bluuebunny/crossref_metadata_2025_split huggingface dataset:
A nanobody interaction with SARS-COV-2 Spike allows the versatile targeting of lentivirus vectors
Authors: Alfadhli Ayna , Bates Timothy A. , Barklis Robin Lid , Romanaggi CeAnn , Tafesse Fikadu G. , Barklis Eric 
Published: August 2024

ABSTRACT

While investigating methods to target gene delivery vectors to specific cell types, we examined the potential of using a nanobody against the SARS-CoV-2 Spike protein receptor-binding domain to direct lentivirus infection of Spike-expressing cells. Using four different approaches, we found that lentiviruses with surface-exposed nanobody domains selectively infect Spike-expressing cells. Targeting is dependent on the fusion function of the Spike protein, and conforms to a model in which nanobody binding to the Spike protein triggers the Spike fusion machinery. The nanobody–Spike interaction also is capable of directing cell–cell fusion and the selective infection of nanobody-expressing cells by Spike-pseudotyped lentivirus vectors. Significantly, cells infected with SARS-CoV-2 are efficiently and selectively infected by lentivirus vectors pseudotyped with a chimeric nanobody protein. Our results suggest that cells infected by any virus that forms syncytia may be targeted for gene delivery by using an appropriate nanobody or virus receptor mimic. Vectors modified in this fashion may prove useful in the delivery of immunomodulators to infected foci to mitigate the effects of viral infections.

IMPORTANCE
We have discovered that lentiviruses decorated on their surfaces with a nanobody against the SARS-CoV-2 Spike protein selectively infect Spike-expressing cells. Infection is dependent on the specificity of the nanobody and the fusion function of the Spike protein and conforms to a reverse fusion model, in which nanobody binding to Spike triggers the Spike fusion machinery. The nanobody–Spike interaction also can drive cell–cell fusion and infection of nanobody-expressing cells with viruses carrying the Spike protein. Importantly, cells infected with SARS-CoV-2 are selectively infected with nanobody-decorated lentiviruses. These results suggest that cells infected by any virus that expresses an active receptor-binding fusion protein may be targeted by vectors for delivery of cargoes to mitigate infections.
Infiltrating monocytes drive cardiac dysfunction in a cardiomyocyte-restricted mouse model of SARS-CoV-2 infection
Authors: Dmytrenko Oleksandr , Das Shibali , Kovacs Attila , Cicka Markus , Liu Meizi , Scheaffer Suzanne M. , Bredemeyer Andrea , Mack Matthias , Diamond Michael S. , Lavine Kory J. 
Published: August 2024

ABSTRACT

Cardiovascular manifestations of coronavirus disease 2019 (COVID-19) include myocardial injury, heart failure, and myocarditis and are associated with long-term disability and mortality. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and antigens are found in the myocardium of COVID-19 patients, and human cardiomyocytes are susceptible to infection in cell or organoid cultures. While these observations raise the possibility that cardiomyocyte infection may contribute to the cardiac sequelae of COVID-19, a causal relationship between cardiomyocyte infection and myocardial dysfunction and pathology has not been established. Here, we generated a mouse model of cardiomyocyte-restricted infection by selectively expressing human angiotensin-converting enzyme 2 (hACE2), the SARS-CoV-2 receptor, in cardiomyocytes. Inoculation of
Myh6-Cre Rosa26
loxP-STOP-loxP-hACE2
mice with an ancestral, non-mouse-adapted strain of SARS-CoV-2 resulted in viral replication within the heart, accumulation of macrophages, and moderate left ventricular (LV) systolic dysfunction. Cardiac pathology in this model was transient and resolved with viral clearance. Blockade of monocyte trafficking reduced macrophage accumulation, suppressed the development of LV systolic dysfunction, and promoted viral clearance in the heart. These findings establish a mouse model of SARS-CoV-2 cardiomyocyte infection that recapitulates features of cardiac dysfunctions of COVID-19 and suggests that both viral replication and resultant innate immune responses contribute to cardiac pathology.

IMPORTANCE
Heart involvement after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection occurs in multiple ways and is associated with worse outcomes in coronavirus disease 2019 (COVID-19) patients. It remains unclear if cardiac disease is driven by primary infection of the heart or immune response to the virus. SARS-CoV-2 is capable of entering contractile cells of the heart in a culture dish. However, it remains unclear how such infection affects the function of the heart in the body. Here, we designed a mouse in which only heart muscle cells can be infected with a SARS-CoV-2 strain to study cardiac infection in isolation from other organ systems. In our model, infected mice show viral infection, worse function, and accumulation of immune cells in the heart. A subset of immune cells facilitates such worsening heart function. As this model shows features similar to those observed in patients, it may be useful for understanding the heart disease that occurs as a part of COVID-19.
The role of lipids in regulating macrophage antifungal immunity
Authors: Rouvray Sophie , Drummond Rebecca A. 
Published: August 2024

ABSTRACT

Macrophages are critical components of the antifungal immune response. Disturbance in the number or function of these innate immune cells can significantly increase susceptibility to invasive fungal infections. Pathogenic fungi cause billions of infections every year and have an unmet clinical need, with many infections associated with unacceptably high mortality rates that primarily affect vulnerable patients with underlying immune defects. Lipid metabolism has been increasingly appreciated to significantly influence macrophage function, particularly of macrophages residing in lipid-rich organs, such as the brain, or macrophages specialized at clearing dead cells including alveolar macrophages in the lungs. In this review, we provide an overview of macrophage lipid metabolism, and discuss how lipid recycling and dysregulation affect key macrophage functions relevant for antifungal immunity including phagocytosis, functional polarization, and inflammasome activation. We focus on the fungal pathogen
Cryptococcus neoformans
, as this is the most common cause of death from fungal infection in humans and because several lines of evidence have already linked lipid metabolism in the regulation of
C. neoformans
and macrophage interactions.
Host-associated microbes mitigate the negative impacts of aquatic pollution
Authors: Diner Rachel E. , Allard Sarah M. , Gilbert Jack A. 
Published: August 2024

ABSTRACT

Pollution can negatively impact aquatic ecosystems, aquaculture operations, and recreational water quality. Many aquatic microbes can sequester or degrade pollutants and have been utilized for bioremediation. While planktonic and benthic microbes are well-studied, host-associated microbes likely play an important role in mitigating the negative impacts of aquatic pollution and represent an unrealized source of microbial potential. For example, aquatic organisms that thrive in highly polluted environments or concentrate pollutants may have microbiomes adapted to these selective pressures. Understanding microbe–pollutant interactions in sensitive and valuable species could help protect human well-being and improve ecosystem resilience. Investigating these interactions using appropriate experimental systems and overcoming methodological challenges will present novel opportunities to protect and improve aquatic systems. In this perspective, we review examples of how microbes could mitigate negative impacts of aquatic pollution, outline target study systems, discuss challenges of advancing this field, and outline implications in the face of global changes.
Influence of stage and age on survival of patients with vulvar cancer in Germany: a retrospective study
Authors: Mack Luisa Carlotta , Hagemeier Anna , Forner Dirk Michael 
Published: August 2024

ObjectivesTo evaluate the 5-year survival rate of patients with vulvar cancer, taking into account prognostic factors (International Federation of Gynecology and Obstetrics (FIGO) stage and age) and the influence of lymph node involvement and tumour size as well as the correlation between FIGO stage and age at onset.DesignRetrospective cohort study.SettingGerman cancer registries.ParticipantsThe study included 17 017 patients diagnosed with vulvar cancer between 2004 and 2014 with follow-up until 2017. Exclusion criteria were incomplete documentation, age<18 years and death certificate only.Primary and secondary outcome measuresThe primary outcome was overall and relative survival according to FIGO stage and age and the distribution of FIGO stages by age group. Secondary outcomes analysed were tumour size and lymph node status as risk factors for mortality.ResultsThe median age at diagnosis was 70 years. The overall 5-year survival rate was 69.5% (95% CI: 68.7% to 70.3%). The 5-year relative survival rates ranged from 91.9% (95% CI: 90.5% to 93.3%) to 21.3% (95% CI: 15.6% to 27.0%) for FIGO I to FIGO IVB and from 89.2% (95% CI: 87.6% to 90.8%) to 68.0% (95% CI: 65.3% to 70.7%) for age groups <55 to >75 years. Younger patients were significantly more often diagnosed with a low FIGO stage (p<0.001). Lymph node status and tumour size were independent factors influencing survival (HR: 1.79 (95% CI: 1.73 to 1.84; p<0.001) and 1.88 (95% CI: 1.80 to 1.96); p<0.001, respectively). The median follow-up time was 57 months.ConclusionNotably, the steepest decline in survival occurred within the first 3 years after diagnosis. Patients with the highest FIGO stages and those in the oldest age group had the worst survival rates. Furthermore, patients in the oldest age group were more likely to be diagnosed at higher stages. Lymph node status and tumour size were additional independent prognostic factors for mortality.
High-exchange ULTrafiltration to enhance recovery after paediatric cardiac surgery (ULTRA): study protocol for a Canadian double-blinded randomised controlled trial
Authors: Bierer Joel , Stanzel Roger , Henderson Mark , Krmpotic Kristina , Andreou Pantelis , Marshall Jean S. , Sapp John , Horne David 
Published: August 2024

IntroductionSurgical repair is the standard of care for most infants and children with congenital heart disease. Cardiopulmonary bypass (CPB) is required to facilitate these operations but elicits a systemic inflammatory response, leading to postoperative organ dysfunction, morbidity and prolonged recovery after the surgery. Subzero-balance ultrafiltration (SBUF) has been shown to extract proinflammatory cytokines continuously throughout the CPB exposure. We hypothesize that a high-exchange SBUF (H-SBUF) will have a clinically relevant anti-inflammatory effect compared with a low-exchange SBUF (L-SBUF).Methods and analysisThe ULTrafiltration to enhance Recovery After paediatric cardiac surgery (ULTRA) trial is a randomised, double-blind, parallel-group randomised trial conducted in a single paediatric cardiac surgery centre. Ninety-six patients less than 15 kg undergoing cardiac surgery with CPB will be randomly assigned to H-SBUF during CPB or L-SBUF during CPB in a 1:1 ratio with stratification by The Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery (STAT) score 1 and STAT score 2–5. The primary outcome is peak postoperative vasoactive-ventilation-renal score. Time series and peak values of vasoactive-ventilation renal score, vasoactive-inotrope score, ventilation index and oxygenation index will be collected. Secondary clinical outcomes include acute kidney injury, ventilator-free days, inotrope-free days, low cardiac output syndrome, mechanical circulatory support, intensive care unit length of stay and operative mortality. Secondary biomarker data include cytokine, chemokine and complement factor concentrations at baseline before CPB, at the end of CPB exposure and 24 hours following CPB. Analyses will be conducted on an intention-to-treat principle.Ethics and disseminationThe study has ethics approval (#1024932 dated August 31, 2021) and enrolment commenced in September 2021. The primary manuscript and any subsequent analyses will be submitted for peer-reviewed publication.Trial registration numberNCT04920643.
Drug providers’ perspectives on antibiotic misuse practices in eastern Ethiopia: a qualitative study
Authors: Edessa Dumessa , Kumsa Fekede Asefa , Dinsa Girmaye , Oljira Lemessa 
Published: August 2024

ObjectiveAntibiotic misuse includes using them to treat colds and influenza, obtaining them without a prescription, not finishing the prescribed course and sharing them with others. Although drug providers are well positioned to advise clients on proper stewardship practices, antibiotic misuse continues to rise in Ethiopia. It necessitates an understanding of why drug providers failed to limit such risky behaviours. This study aimed to explore drug providers’ perspectives on antibiotic misuse practices in eastern Ethiopia.SettingThe study was conducted in rural Haramaya district and Harar town, eastern Ethiopia.Design and participantsAn exploratory qualitative study was undertaken between March and June 2023, among the 15 drug providers. In-depth interviews were conducted using pilot-tested, semistructured questions. The interviews were transcribed verbatim, translated into English and analysed thematically. The analyses considered the entire dataset and field notes.ResultsThe study identified self-medication pressures, non-prescribed dispensing motives, insufficient regulatory functions and a lack of specific antibiotic use policy as the key contributors to antibiotic misuse. We found previous usage experience, a desire to avoid extra costs and a lack of essential diagnostics and antibiotics in public institutions as the key drivers of non-prescribed antibiotic access from private drug suppliers. Non-prescribed antibiotic dispensing in pharmacies was driven by client satisfaction, financial gain, business survival and market competition from informal sellers. Antibiotic misuse in the setting has also been linked to traditional and ineffective dispensing audits, inadequate regulatory oversights and policy gaps.ConclusionThis study highlights profits and oversimplified access to antibiotics as the main motivations for their misuse. It also identifies the traditional antibiotic dispensing audit as an inefficient regulatory operation. Hence, enforcing specific antibiotic usage policy guidance that entails an automated practice audit, a responsible office and insurance coverage for persons with financial limitations can help optimise antibiotic use while reducing resistance consequences.
Patient pathways for four major chronic respiratory diseases in England between 2008 and 2021
Authors: Ioannides Anne E , Morgan Ann D , Quint Jennifer K 
Published: August 2024

BackgroundNot all chronic diseases have clear pathways and time targets for diagnosis. We explored pathways and timings for four major chronic respiratory diseases in England.MethodsUsing deidentified electronic healthcare records from Clinical Practice Research Datalink Aurum linked to Hospital Episode Statistics, we derived cohorts of patients diagnosed with asthma, chronic obstructive pulmonary disease (COPD), ILD or bronchiectasis at three time periods (2008/2009, 2018/2019 and 2020/2021). We followed people 2 years before and 2 years after diagnosis, calculating the proportion of people who presented with symptoms, underwent diagnostic tests, were treated and consulted healthcare (primary or secondary) and calculated time intervals between events. We repeated analyses by socioeconomic status and geographical region.ResultsWe descriptively studied patient pathways for 429 619 individuals across all time frames and diseases. Most people (>87%) had first evidence of diagnosis in primary care. The proportion of people reporting symptoms prior to diagnosis was similar for asthma, COPD and ILD (41.0%–57.9%) and higher in bronchiectasis (67.9%–71.8%). The proportion undergoing diagnostic tests was high for COPD and bronchiectasis (77.6%–89.2%) and lower for asthma (14%–32.7%) and ILD (2.6%–3.3%). The proportion of people undergoing diagnostic tests decreased in 2020/2021 for all diseases, mostly COPD. Time (months) (median (IQR)) between symptoms and diagnosis, averaged over three time periods, was lowest in asthma (~7.5 (1.3–16.0)), followed by COPD (~8.6 (1.8–17.2)), ILD (~10.1 (3.6–18.0)) and bronchiectasis (~13.5 (5.9–19.8)). Time from symptoms to diagnosis increased by ~2 months in asthma and COPD over the three time periods. Although most patients were symptomatically treated prior to diagnosis, time between diagnosis and postdiagnostic treatment was around 4 months for ILD, 3 months for bronchiectasis and instantaneous for asthma and COPD. Socioeconomic status and regional trends showed little disparity.ConclusionCurrent pathways demonstrate missed opportunities to diagnose and manage disease and to improve disease coding.
Physical activity modification over time according to socioeconomic position: results from the EPIC-Italy cohort study
Authors: Franco Matteo , Facchini Luigi , Sacerdote Carlotta , Masala Giovanna , Manfredi Luca , Dansero Lucia , Bendinelli Benedetta , Assedi Melania , Vitale Valentina , Pala Valeria , Caini Saverio , Ricceri Fulvio 
Published: August 2024

ObjectivesOur study aimed to investigate how physical activity (PA) changes over an 11-year follow-up among adults from different socioeconomic positions (SEP) near retirement age. Moreover, an analysis of different PA types is considered.MethodsWe used data from the EPIC-Italy cohort. We evaluated PA using the Cambridge Physical Activity Index (CPAI) and the metabolic equivalent of tasks (MET) per hour of activity for recreational PA and household PA. Educational level was assessed using the Relative Index of Inequality (RII). Occupational classes were classified according to LIFEPATH Consortium knowledge. Logistic regression was used to analyse PA among SEP and changes during follow-up. Analyses were also conducted separately for sex.ResultsThe higher educated were more prevalent in the higher quartile of recreational PA than the lower educated both at baseline and follow-up (37% vs 28% and 37% vs 27%, respectively). At the baseline, the lower educated had a higher risk of being physically inactive than the higher educated based on recreational PA (overall OR: 1.50, 95% CI 1.40 to 1.60). Manual workers did not show a higher risk of less PA than professionals/managers (overall OR: 1.03, 95% CI 0.91 to 1.16).At follow-up, the lower educated and manual workers showed a higher risk of being physically inactive (lower educated OR: 1.46, 95% CI 1.37 to 1.56; manual worker OR: 1.33, 95% CI 1.18 to 1.50). The analyses of changes in PA showed that those who were less educated or manual workers had a higher risk of worsening their PA during the follow-up period, particularly women in recreational PA and men in CPAI measurement.ConclusionIndividuals who had a disadvantaged SEP showed a higher risk of performing less PA over time.
Prevalence of electrocardiographic markers associated with myocardial fibrosis in masters athletes: a cohort study
Authors: Kramer Tilmann , Ventovuori Ville , Heinonen Ari , Parkkari Jari , Korhonen Marko T , Rovio Anja , Hoenemann Jan-Niklas , Möstl Stefan , Sies Wolfram , Kaiser-Stolz Claudia , Chilibeck Philip , Tanaka Hirofumi , Kramer Mira , Rittweger Joern , Hautala Arto J 
Published: August 2024

ObjectivesMyocardial fibrosis (MF) is associated with an increased predisposition to adverse cardiac events. The accumulation of high-volume and high-intensity exercise over an extended duration potentially increases the risk of MF. Specific electrocardiographic markers have been correlated with the presence of MF. This study assessed the prevalence of MF-related electrocardiographic markers in a Track and Field Master Athletics Cohort (TaFMAC).MethodsTwelve-lead resting electrocardiograms (ECGs) were conducted on 155 athletes (90 males and 65 females) participating in the World Masters Athletics 2022. The ECG markers associated with MF, including pathological Q waves, inverted T waves, fragmented QRS complex, and prolonged QRS complex, were compared among different athletic specialities (endurance athletes n=51, sprinters n=69 and strength and power n=35).ResultsOverall, 71 instances of MF-related markers were identified from 155 ECG recordings (46%). Fragmented QRS emerged as the most common marker, with a prevalence of 29% in endurance and strength and power athletes, and 35% in sprinters. No significant group differences were observed in the prevalence of MF markers, whether analysed collectively (p=0.467) or individually (pathological Q waves p=0.367, inverted T waves p=0.309, fragmented QRS complex p=0.747 and prolonged QRS complex p=0.132).ConclusionsThe prevalence of MF markers, as determined by resting ECG, was evident in nearly half of masters athletes, irrespective of sex and sporting specialisation. These findings suggest resting ECG as a promising non-invasive method for the early identification of MF in athlete’s hearts.
Socioeconomic status across the early life course predicts gene expression signatures of disease and senescence
Authors: Potente Cecilia , Bodelet Julien , Himeri Hira , Cole Steve , Harris Kathleen , Shanahan Michael 
Published: August 2024

BackgroundSocioeconomic status (SES) is associated with many chronic diseases, indicators of senescence and mortality. However, the changing salience of SES in the prediction of adult health is not well understood. Using mRNA-seq abundance data from wave V of the National Longitudinal Study of Adolescent to Adult Health (Add Health), we examine the extent to which SES across the early life course is related to gene expression-based signatures for chronic diseases, senescence and inflammation in the late 30s.MethodsWe use Bayesian methods to identify the most likely model of life course epidemiology (critical, sensitive and accumulation models) that characterises the changing importance of parental SES and SES during young (ages 27–30) and mid-adulthood (ages 36–39) in the prediction of the signatures.ResultsFor most signatures, SES is an important predictor in all periods, although parental SES or SES during young adulthood are often the most predictive. For three signatures (components of diabetes, inflammation and ageing), critical period models involving the exclusive salience of SES in young adulthood (for diabetes) or parental SES (for inflammation and ageing) are most probable. The observed associations are likely mediated by body mass index.ConclusionModels of life course patterns of SES may inform efforts to identify age-specific mechanisms by which SES is associated with health at different points in life and they also suggest an enhanced approach to prediction models that recognise the changing salience of risk factors.