Targeting cellular cathepsins inhibits hepatitis E virus entry.

BACKGROUND AND AIMS: The hepatitis E virus (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 potentials of cellular proteases 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 EC50 of ~ 0.01 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.

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.

Intranasal insulin treatment ameliorates spatial memory, muscular strength, and frailty deficits in 5xFAD mice.

The 5xFAD mouse model shows age-related weight loss as well as cognitive and motor deficits. Metabolic dysregulation, especially impaired insulin signaling, is also present in AD. This study examined whether intranasal delivery of insulin (INI) at low (0.875 U) or high (1.750 U) doses would ameliorate these deficits compared to saline in 10-month-old female 5xFAD and B6SJL wildtype (WT) mice. INI increased forelimb grip strength in the wire hang test in 5xFAD mice in a dose-dependent manner but did not improve the performance of 5xFAD mice on the balance beam. High INI doses reduced frailty scores in 5xFAD mice and improved spatial memory in both acquisition and reversal probe trials in the Morris water maze. INI increased swim speed in 5xFAD mice but had no effect on object recognition memory or working memory in the spontaneous alternation task, nor did it improve memory in the contextual or cued fear memory tasks. High doses of insulin increased the liver, spleen, and kidney weights and reduced brown adipose tissue weights. P-Akt signaling in the hippocampus was increased by insulin in a dose-dependent manner. Altogether, INI increased strength, reduced frailty scores, and improved visual spatial memory. Hypoglycemia was not present after INI, however alterations in tissue and organ weights were present. These results are novel and important as they indicate that intra-nasal insulin can reverse cognitive, motor and frailty deficits found in this mouse model of AD.

The World Federation of Chiropractic Global Patient Safety Task Force: a call to action.

BACKGROUND: The Global Patient Safety Action Plan, an initiative of the World Health Organization (WHO), draws attention to patient safety as being an issue of utmost importance in healthcare. In response, the World Federation of Chiropractic (WFC) has established a Global Patient Safety Task Force to advance a patient safety culture across all facets of the chiropractic profession. This commentary aims to introduce principles and call upon the chiropractic profession to actively engage with the Global Patient Safety Action Plan beginning immediately and over the coming decade. MAIN TEXT: This commentary addresses why the chiropractic profession should pay attention to the WHO Global Patient Safety Action Plan, and what actions the chiropractic profession should take to advance these objectives. Each strategic objective identified by WHO serves as a focal point for reflection and action. Objective 1 emphasizes the need to view each clinical interaction as a chance to improve patient safety through learning. Objective 2 urges the implementation of frameworks that dismantle systemic obstacles, minimizing human errors and strengthening patient safety procedures. Objective 3 supports the optimization of clinical process safety. Objective 4 recognizes the need for patient and family engagement. Objective 5 describes the need for integrated patient safety competencies in training programs. Objective 6 explains the need for foundational data infrastructure, ecosystem, and culture. Objective 7 emphasizes that patient safety is optimized when healthcare professionals cultivate synergy and partnerships. CONCLUSIONS: The WFC Global Patient Safety Task Force provides a structured framework for aligning essential considerations for patient safety in chiropractic care with WHO strategic objectives. Embracing the prescribed action steps offers a roadmap for the chiropractic profession to nurture an inclusive and dedicated culture, placing patient safety at its core. This commentary advocates for a concerted effort within the chiropractic community to commit to and implement these principles for the collective advancement of patient safety.

Estrogen Receptor, Progesterone Receptor, and Human Epidermal Growth Factor Receptor 2 Expression Rates in Invasive Breast Carcinoma: A Study of 21 Institutions.

CONTEXT.­: Laboratories performing predictive marker testing for breast carcinoma are encouraged to compare patient results to published benchmarks. OBJECTIVE.­: To collect expression rates for estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) in invasive breast carcinoma from multiple laboratories. DESIGN.­: Participants submitted data from up to 50 primary cases during the study period. Participants reported ER, PgR, and HER2 results in addition to demographic and histologic information. Participants also provided annual institution-level expression rates. RESULTS.­: A total of 21 institutions submitted data for 687 cases. Aggregate positivity rates for ER and PgR were 85.6% and 75.1%, respectively. Receptor positivity rates were higher in well-differentiated (grade 1) tumors (ER, 97.4%; PgR, 88.0%) compared with moderately differentiated (grade 2) tumors (ER, 92.4%; PgR, 84.0%) and poorly differentiated (grade 3) tumors (ER, 61.8%; PgR, 48.0%). Expression rates were higher in postmenopausal women (ER, 87.2%) than premenopausal women (ER, 79.6%) and higher in lobular carcinomas (ER, 98.7%; PgR, 85.3%) than ductal carcinomas (ER, 84.1%; PgR, 74.5%). The aggregate HER2 positivity (score 3+) rate was 9.0%. The aggregate HER2 equivocal (score 2+) rate was 14.5%. Of 81 equivocal (score 2+) cases, 70 (86.4%) were nonamplified. CONCLUSIONS.­: The data from this study provide multi-institutional benchmark data to assist laboratories performing periodic comparisons as part of a quality management program. Overall expression rates were generally similar to those of other published reports, with the exception of the ER-negative and HER2-positive rates, both of which were somewhat lower.

The risk associated with organophosphorus nerve agents: from their discovery to their unavoidable threat, current medical countermeasures and perspectives.

The first organophosphorus nerve agent was discovered accidently during the development of pesticides, shortly after the first use of chemical weapons (chlorine, phosgene) on the battlefield during World War I. Despite the Chemical Weapons Convention banning these substances, they have still been employed in wars, terrorist attacks or political assassinations. Characterised by their high lethality, they target the nervous system by inhibiting the acetylcholinesterase (AChE) enzyme, preventing neurotransmission, which, if not treated rapidly, inevitably leads to serious injury or the death of the person intoxicated. The limited efficacy of current antidotes, known as AChE reactivators, pushes research towards new treatments. Numerous paths have been explored, from modifying the original pyridinium oximes to developing hybrid reactivators seeking a better affinity for the inhibited AChE. Another crucial approach resides in molecules more prone to cross the blood-brain barrier: uncharged compounds, bio-conjugated reactivators or innovative formulations. Our aim is to raise awareness on the threat and toxicity of organophosphorus nerve agents and to present the main synthetic efforts deployed since the first AChE reactivator, to tackle the task of efficiently treating victims of these chemical warfare agents.

Efficacy and implementation of exercise-based smoking cessation treatment for adults with high anxiety sensitivity (STEP): Study protocol for a randomized controlled trial.

Anxiety sensitivity (AS), reflecting the fear of bodily sensations, is a transdiagnostic vulnerability factor that underpins both affective psychopathology and smoking. Phase II research supports the efficacy of a 15-week community-based intervention (STEP) that combines high-intensity exercise offered by the YMCA with standard smoking cessation treatment (tobacco quitline and nicotine replacement therapy) for sedentary smokers with elevated AS. This Phase III study aims to enroll 360 adults to evaluate whether STEP efficacy for achieving smoking abstinence generalizes to Black and Hispanic smokers with elevated AS.

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.

Idiopathic intracranial hypertension and obstetric and neonatal outcomes: A 1:20 matched study from a population database.

OBJECTIVE: Idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri, is a common pathology in reproductive-aged women, although data regarding pregnancy outcomes are scarce. In the present study, we aimed to compare pregnancy and perinatal outcomes between women who suffered from IIH to those who did not. METHODS: A retrospective cohort study using the Healthcare Cost and Utilization Project, Nationwide Inpatient Sample. All pregnant women who delivered or had a maternal death in the US (2004-2014) were included. Women with an ICD-9 diagnosis of IIH before or during pregnancy were matched to controls without IIH according to age, race, insurance type, and income quartile, in a 1:20 ratio. Pregnancy, delivery, and neonatal outcomes were compared between the two groups. RESULTS: Overall, 9 096 788 deliveries were identified. Of these, 1454 women (0.016%) had a diagnosis of IIH (study group) and were compared to 29 080 women without IIH (control group). Women with IIH, compared to those without, were more likely to be obese (body mass index >30 kg/m2) and suffer from pregestational diabetes mellitus and chronic hypertension (P < 0.001, all). After adjusting for confounders, patients in the IIH group, compared to those without, had a higher rate of pregnancy-induced hypertension (aOR 1.82, 95% CI: 1.57-2.1, P < 0.001), pre-eclampsia (aOR 1.98, 95% CI: 1.61-2.45, P < 0.001), preterm delivery (aOR 1.88, 95% CI: 1.59-2.23, P < 0.001), CD (aOR 2.41, 95% CI: 2.12-2.73, P < 0.001), wound complications (aOR 3.2, 95% CI: 1.89-5.42, P < 0.001), and congenital anomalies (aOR 2.18, 95% CI: 1.4-3.4, P < 0.001). CONCLUSION: Women with IIH had a higher incidence of obstetrical complications, including preterm deliveries, hypertensive disorders of pregnancy, and 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.

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.

Improving the Reliability of Peer Review Without a Gold Standard.

Peer review plays a crucial role in accreditation and credentialing processes as it can identify outliers and foster a peer learning approach, facilitating error analysis and knowledge sharing. However, traditional peer review methods may fall short in effectively addressing the interpretive variability among reviewing and primary reading radiologists, hindering scalability and effectiveness. Reducing this variability is key to enhancing the reliability of results and instilling confidence in the review process. In this paper, we propose a novel statistical approach called "Bayesian Inter-Reviewer Agreement Rate" (BIRAR) that integrates radiologist variability. By doing so, BIRAR aims to enhance the accuracy and consistency of peer review assessments, providing physicians involved in quality improvement and peer learning programs with valuable and reliable insights. A computer simulation was designed to assign predefined interpretive error rates to hypothetical interpreting and peer-reviewing radiologists. The Monte Carlo simulation then sampled (100 samples per experiment) the data that would be generated by peer reviews. The performances of BIRAR and four other peer review methods for measuring interpretive error rates were then evaluated, including a method that uses a gold standard diagnosis. Application of the BIRAR method resulted in 93% and 79% higher relative accuracy and 43% and 66% lower relative variability, compared to "Single/Standard" and "Majority Panel" peer review methods, respectively. Accuracy was defined by the median difference of Monte Carlo simulations between measured and pre-defined "actual" interpretive error rates. Variability was defined by the 95% CI around the median difference of Monte Carlo simulations between measured and pre-defined "actual" interpretive error rates. BIRAR is a practical and scalable peer review method that produces more accurate and less variable assessments of interpretive quality by accounting for variability within the group's radiologists, implicitly applying a standard derived from the level of consensus within the group across various types of interpretive findings.

Effect of a Patient Portal Reminder Message After No-Show on Appointment Reattendance in Ophthalmology: A Randomized Clinical Trial.

PURPOSE: To assess the efficacy of electronic health record (EHR) messaging for re-engaging patients with ophthalmology care after a missed appointment. DESIGN: Prospective, randomized clinical trial. METHODS: The study setting was an academic ophthalmology department. The patient population comprised of return patients age 18 years or older with an appointment "no show," or missed appointment. Over 2 phases of recruitment, 362 patients with an active patient portal in the EHR were selected consecutively each business day. Patients were randomized using a web-based tool to receive a reminder to reschedule via a standard mailed letter only (control) or the mailed letter plus an electronic message through the EHR within 1 business day of the missed appointment (intervention). Reengagement with eye care was defined as attendance of a rescheduled appointment within 30 days of the no-show visit. Patient charts were reviewed for demographic and clinical data. RESULTS: The average age of recruited patients was 59.9 years, just under half of the sample was male (42.5%, 154/362), and most patients were White (56.9%, 206/362) or Black (36.2%, 131/362). Patients were most commonly recruited from the retina service (39.2%, 142/362) followed by the glaucoma service (29.3%, 106/362). Many patients in this study had previous no-show appointments, with an average no-show rate of 18.8% out of all scheduled visits across our health system. In total, 22.2% (42/189) of patients in the intervention group attended a follow-up appointment within 30 days of their no-show visit compared to 11.6% (20/173) of the control group (OR, 2.186; 95% CI, 1.225-3.898; P = .008). When including only the 74 patients in the intervention group who read the intervention message in the patient portal, 28.4% (21/74) attended a follow-up compared to 11.6% (20/173) of the control group (P = .001). CONCLUSIONS: EHR-based reminder messages sent within a business day of a missed appointment may promote re-engagement in ophthalmology care after appointment no-show.

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.

Pregnancy, delivery and neonatal outcomes in women with a cerebrovascular-accident history prior to delivery - Evaluation of a population database.

Objective: Cerebrovascular accidents (CVA) in childbearing-age women are rare. We aimed to evaluate the association between CVA events prior to delivery and obstetrical and neonatal outcomes. Methods: A retrospective cohort study was conducted using data from the Healthcare Cost and Utilization Project, Nationwide Inpatient Sample (HCUP-NIS) database. All pregnant women who delivered or had a maternal death in the US from 2004 to 2014 were included in the study. We performed a comparison between women with an ICD-9 diagnosis of CVA before the delivery admission and those without. Obstetrical and neonatal outcomes were compared between the two groups. Results: In total, 9,096,788 women fulfilled the inclusion criteria. Among them, 695 women (7.6 per 100,000) were diagnosed with a CVA before delivery. Women with a history of CVA, compared to those without, were more likely to be Black, older than 35 years of age, and suffer from obesity, chronic hypertension, pregestational diabetes, and thyroid disease. Patients with a prior CVA, compared to those without, had higher rates of pregnancy-induced hypertension (aOR 6.41, 95% CI 5.03-8.39, p < 0.001), preeclampsia (aOR 7.65, 95% CI 6.03-9.71, p < 0.001), and eclampsia (aOR 171.56, 95% CI 124.63-236.15, p < 0.001). Additionally, they had higher rates of preterm delivery (aOR 1.72, 95% CI 1.33-2.22,p = 0.003), cesarean section (aOR 2.69, 95% CI 2.15-3.37, p < 0.001), and maternal complications such as a peripartum hysterectomy (aOR 11.62, 95% CI 5.77-23.41, p < 0.001), postpartum hemorrhage (aOR 3.39, 95 % CI 2.52-4.54, p < 0.001), disseminated intravascular coagulation (aOR 16.32, 95% CI 11.33-23.52, p < 0.001), venous thromboembolism (aOR 45.08, 95% CI 27.17-74.8, p < 0.001), and maternal death (aOR 486.11, 95% CI 307.26-769.07, p < 0.001). Regarding neonatal outcomes, patients with a prior CVA, compared to those without, had a higher rate of intrauterine fetal demise and congenital anomalies. Conclusion: Women with a CVA event before delivery have a significantly higher incidence of maternal complications, including hypertensive disorders of pregnancy, and neonatal complications, such as intrauterine fetal demise and congenital anomalies. Rates of maternal death were dramatically increased, and this association requires further evaluation.

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.

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.

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.

Association between maternal hypertension and infant neurodevelopment in extremely preterm infants.

OBJECTIVE: To examine the association between maternal hypertension during pregnancy and neurodevelopmental impairment (NDI) at 24 months post-menstrual age in extremely preterm infants. STUDY DESIGN: Using data from two tertiary neonatal units (2011-2017) for infants born at 23 + 0 to 28 + 6 weeks, we investigated outcomes of NDI related to maternal hypertension and small-for-gestational-age (SGA) status. RESULTS: Of 1019 pre-term infants, 647 had complete data and were included in the analysis. Ninety-six (15%) had maternal hypertension exposure; 25 (4%) were also SGA. Infants with maternal hypertension showed a higher odds of any NDI (aOR: 2.29, 95% CI = 1.36-3.87) and significant NDI (aOR: 2.01, 95% CI = 1.02-3.95). The combination of hypertension and SGA further elevated this risk (aOR for any NDI: 4.88, 95% CI = 1.80-13.22; significant NDI: 6.91, 95% CI = 2.50-19.12). CONCLUSION: Maternal hypertension during pregnancy elevates the risk of NDI in extremely preterm infants, more so when combined with SGA.

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.