Miracle-dz/UniFAR-FTUs huggingface dataset:
APOE ɛ4 dose associates with increased brain iron and β-amyloid via blood–brain barrier dysfunction

Objective To examine the effect of apolipoprotein E (APOE) ɛ4 dose on blood–brain barrier (BBB) clearance function, evaluated using an advanced MRI technique and analyse its correlation with brain iron and β-amyloid accumulation in the early stages of the Alzheimer’s continuum. Methods In this single-centre observational prospective cohort study, 24 APOE ɛ4 non-carriers, 22 heterozygotes and 20 homozygotes in the early stages of the Alzheimer’s continuum were scanned with diffusion-prepared arterial spin labelling, which estimates the water exchange rate across the BBB (kw). Participants also underwent quantitative susceptibility mapping, [11C]Pittsburgh compound B-positron emission tomography and neuropsychological testing. Using an atlas-based approach, we compared the regional kw of the whole brain among the groups and analysed its correlation with the neuroradiological and neuropsychological findings. Results The BBB kw values in the neocortices differed significantly among the groups (APOE ɛ4 non-carriers>heterozygotes>homozygotes). These values correlated with brain iron levels (frontal lobe: r=−0.476, 95% CI=−0.644 to −0.264, p=0.011; medial temporal lobe: r=−0.455, 95% CI=−0.628 to −0.239, p=0.017), β-amyloid loads (frontal lobe: r=−0.504, 95% CI=−0.731 to −0.176, p=0.015; medial temporal lobe: r=−0.452, 95% CI=−0.699 to −0.110, p=0.036) and neuropsychological scores, after adjusting for age, sex and APOE ɛ4 dose. Interpretation Our results suggest that an increased APOE ɛ4 dose is associated with decreased effective brain-waste clearance, such as iron and β-amyloid, through the BBB.
Preventing invasive meningococcal disease in early infancy

ABSTRACT This review considers the pathogenesis, diagnosis, and epidemiology of invasive meningococcal disease in infants, to examine and critique meningococcal disease prevention in this population through vaccination. High rates of meningococcal disease and poor outcomes, particularly for very young infants, highlight the importance of meningococcal vaccination in early infancy. Although effective and safe meningococcal vaccines are available for use from 6 weeks of age, they are not recommended globally. Emerging real-world data from the increased incorporation of these vaccines within immunization programs inform recommendations regarding effectiveness, appropriate vaccination schedule, possible long-term safety effects, and persistence of antibody responses. Importantly, to protect infants from IMD, national vaccination recommendations should be consistent with available data regarding vaccine safety, effectiveness, and disease risk.
Evaluation of the biocontrol activity of Frateuria defendens-derived metabolites against mollicutes

ABSTRACT Frateuria defendens is a candidate biocontrol agent that has been shown to reduce phytoplasma-related disease symptoms in grapevines and periwinkle plants. While a crude filtrate prepared from F. defendens can inhibit mollicute growth, the specific growth parameters for this bacterium, necessary to enhance this protective inhibitory response, remain unknown. Moreover, the separation of filtrate preparations from bacterial cells via centrifugation and filtration is laborious and time-consuming. As such, the present study was conducted to define the optimal growth conditions associated with maximal inhibitory activity of F. defendens and to establish a better approach to separating these bacterial cells from their secreted metabolites. To conduct these analyses, F. defendens was cultured in a range of media types, while associated inhibitory effects were tested in vitro using Spiroplasma melliferum as a model mollicute bacterium, and in planta using phytoplasma-infected periwinkle plantlets. These analyses revealed F. defendens growth patterns change based upon media composition, with filtrates prepared from a specific rich medium (S-medium) exhibiting beneficial activities, including the inhibition of S. melliferum and enhanced plant growth. When F. defendens cells were grown within semi-permeable, membrane-coated Small Bioreactor Platform (SBP) capsules, they could be more readily separated from the secreted metabolite fraction, obviating the need for filtration and/or centrifugation. This study is the first to have reported the use of SBP capsules to separate bacterial cells from their secreted metabolites under sterile conditions while retaining the ability of these metabolites to inhibit S. melliferum growth and to benefit the host plant. The results highlight promising new approaches to the effective biocontrol of phytoplasma-driven diseases in grapevines and other economically important plant species.
Gene expression profile of chronic oral graft-versus-host disease

Among the complications observed after allogeneic hematopoietic stem cell transplantation, graft-versus-host disease (GVHD) is the primary cause of post-transplant mortality. The oral cavity is the second most affected organ target in chronic GVHD. Tissue damage results from the upregulation of inflammatory mediators, which play a critical role in the immunopathogenesis of the disease. This case series observational study aims to evaluate the participation of cytokines, chemokines, transcription factors, and heat shock proteins in the pathogenesis of oral GVHD (oGVHD), describing the mRNA expression of 28 genes selected. Peripheral blood mononuclear cells were isolated from six participants with oGVHD and two without GVHD, and relative expression of transcripts with established roles as inflammatory mediators was determined in triplicate using the human RT2 Profiler™ PCR Array. The gene expression levels in the group with oGVHD were mainly up-regulated compared to those without GVHD. PBMC from oGVDH expressed consistently higher IFN-γ, TNF, IL-1β, CCL2, HSP60 (HSPD1) and HSP90 (HSP90B1). These results can provide a basis for developing new molecular diagnostics and targets therapies for the clinical management of oGVHD.
Genetics and genomics of bone marrow failure syndrome

Inherited bone marrow failure syndrome (IBMFS) is a group of clinically heterogeneous disorders characterized by significant hematological cytopenias of one or more hematopoietic cell lineages and is associated with an increased risk of cancer. The genetic etiology of IBMFS includes germline mutations impacting several key biological processes, such as DNA repair, telomere biology, and ribosome biogenesis, which may cause four major syndromes: Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome. Although the clinical features of some patients may be typical of a particular IBMFS, overlapping and atypical clinical manifestations and variable penetrance pose diagnostic challenges. Here, we review the clinical and genetic features of the major forms of IBMFS and discuss their molecular genetic diagnosis. Next-generation sequencing-based gene panel testing or whole exome sequencing will help elucidate the genetic causes and underlying mechanisms of this genetically heterogeneous group of diseases.
Influence of pulse duration and water/air cooling ratio on the efficiency of Er:YAG 2940 nm laser in debonding of porcelain laminate veneers: An in vitro study

To determine the effectiveness of different pulse durations (PD) and the water/air (W/A) cooling ratio of the Er:YAG 2940 nm laser that are required for debonding porcelain laminate veneers (PLV), by investigation of the needed time for PLV debonding (DT) and the changes in dental pulp temperature.
Correlation of theophylline levels in rat exhaled breath and lung tissue after its intravenous injection

It is important to know the drug level in the target tissue to determine its dose. Some methods rely on blood levels of a drug to estimate its concentration in the tissues, which can be inaccurate. We thought that drug levels in exhaled breath aerosol (EBA) to give a more accurate value of the level of a test drug in the lung. Rats were intravenously injected with the bronchodilator theophylline and exhaled breath was collected up to 10–20 min after administration. Immediately after breath collection, lung, liver, kidney, and blood were collected and the pharmacokinetics were examined using these samples. Awake free-moving rats were used to efficiently collect exhaled breath from rats with low tidal volume. The amount of exhaled breath of rats was estimated by the amount of exhaled water vapor, and the drug concentration in exhaled breath sample was expressed by the amount of water vapor as the denominator. By using the active sampling method in which the adsorbent is sucked by a pump, theophylline in rat exhaled breath could be measured accurately. When the correlation of theophylline concentration in each sample was examined, a high correlation (r 2 = 0.74) was found only in exhaled breath and lung tissue. EBA was considered better than blood in pharmacokinetic analysis of lung tissue.
Radiomics-Based Machine Learning for Outcome Prediction in a Multicenter Phase II Study of Programmed Death-Ligand 1 Inhibition Immunotherapy for Glioblastoma

BACKGROUND AND PURPOSE: Imaging assessment of an immunotherapy response in glioblastoma is challenging due to overlap in the appearance of treatment-related changes with tumor progression. Our purpose was to determine whether MR imaging radiomics-based machine learning can predict progression-free survival and overall survival in patients with glioblastoma on programmed death-ligand 1 inhibition immunotherapy. MATERIALS AND METHODS: Post hoc analysis was performed of a multicenter trial on the efficacy of durvalumab in glioblastoma (n = 113). Radiomics tumor features on pretreatment and first on-treatment time point MR imaging were extracted. The random survival forest algorithm was applied to clinical and radiomics features from pretreatment and first on-treatment MR imaging from a subset of trial sites (n = 60–74) to train a model to predict long overall survival and progression-free survival and was tested externally on data from the remaining sites (n = 29–43). Model performance was assessed using the concordance index and dynamic area under the curve from different time points. RESULTS: The mean age was 55.2 (SD, 11.5) years, and 69% of patients were male. Pretreatment MR imaging features had a poor predictive value for overall survival and progression-free survival (concordance index = 0.472–0.524). First on-treatment MR imaging features had high predictive value for overall survival (concordance index = 0.692–0.750) and progression-free survival (concordance index = 0.680–0.715). CONCLUSIONS: A radiomics-based machine learning model from first on-treatment MR imaging predicts survival in patients with glioblastoma on programmed death-ligand 1 inhibition immunotherapy.
The Effectiveness of Pfizer-BioNTech and Oxford-AstraZeneca Vaccines to Prevent Severe COVID-19 in Costa Rica: Nationwide, Ecological Study of Hospitalization Prevalence

Background The Costa Rican COVID-19 vaccination program has used Pfizer-BioNTech and Oxford-AstraZeneca vaccines. Real-world estimates of the effectiveness of these vaccines to prevent hospitalizations range from 90%-98% for two doses and from 70%-91% for a single dose. Almost all of these estimates predate the Delta variant. Objective The aim of this study is to estimate the dose-dependent effectiveness of COVID-19 vaccines to prevent severe illness in real-world conditions in Costa Rica, after the Delta variant became dominant. Methods This observational study is a secondary analysis of hospitalization prevalence. The sample is all 3.67 million adult residents living in Costa Rica by mid-2021. The study is based on public aggregated data of 5978 COVID-19–related hospital records from September 14, 2021, to October 20, 2021, and 6.1 million vaccination doses administered to determine hospitalization prevalence by dose-specific vaccination status. The intervention retrospectively evaluated is vaccination with Pfizer-BioNTech (78%) and Oxford-AstraZeneca (22%). The main outcome studied is being hospitalized. Results Vaccine effectiveness against hospitalization (VEH) was estimated as 93.4% (95% CI 93.0-93.9) for complete vaccination and 76.7% (95% CI 75.0-78.3) for single-dose vaccination among adults of all ages. VEH was lower and more uncertain among older adults aged ≥58 years: 92% (95% CI 91%-93%) for those who had received full vaccination and 64% (95% CI 58%-69%) for those who had received partial vaccination. Single-dose VEH declined over time during the study period, especially in the older age group. Estimates were sensitive to possible errors in the population count used to determine the residual number of unvaccinated people when vaccine coverage is high. Conclusions The Costa Rican COVID-19 vaccination program that administered Pfizer-BioNTech and Oxford-AstraZeneca vaccines seems to be highly effective at preventing COVID-19–related hospitalization after the Delta variant became dominant. Even a single dose seems to provide some degree of protection, which is good news for people whose second dose of the Pfizer-BioNTech vaccine was postponed several weeks to more rapidly increase the number of people vaccinated with a first dose. Timely monitoring of vaccine effectiveness is important to detect eventual failures and motivate the public to get vaccinated by providing information regarding the effectiveness of the vaccines.
The Giardia ventrolateral flange is a lamellar membrane protrusion that supports attachment

Attachment to the intestinal epithelium is critical to the lifestyle of the ubiquitous parasite Giardia lamblia. The ventrolateral flange is a sheet-like membrane protrusion at the interface between parasites and attached surfaces. This structure has been implicated in attachment, but its role has been poorly defined. Here, we identified a novel actin associated protein with putative WH2-like actin binding domains we named Flangin. Flangin complexes with Giardia actin (GlActin) and is enriched in the ventrolateral flange making it a valuable marker for studying the flanges’ role in Giardia biology. Live imaging revealed that the flange grows to around 1 μm in width after cytokinesis, then remains uniform in size during interphase, grows in mitosis, and is resorbed during cytokinesis. A flangin truncation mutant stabilizes the flange and blocks cytokinesis, indicating that flange disassembly is necessary for rapid myosin-independent cytokinesis in Giardia. Rho family GTPases are important regulators of membrane protrusions and GlRac, the sole Rho family GTPase in Giardia, was localized to the flange. Knockdown of Flangin, GlActin, and GlRac result in flange formation defects. This indicates a conserved role for GlRac and GlActin in forming membrane protrusions, despite the absence of canonical actin binding proteins that link Rho GTPase signaling to lamellipodia formation. Flangin-depleted parasites had reduced surface contact and when challenged with fluid shear force in flow chambers they had a reduced ability to remain attached, confirming a role for the flange in attachment. This secondary attachment mechanism complements the microtubule based adhesive ventral disc, a feature that may be particularly important during mitosis when the parental ventral disc disassembles in preparation for cytokinesis. This work supports the emerging view that Giardia’s unconventional actin cytoskeleton has an important role in supporting parasite attachment.
Longitudinal Cognitive Changes in Genetic Frontotemporal Dementia Within the GENFI Cohort

Background and Objectives Disease-modifying therapeutic trials for genetic frontotemporal dementia (FTD) are underway, but sensitive cognitive outcome measures are lacking. The aim of this study was to identify such cognitive tests in early stage FTD by investigating cognitive decline in a large cohort of genetic FTD pathogenic variant carriers and by investigating whether gene-specific differences are moderated by disease stage (asymptomatic, prodromal, and symptomatic). Methods C9orf72, GRN, and MAPT pathogenic variant carriers as well as controls underwent a yearly neuropsychological assessment covering 8 cognitive domains as part of the Genetic FTD Initiative, a prospective multicenter cohort study. Pathogenic variant carriers were stratified according to disease stage using the global Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center (NACC) FTLD score (0, 0.5, or ≥1). Linear mixed-effects models were used to investigate differences between genetic groups and disease stages as well as the 3-way interaction between time, genetic group, and disease stage. Results A total of 207 C9orf72, 206 GRN, and 86 MAPT pathogenic variant carriers and 255 controls were included. C9orf72 pathogenic variant carriers performed lower on attention, executive function, and verbal fluency from CDR plus NACC FTLD 0 onwards, with relatively minimal decline over time regardless of the CDR plus NACC FTLD score (i.e., disease progression). The cognitive profile in MAPT pathogenic variant carriers was characterized by lower memory performance at CDR plus NACC FTLD 0.5, with decline over time in language from the CDR plus NACC FTLD 0.5 stage onwards, and executive dysfunction rapidly developing at CDR plus NACC FTLD ≥1. GRN pathogenic variant carriers declined on verbal fluency and visuoconstruction in the CDR plus NACC FTLD 0.5 stage, with progressive decline in other cognitive domains starting at CDR plus NACC FTLD ≥1. Discussion We confirmed cognitive decline in the asymptomatic and prodromal stage of genetic FTD. Specifically, tests for attention, executive function, language, and memory showed clear differences between genetic groups and controls at baseline, but the speed of change over time differed depending on genetic group and disease stage. This confirms the value of neuropsychological assessment in tracking clinical onset and progression and could inform clinical trials in selecting sensitive end points for measuring treatment effects as well as characterizing the best time window for starting treatment.
Prevalence of Sleep Disturbance in Patients With Cancer: A Systematic Review and Meta-Analysis

Sleep disturbance is one of the most common and troubling symptoms that harm the quality of life throughout all phases of treatment and stages of the illness among patients with cancer. The aim of this meta-analysis is to examine the present status of sleep disturbance prevalence in patients with cancer. The following databases were searched: PubMed, CINAHL, MEDLINE, EMBASE, PsycINFO, from inception to April 2021. Prevalence rates were pooled with meta-analysis using a random-effects model. A total of 160 studies (N = 46,279) published between 1998 and 2021 met the inclusion criteria. The overall prevalence of sleep disturbance was 60.7% (26,448/46,279 participants, 95% CI 58.1–63.3%) with significant heterogeneity between studies (p < .000, τ2 = .0000, I2 = 96.4%). This meta-analysis highlights the importance of developing optimal monitoring strategies to reduce sleep disturbance and improve the quality of life of cancer patients.
Conformational heterogeneity of UCAAUC RNA oligonucleotide from molecular dynamics simulations, SAXS, and NMR experiments

We describe the conformational ensemble of the single-stranded r(UCAAUC) oligonucleotide obtained using extensive molecular dynamics (MD) simulations and Rosetta's FARFAR2 algorithm. The conformations observed in MD consist of A-form-like structures and variations thereof. These structures are not present in the pool generated using FARFAR2. By comparing with available nuclear magnetic resonance (NMR) measurements, we show that the presence of both A-form-like and other extended conformations is necessary to quantitatively explain experimental data. To further validate our results, we measure solution X-ray scattering (SAXS) data on the RNA hexamer and find that simulations result in more compact structures than observed from these experiments. The integration of simulations with NMR via a maximum entropy approach shows that small modifications to the MD ensemble lead to an improved description of the conformational ensemble. Nevertheless, we identify persisting discrepancies in matching experimental SAXS data.
The Role of Transdiagnostic Variables within Gender Differences in Adolescents' Self Reports of Suicidal Ideation and Suicide Attempts.

BACKGROUND The incidence of suicide attempts peaks during adolescence, with adolescent girls having a higher rate of attempts than boys. Depression is one of the main risk factors of suicidal behaviour and yet not all adolescents with suicidal ideation or attempting suicide have a diagnosable depressive disorder. The present study examined the unique contributions to suicidal ideation and attempting suicide of cognitive processes known to be associated with depression and anxiety, but which are also transdiagnostic: anomalous perception of reality, intolerance of uncertainty, and rumination. METHOD 605 adolescents (M= 13.22, SD= 1.03, 47% girls) were evaluated in a cross-sectional study. RESULTS Multiple linear regression showed that the anomalous perception of reality and intolerance of uncertainty were uniquely associated with the severity of suicidal ideation, even when accounting for symptoms of depression and anxiety, but only amongst girls. In a logistic regression, self-reported depression symptoms, and not underlying cognitive processes, predicted the likelihood of a person having attempted suicide versus not having done so. CONCLUSIONS In adolescent girls, less frequently evaluated transdiagnostic variables may have an important impact on suicidal ideation. However, depression symptoms, and not these transdiagnostic variables, seem to be the greatest contributor to attempting suicide.
Association of Influenza Vaccination With Cardiovascular Risk

Key Points Question Is seasonal influenza vaccination associated with lower rates of adverse cardiovascular events? Findings In this meta-analysis of 6 randomized clinical trials including 9001 adults who were randomized to influenza vaccination vs matching placebo or standard care, 3.6% of vaccinated patients developed a major adverse cardiovascular event within 12 months compared with 5.4% of those who received placebo or control, a 1.8% significant difference translating into a number needed to vaccinate of 56 patients to prevent 1 event. Higher-risk patients with recent acute coronary syndrome had 45% reduced risk. Meaning These results suggest that clinicians and policy makers should continue to counsel high-risk patients on the cardiovascular benefits of seasonal influenza vaccination.