The repeated COVID-19 outbreaks, despite global vaccination, highlights the need for booster doses. Here, we present the outcomes, up until day 90 post vaccination, of a randomized, double-blind, placebo-controlled phase 1 clinical trial of the mRNA-based vaccine candidate; COReNAPCIN(R), as a booster dose in adults aged 18-50 who had previously received three doses of inactivated vaccines. In the study, 30 participants randomly (2:2:1) received 25 g, or 50 g of COReNAPCIN(R), or placebo. The results indicated that COReNAPCIN(R) was well tolerated in vaccinated individuals in both groups with no life-threatening or other serious adverse events. The most noticeable solicited adverse events were pain at the site of injection, fatigue and myalgia. Regarding the immunogenicity, given the seroprevalence of SARS-CoV-2 antibodies due to the vaccination history for all, and previous SARS-CoV-2 infection for some participants, the recipients of COReNAPCIN(R), two weeks post vaccination, showed significant fold increases in the level of anti-RBD (6.6 and 8.1 folds) or anti-spike (11.5 and 21.7 folds), and potent neutralizing antibodies (10.2 and 8.4 folds) in 25 and 50 g groups, respectively, while no meaningful changes were observed in the placebo group. Additionally, the significant increase in the spike-specific IFN-{Upsilon} T-cell response upon vaccination, underscores the activation of cellular immunity. Altogether, the favorable safety, tolerability, and immunogenicity profile of COReNAPCIN(R) support its further clinical development. Trial registration number: IRCT20230131057293N1 | Make paid
There is a growing interest in incorporating white matter fibre-specific microstructural properties into structural connectomes to obtain a more quantitative assessment of brain connectivity. In a developmental sample aged 8-18 years, we studied age-related patterns of microstructure-informed network properties locally and globally. First, we computed the diffusion-weighted signal fraction associated with each tractography-reconstructed streamline. Then, we generated microstructure-informed connectomes from diffusion MRI data using the convex optimization modelling for microstructure-informed tractography (COMMIT) approach. Finally, we estimated network characteristics in eight functionally defined networks (visual, somatomotor, dorsal attention, ventral attention, limbic, frontoparietal, default mode and subcortical networks). Our findings reveal that throughout child and adolescent development, global efficiency increases in the visual, somatomotor, and default mode networks, and mean strength increases in the somatomotor and visual networks. Nodes belonging to the dorsal and ventral visual pathways demonstrate the largest age-dependence in local efficiency, supporting previous evidence of protracted maturation of dorsal and ventral visual pathways. Our results provide compelling evidence that there is a prolonged development of visual association cortices. | Make paid
Sle1 and Faslpr are two lupus susceptibility loci that lead to manifestations of systemic lupus erythematosus. To evaluate dosage effects of FASlpr in determining cellular and serological phenotypes associated with lupus, we developed a new C57BL/6 (B6) congenic lupus strain, B6.Sle1/Sle1.Faslpr/+ (sle1homo.lprhet) and compared it with B6.Faslpr/lpr (lprhomo), B6.Sle1/Sle1 (sle1homo), and B6.Sle1/Sle1.Faslpr/lpr (sle1homo.lprhomo) strains. Whereas Sle1homo.lprhomo mice exhibited profound lymphoproliferation and early mortality, sle1homo.lprhet mice had a lifespan comparable to B6 mice, with no evidence of splenomegaly or lymphadenopathy. Compared to B6 monogenic lupus strains, sle1homo.lprhet mice exhibited significantly elevated serum anti-dsDNA antibodies and increased proteinuria. Additionally, Sle1homo.lprhet T cells had an increased propensity to differentiate into Th1 cells. Gene dose effects of Faslpr were noted in upregulating serum IL-1, IL-2, and IL-27. Taken together, sle1homo.lprhet mice emerge as a more faithful model of human SLE, ideal for genetic studies, autoantibody repertoire investigation, and for exploring Th1 effector cell skewing. | Make paid
The corpus callosum is composed of several subregions, distinct in cellular and functional organization. This organization scheme may render these subregions differentially vulnerable to the aging process. Callosal integrity may be further compromised by vascular risk factors, which negatively influence white matter health. Here, we test the retrogenesis, or first in - last out, framework of aging, hypothesizing an anterior-to-posterior gradient of vulnerability to aging and effects of vascular health on that gradient. In 174 healthy adults across the adult lifespan (mean age=53.56 +- 18.90 , range=20-94 years old, 58.62% women), measures of pulse pressure and diffusion-weighted imaging was conducted. An ROI-based deterministic tractography approach was utilized to extract from each of five callosal subregion tracts, mean fractional anisotropy (FA), radial diffusivity (RD) and axial diffusivity (AD), serving as estimates of microstructural integrity. Pulse pressure is a proxy of arterial stiffness. General linear models tested effects of age, hypertension, and pulse pressure on these metrics. No significant effects of hypertensive diagnosis on callosal microstructure were observed, rather, significant main effects of age and age x pulse pressure interactions were observed, whereby older age and elevated pulse pressure were associated with poorer FA, AD, and RD. Age effects revealed non-linear components and occurred along an anterior-posterior gradient of severity in the callosum. This gradient disappeared when pulse pressure was considered. These results indicate that age-related deterioration across the callosum is regionally variable, and that arterial stiffness alters this aging pattern. | Make paid
Phospholipase C-gamma 2 (PLC{gamma}2) is highly expressed in hematopoietic and immune cells, where it is a key signalling node enabling diverse cellular functions. Within the periphery, gain-of-function (GOF) PLC{gamma}2 variants, such as the strongly hypermorphic S707Y, cause severe immune dysregulation. The milder hypermorphic mutation PLC{gamma}2 P522R increases longevity and confers protection in central nervous system (CNS) neurodegenerative disorders, implicating PLC{gamma}2 as a novel therapeutic target for treating these CNS indications. Currently, nothing is known about what consequences strong PLC{gamma}2 GOF has on CNS functionality, and more precisely on the specific biological functions of microglia. Using the PLC{gamma}2 S707Y variant as a model of chronic activation we investigated the functional consequences of strong PLC{gamma}2 GOF on human microglia. PLC{gamma}2 S707Y expressing human inducible pluripotent stem cells (hiPSC)-derived microglia exhibited hypermorphic enzymatic activity under both basal and stimulated conditions, compared to PLC{gamma}2 wild type. Despite the increase in PLC{gamma}2 enzymatic activity, the PLC{gamma}2 S707Y hiPSC-derived microglia display diminished functionality for key microglial processes including phagocytosis and cytokine secretion upon inflammatory challenge. RNA sequencing revealed a downregulation of genes related to innate immunity and response, providing molecular support for the phenotype observed. Our data suggests that chronic activation of PLC{gamma}2 elicits a detrimental phenotype that is contributing to unfavourable CNS functions, and informs on the therapeutic window for targeting PLC{gamma}2 in the CNS. Drug candidates targeting PLC{gamma}2 will need to precisely mimic the effects of the PLC{gamma}2 P522R variant on microglial function, but not those of the PLC{gamma}2 S707Y variant. | Make paid
Respirometry provides a direct measure of an organism s respiration, which is a significant component of its metabolic rate. Amongst ants, variations in lifespan between different social castes (such as workers and queens) can be substantial, varying according to the species. As metabolic rate is higher in short-living species, we aimed to establish how metabolic rate and longevity may have coevolved within ant s casts. As a first methodological step, we validate here the use of a Clark electrode initially design for measuring mitochondrial respiration control pathways, for flow-through oxygen consumption in ant, by comparison with stop flow oxygen consumption and carbon dioxide production utilizing the indirect calorimetry methodology. The global aim is to provide a reliable methodology to conduct accurate comparisons of metabolic rates within and among ant species. As expected, using Clarck electrode entails high time resolution and revealed that queens and workers exhibited discontinuous respiration, with episodes of apnea up to 20 minutes. | Make paid
It was recently shown that in anteriolateral entorhinal cortex layer II neurons (ECLII neurons) in McGill-R-Thy1-APP homozygous transgenic rats (a model commonly used to study Alzheimer's disease (AD)), the glycoprotein reelin and intracellular amyloid-{beta} (A{beta}) engage in a direct protein-protein interaction. Numerous studies of the human brain supported by experimental results from rodent and cell models point to a role for intracellular oligomeric A{beta} in the onset of AD. If reelin functions as a sink for intracellular A{beta} and if the binding to reelin makes A{beta} physiologically inert, it implies that reelin may prevent the neuron from being exposed to the detrimental effects typically associated with oligomeric A{beta}. Considering that reelin expression is extraordinarily high in the major subset of ECLII neurons compared to most other cortical neurons, such a protective role appears very difficult to reconcile with the fact that ECLII is clearly a major cradle for the onset of AD in humans. Here we show that this conundrum may be resolved if ECLII neurons have a much higher maximum production capacity of A{beta} than neurons expressing low levels of reelin. We provide a rationale for why this difference has evolved, and argue that the higher maximum production capacity of A{beta} in ECLII neurons may in a senescent A{beta}-inducing physiology predispose these neurons to initiate AD development. | Make paid
Coarctation of the aorta (CoA) is a common congenital cardiovascular lesion that typically presents as a localized narrowing of the proximal descending thoracic aorta just distal to the left subclavian artery. While improvements in surgical and catheter-based techniques have increased short-term survival, there is a high long-term risk of hypertension after CoA correction and a reduced average lifespan despite treatment. Computational models can be used to estimate ventricular and arterial remodeling, potentially serving as key tools in developing a mechanistic understanding of the interplay between pre-correction hemodynamics, post-correction recovery, and long-term hypertension risk. In this study, we developed a lumped parameter model of the heart and circulation to simulate aortic coarctation. We then used the model to estimate changes in ventricular thickness and ascending aortic compliance from imaging and catheterization data collected in rabbits with untreated and corrected CoA that used the current putative clinical treatment threshold (>= 20 mmHg). Model outputs were compared to reported stroke volume, ejection fraction, systolic and diastolic ascending aortic pressures, peak ascending aortic flow, mean and peak aortic blood pressure gradients, and upper-to-lower body flow split, with all results falling within one standard deviation of the data for control, untreated CoA, and corrected CoA groups. In the untreated CoA and corrected simulations, a decrease in ascending aortic compliance was necessary to match reported hemodynamics, suggesting the rabbits exposed to CoA >= 20 mmHg underwent vascular remodeling that persisted after repair. | Make paid
Background Numerous studies have shown that elderly women with endometrial cancer (EC) have a higher risk of recurrence and cancer-related death. It is, however, unclear whether aging is a causal prognostic factor, or whether other risk factors become increasingly common with age. We address to this with a unique multi-method study design using state of the art statistical and causal inference techniques on datasets of three large randomised trials. Methods Data of 1801 women participating in the randomised PORTEC-1, -2 and -3 trials were used for statistical analyses and causal inference. The cohort included 714 patients with intermediate-risk EC, 427 high-intermediate risk EC patients and 660 high-risk EC patients. Associations of age with clinicopathological and molecular features were analysed using non-parametric tests. Multivariable competing risk analyses were performed to determine the independent prognostic value of age. To analyse age as a causal prognostic variable a deep learning Causal Inference model called AutoCI was used. Findings Median follow-up was 12.3 years for PORTEC-1, 10.5 years for PORTEC-2 and 6.1 years for PORTEC-3. Both overall recurrence and EC-specific deaths significantly increased with age. Moreover, elderly women had a higher incidence of deep myometrial invasion, serous tumour histology and p53abn tumours. Age was an independent risk factor for both overall recurrence (HR 1.02 per year, 95%CI 1.01-1.04; p=0.0012) and EC-specific death (HR 1.03 per year, 95%CI 1.01-1.05; p=0.0012), and was identified as a significant causal variable. Interpretation This study shows that advanced age is associated with more aggressive tumour features, and independently and causally related to worse oncological outcomes. Therefore, treatment for endometrial cancer in elderly women should not be de-escalated based on their age alone. Funding The PORTEC-1, -2 and -3 trials and the associated translational studies are supported by the Dutch Cancer Society. | Make paid
Objective: To evaluate the feasibility of a nurse-led antimicrobial stewardship (AMS) program in two Australian residential aged care homes (RACHs) to inform a stepped-wedged, cluster randomised controlled trial (SW-cRCT). Methods: A mixed-methods pilot study of a nurse-led AMS program was performed in two RACHs in Victoria, Australia between July and December 2019. The AMS program comprised education, infection assessment and management guidelines, and documentation to support appropriate antimicrobial use in urinary, lower respiratory and skin/soft tissue infections. The program was implemented over three phases over five months: 1) pre-implementation education and integration (1-month); 2) implementation of the intervention (3-months); 3) post-intervention evaluation (1-month). Baseline RACH and resident data and weekly infection and antimicrobial usage was collected. Feedback on intervention resources and implementation barriers were identified from semi-structured interviews, online staff questionnaire and researcher field notes. Results: Six key barriers to implementation of the intervention were identified and used to refine the intervention; aged care staffing and capacity, access to education, resistance to practice change, role of staff in AMS, leadership and ownership of the intervention at the RACH and organisation-level, and expectations from family. A total 61 antimicrobials were prescribed for 40 residents over the 3-month intervention period. Overall, 48% of antibiotics did not meet the minimum criteria for appropriate initiation (respiratory 73%; urinary: 54%; skin/soft tissue: 0%). Conclusions: Several barriers and opportunities to improve the implementation of AMS in RACHs were identified. Findings were used to inform a revised intervention to be evaluated in a larger SW-cRCT. | Make paid
Introduction Pre-exposure Prophylaxis (PrEP) is a daily pill intended to reduce the risk of acquiring Human Immunodeficiency Virus (HIV) when taken as prescribed. It is strongly recommended for Men who have sex with Men (MSM) at high risk of HIV transmission to minimize infection risk. Despite its proven effectiveness, there is a lack of information about awareness and willingness to use PrEP among Rwandan MSM. In the context of HIV acquisition, the purpose of this study was to ascertain the awareness and willingness to use PrEP among high-risk Rwandan MSM. The findings of this research will provide valuable perspectives to mold policy and direct the effective execution of PrEP within the country. Method This is a cross-sectional study design that utilized a web-based survey conducted between April and June 2019 to assess awareness and willingness to use PrEP among sexually active MSM in Rwanda. A snowball sampling technique was used to recruit participants who were contacted via social medial such as WhatsApp and e-mail. To be eligible, participants were supposed to be sexually active, aged [≥]18 years, self-identify as MSM, residence in Rwanda, self-reported engagement in receptive or insertive anal sex in the last 12 months, and self-reported HIV-negative sero-status. We assessed two primary outcomes: PrEP awareness (having ever heard of PrEP) and willingness to use PrEP within one month of completing the survey. Multivariable logistic regression was performed to identify participant characteristics associated with PrEP awareness and willingness to use it. Results Among the 521 participants included in the analysis, 63% were aged below 24 years. The majority (73%) demonstrated awareness of PrEP. Factors associated with PrEP awareness included residing outside of the capital, Kigali, as opposed to living in Kigali (adjusted odds ratio [aOR] 2.35, 95% confidence interval [CI] 1.40-3.97), being in the age groups 18-24 years (aOR 2.28, 95% CI: 1.03-5.01) or 25-29 years (aOR 3.06, 95% CI 1.35-6.93) compared to those aged 30 or older, having higher education levels, such as completing secondary education (aOR 1.76, 95% CI 1.01-3.06) or university education (aOR 2.65, 95% CI 1.18-5.96) in contrast to having no education. Lastly, perceiving a benefit from PrEP (aOR 9.52, 95% CI 4.27-21.22), and engaging in vaginal sex with a woman using a condom in the last 12 months (aOR 1.82, 95% CI 1.14-2.91) versus not. Impressively, 96% of participants expressed a strong willingness to use PrEP. Conclusion Among Rwandan MSM, there is a high level of awareness of PrEP, notably associated with factors such as residing outside Kigali, younger age, higher education, perceived benefits of PrEP and condom use during vaginal sex in the past year. Furthermore, a significant portion of participants demonstrated an intense desire to use PrEP, suggesting promising possibilities for its extensive implementation among this group of people. The findings from this study emphasize the importance of implementing highly focused awareness campaigns, personalized intervention, and comprehensive sexual health education programs in order to enhance the adoption of PrEP and bolster HIV prevention initiatives among the Rwandan population of MSM | Make paid
Most infections with pandemic Vibrio cholerae are thought to result in subclinical disease and are not captured by surveillance. Previous estimates of the ratio of infections to clinical cases have varied widely (2 to 100). Understanding cholera epidemiology and immunity relies on the ability to translate between numbers of clinical cases and the underlying number of infections in the population. We estimated the infection incidence during the first months of an outbreak in a cholera-naive population using a Bayesian vibriocidal antibody titer decay model combining measurements from a representative serosurvey and clinical surveillance data. 3,880 suspected cases were reported in Grande Saline, Haiti, between 20 October 2010 and 6 April 2011 (clinical attack rate 18.4%). We found that more than 52.6% (95% Credible Interval (CrI) 49.4-55.7) of the population [≥]2 years showed serologic evidence of infection, with a lower infection rate among children aged 2-4 years (35.5%; 95%CrI 24.2-51.6) compared with people [≥]5 years (53.1%; 95%CrI 49.4-56.4). This estimated infection rate, nearly three times the clinical attack rate, with underdetection mainly seen in those [≥]5 years, has likely impacted subsequent outbreak dynamics. Our findings show how seroincidence estimates improve understanding of links between cholera burden, transmission dynamics and immunity. | Make paid
Aberrant fetal gene expression facilitates tumor-specific cellular plasticity by hijacking molecular programs of embryogenesis. Persistent fetal gene signatures in childhood malignancies are typically explained by their prenatal origins. In contrast, reactivation of fetal gene expression is considered a consequence of oncofetal reprogramming (OFR) in adult malignancies and is associated with aggressive disease. To date, OFR has not been described in the context of childhood malignancies. Here, we performed a comprehensive multi-layered molecular characterization of juvenile myelomonocytic leukemia (JMML) and identified OFR as a hallmark of aggressive JMML. We observed that hematopoietic stem cells (HSCs) aberrantly express mixed developmental programs in JMML. Expression of fetal gene signatures combined with a postnatal epigenetic landscape suggested OFR, which was validated in a JMML mouse model, demonstrating that postnatal activation of RAS signaling is sufficient to induce fetal gene signatures. Integrative analysis identified the fetal HSC maturation marker CD52 as a novel therapeutic target for aggressive JMML. Anti-CD52 treatment depleted human JMML HSCs and disrupted disease propagation in vivo. In summary, this study implicates OFR, defined as postnatal acquisition of fetal transcription signatures, in the pathobiology of a childhood malignancy. We provide evidence for the direct involvement of oncogenic RAS signaling in OFR. Finally, we demonstrate how OFR can be leveraged for the development of novel treatment strategies. | Make paid
Stem cells preferentially use glycolysis instead of oxidative phosphorylation and this metabolic rewiring plays an instructive role in their fate; however, the underlying molecular mechanisms remain largely unexplored. PIWI-interacting RNAs (piRNAs) and PIWI proteins have essential functions in a range of adult stem cells across species. Here, we show that piRNAs and the PIWI protein Aubergine (Aub) are instrumental in activating glycolysis in Drosophila germline stem cells (GSCs). High glycolysis is required for GSC self-renewal and aub loss-of-function induces a metabolic switch in GSCs leading to their differentiation. Aub directly binds glycolytic mRNAs and Enolase mRNA regulation by Aub depends on its 5'UTR. Furthermore, deletion of a piRNA target site in Enolase 5'UTR leads to GSC loss. These data reveal an Aub/piRNA function in translational activation of glycolytic mRNAs in GSCs, and pinpoint a new mode of regulation of metabolic reprogramming in stem cells based on small RNAs. | Make paid
Parkinsons disease (PD), one of the most common aging-associated neurodegenerative disorders, is characterised by nigrostriatal pathway dysfunction, caused by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the midbrain and the dopamine depletion in the striatum. State of the art, human in vitro models are enabling the study of the dopaminergic neurons loss, but not the dysregulation of the dopaminergic network in the nigrostriatal pathway. Additionally, these models do not incorporate aging characteristics which potentially contribute to the development of PD. Therefore, it is conceivable that research conducted using these models overlooked numerous processes that contribute to diseases phenotypes. Here we present a nigrostriatal pathway model based on midbrain-striatum assembloids with inducible aging. We show that these assembloids are capable of developing characteristics of the nigrostriatal connectivity, with catecholamine release from the midbrain to striatum and synapse formation between midbrain and striatal neurons. Moreover, Progerin-overexpressing assembloids acquire aging traits that lead to early phenotypes of PD. This new model shall help to reveal the contribution of aging as well as nigrostriatal connectivity to the onset and progression of PD. | Make paid
Background: Genetic cardiomyopathies caused by mutations in the dystrophin gene (DMD) are only partially responsive to current pharmacological heart failure treatments, although dilated and arrhythomogenic phenotypes of cardiomyopathy are frequent. Objective: In this study, we tested whether a normalization of Ca2+-handling by forced expression of SERCA2a in cardiomyocytes mitigates heart failure and arrhythmogenesis in a pig model for Duchenne muscular dystrophy (DMD) in pigs. Methods and results: Male offspring of pigs lacking DMD exon 52 are characterized by heart failure with reduced ejection fraction (HFrEF, EF 34.5{+/-}1.8% vs. 49.2{+/-}1.0% in control hearts), arrhythmogenesis due to large apical regions of reduced action potential (AP) amplitude and sudden cardiac death with a lifespan of usually less than 4 months. Slow antegrade intracoronary infusion of AAV1.SERCA2a (3x1013 virus genomes (vg) per pig) improved left ventricular ejection fraction (EF 47.3{+/-}2.0%, p<0.05) to a similar extent as germline editing of DMD{Delta}52 to DMD{Delta}51-52, inducing a Becker dystrophy (BMD) genotype (EF 46.7{+/-}3.8%). Moreover, AAV.Serca2a significantly reduced myocardial inflammation and fibrosis and areas of reduced AP amplitude. Conclusions: In DMD pigs, 3x1013vg/heart of GMP-grade AAV1.SERCA2a sufficed to normalize left ventricular function, and improved electrical vulnerability of the heart. Hence, AAV.SERCA2a may serve as a treatment option for DMD cardiomyopathy. | Make paid
Ribosomal DNA (rDNA) genes encode the structural RNAs of the ribosome and are present in hundreds of copies in mammalian genomes. Age-linked DNA hypermethylation throughout the rDNA constitutes a robust methylation clock that accurately reports age, yet the consequences of hypermethylation on rDNA function are unknown. We confirmed that pervasive hypermethylation of rDNA occurs during mammalian aging and senescence while rDNA copy number remains stable. We found that DNA methylation is exclusively found on the promoters and gene bodies of inactive rDNA. To model the effects of age-linked methylation on rDNA function, we directed de novo DNA methylation to the rDNA promoter or gene body with a nuclease-dead Cas9 (dCas9) DNA methyltransferase fusion enzyme in human cells. Hypermethylation at each target site had no detectable effect on rRNA transcription, nucleolar morphology, or cellular growth rate. Instead, human UBF and Pol I remain bound to rDNA promoters in the presence of increased DNA methylation. These data suggest that promoter methylation is not sufficient to impair transcription of the human rDNA and imply that the human rDNA transcription machinery may be resilient to age-linked rDNA hypermethylation. | Make paid
Importance. While hormone therapy (HT) in perimenopausal women can increase risk for venous thromboembolism (VTE), it is unclear to what extent statins may reduce HT-related risk. Objective. To estimate VTE risk in 50-64-year-old women taking HT with or without statins and by statin intensity. Design. A nested case-control study. Setting. A US, commercially insured claims database. Participants. Women aged 50-64 with at least one year of continuous membership between 2008-2019. Exposure. Filled prescriptions for estrogens, progestogens, and statins were recorded in 12 months prior to index. Recent HT was defined as any estrogen or progestogen exposure within 60 days before the index date. Current statin exposure was defined as 90 or more days of continuous exposure prior to and including the index date. Statin intensity was defined by the statin exposure 30 days prior to index. Main Outcomes and Measures. Cases were identified with VTE diagnoses (ICD codes) preceded by at least 12 months without VTE and followed within 30 days by anticoagulation, an inferior vena cava filter placement, or death. Controls were matched to cases (10:1) on date and age. Conditional logistic regression models estimated risk for HT and statin exposures with odds ratios (OR), adjusted for comorbidities. Results. The total sample (mean age 57.5) included 20,359 cases and 203,590 matched controls; 9% had recent HT exposure and 16% had current statin exposure. In adjusted models, the OR for any recent HT exposure was 1.51 (95%CI:1.43-1.60) compared to no recent HT exposure. The OR for current statin therapy was 0.88 (95%CI:0.84-0.93) compared to no current statin exposure. The OR was 1.53 (95%CI:1.44-1.63) for those with HT without statins, 1.25 (95%CI:1.10-1.43) with HT with statins, and 0.89 (95%CI:0.85-0.94) with statins without HT compared to no recent HT and no current statins. HT with statin therapy had a 18% significantly lower OR than HT without statins (OR=0.82,95%CI:0.71-0.94) and greater risk reduction with higher intensity statins. Conclusions and Relevance. In this case-control study, statin therapy was associated with reduced risk of VTE in women taking HT with greater risk reduction with high-intensity statins. | Make paid
Cervical cancer is the leading cause of cancer in low- and middle-income countries, despite being a preventable disease. Uganda, which lacks an effective screening program, has one of the highest cervical cancer incidence rates in the world. Mobile health (mHealth) technology has the potential to improve healthcare-seeking behaviors and access to cervical cancer screening. This study aims to describe the connection between mobile phone access and healthcare-seeking behaviors in rural Uganda. This cross-sectional study recruited participants from January 23 to August 24, 2023. Women were eligible if they had no prior screening or treatment for cervical cancer in the past 5 years, were aged 30 to 49 years old, and were residents of the South Busoga Forest reserve. Each participant completed a 43-item survey which included questions on demographics, previous health service usage, and opinions on cervical cancer prevention. All data was analyzed using descriptive statistics and chi-square tests. Of the 1434 participants included in the analysis, 91.4% reported having access to a mobile phone. Most respondents were aged 30-40 years, were married or in a relationship, had [≤] primary education, and were farmers. Participants with access to a mobile phone were significantly more likely to report attending a healthcare outreach visit (access = 87.3%, no access = 72.6%, p<0.001) or visiting a health centre (access = 96.9%, no access = 93.5%, p<0.001). Participants in both groups had largely positive attitudes around and good knowledge of cervical cancer screening. While attendance to healthcare outreach visits or health centres was high amongst participants, those with mobile phone access were more likely to seek healthcare services. Further inquiry into this association between mobile phone access and healthcare-seeking behaviour is needed to optimize the improvements to cervical cancer screening when implementing interventions such as mHealth technology. | Make paid
Background: The first wave of the Corona Monitoring Nationwide (RKI-SOEP) Study drawn from the German Socio-Economic Panel proved a low pre-vaccine SARS-CoV-2 seroprevalence in the German adult population of 2.1%. Methods: In this second wave of the study (RKI-SOEP-2, November 2021-March 2022), we used combined serological and self-reported data on infection and vaccination to estimate the prevalence of SARS-CoV-2-specific anti-spike and/or anti-nucleocapsid IgG antibodies (combined seroprevalence), past infection, and basic immunization in individuals aged 14+. Findings: Combined seroprevalence was 90.7% (95% CI 89.7% - 91.6%) without correction for antibody waning and 94.6% (95% CI 93.6% - 95.7%) with correction. While 1 in 10 individuals had been infected (9.9%, 95% CI 9.0% - 10.9%), 9 in 10 had at least a basic immunization (90%, 95% CI 88.9%-90.9%). Population-weighted estimates differed by age, region, and socioeconomic deprivation. Infection-induced seroprevalence with correction for antibody waning was 1.55 (95% CI 1.3 - 1.8) times higher than the cumulative proportion based on national surveillance data. Interpretation: At the beginning of the SARS-CoV-2-Omicron wave, the vast majority of the population had been vaccinated, infected, or both. Our results show how large-scale vaccination, but not a high infection rate, was able to fill the immunity gap, especially in older individuals (aged 65+) who are known to be at higher risk of severe COVID-19. Our data point towards a targeted demographically and regionally stratified mitigation strategy, to optimize future pandemic mitigation efforts. | Make paid
The evolution of flowering time is often attributed to variation of pollinator rates over time. This study proposes that flowering time can evolve through siring success variation among individuals caused by differential pollen dispersal timing (a result of flowering time variation itself). Quantitative genetic models show that earlier flowering evolves under low pollen removal rates, high pollen deposition rates, and a slow decline in the fertilization ability of removed pollen. Variations in pollen dispersal timing also select for a stable variance in flowering time, which is larger when pollen removal rates are either very low or high, pollen deposition rates are moderate, and the fertilization ability of removed pollen declines more rapidly. Also, a model on the coevolution of flower longevity and flowering time predicts that under constant pollination rates, non-random mating results in a weak correlation between late flowering and longer-lived flowers. This baseline finding suggests that the observed correlation between late flowering and shorter flowering duration in nature is influenced by other factors, such as declining pollination rates during late-stage flowering. I discuss the role of altered pollination rates under climate change during flowering time evolution and the importance of distinguishing between pollen removal and deposition rates. | Make paid
To increase antibody affinity against pathogens, positively selected GC-B cells initiate cell division in the light zone (LZ) of germinal centres (GCs). Among those, higher-affinity clones migrate to the dark zone (DZ) and vigorously proliferate by relying on oxidative phosphorylation (OXPHOS). However, it remains unknown how positively selected GC-B cells adapt their metabolism for cell division in the glycolysis-dominant, cell cycle arrest-inducing, hypoxic LZ microenvironment. Here, we show that microRNA (miR)-155 mediates metabolic reprogramming during positive selection to protect high-affinity clones. Transcriptome examination and mass spectrometry analysis revealed that miR-155 regulates H3K36me2 levels by directly repressing hypoxia-induced histone lysine demethylase, Kdm2a. This is indispensable for enhancing OXPHOS through optimizing the expression of vital nuclear mitochondrial genes under hypoxia. The miR-155-Kdm2a interaction is crucial to prevent excessive production of reactive oxygen species and apoptosis. Thus, miR-155-mediated epigenetic regulation promotes mitochondrial fitness in high-affinity clones, ensuring their expansion and consequently affinity maturation. | Make paid
Triple-Negative Breast Cancer (TNBC) has profound unmet medical need globally for its devastating clinical outcome associated with rapid metastasis and lack of targeted therapies. Recently, lipid metabolic reprogramming has emerged as a major driver of breast cancer metastasis. Here, we unveil a strong association between the heightened expression of fatty acid metabolic enzyme, acyl-CoA synthetase 4 (ACSL4) and TNBC, which is primarily attributed by the selective absence of progesterone receptor (PR). Loss of ACSL4 function, either through genetic ablation or pharmacological inhibition significantly reduces metastatic potential of TNBC. Global transcriptome analysis reveals that ACSL4 activity markedly influences the gene expression pattern associated with TNBC migration. Mechanistically, ACSL4 alters fatty acid oxidation (FAO) and cellular acetyl-CoA levels, leading to the hyper- acetylation of particularly H3K27Ac and H3K9Ac marks resulting in overexpression of SNAIL during the course of TNBC metastatic spread to lymph node and lungs. Further, human TNBC metastasis exhibits positive correlation between ACSL4 and SNAIL expression. Altogether, our findings provide new molecular insights regarding the intricate interplay between metabolic alterations and epigenetic modifications, intertwined to orchestrate TNBC metastasis and posit a rational understanding for the development of ACSL4 inhibitors as a targeted therapy against TNBC. | Make paid
Animals alter their feeding behavior when infected to help combat various parasites. However, parasites can manipulate host foraging behavior to increase their own development, survival and transmission. Using Nutritional Geometry, we investigated the role of key nutrients: amino acids (AA) and carbohydrates (C) in a host-parasite system: the entomopathogenic fungus, Metarhizium brunneum, and the ant, Linepithema humile. We show that the fungus grew and produced most spores on protein-rich diets (AA:C of 1:4). When facing food combinations, it exploited the two complementary food resources to reach the same performance as on its optimal diet, revealing the ability of fungal pathogen to solve complex nutritional challenges. When ants were fed on this optimal fungal diet, their lifespan decreased when healthy, yet not when Metarhizium-infected, compared to their favoured carbohydrate-rich diet. Interestingly, when the ants were given a binary choice between different diets, the foragers of uninfected colonies avoided intake of the fungal optimum diet, whilst choosing it when infected. Experimental disentanglement of full pathogenic infection and pure immune response to fungal cell wall material, combined with immune measurements, allowed us to conclude that this change of nutritional choice in infected ants did not result from pathogen manipulation, but likely represents a compensation of the host to counterbalance the use of amino acids costs during the immune response. The observed change in foraging behavior in infected colonies towards an otherwise harmful diet, therefore suggests to be a collective compensatory mechanism for the individual cost of immunity. | Make paid
Decidualization or the differentiation of endometrial stromal cells (eSCs) into secretory decidual cells is required for successful implantation and pregnancy in menstruating species. Endometriosis, a condition accompanied by chronic pelvic pain and infertility, is observed in humans and a few species that menstruate. Several studies report that endometriosis is accompanied by significantly compromised decidualization, and this may explain some of the associated infertility. Current pharmacologics treat symptoms of endometriosis but do not alter disease progression. Sampsons theory of retrograde menstruation is the most commonly accepted mechanism that explains the delivery of menstrual tissues to the peritoneal cavity where most endometriosis lesions develop. However, the exact etiology of endometriosis remains unknown. Recent studies support that cellular senescence, a phenotype found in shed menstrual tissues, impairs decidualization. Additionally, a senolytic agent, quercetin, has been reported to improve female fertility and reduce endometriosis in pre-clinical models. We examined the effect of quercetin on decidualization and stromal cell function using cultured eSCs isolated from menstrual effluent obtained from healthy, unaffected controls and endometriosis patients. Quercetin significantly inhibits eSC proliferation and improves decidualization of eSCs obtained from both endometriosis patients and controls. Mechanistic studies using eSCs reveal that quercetin rapidly blocks AKT, ERK1/2, and PRAS40 phosphorylation and inhibits the production of IL-6 and MMP3, prominent products of the senescence-associated secretory phenotype (SASP). Additionally, quercetin promotes both p53 phosphorylation and total p53 protein levels in eSCs and this is accompanied by increased apoptosis and the loss of larger beta-galactosidase-expressing eSCs with a senescence phenotype. This is the first study to reveal that quercetin enhances decidualization via senolytic and pro-apoptotic activities downstream of AKT signaling in controls and patients with endometriosis. These results support further investigating quercetin as a treatment for endometriosis and associated infertility. | Make paid
Introduction Challenges in social communication and interaction are common among school-aged autistic children in mainstream society settings. Although social skills group training (SSGT) is effective in promoting positive psycho-social functioning outcomes in autistic children, there is no standardised evidence-based SSGT in Mainland China to date. Therefore, the main aim of this study is to evaluate the feasibility and acceptability of the culturally-adapted 16-session version of the KONTAKTTM programme in Chinese autistic children. In addition, this study will provide preliminary effectiveness and cost-effectiveness data on the 16-session Chinese version of KONTAKTTM. Methods and analysis This is a randomised, single-blinded, wait-list controlled feasibility study with 36 autistic children aged 8-12 years with Intelligence Quotient over 70. They will be assigned to either the immediate training group (ITG) or the delayed training group (DTG) based on gender. Feasibility will be measured by the mixed-methods data of acceptability and adherence of participants, parents, and providers. Preliminary effectiveness and cost-effectiveness will be assessed by quantitative data collected at five-time points. The main outcome is the improvement in social skills as measured by the Contextual Assessment of Social Skills (CASS). Other outcomes include autism traits, adaptive functioning, self-assertiveness, psycho-social functioning, parental reflective functioning, and school support. Common process factors and their effects on outcomes will also be explored. Cost-effectiveness will consider both societal and healthcare perspectives. Ethics and dissemination The current study protocol has been reviewed and ethics approval obtained from the Ethical Board Committee at the Third Affiliated Hospital of Sun Yat-sen University (II2023-119-01). The trial has pre-registered in Chinese Clinical Trials (ChiCTR2300072136) on 05 June 2023. The results of this trial will be actively disseminated through manuscript publications and conference presentations. | Make paid
Background: Low back pain (LBP) is one of the most frequently occurring musculoskeletal disorders, and factors such as lifestyle as well as individual characteristics are associated with LBP. The purpose of this study was to develop and compare efficient low back pain prediction models using easily obtainable demographic and lifestyle factors. Methods: Data from adult men and women aged 50 years or older collected from the Korean National Health and Nutrition Examination Survey (KNHANES) were used. The dataset included 22 predictor variables, including demographic, physical activity, occupational, and lifestyle factors. Four machine learning algorithms, including XGBoost, LGBM, CatBoost, and RandomForest, were used to develop predictive models. Results: All models achieved an accuracy greater than 0.8, with the LGBM model outperforming the others with an accuracy of 0.830. The CatBoost model had the highest sensitivity (0.804), while the LGBM model showed the highest specificity (0.884) and F1-Score (0.821). Feature importance analysis revealed that EQ-5D was the most critical variable across all models. Conclusion: In this study, an efficient LBP prediction model was developed using easily accessible variables. Using this model, it may be helpful to identify the risk of LBP in advance or establish prevention strategies in subjects who have difficulty accessing medical facilities. | Make paid
Age-related changes in DNA methylation (DNAm) form the basis for the development of most robust predictors of age, epigenetic clocks, but a clear mechanistic basis for exactly what part of the aging process they quantify is lacking. Here, to clarify the nature of epigenetic aging, we juxtapose the aging dynamics of tissue and single-cell DNAm (scDNAm) with scDNAm changes during early development, and corroborate our analyses with a single-cell RNAseq analysis within the same multi-omics dataset. We show that epigenetic aging involves co-regulated changes, but it is dominated by the stochastic component, and this agrees with transcriptional coordination patterns. We further support the finding of stochastic epigenetic aging by direct tissue and single-cell DNAm analyses and modeling of aging DNAm trajectories with a stochastic process akin to radiocarbon decay. Finally, we describe a single-cell algorithm for the identification of co-regulated and stochastic CpG clusters showing consistent transcriptomic coordination patterns, providing new opportunities for targeting aging and evaluating longevity interventions. | Make paid
INTRODUCTION: Discovery of the associations between brain structural connectivity and clinical and demographic variables can help to better understand the vulnerability and resilience of the brain architecture to neurodegenerative diseases and to discover biomarkers. METHODS: We used four diffusion-MRI databases, three related to Alzheimer's disease, to exploratorily correlate structural connections between 85 brain regions with non-MRI variables, while stringently correcting the significance values for multiple testing and ruling out spurious correlations via careful visual inspection. We repeated the analysis with brain connectivity augmented with multi-synaptic neural pathways. RESULTS: We found 85 and 100 significant relationships with direct and augmented connectivity, respectively, which were generally stronger for augmented connectivity. Age was consistently linked to decreased connectivity, and healthier clinical scores were generally linked to increased connectivity. DISCUSSION: Our findings help to elucidate which structural brain networks are affected in Alzheimer's disease and aging and highlight the importance of including indirect connections. | Make paid
Brain structural circuitry shapes a richly patterned functional synchronization, supporting for complex cognitive and behavioural abilities. However, how coupling of structural connectome (SC) and functional connectome (FC) develops and its relationships with cognitive functions and transcriptomic architecture remain unclear. We used multimodal magnetic resonance imaging data from 439 participants aged 5.67 to 21.92 years to predict functional connectivity by incorporating intracortical and extracortical structural connectivity, characterizing SC-FC coupling. Our findings revealed that SC-FC coupling was strongest in the visual and somatomotor networks, consistent with evolutionary expansion, myelin content, and functional principal gradient. As development progressed, SC-FC coupling exhibited heterogeneous alterations dominated by an increase in cortical regions, broadly distributed across the somatomotor, frontoparietal, dorsal attention, and default mode networks. Moreover, we discovered that SC-FC coupling significantly predicted individual variability in general intelligence, mainly influencing frontoparietal and default mode networks. Finally, our results demonstrated that the heterogeneous development of SC-FC coupling is positively associated with genes in oligodendrocyte-related pathways and negatively associated with astrocyte-related genes. This study offers insight into the maturational principles of SC-FC coupling in typical development and developmental disorders. | Make paid