TMPRSS2-mediated SARS-CoV-2 uptake boosts innate immune activation, enhances cytopathology, and drives convergent virus evolution.

The accessory protease transmembrane protease serine 2 (TMPRSS2) enhances severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uptake into ACE2-expressing cells, although how increased entry impacts downstream viral and host processes remains unclear. To investigate this in more detail, we performed infection assays in engineered cells promoting ACE2-mediated entry with and without TMPRSS2 coexpression. Electron microscopy and inhibitor experiments indicated TMPRSS2-mediated cell entry was associated with increased virion internalization into endosomes, and partially dependent upon clathrin-mediated endocytosis. TMPRSS2 increased panvariant uptake efficiency and enhanced early rates of virus replication, transcription, and secretion, with variant-specific profiles observed. On the host side, transcriptional profiling confirmed the magnitude of infection-induced antiviral and proinflammatory responses were linked to uptake efficiency, with TMPRSS2-assisted entry boosting early antiviral responses. In addition, TMPRSS2-enhanced infections increased rates of cytopathology, apoptosis, and necrosis and modulated virus secretion kinetics in a variant-specific manner. On the virus side, convergent signatures of cell-uptake-dependent innate immune induction were recorded in viral genomes, manifesting as switches in dominant coupled Nsp3 residues whose frequencies were correlated to the magnitude of the cellular response to infection. Experimentally, we demonstrated that selected Nsp3 mutations conferred enhanced interferon antagonism. More broadly, we show that TMPRSS2 orthologues from evolutionarily diverse mammals facilitate panvariant enhancement of cell uptake. In summary, our study uncovers previously unreported associations, linking cell entry efficiency to innate immune activation kinetics, cell death rates, virus secretion dynamics, and convergent selection of viral mutations. These data expand our understanding of TMPRSS2's role in the SARS-CoV-2 life cycle and confirm its broader significance in zoonotic reservoirs and animal models.

Unraveling the dynamics of hepatitis C virus adaptive mutations and their impact on antiviral responses in primary human hepatocytes.

Hepatitis C virus (HCV) infection progresses to chronicity in the majority of infected individuals. Its high intra-host genetic variability enables HCV to evade the continuous selection pressure exerted by the host, contributing to persistent infection. Utilizing a cell culture-adapted HCV population (p100pop) which exhibits increased replicative capacity in various liver cell lines, this study investigated virus and host determinants that underlie enhanced viral fitness. Characterization of a panel of molecular p100 clones revealed that cell culture adaptive mutations optimize a range of virus-host interactions, resulting in expanded cell tropism, altered dependence on the cellular co-factor micro-RNA 122 and increased rates of virus spread. On the host side, comparative transcriptional profiling of hepatoma cells infected either with p100pop or its progenitor virus revealed that enhanced replicative fitness correlated with activation of endoplasmic reticulum stress signaling and the unfolded protein response. In contrast, infection of primary human hepatocytes with p100pop led to a mild attenuation of virion production which correlated with a greater induction of cell-intrinsic antiviral defense responses. In summary, long-term passage experiments in cells where selective pressure from innate immunity is lacking improves multiple virus-host interactions, enhancing HCV replicative fitness. However, this study further indicates that HCV has evolved to replicate at low levels in primary human hepatocytes to minimize innate immune activation, highlighting that an optimal balance between replicative fitness and innate immune induction is key to establish persistence. IMPORTANCE: Hepatitis C virus (HCV) infection remains a global health burden with 58 million people currently chronically infected. However, the detailed molecular mechanisms that underly persistence are incompletely defined. We utilized a long-term cell culture-adapted HCV, exhibiting enhanced replicative fitness in different human liver cell lines, in order to identify molecular principles by which HCV optimizes its replication fitness. Our experimental data revealed that cell culture adaptive mutations confer changes in the host response and usage of various host factors. The latter allows functional flexibility at different stages of the viral replication cycle. However, increased replicative fitness resulted in an increased activation of the innate immune system, which likely poses boundary for functional variation in authentic hepatocytes, explaining the observed attenuation of the adapted virus population in primary hepatocytes.

Targeting cellular cathepsins inhibits hepatitis E virus entry.

BACKGROUND AND AIMS: HEV is estimated to be responsible for 70,000 deaths annually, yet therapy options remain limited. In the pursuit of effective antiviral therapies, targeting viral entry holds promise and has proven effective for other viruses. However, the precise mechanisms and host factors required during HEV entry remain unclear. Cellular proteases have emerged as host factors required for viral surface protein activation and productive cell entry by many viruses. Hence, we investigated the functional requirement and therapeutic potential of cellular protease during HEV infection. APPROACH AND RESULTS: Using our established HEV cell culture model and subgenomic HEV replicons, we found that blocking lysosomal cathepsins (CTS) with small molecule inhibitors impedes HEV infection without affecting replication. Most importantly, the pan-cathepsin inhibitor K11777 suppressed HEV infections with an EC 50 of ~0.02 nM. Inhibition by K11777, devoid of notable toxicity in hepatoma cells, was also observed in HepaRG and primary human hepatocytes. Furthermore, through time-of-addition and RNAscope experiments, we confirmed that HEV entry is blocked by inhibition of cathepsins. Cathepsin L (CTSL) knockout cells were less permissive to HEV, suggesting that CTSL is critical for HEV infection. Finally, we observed cleavage of the glycosylated ORF2 protein and virus particles by recombinant CTSL. CONCLUSIONS: In summary, our study highlights the pivotal role of lysosomal cathepsins, especially CTSL, in the HEV entry process. The profound anti-HEV efficacy of the pan-cathepsin inhibitor K11777, especially with its notable safety profile in primary cells, further underscores its potential as a therapeutic candidate.

Repurposing screen identifies novel candidates for broad-spectrum coronavirus antivirals and druggable host targets.

Libraries composed of licensed drugs represent a vast repertoire of molecules modulating physiological processes in humans, providing unique opportunities for the discovery of host-targeting antivirals. We screened the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) repurposing library with approximately 12,000 molecules for broad-spectrum coronavirus antivirals and discovered 134 compounds inhibiting an alphacoronavirus and mapping to 58 molecular target categories. Dominant targets included the 5-hydroxytryptamine receptor, the dopamine receptor, and cyclin-dependent kinases. Gene knock-out of the drugs' host targets including cathepsin B and L (CTSB/L; VBY-825), the aryl hydrocarbon receptor (AHR; Phortress), the farnesyl-diphosphate farnesyltransferase 1 (FDFT1; P-3622), and the kelch-like ECH-associated protein 1 (KEAP1; Omaveloxolone), significantly modulated HCoV-229E infection, providing evidence that these compounds inhibited the virus through acting on their respective host targets. Counter-screening of all 134 primary compound candidates with SARS-CoV-2 and validation in primary cells identified Phortress, an AHR activating ligand, P-3622-targeting FDFT1, and Omaveloxolone, which activates the NFE2-like bZIP transcription factor 2 (NFE2L2) by liberating it from its endogenous inhibitor KEAP1, as antiviral candidates for both an Alpha- and a Betacoronavirus. This study provides an overview of HCoV-229E repurposing candidates and reveals novel potentially druggable viral host dependency factors hijacked by diverse coronaviruses.

Compensation of inner retina to early-stage photoreceptor degeneration in a RhoP23H/+ mouse model of retinitis pigmentosa.

Retinitis pigmentosa (RP) is an inherited retinal disorder characterized by the degeneration of photoreceptors. RhoP23H/+ mice, which carry a Pro23His mutation in the RHODOPSIN (Rho) gene, are one of the most studied animal models for RP. However, except for the photoreceptors, other retinal neural cells have not been fully investigated in this model. Here, we record the temporal changes of the retina by optical coherence tomography (OCT) imaging of the RhoP23H/+ mice, from early to mid-phase of retinal degeneration. Based on thickness analysis, we identified a natural retinal thickness adaption in wild-type mice during early adulthood and observed morphological compensation of the inner retina layer to photoreceptor degeneration in the RhoP23H/+ mice, primarily on the inner nuclear layer (INL). RhoP23H/+ mice findings were further validated via: histology showing the negative correlation of INL and ONL thicknesses; as well as electroretinogram (ERG) showing an increased b-wave to a-wave ratio. These results unravel the sequential morphologic events in this model and suggest a better understanding of retinal degeneration of RP for future studies.

MicroRNAs modulate SARS-CoV-2 infection of primary human hepatocytes by regulating the entry factors ACE2 and TMPRSS2.

BACKGROUND AND AIMS: Severe acute respiratory syndrome coronavirus (SARS-CoV-2) preferentially infects the respiratory tract; however, several studies have implicated a multi-organ involvement. Hepatic dysfunctions caused by SARS-CoV-2 infection have been increasingly recognized and described to correlate with disease severity. To elucidate molecular factors that could contribute towards hepatic infection, we concentrated on microRNAs (miRNAs), a class of small non-coding RNAs that modulate various cellular processes and which are reported to be differentially regulated during liver injury. We aimed to study the infection of primary human hepatocytes (PHH) with SARS-CoV-2 and to evaluate the potential of miRNAs for modulating viral infection. METHODS: We analysed liver autopsies from a coronavirus disease 19 (COVID-19)-positive cohort for the presence of viral RNA using Nanopore sequencing. PHH were used for the infection with SARS-CoV-2. The candidate miRNAs targeting angiotensin converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) were identified using in silico approaches. To discover the potential regulatory mechanism, transfection experiments, qRT-PCRs, western blots and luciferase reporter assays were performed. RESULTS: We could detect SARS-CoV-2 RNA in COVID-19-positive liver autopsies. We show that PHH express ACE2 and TMPRSS2 and can be readily infected with SARS-CoV-2, resulting in robust replication. Transfection of selected miRNA mimics reduced SARS-CoV-2 receptor expression and SARS-CoV-2 burden in PHH. In silico and biochemical analyses supported a potential direct binding of miR-141-3p to the SARS-CoV-2 genome. CONCLUSION: We confirm that PHH are susceptible to SARS-CoV-2 infection and demonstrate selected miRNAs targeting SARS-CoV-2 entry factors and/or the viral genome reduce viral loads. These data provide novel insights into hepatic susceptibility to SARS-CoV-2 and associated dysfunctions in COVID-19.

The Relationship Between Perceived Uncontrollable Mortality Risk and Health Effort: Replication, Secondary Analysis, and Mini Meta-analysis.

BACKGROUND: The Uncontrollable Mortality Risk Hypothesis (UMRH) states that those who are more likely to die due to factors beyond their control should be less motivated to invest in preventative health behaviors. Greater levels of perceived uncontrollable mortality risk (PUMR) have been associated with lower health effort in previous research, but the topic remains understudied. PURPOSE: To examine the evidence for the UMRH by replicating a previous study investigating the effects of PUMR on social gradients in health effort, and conducting a mini meta-analysis of the overall relationship between PUMR and health effort. METHODS: We replicated Pepper and Nettle (2014), who reported a negative relationship between PUMR and health effort, and that the positive effect of subjective socioeconomic position on health effort was explained away by PUMR. We also compared the predictive effect of PUMR on health effort with that of dimensions from the Multidimensional Health Locus of Control scale-a well-used measure of a similar construct, which is frequently found to be associated with health behavior. Finally, we conducted a mini meta-analysis of the relationship between PUMR and health effort from the available research. RESULTS: PUMR was negatively associated with health effort, and mediated 24% of the total effect of subjective socioeconomic position on health effort, though this mediation effect was weaker than in Pepper and Nettle (2014). PUMR was shown to be a substantially stronger predictor of health effort than the relevant dimensions of the MHLC scale. Finally, our mini meta-analysis indicated a medium-sized negative relationship between PUMR and health effort. CONCLUSIONS: Our findings offer support for the role of PUMR in mediating the relationship between subjective socioeconomic position and health effort. The results highlight the importance of measuring and understanding PUMR in studying socioeconomic inequalities in health behaviors. We discuss potential areas for future research, including determining the accuracy of PUMR, investigating influential cues, examining the role of media in shaping risk perceptions, and understanding individuals' awareness of their own perceptions of mortality risk.

Previous research suggests that people who are more likely to die due to uncontrollable factors are less motivated to look after their health. This is because they are less likely to live to see the long-term benefits of a healthy lifestyle. The purpose of this study is to examine and expand upon previous research investigating the relationship between perceptions of uncontrollable mortality risk and the amount of effort people devote to their health. Our findings support past research and show that the more people feel their risk of dying is out of their control, the less effort they put into looking after their health. Our analysis suggests there is a medium-strength relationship between perceived uncontrollable mortality risk and health effort, which we argue warrants further empirical investigation. The strength of this relationship emphasizes the importance of improving the safety of people's living environments and highlights the positive impact that this can have on health behaviors.

The association between attention deficit hyperactivity disorder and pregnancy, delivery and neonatal outcomes-an evaluation of a population database.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is one of the more common neuropsychiatric disorders in women of reproductive age. Our objective was to compare perinatal outcomes between women with an ADHD diagnosis and those without. METHODS: A retrospective population-based cohort study utilizing the Healthcare Cost and Utilization Project, Nationwide Inpatient Sample (HCUP-NIS) United States database. The study included all women who either delivered or experienced maternal death from 2004 to 2014. Perinatal outcomes were compared between women with an ICD-9 diagnosis of ADHD and those without. RESULTS: Overall, 9,096,788 women met the inclusion criteria. Amongst them, 10,031 women had a diagnosis of ADHD. Women with ADHD, compared to those without, were more likely to be younger than 25 years of age; white; to smoke tobacco during pregnancy; to use illicit drugs; and to suffer from chronic hypertension, thyroid disorders, and obesity (p < 0.001 for all). Women in the ADHD group, compared to those without, had a higher rate of hypertensive disorders of pregnancy (HDP) (aOR 1.36, 95% CI 1.28-1.45, p < 0.001), cesarean delivery (aOR 1.19, 95% CI 1.13-1.25, p < 0.001), chorioamnionitis (aOR 1.34, 95% CI 1.17-1.52, p < 0.001), and maternal infection (aOR 1.33, 95% CI 1.19-1.5, p < 0.001). Regarding neonatal outcomes, patients with ADHD, compared to those without, had a higher rate of small-for-gestational-age neonate (SGA) (aOR 1.3, 95% CI 1.17-1.43, p < 0.001), and congenital anomalies (aOR 2.77, 95% CI 2.36-3.26, p < 0.001). CONCLUSION: Women with a diagnosis of ADHD had a higher incidence of a myriad of maternal and neonatal complications, including cesarean delivery, HDP, and SGA neonates.

Obstetric and perinatal outcomes in women with cerebrovascular accident vs. transient ischemic attack: an evaluation of a population database.

PURPOSE: Cerebrovascular accidents (CVAs) and transient ischemic attacks (TIAs) are uncommon neurologic events in women of childbearing age. We aimed to compare pregnancy, delivery, and neonatal outcomes between women who suffered from a CVA and those who experienced a TIA. METHODS: A retrospective population-based cohort study was performed using the Healthcare Cost and Utilization Project, Nationwide Inpatient Sample. Included were all pregnant women who delivered or had a maternal death in the US between 2004 and 2014. We compared women with an ICD-9 diagnosis of a CVA before or during pregnancy to those diagnosed with a TIA before, during the pregnancy, or during the delivery admission. Pregnancy and perinatal outcomes were compared between the two groups, using multivariate logistic regression to control for confounders. RESULTS: Among 9,096,788 women in the database, 898 met the inclusion criteria. Of them, 706 women (7.7/100,000) had a CVA diagnosis, and 192 (2.1/100,000) had a TIA diagnosis. Women with a CVA, compared to those with a TIA, had a higher rate of pregnancy-induced hypertension (aOR 3.82,95%CI 2.14-6.81, p < 0.001); preeclampsia (aOR 2.6,95%CI 1.3-5.2, p = 0.007), eclampsia (aOR 13.78,95% CI 1.84-103.41, p < 0.001); postpartum hemorrhage (aOR 4.52,95%CI 1.31-15.56, p = 0.017), blood transfusion (aOR 5.57,95%CI 1.65-18.72, p = 0.006), and maternal death (54 vs. 0 cases, 7.6% vs. 0%), with comparable neonatal outcomes. CONCLUSION: Women diagnosed with a CVA before or during pregnancy had a higher incidence of myriad maternal complications, including hypertensive disorders of pregnancy, postpartum hemorrhage, and death, compared to women with a TIA diagnosis, with comparable neonatal outcomes, stressing the different prognoses of these two conditions, and the importance of these patients' diligent follow-up and care.

Biblical Foundations for Interprofessional Collaboration in Nursing.

ABSTRACT: Interprofessional collaboration is an essential competency for nurses in today's complex healthcare environment. The Interprofessional Education Collaborative (IPEC) four competencies of values, teamwork, roles, and communication provide the organizing framework for effective interprofessional collaboration. In this article, the four competencies are used to explore biblical underpinnings and principles of collaboration for Christian nurses, showing how interprofessional collaboration helps achieve one's faith-based and professional commitments.

A robust regression analysis method to determine the significance of trends in concentrations of heavy metals in UK ambient air and improve network design and emission inventories.

A novel application of the Theil-Sen robust regression method for determining the temporal trends in the concentration of heavy metals in UK ambient air over the period 2005-2020 is presented and compared to other regression methods. We have demonstrated improvements over non-robust methods of regression, proving the ability to tease out trends that are small with respect to the variability of the concentration measurement. The method is used to identify, in general, large and significant trends in the concentrations of Ni, As, Pb and V over the period 2005-2020, either across the UK as a whole or at groupings of site classifications in the UK. These trends have been compared to trends in emission data determined in the same manner. Although the results for most metals provide confidence that the UK metal network of monitoring sites is successful in appropriately capturing changes in emissions, a key finding of this work is the disagreement between trends in measured concentrations and emissions for Cu, Mn and Ni, for which we suggest improvements in future network design. The results also indicate that UK emission data for V should be reviewed, as we propose that the rate of reduction of V emissions is likely to have been overestimated.

1-Butyl-3-methylimidazolium tetrafluoroborate as suitable solvent for BF3: the case of alkyne hydration. Chemistry vs electrochemistry.

In order to replace the expensive metal/ligand catalysts and classic toxic and volatile solvents, commonly used for the hydration of alkynes, the hydration reaction of alkynes was studied in the ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate (BMIm-BF4) adding boron trifluoride diethyl etherate (BF3·Et2O) as catalyst. Different ionic liquids were used, varying the cation or the anion, in order to identify the best one, in terms of both efficiency and reduced costs. The developed method was efficaciously applied to different alkynes, achieving the desired hydration products with good yields. The results obtained using a conventional approach (i.e., adding BF3·Et2O) were compared with those achieved using BF3 electrogenerated in BMIm-BF4, demonstrating the possibility of obtaining the products of alkyne hydration with analogous or improved yields, using less hazardous precursors to generate the reactive species in situ. In particular, for terminal arylalkynes, the electrochemical route proved to be advantageous, yielding preferentially the hydration products vs the aldol condensation products. Importantly, the ability to recycle the ionic liquid in subsequent reactions was successfully demonstrated.

Measuring the replicability of our own research.

In the study of transgenic mouse models of neurodevelopmental and neurodegenerative disorders, we use batteries of tests to measure deficits in behaviour and from the results of these tests, we make inferences about the mental states of the mice that we interpret as deficits in "learning", "memory", "anxiety", "depression", etc. This paper discusses the problems of determining whether a particular transgenic mouse is a valid mouse model of disease X, the problem of background strains, and the question of whether our behavioural tests are measuring what we say they are. The problem of the reliability of results is then discussed: are they replicable between labs and can we replicate our results in our own lab? This involves the study of intra- and inter- experimenter reliability. The variables that influence replicability and the importance of conducting a complete behavioural phenotype: sensory, motor, cognitive and social emotional behaviour are discussed. Then the thorny question of failure to replicate is examined: Is it a curse or a blessing? Finally, the role of failure in research and what it tells us about our research paradigms is examined.

The Uncontrollable Mortality Risk Hypothesis: Theoretical foundations and implications for public health.

The 'Uncontrollable Mortality Risk Hypothesis' employs a behavioural ecological model of human health behaviours to explain the presence of social gradients in health. It states that those who are more likely to die due to factors beyond their control should be less motivated to invest in preventative health behaviours. We outline the theoretical assumptions of the hypothesis and stress the importance of incorporating evolutionary perspectives into public health. We explain how measuring perceived uncontrollable mortality risk can contribute towards understanding socioeconomic disparities in preventative health behaviours. We emphasize the importance of addressing structural inequalities in risk exposure, and argue that public health interventions should consider the relationship between overall levels of mortality risk and health behaviours across domains. We suggest that measuring perceptions of uncontrollable mortality risk can capture the unanticipated health benefits of structural risk interventions, as well as help to assess the appropriateness of different intervention approaches.

Age-related changes in species-typical behaviours in the 5xFAD mouse model of Alzheimer's disease from 4 to 16 months of age.

Alzheimer's disease (AD) patients show age-related decreases in the ability to perform activities of daily living and the decline in these activities is related to the severity of neurobiological deterioration underlying the disease. The 5xFAD mouse model of AD shows age-related impairments in sensory- motor and cognitive function, but little is known about changes in species-typical behaviours that may model activities of daily living in AD patients. Therefore, we examined species-typical behaviours used as indices of exploration (rearing) and compulsivity (grooming) across six tests of anxiety-like behaviour or motor function in female 5xFAD mice from 3 to 16 months of age. Robust decreases in rearing were found in 5xFAD mice across all tests after 9 months of age, although few differences were observed in grooming. A fine-scale analysis of grooming, however, revealed a previously unresolved and spatially restricted pattern of grooming in 5xFAD mice at 13-16 months of age. We then examined changes in species-typical behaviours in the home-cage, and show impaired nest building in 5xFAD mice at all ages tested. Lastly, we examined the relationship between reduced species typical behaviours in 5xFAD mice and the presentation of freezing behaviour, a commonly used measure of memory for conditioned fear. These results showed that along with cognitive and sensory-motor behaviour, 5xFAD mice have robust age-related impairments in species-typical behaviours. Therefore, species typical behaviours in 5xFAD mice may help to model the decline in activities of daily living observed in AD patients, and may provide useful behavioural phenotypes for evaluating the pre-clinical efficacy of novel therapeutics for AD.

Three-dimensional geometric morphometric analyses of humerus ecomorphology: New perspectives for paleohabitat reconstruction in carnivorans and ungulates.

Long bone ecomorphology has proven effective for paleohabitat reconstructions across a wide range of mammalian clades. Still, there is no comprehensive framework to allow interpretation of long bone morphological variation within and between different monophyletic groups. Here, we investigated the use of humerus morphometry to classify living members of the orders Carnivora and ungulates based on their preferred habitats. Using geometric morphometrics, we extracted three different kinds of humerus shape data describing interspecific variation with and without accounting for evolutionary allometry and phylogenetic signal. The traditional a priori categorization of species in open, mixed, and closed habitats was employed in combination with selected subsets of shape variables to identify the best-predictive models for habitat adaptation. These were identified based on the statistical performance of phylogenetic and non-phylogenetic discriminant analyses and then applied to predict habitats on a subsample of fossil species. Size-free shape data combined with phylogenetic discriminant analyses showed the highest rate of accuracy in habitat classification for a combined sample of carnivorans and ungulates. Conversely, when the two groups were investigated separately, traditional shape data analyzed with phylogenetic discriminant function analyses provided models with the greatest predictive power. By combining carnivorans and ungulates within the same methodological framework we identified common adaptive features in closed habitat-adapted species that show compressed epiphyses, while open habitat-adapted species have expanded epiphyses. These morphologies evolved to allow significant degree of direction switches during locomotion in closed habitats compared to open habitat-adapted species whose forelimb joints evolved to stabilize articulations for increasing speed.

Transient ischemic attack and pregnancy, delivery and neonatal outcomes-An evaluation of a population database.

OBJECTIVE: Transient ischemic attack (TIA) is rare in women of reproductive age. We aimed to compare perinatal outcomes between women who suffered from a TIA to those who did not. METHODS: A retrospective population-based cohort study utilizing the Healthcare Cost and Utilization Project, Nationwide Inpatient Sample (HCUP-NIS). All women who delivered or had a maternal death in the US (2004-2014) were included in the study. Pregnancy, delivery, and neonatal outcomes were compared between women with an ICD-9 diagnosis of a TIA to those without. RESULTS: Overall, 9 096 788 women met the inclusion criteria. Of these, 203 women (2.2/100000) had a TIA (either before or during pregnancy). Women with TIA, compared to those without, were more likely to be older than 35 years of age, white, in the highest income quartile, be insured by private insurance and suffer from obesity and chronic hypertension. Patients in the TIA group, compared to those without, had a higher rate of pregnancy-induced hypertension (aOR 2.5, 95% CI: 1.55-4.05, P < 0.001), pre-eclampsia (aOR 3.77, 95% CI: 2.15-6.62, P < 0.001), eclampsia (aOR 28.05, 95% CI: 6.91-113.95, P < 0.001), preterm delivery (aOR 1.78, 95% CI: 1.03-3.07, P = 0.039), and maternal complications such as deep vein thrombosis (aOR 33.3, 95% CI: 8.07-137.42, P < 0.001). Regarding neonatal outcomes, patients with a TIA, compared to those without, had a higher rate of congenital anomalies (aOR 7.04, 95% CI: 2.86-17.32, P < 0.001). CONCLUSION: Women with a TIA diagnosis before or during pregnancy had a higher rate of maternal complications, including hypertensive disorders of pregnancy and venous thromboembolism, as well as an increased risk of congenital anomalies.

Host determinants and responses underlying SARS-CoV-2 liver tropism.

Hepatic sequelae are frequently reported in coronavirus disease 2019 cases and are correlated with increased disease severity. Therefore, a detailed exploration of host factors contributing to hepatic impairment and ultimately infection outcomes in patients is essential for improved clinical management. The causes of hepatic injury are not limited to drug-mediated toxicity or aberrant host inflammatory responses. Indeed, multiple studies report the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in liver autopsies and the susceptibility of explanted human hepatocytes to infection. In this review, we confirm that hepatic cells express an extensive range of factors implicated in SARS-CoV-2 entry. We also provide an overview of studies reporting evidence for direct infection of liver cell types and the infection-induced cell-intrinsic processes that likely contribute to hepatic impairment.

Synthesis and Bioapplication of Emerging Nanomaterials of Hafnium.

A significant amount of progress in nanotechnology has been made due to the development of engineered nanoparticles. The use of metallic nanoparticles for various biomedical applications has been extensively investigated. Biomedical research is highly focused on them because of their inert nature, nanoscale structure, and similar size to many biological molecules. The intrinsic characteristics of these particles, including electronic, optical, physicochemical, and surface plasmon resonance, that can be altered by altering their size, shape, environment, aspect ratio, ease of synthesis, and functionalization properties, have led to numerous biomedical applications. Targeted drug delivery, sensing, photothermal and photodynamic therapy, and imaging are some of these. The promising clinical results of NBTXR3, a high-Z radiosensitizing nanomaterial derived from hafnium, have demonstrated translational potential of this metal. This radiosensitization approach leverages the dependence of energy attenuation on atomic number to enhance energy-matter interactions conducive to radiation therapy. High-Z nanoparticle localization in tumor issue differentially increases the effect of ionizing radiation on cancer cells versus nearby healthy ones and mitigates adverse effects by reducing the overall radiation burden. This principle enables material multifunctionality as contrast agents in X-ray-based imaging. The physiochemical properties of hafnium (Z = 72) are particularly advantageous for these applications. A well-placed K-edge absorption energy and high mass attenuation coefficient compared to elements in human tissue across clinical energy ranges leads to significant attenuation. Chemical reactivity allows for variety in nanoparticle synthesis, composition, and functionalization. Nanoparticles such as hafnium oxide exhibit excellent biocompatibility due to physiochemical inertness prior to incidence with ionizing radiation. Additionally, the optical and electronic properties are applicable in biosensing, optical component coatings, and semiconductors. The wide interest has prompted extensive research in design and synthesis to facilitate property fine-tuning. This review summarizes synthetic methods for hafnium-based nanomaterials and applications in therapy, imaging, and biosensing with a mechanistic focus. A discussion and future perspective section highlights clinical progress and elaborates on current challenges. By focusing on factors impacting applicational effectiveness and examining limitations this review aims to support researchers and expedite clinical translation of future hafnium-based nanomedicine.