A Randomized Embedded Multifactorial Adaptive Platform for Extra Corporeal Membrane Oxygenation (REMAP ECMO) - Design and Rationale of the Left Ventricular Unloading trial domain.

BACKGROUND: The use of Extracorporeal Membrane Oxygenation (ECMO) remains associated with high rates of complications, weaning failure and mortality which can be partly explained by a knowledge gap on how to properly manage patients on ECMO support. To address relevant patient management issues, we designed a "Randomized Embedded Multifactorial Adaptive Platform (REMAP)" in the setting of ECMO (REMAP ECMO) and a first embedded randomized controlled trial (RCT) investigating the effects of routine early left ventricular (LV) unloading through intra-aortic balloon pumping (IABP). METHODS: REMAP ECMO describes a registry-based platform allowing for the embedding of multiple response adaptive RCTs (trial domains) which can perpetually address the effect of relevant patient management issues on ECMO weaning success. A first trial domain studies the effects of LV unloading by means of an IABP as an adjunct to veno-arterial (V-A) ECMO versus V-A ECMO alone on ECMO weaning success at 30 days in adult cardiogenic shock patients admitted to the Intensive Care Unit (ICU). The primary outcome of this trial is "successful weaning from ECMO" being defined as a composite of survival without the need for mechanical circulatory support, heart transplantation, or left ventricular assist device (LVAD) at 30 days after initiation of ECMO. Secondary outcomes include the need for interventional escalation of LV unloading strategy, mechanistic endpoints, survival characteristics until one year after ECMO initiation, and quality of life. Trial data will be analysed using a Bayesian statistical framework. The adaptive design allows for a high degree of flexibility, such as response adaptive randomization and early stopping of the trial for efficacy or futility. The REMAP ECMO LV unloading study is approved by the Medical Ethical Committee of the Erasmus Medical Center and is publicly registered. CONCLUSION: This REMAP ECMO trial platform enables the efficient roll-out of multiple RCTs on relevant patient management issues. A first embedded trial domain will compare routine LV unloading by means of an IABP as an adjunct to V-A ECMO versus V-A ECMO alone. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05913622.

Unveiling cellular and molecular aspects of ascending thoracic aortic aneurysms and dissections.

Ascending thoracic aortic aneurysm (ATAA) remains a significant medical concern, with its asymptomatic nature posing diagnostic and monitoring challenges, thereby increasing the risk of aortic wall dissection and rupture. Current management of aortic repair relies on an aortic diameter threshold. However, this approach underestimates the complexity of aortic wall disease due to important knowledge gaps in understanding its underlying pathologic mechanisms.Since traditional risk factors cannot explain the initiation and progression of ATAA leading to dissection, local vascular factors such as extracellular matrix (ECM) and vascular smooth muscle cells (VSMCs) might harbor targets for early diagnosis and intervention. Derived from diverse embryonic lineages, VSMCs exhibit varied responses to genetic abnormalities that regulate their contractility. The transition of VSMCs into different phenotypes is an adaptive response to stress stimuli such as hemodynamic changes resulting from cardiovascular disease, aging, lifestyle, and genetic predisposition. Upon longer exposure to stress stimuli, VSMC phenotypic switching can instigate pathologic remodeling that contributes to the pathogenesis of ATAA.This review aims to illuminate the current understanding of cellular and molecular characteristics associated with ATAA and dissection, emphasizing the need for a more nuanced comprehension of the impaired ECM-VSMC network.

MicroRNA-216a is essential for cardiac angiogenesis.

While it is experimentally supported that impaired myocardial vascularization contributes to a mismatch between myocardial oxygen demand and supply, a mechanistic basis for disruption of coordinated tissue growth and angiogenesis in heart failure remains poorly understood. Silencing strategies that impair microRNA biogenesis have firmly implicated microRNAs in the regulation of angiogenesis, and individual microRNAs prove to be crucial in developmental or tumor angiogenesis. A high-throughput functional screening for the analysis of a whole-genome microRNA silencing library with regard to their phenotypic effect on endothelial cell proliferation as a key parameter, revealed several anti- and pro-proliferative microRNAs. Among those was miR-216a, a pro-angiogenic microRNA which is enriched in cardiac microvascular endothelial cells and reduced in expression under cardiac stress conditions. miR-216a null mice display dramatic cardiac phenotypes related to impaired myocardial vascularization and unbalanced autophagy and inflammation, supporting a model where microRNA regulation of microvascularization impacts the cardiac response to stress.

Evaluation of an Infection surveillance program in residential aged care facilities in Victoria, Australia.

BACKGROUND: Infection surveillance is a key element of infection prevention and control activities in the aged care sector. In 2017, a standardised infection surveillance program was established for public residential aged care services in Victoria, Australia. This program will soon be expanded to a national level for all Australian residential aged care facilities. It has not been evaluated since its inception. METHODS: The current study aimed to evaluate the Victorian Healthcare Associated Infection Surveillance System (VICNISS) Coordinating Centre Aged Care Infection Indicator Program (ACIIP), to understand its performance and functionality. A mixed methods evaluation was performed using the Updated Guidelines for Evaluating Public Health Surveillance Systems developed by the United States Centers for Disease Control and Prevention as a framework. VICNISS staff who coordinate and manage the ACIIP were invited to participate in interviews. Residential aged care staff who use the program were invited to participate in a survey. Document analysis was also performed. RESULTS: Four VICNISS staff participated in the interviews and 38 aged care staff participated in the survey. The ACIIP is stable and able to be adapted quickly to changing definitions for infections. Users found the system relatively easy to use but have difficulties after the long intervals between data entry year on year. VICNISS staff provide expert guidance which benefits users. Users appreciated the benefit of participating and many use the data for improving local practice. CONCLUSIONS: The ACIIP is a usessful state-wide infection surveillance program for aged care. Further development of data validation, IT system capacity and models for education and user support will be required to support future scalability.

Automatic tablet-based monoplane quantification of stroke volume and left ventricular ejection fraction: A comparative assessment against computer-based biplane and monoplane tools.

BACKGROUND: Point-of-care cardiovascular left ventricle ejection fraction (LVEF) quantification is established, but automatic tablet-based stroke volume (SV) quantification with handheld ultrasound (HAND) devices is unexplored. We evaluated a tablet-based monoplane LVEF and LV volume quantification tool (AutoEF) against a computer-based tool (Tomtec) for LVEF and SV quantification. METHODS: Patients underwent HAND scans, and LVEF and SV were quantified using AutoEF and computer-based software that utilized either apical four-chamber views (Auto Strain-monoplane [AS-mono]) or both apical four-chamber and apical two-chamber views (Auto Strain-biplane [AS-bi]). Correlation and Bland-Altman analysis were used to compare AutoEF with AS-mono and AS-bi. RESULTS: Out of 43 participants, eight were excluded. AutoEF showed a correlation of .83 [.69:.91] with AS-mono for LVEF and .68 [.44:.82] for SV. The correlation with AS-bi was .79 [.62:.89] for LVEF and .66 [.42:.81] for SV. The bias between AutoEF and AS-mono was 4.88% [3.15:6.61] for LVEF and 17.46 mL [12.99:21.92] for SV. The limits of agreement (LOA) were [-5.50:15.26]% for LVEF and [-8.02:42.94] mL for SV. The bias between AutoEF and AS-bi was 6.63% [5.31:7.94] for LVEF and 20.62 mL [16.18:25.05] for SV, with LOA of [-1.20:14.47]% for LVEF and [-4.71:45.94] mL for SV. CONCLUSION: LVEF quantification with AutoEF software was accurate and reliable, but SV quantification showed limitations, indicating non-interchangeability with neither AS-mono nor AS-bi. Further refinement of AutoEF is needed for reliable SV quantification at the point of care.

Genomic instability in the naturally and prematurely aged myocardium.

Genomic instability, the unresolved accumulation of DNA variants, is hypothesized as one of the contributors to the natural aging process. We assessed the frequency of unresolved DNA damage reaching the transcriptome of the murine myocardium during the course of natural aging and in hearts from four distinct mouse models of premature aging with established aging-related cardiac dysfunctions. RNA sequencing and variant calling based on total RNA sequencing was compared between hearts from naturally aging mice, mice with cardiomyocyte-specific deficiency of Ercc1, a component of the DNA repair machinery, mice with reduced mitochondrial antioxidant capacity, Tert-deficient mice with reduced telomere length, and a mouse model of human Hutchinson-Gilford progeria syndrome (HGPS). Our results demonstrate that no enrichment in variants is evident in the naturally aging murine hearts until 2 y of age from the HGPS mouse model or mice with reduced telomere lengths. In contrast, a dramatic accumulation of variants was evident in Ercc1 cardiomyocyte-specific knockout mice with deficient DNA repair machinery, in mice with reduced mitochondrial antioxidant capacity, and in the intestine, liver, and lung of naturally aging mice. Our data demonstrate that genomic instability does not evidently contribute to naturally aging of the mouse heart in contrast to other organs and support the contention that the endogenous DNA repair machinery is remarkably active to maintain genomic integrity in cardiac cells throughout life.

Molecular drivers of insecticide resistance in the Sahelo-Sudanian populations of a major malaria vector Anopheles coluzzii.

BACKGROUND: Information on common markers of metabolic resistance in malaria vectors from countries sharing similar eco-climatic characteristics can facilitate coordination of malaria control. Here, we characterized populations of the major malaria vector Anopheles coluzzii from Sahel region, spanning four sub-Saharan African countries: Nigeria, Niger, Chad and Cameroon. RESULTS: Genome-wide transcriptional analysis identified major genes previously implicated in pyrethroid and/or cross-resistance to other insecticides, overexpressed across the Sahel, including CYP450s, glutathione S-transferases, carboxylesterases and cuticular proteins. Several, well-known markers of insecticide resistance were found in high frequencies-including in the voltage-gated sodium channel (V402L, I940T, L995F, I1527T and N1570Y), the acetylcholinesterase-1 gene (G280S) and the CYP4J5-L43F (which is fixed). High frequencies of the epidemiologically important chromosomal inversion polymorphisms, 2La, 2Rb and 2Rc, were observed (~80% for 2Rb and 2Rc). The 2La alternative arrangement is fixed across the Sahel. Low frequencies of these inversions (<10%) were observed in the fully insecticide susceptible laboratory colony of An. coluzzii (Ngoussou). Several of the most commonly overexpressed metabolic resistance genes sit in these three inversions. Two commonly overexpressed genes, GSTe2 and CYP6Z2, were functionally validated. Transgenic Drosophila melanogaster flies expressing GSTe2 exhibited extremely high DDT and permethrin resistance (mortalities <10% in 24h). Serial deletion of the 5' intergenic region, to identify putative nucleotide(s) associated with GSTe2 overexpression, revealed that simultaneous insertion of adenine nucleotide and a transition (T->C), between Forkhead box L1 and c-EST putative binding sites, were responsible for the high overexpression of GSTe2 in the resistant mosquitoes. Transgenic flies expressing CYP6Z2 exhibited marginal resistance towards 3-phenoxybenzylalcohol (a primary product of pyrethroid hydrolysis by carboxylesterases) and a type II pyrethroid, α-cypermethrin. However, significantly higher mortalities were observed in CYP6Z2 transgenic flies compared with controls, on exposure to the neonicotinoid, clothianidin. This suggests a possible bioactivation of clothianidin into a toxic intermediate, which may make it an ideal insecticide against populations of An. coluzzii overexpressing this P450. CONCLUSIONS: These findings will facilitate regional collaborations within the Sahel region and refine implementation strategies through re-focusing interventions, improving evidence-based, cross-border policies towards local and regional malaria pre-elimination.

Lichen biomonitoring to assess spatial variability, potential sources and human health risks of polycyclic aromatic hydrocarbons (PAHs) and airborne metal concentrations in Manchester (UK).

Airborne metals and organic pollutants are linked to severe human health impacts, i.e. affecting the nervous system and being associated with cancer. Airborne metals and polycyclic aromatic hydrocarbons (PAHs) in urban environments are derived from diverse sources, including combustion and industrial and vehicular emissions, posing a threat to air quality and subsequently human health. A lichen biomonitoring approach was used to assess spatial variability of airborne metals and PAHs, identify potential pollution sources and assess human health risks across the City of Manchester (UK). Metal concentrations recorded in lichen samples were highest within the city centre area and along the major road network, and lichen PAH profiles were dominated by 4-ring PAHs (189.82 ng g-1 in Xanthoria parietina), with 5- and 6-ring PAHs also contributing to the overall PAH profile. Cluster analysis and pollution index factor (PIF) calculations for lichen-derived metal concentrations suggested deteriorated air quality being primarily linked to vehicular emissions. Comparably, PAH diagnostic ratios identified vehicular sources as a primary cause of PAH pollution across Manchester. However, local more complex sources (e.g. industrial emissions) were further identified. Human health risk assessment found a "moderate" risk for adults and children by airborne potential harmful element (PHEs) concentrations, whereas PAH exposure in Manchester is potentially linked to 1455 (ILCR = 1.45 × 10-3) cancer cases (in 1,000,000). Findings of this study indicate that an easy-to-use lichen biomonitoring approach can aid to identify hotspots of impaired air quality and potential human health impacts by airborne metals and PAHs across an urban environment, particularly at locations that are not continuously covered by (non-)automated air quality measurement programmes.

HPV-related oropharyngeal carcinoma remains infrequent over 25 years in a Brazilian Oral Pathology Center: A cross-sectional study with literature review.

BACKGROUND: The aim was to evaluate the frequency, clinicopathological features, and HPV status of oropharyngeal squamous cell carcinoma (OP-SCC) and benign HPV-related epithelial lesions of the oropharynx over the last 25 years. Moreover, a literature review was performed to investigate HPV frequency in OP-SCC samples diagnosed in Brazilian Centers. MATERIAL AND METHODS: A cross-sectional study analyzed OP-SCC, squamous papilloma, verruca vulgaris, and condyloma accuminatum, diagnosed from 1997 to 2021. HPV status of OP-SCC was determined by immunohistochemistry and "in situ" hybridization. Bivariate statistics were performed (p≤0.05). For the literature review, MEDLINE/PubMed, Web of Science, EMBASE, and Scopus were searched. Two independent reviewers assessed the studies for eligibility. RESULTS: Cross-sectional: 211 OP-SCC (63.0%) and 124 benign lesions (37.0%) were included. OP-SCC frequency increased gradually over time, whereas benign lesions had steady trends. OP-SCC affected more males (n= 171; 81.0%), though the relative frequency in females rose over time. Smoking (n= 127; 60.2%) was common in OP-SCC. Nineteen OP-SCC (13.0%) were positive for HPV. HPV-positive and HPV-negative tumors had similar clinicopathological features (p>0.05). Benign lesions predominated in middle-aged (n= 32; 26.7%) women (n= 71; 57.3%), in the soft palate (n=101; 81.5%). LITERATURE REVIEW: 32 studies were included, and in 60% of them, HPV frequency in OP-SCC was less than 25%. CONCLUSIONS: OP-SCC prevalence has been increasing, and it was mostly associated with smoking and alcohol rather than with HPV infection in Brazil. Benign lesions had a stationary frequency over the evaluated period.

Oral cancer prediction by noninvasive genetic screening.

Oral squamous cell carcinomas (OSCCs) develop in genetically altered epithelium in the mucosal lining, also coined as fields, which are mostly not visible but occasionally present as white oral leukoplakia (OL) lesions. We developed a noninvasive genetic assay using next-generation sequencing (NGS) on brushed cells to detect the presence of genetically altered fields, including those that are not macroscopically visible. The assay demonstrated high accuracy in OL patients when brush samples were compared with biopsies as gold standard. In a cohort of Fanconi anemia patients, detection of mutations in prospectively collected oral brushes predicted oral cancer also when visible abnormalities were absent. We further provide insight in the molecular landscape of OL with frequent changes of TP53, FAT1 and NOTCH1. NGS analysis of noninvasively collected samples offers a highly accurate method to detect genetically altered fields in the oral cavity, and predicts development of OSCC in high-risk individuals. Noninvasive genetic screening can be employed to screen high-risk populations for cancer and precancer, map the extension of OL lesions beyond what is visible, map the oral cavity for precancerous changes even when visible abnormalities are absent, test accuracy of promising imaging modalities, monitor interventions and determine genetic progression as well as the natural history of the disease in the human patient.

Effect of vitamin K supplementation on serum calcification propensity and arterial stiffness in vitamin K-deficient kidney transplant recipients: A double-blind, randomized, placebo-controlled clinical trial.

Vitamin K deficiency is common among kidney transplant recipients (KTRs) and likely contributes to progressive vascular calcification and stiffness. In this single-center, randomized, double-blind, placebo-controlled trial, we aimed to investigate the effects of vitamin K supplementation on the primary end point, serum calcification propensity (calciprotein particle maturation time, T50), and secondary end points arterial stiffness (pulse wave velocity [PWV]) and vitamin K status in 40 vitamin K-deficient KTRs (plasma dephosphorylated uncarboxylated matrix Gla protein [dp-ucMGP] ≥500 pmol/L). Participants (35% female; age, 57 ± 13 years) were randomized 1:1 to vitamin K2 (menaquinone-7, 360 µg/day) or placebo for 12 weeks. Vitamin K supplementation had no effect on calcification propensity (change in T50 vs baseline +2.3 ± 27.4 minutes) compared with placebo (+0.8 ± 34.4 minutes; Pbetween group = .88) but prevented progression of PWV (change vs baseline -0.06 ± 0.26 m/s) compared with placebo (+0.27 ± 0.43 m/s; Pbetween group = .010). Vitamin K supplementation strongly improved vitamin K status (change in dp-ucMGP vs baseline -385 [-631 to -269] pmol/L) compared with placebo (+39 [-188 to +183] pmol/L; Pbetween group < .001), although most patients remained vitamin K-deficient. In conclusion, vitamin K supplementation did not alter serum calcification propensity but prevented progression of arterial stiffness, suggesting that vitamin K has vascular effects independent of calciprotein particles. These results set the stage for longer-term intervention studies with vitamin K supplementation in KTRs. TRIAL REGISTRY: EU Clinical Trials Register (EudraCT Number: 2019-004906-88) and the Dutch Trial Register (NTR number: NL7687).

γ-Glutamyl carboxylase mutations differentially affect the biological function of vitamin K-dependent proteins.

γ-Glutamyl carboxylase (GGCX) is an integral membrane protein that catalyzes posttranslational carboxylation of a number of vitamin K-dependent (VKD) proteins involved in a wide variety of physiologic processes, including blood coagulation, vascular calcification, and bone metabolism. Naturally occurring GGCX mutations are associated with multiple distinct clinical phenotypes. However, the genotype-phenotype correlation of GGCX remains elusive. Here, we systematically examined the effect of all naturally occurring GGCX mutations on the carboxylation of 3 structure-function distinct VKD proteins in a cellular environment. GGCX mutations were transiently introduced into GGCX-deficient human embryonic kidney 293 cells stably expressing chimeric coagulation factor, matrix Gla protein (MGP), or osteocalcin as VKD reporter proteins, and then the carboxylation efficiency of these reporter proteins was evaluated. Our results show that GGCX mutations differentially affect the carboxylation of these reporter proteins and the efficiency of using vitamin K as a cofactor. Carboxylation of these reporter proteins by a C-terminal truncation mutation (R704X) implies that GGCX's C terminus plays a critical role in the binding of osteocalcin but not in the binding of coagulation factors and MGP. This has been confirmed by probing the protein-protein interaction between GGCX and its protein substrates in live cells using bimolecular fluorescence complementation and chemical cross-linking assays. Additionally, using a minigene splicing assay, we demonstrated that several GGCX missense mutations affect GGCX's pre-messenger RNA splicing rather than altering the corresponding amino acid residues. Results from this study interpreted the correlation of GGCX's genotype and its clinical phenotypes and clarified why vitamin K administration rectified bleeding disorders but not nonbleeding disorders.

Comparison of two hybrid sentinel node tracers: indocyanine green (ICG)-99mTc-nanocolloid vs. ICG-99mTc-nanoscan from a nuclear medicine and surgical perspective.

BACKGROUND: Lymph node (LN) metastasis is a relevant predictor for survival in patients with a.o. penile cancer (PeCa), malignant melanoma. The sentinel node (SN) procedure comprises targeted resection of the first tumour-draining SNs. Here, the hybrid tracer indocyanine green (ICG)-99mTc-nanocolloid has been used for several years to combine optical and nuclear detection. Recently, the resource of the nanocolloid precursor stopped production and the precursor was replaced by a different but chemically comparable colloid, nanoscan. Our aim was to study the performance of ICG-99mTc-nanoscan compared to ICG-99mTc-nanocolloid from a nuclear and surgical perspective. METHODS: Twenty-four patients with either PeCa or head-and-neck (H&N) melanoma and scheduled for a SN procedure were included. The initial group (n = 11) received ICG-99mTc-nanocolloid until no longer available; the second group (n = 13) received ICG-99mTc-nanoscan. Tracer uptake was assessed on lymphoscintigraphy and single-photon emission (SPECT). Intraoperatively, SNs were identified using gamma tracing and fluorescence imaging. Ex vivo (back-table) measurements were conducted to quantify the fluorescence emissions. Chemical analysis was performed to compare the ICG assembly on both precursors. RESULTS: The mean tracer uptake in the SNs was similar for ICG-99mTc-nanocolloid (2.2 ± 4.3%ID) and ICG-99mTc-nanoscan (1.8 ± 2.6%ID; p = 0.68). 3 SNs (interquartile range (IQR) 3-4) were detected on lymphoscintigraphy in PeCa patients receiving ICG-99mTc-nanoscan compared to 2 SNs (IQR 2-3) in PeCa patients receiving ICG-99mTc-nanocolloid (p = 0.045), no differences were observed in H&N patients. Back-table measurements of resected SNs revealed a lower total fluorescence intensity in the ICG-99mTc-nanoscan group (24*109 arbitrary units (A.U) IQR 1.6*109-14*109 in the ICG-99mTc-nanocolloid group versus 4.6*109 A.U. IQR 2.4*109-42*109 in the ICG-99mTc-nanoscan group, p = 0.0054). This was consistent with a larger degree of "stacked" ICG observed in the nanoscan formulation. No tracer-related adverse events were reported. CONCLUSIONS: Based on this retrospective analysis, we can conclude that ICG-99mTc-nanoscan has similar capacity for SN identification as ICG-99mTc-nanocolloid and can safely be implemented in SN procedures.

The role of differentiated dysplasia in the prediction of malignant transformation of oral leukoplakia.

OBJECTIVE: Oral leukoplakia is the most common oral potentially malignant disorder. Malignant transformation of oral leukoplakia occurs at an annual rate of 1%-7%. WHO-defined classic epithelial dysplasia is an important predictor of malignant transformation of oral leukoplakia, but we have previously shown in a proof of concept study that prediction improves by incorporation of an architectural pattern of dysplasia, also coined as differentiated dysplasia. We aimed to analyze this finding in a larger cohort of patients. METHOD: For this retrospective study 176 oral leukoplakia patients were included. Biopsies for all patients were assessed for the presence of dysplasia and analyzed for cytokeratin 13 and 17 expression. Moreover, the inter-observer agreement for the diagnosis of differentiated dysplasia was determined. RESULTS: In total, 33 of 176 patients developed oral squamous cell carcinoma during follow-up. Presence of classic epithelial dysplasia increased cancer risk two-fold (HR = 2.18, p = 0.026). Lesions without classic epithelial dysplasia could be further risk-stratified by the presence of differentiated dysplasia (HR = 7.36, p < 0.001). Combined classic epithelial and differentiated dysplasia imparted a seven-fold increased risk of malignant transformation (7.34, p = 0.001). Inter-observer agreement for the diagnosis of dysplasia, including differentiated dysplasia, was moderate (κ = 0.56, p < 0.001). DISCUSSION: This study emphasizes the importance of the recognition of the architectural pattern of differentiated dysplasia as a separate entity for risk prediction of malignant transformation of oral leukoplakia. Presence of any pattern of dysplasia results in accurate prediction of malignant transformation risk of oral leukoplakia.

Detecting evidence of invasive fungal infections in cytology and histopathology reports enriched with concept-level annotations.

Invasive fungal infections (IFIs) are particularly dangerous to high-risk patients with haematological malignancies and are responsible for excessive mortality and delays in cancer therapy. Surveillance of IFI in clinical settings offers an opportunity to identify potential risk factors and evaluate new therapeutic strategies. However, manual surveillance is both time- and resource-intensive. As part of a broader project aimed to develop a system for automated IFI surveillance by leveraging electronic medical records, we present our approach to detecting evidence of IFI in the key diagnostic domain of histopathology. Using natural language processing (NLP), we analysed cytology and histopathology reports to identify IFI-positive reports. We compared a conventional bag-of-words classification model to a method that relies on concept-level annotations. Although the investment to prepare data supporting concept annotations is substantial, extracting targeted information specific to IFI as a pre-processing step increased the performance of the classifier from the PR AUC of 0.84 to 0.92 and enabled model interpretability. We have made publicly available the annotated dataset of 283 reports, the Cytology and Histopathology IFI Reports corpus (CHIFIR), to allow the clinical NLP research community to further build on our results.

Intercellular transfer of miR-200c-3p impairs the angiogenic capacity of cardiac endothelial cells.

As mediators of intercellular communication, extracellular vesicles containing molecular cargo, such as microRNAs, are secreted by cells and taken up by recipient cells to influence their cellular phenotype and function. Here we report that cardiac stress-induced differential microRNA content, with miR-200c-3p being one of the most enriched, in cardiomyocyte-derived extracellular vesicles mediates functional cross-talk with endothelial cells. Silencing of miR-200c-3p in mice subjected to chronic increased cardiac pressure overload resulted in attenuated hypertrophy, smaller fibrotic areas, higher capillary density, and preserved cardiac ejection fraction. We were able to maximally rescue microvascular and cardiac function with very low doses of antagomir, which specifically silences miR-200c-3p expression in non-myocyte cells. Our results reveal vesicle transfer of miR-200c-3p from cardiomyocytes to cardiac endothelial cells, underlining the importance of cardiac intercellular communication in the pathophysiology of heart failure.

Insulin-like growth factor 1 and the hormonal mediation of sibling rivalry.

In altricial animals, young are completely dependent on parents for provisioning. The ability to outcompete siblings to receive parental provisioning has clear fitness benefits, and may be mediated by hormones that influence growth. We analyzed the effects of insulin-like growth factor 1 (IGF-1) on body size, growth, and sibling rivalry in eastern bluebirds (Sialia sialis). To determine whether IGF-1 is upregulated in response to the competitive environment, we manipulated brood sizes and examined the effect on IGF-1 levels, nestling body size, growth rate, and behavior. In a separate experiment, we injected nestlings with exogenous IGF-1 to study its impacts on body size, growth rate, and sibling competition. Brood size manipulation did not influence endogenous IGF-1 levels, but male nestlings with higher IGF-1 levels early in the nestling period tended to have greater mass gain than males with lower IGF-1 levels. Nestlings with higher IGF-1 levels also tended to be fed more frequently by parents. In the injection experiment, IGF-1 injected individuals tended to be heavier than vehicle injected young by the end of the nestling period, which suggests that IGF-1 can influence mass gain in bluebirds. IGF-1 has been proposed to be a mediator of life-history strategies and post-hatching behavior. Our results suggest that although bluebird nestlings do not adaptively elevate IGF-1 in response to the presence or number of siblings, IGF-1 may influence growth during the nestling period. These findings shed light on sibling competition, life history strategies, and the hormones that underlie them.

Prevalence and risk factors of gestational diabetes in the health region of Lleida: a retrospective observational cohort study.

BACKGROUND: Diabetes is a very common metabolic condition during pregnancy. The number of cases increases with age and obesity. The prevalence of pre-gestational diabetes and gestational diabetes (GD) differs between different ethnic groups. OBJECTIVE: The aim of the study was to analyse the prevalence of pre-gestational diabetes and GD in the health region of Lleida. We also studied the GD risk factors during pregnancy according to the country of origin of the pregnant woman. METHODS: We performed a retrospective observational cohort study among pregnant women between 2012 and 2018 in the health region of Lleida. A multivariate model was performed with the different variables analysed by calculating the regression coefficient and its 95% confidence interval (CI). RESULTS: In our sample of 17,177 pregnant women, we observed a prevalence of pre-gestational diabetes and GD of 8.2% and 6.5%, respectively. We found a relationship of gestational diabetes with different factors: age, with 6.8% in 30-34 year-old women and 11.3% in women over 35 (OR 1.78 and 3.29, respectively); overweight, with 8.29% (OR 1.89); and obesity, with 12.9% (OR 3.15). Finally, women from Asia and the Middle East and the Maghreb had a higher risk of diabetes, with 12.2% (OR 2.1) and 9.91% (OR 1.3), respectively, and Sub-Saharan women had a lower risk of it 6.07% (OR 0.71). CONCLUSIONS: GD has different risk factors, such as age, overweight, and obesity. Non-related conditions include hypothyroidism, arterial hypertension, and dyslipidaemia. Finally, pregnant women from the Maghreb, and Asia and the Middle East, are at higher risk of developing diabetes during pregnancy; meanwhile, Sub-Saharan origin is protector factor.

Management of Patients with Suspected or Confirmed Antibiotic Allergy: Executive Summary of Guidelines from the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), the Spanish Society of Allergy and Clinical Immunology (SEAIC), the Spanish Society of Hospital Pharmacy (SEFH) and the Spanish Society of Intensive Medicine and Coronary Care Units (SEMICYUC).

Suspected or confirmed antibiotic allergy is a frequent clinical circumstance that influences antimicrobial prescription and often leads to the avoidable use of less efficacious and/or more toxic or costly drugs than first-line antimicrobials. Optimizing antimicrobial therapy in patients with antibiotic allergy labels has become one of the priorities of antimicrobial stewardship programs in several countries. These guidelines aim to make recommendations for the systematic approach to patients with suspected or confirmed antibiotic allergy based on current evidence. An expert panel (11 members of various scientific societies) formulated questions about the management of patients with suspected or confirmed antibiotic allergy. A systematic literature review was performed by a medical librarian. The questions were distributed among panel members who selected the most relevant references, summarized the evidence, and formulated graded recommendations when possible. The answers to all the questions were finally reviewed by all panel members. A systematic approach to patients with suspected or confirmed antibiotic allergy was recommended to improve antibiotic selection and, consequently, clinical outcomes. A clinically oriented, 3-category risk-stratification strategy was recommended for patients with suspected antibiotic allergy. Complementary assessments should consider both clinical risk category and preferred antibiotic agent. Empirical therapy recommendations for the most relevant clinical syndromes in patients with suspected or confirmed ß-lactam allergy were formulated, as were recommendations on the implementation and monitoring of the impact of the guidelines. Antimicrobial stewardship programs and allergists should design and implement activities that facilitate the most appropriate use of antibiotics in these patients.

Associations between clinical and histopathological characteristics in oral leukoplakia.

OBJECTIVES: To identify possible associations between patients' demographics and habits and the clinical aspects and histopathological characteristics of oral leukoplakia (OL) at patients' first visit. METHOD: A total of 140 consecutive patients with OL at a single institute between 1997 and 2019. All biopsies were microscopically examined for classic dysplasia (CD) (WHO definition oral epithelial dysplasia) and differentiated dysplasia (DD) known from differentiated vulvar intraepithelial neoplasia. Clinical characteristics were correlated to histopathological diagnosis and odds ratios (OR) were calculated. RESULTS: A total of 96 females and 44 males, mean age 58 years, were presented. OLs were found mainly on the tongue (41%) and floor of mouth (FOM) (18%). Homogeneous OLs (58%) were associated with smoking, FOM and size <2cm and non-homogeneous OLs (42%) with non-smokers. No dysplasia was present in 40% and any dysplasia (AD) in 60%. Tongue OLs were correlated with AD (OR:6.0) and CD (OR:5.7). FOM OLs were correlated with CD (OR:4.5). DD was correlated with non-homogeneous OLs (OR:2.6). CONCLUSIONS: CD was most frequently observed in tongue and FOM OLs, while DD was associated with non-homogeneous OLs. In this series of patients, there was no consistent reliable association between the clinical and histopathological features and clinical characteristics can therefore not substitute microscopic examination of biopsies.