstone of current methods to study transcription and its DNA-dependent processes but it is prone to mask potential relations among multiple DNA elements. We developed a systematic approach to align genomic signals to multiple locations simultaneously by expanding the dimensionality of the genomic-coordinate space. We analyzed transcription in human and uncovered a complex dependence on the relative position of neighboring transcription start sites (TSSs) that is consistently conserved among cell types. The dependence ranges from enhancement to suppression of transcription depending on the relative distances to the TSSs, their intragenic position, and the transcriptional activity of the gene. Our results reveal a conserved hierarchy of alternative TSS usage within a previously unrecognized level of genomic organization and provide a general methodology to analyze complex functional relationships among multiple types of DNA elements.
ProtView: A versatile tool for in silico protease evaluation and selection in a proteomic and proteogenomic context
Authors: Puliasis Sophia S. , Lewandowska Dominika , Hemsley Piers , Zhang Runxuan
Published: September 2021

Tools have been created to generate in silico proteome digests with different protease enzymes and provide useful information for selecting optimal digest schemes for specific needs. This can save on time and resources and generate insights on the observable proteome. However, there remains a need for a tool that evaluates digest schemes beyond protein and amino acid coverages in the proteomic domain. Here, we present ProtView, a versatile in-silico protease/protease combination and digest evaluation workflow that maps in silico digested peptides to both protein and genome references, so that the potential observable sections of the proteome, transcriptome and genome can be identified. This supports the identification and quantification of the proteomic evidence of transcriptional, co-transcriptional, post-transcriptional and translational regulations. Benchmarking against biological data comparing multiple proteases shows that ProtView can correctly estimate the relative performances among the digest schemes. ProtView provides this information in a way that is easy to interpret, allowing for digest schemes to be evaluated before carrying out an analysis, in a broader context to optimize proteomic and proteogenomic experiments. ProtView is available at https://github.com/SSPuliasis/ProtView.
Modelling rheumatoid arthritis: A hybrid modelling framework to describe pannus formation in a small joint
Authors: Macfarlane Fiona R , Chaplain Mark AJ , Eftimie Raluca
Published: September 2021

Rheumatoid arthritis (RA) is a chronic inflammatory disorder that causes pain, swelling and stiffness in the joints, and negatively impacts the life of affected patients. The disease does not have a cure yet, as there are still many aspects of this complex disorder that are not fully understood. While mathematical models can shed light on some of these aspects, to date there are few such models that can be used to better understand the disease. As a first step in the mechanistic understanding of RA, in this study we introduce a new hybrid mathematical modelling framework that describes pannus formation in a small proximal interphalangeal (PIP) joint. We perform numerical simulations with this new model, to investigate the impact of different levels of immune cells (macrophages and fibroblasts) on the degradation of bone and cartilage. Since many model parameters are unknown and cannot be estimated due to a lack of experiments, we also perform a sensitivity analysis of model outputs to various model parameters (single parameters or combinations of parameters). Finally, we discuss how our model could be applied to investigate current treatments for RA, for example, methotrexate, TNF-inhibitors or tocilizumab, which can impact different model parameters.
Schema Playground: A tool for authoring, extending, and using metadata schemas to improve FAIRness of biomedical data
Authors: Cano Marco , Tsueng Ginger , Zhou Xinghua , Hughes Laura D. , Mullen Julia L. , Xin Jiwen , Su Andrew I. , Wu Chunlei
Published: September 2021

Background

Biomedical researchers are strongly encouraged to make their research outputs more Findable, Accessible, Interoperable, and Reusable (FAIR). While many biomedical research outputs are more readily accessible through open data efforts, finding relevant outputs remains a significant challenge. Schema.org is a metadata vocabulary standardization project that enables web content creators to make their content more FAIR. Leveraging schema.org could benefit biomedical research resource providers, but it can be challenging to apply schema.org standards to biomedical research outputs. We created an online browser-based tool that empowers researchers and repository developers to utilize schema.org or other biomedical schema projects.

Results

Our browser-based tool includes features which can help address many of the barriers towards schema.org-compliance such as: The ability to easily browse for relevant schema.org classes, the ability to extend and customize a class to be more suitable for biomedical research outputs, the ability to create data validation to ensure adherence of a research output to a customized class, and the ability to register a custom class to our schema registry enabling others to search and re-use it. We demonstrate the use of our tool with the creation of the Outbreak.info schema—a large multi-class schema for harmonizing various COVID-19 related resources.

Conclusions

We have created a browser-based tool to empower biomedical research resource providers to leverage schema.org classes to make their research outputs more FAIR.