Psychometric Properties of the Generalized Anxiety Disorder Scale (GAD-7) in Older Adults With Advanced Cancer.

OBJECTIVES: Over half of new cancer diagnoses occur in patients aged 65 or older, with up to 40% experiencing anxiety. The American Society of Clinical Oncology recommends using the Generalized Anxiety Disorder Scale (GAD-7) for anxiety screening, but the GAD-7 psychometric properties in this population are unknown. This study examined the GAD-7's reliability, validity, and item parameters, comparing its utility with the GAD-2 in older adults with cancer. METHODS: This cross-sectional secondary analysis of a nationwide multi-site two-arm cluster randomized trial in older adults (≥ 70) with advanced cancer. The GAD-7 was administered at baseline. Properties were evaluated with Cronbach's α, Pearson correlation coefficients, and a 2-parameter logistic model. Logistic regression models compared the GAD-2 and GAD-7. RESULTS: The sample included 718 participants (Mean age = 77, SD = 5) with mild anxiety (M = 3.74, SD = 4.74). Internal consistency was strong (Cronbach's alpha = 0.89) and item-total correlations ranged 0.53 to 0.78. Item 2 (Not being able to stop or control worrying) was the most discriminating and item 5 (Being so restless that it is hard to sit still) was least discriminating. Area Under the Curve (AUC) analyses demonstrated the GAD-2 had a 0.93-0.96 AUC. CONCLUSIONS: Establishing the psychometric properties of anxiety screening measures is crucial in the older adults with cancer to maximize referral efficiency and accuracy. This study indicates that the GAD-7 is reliable and valid for older adults with cancer. Analyses suggest the GAD-2 may be as sufficient as the GAD-7 in identifying anxiety in older adults with cancer, thereby reducing assessment burden.

Antimicrobial Activity of Ardisia serrata (Cavs.) Pers. Ethanolic and Aqueous Leaf Extract on the Growth and Biofilm Formation of Selected Bacterial Isolates.

Background: Ardisia serrata (Aunasin) is an endemic Philippine plant of the family Primulaceae, with several studies showing the genus Ardisia as having potential antibacterial, antiangiogenic, cytotoxic, and antipyretic properties. Objective: This study aims to determine the antibacterial and antibiofilm-forming activity of Ardisia serrata ethanolic and aqueous extracts on Escherichia coli, Methicillin-Sensitive Staphylococcus aureus (MSSA), and Methicillin-Resistant Staphylococcus aureus (MRSA). Methods: This is an experimental study testing the activity against bacterial strains of E. coli, MSSA, and MRSA using ethanolic and aqueous extracts of A. serrata leaves. Microtiter susceptibility and biofilm inhibition assays were done with two-fold dilutions of the extract against the selected strains using spectrophotometry with optical density (OD) at 600 nm and 595 nm, respectively, to quantify bacterial growth and biofilm inhibition. The bacterial susceptibility and biofilm inhibition activity was reported as percent inhibition (PI). Minimum inhibitory concentration (MIC), and minimum biofilm inhibition concentration (MBIC) values were obtained using logarithmic regression of the PI values. Results: A. serrata ethanolic extracts showed weak growth inhibitory activity against MSSA and MRSA with minimum inhibitory concentration (MIC) values of 2.6192 and 3.2988 mg/mL, respectively, but no biofilm inhibition activity was noted, while the aqueous extracts exhibited negligible biofilm inhibition activity against MSSA and MRSA with minimum biofilm inhibition concentration (MBIC) values of 13.5972 and 8964.82 mg/mL, respectively, and with no growth inhibition activity. Both ethanolic and aqueous extracts showed no growth inhibition and biofilm inhibition activities against E. coli. CONCLUSION: Staphylococcus aureus is susceptible to the bioactivity of the leaf extracts of A. serrata and has potential to be used as an antibacterial in the treatment of infectious diseases.

Traumatic Brain Injury Exacerbates Alcohol Consumption and Neuroinflammation with Decline in Cognition and Cholinergic Activity.

Traumatic brain injury (TBI) is a global health challenge, responsible for 30% of injury-related deaths and significantly contributing to disability. Annually, over 50 million TBIs occur worldwide, with most adult patients at emergency departments showing alcohol in their system. TBI is also a known risk factor for alcohol abuse, yet its interaction with alcohol consumption remains poorly understood. In this study, we demonstrate that the fluid percussion injury (FPI) model of TBI in mice significantly increases alcohol consumption and impairs cognitive function. At cellular levels, FPI markedly reduced the number and activity of striatal cholinergic interneurons (CINs) while increasing microglial cells. Notably, depleting microglial cells provided neuroprotection, mitigating cholinergic loss and enhancing cholinergic activity. These findings suggest that TBI may promote alcohol consumption and impair cognitive abilities through microglia activation and consequently reduced cholinergic function. Our research provides critical insights into the mechanisms linking TBI with increased alcohol use and cognitive deficits, potentially guiding future therapeutic strategies.

Machine Learning Assessment of Gestational Age in Accelerated Maturation, Delayed Maturation, Villous Edema, Chorangiosis, and Intrauterine Fetal Demise.

CONTEXT.­: Assessment of placental villous maturation is among the most common tasks in perinatal pathology. However, the significance of abnormalities in morphology is unclear and interobserver variability is significant. OBJECTIVE.­: To develop a machine learning model of placental maturation across the second and third trimesters and quantify the impact of different pathologist-diagnosed abnormalities of villous morphology. DESIGN.­: Digitize placental villous slides from more than 2500 placentas at 12.0 to 42.6 weeks. Build whole slide learning models to estimate obstetrician-determined gestational age for cases with appropriate maturation and normal morphology. Define the model output as "placental age" and compare it to the chronologic gestational age. RESULTS.­: Our model showed an r2 of 0.864 and mean absolute error of 1.62 weeks for placentas with appropriate maturation in the test set. Pathologist diagnosis of accelerated maturation was associated with a 2.56-week increase in placental age (±2.91 weeks, P < .001), while delayed maturation was associated with a 0.92-week decrease in placental age (±1.82 weeks, P < .001). Intrauterine fetal demise causes diverse changes to placental age, driven by the nature of the demise. We tested the impact of training a model, using all live births. The resulting r2 was 0.874 and mean absolute error was 1.73 weeks. Furthermore, by including cases with abnormal maturation in the training data, the effect size of accelerated maturation was blunted to only 0.56 ± 2.35 weeks (P < .001). CONCLUSIONS.­: We show that various abnormalities of villous maturation and morphology correlate with abnormalities in placental age. This "no pathologist" model could be useful in situations where pathologists are unavailable or the need for consistency outweighs the utility of expertise.

A systematic review of cost-effectiveness of treating out of hospital cardiac arrest and the implications for resource-limited health systems.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is a prevalent condition with high mortality and poor outcomes even in settings where extensive emergency care resources are available. Interventions to address OHCA have had limited success, with survival rates below 10% in national samples of high-income countries. In resource-limited settings, where scarcity requires careful priority setting, more data is needed to determine the optimal allocation of resources. OBJECTIVE: To establish the cost-effectiveness of OHCA care and assess the affordability of interventions across income settings. METHODS: The authors conducted a systematic review of economic evaluations on interventions to address OHCA. Six databases (PubMed, EMBASE, Global Health, Cochrane, Global Index Medicus, and Tuft's Cost-Effectiveness Registry) were searched in September 2023. Included studies were (1) economic evaluations (beyond a simple costing exercise); and (2) assessed an intervention in the chain of survival for OHCA. Article quality was assessed using the CHEERs checklist and data summarised. Findings were reported by major themes identified by the reviewers. Based upon the results of the cost-effectiveness analyses we then conduct an analysis for the progressive realization of the OHCA chain of survival from the perspective of decision-makers facing resource constraints. RESULTS: Four hundred and sixty-eight unique articles were screened, and 46 articles were included for final data abstraction. Studies predominantly used a healthcare sector perspective, modeled for all patients experiencing non-traumatic cardiac OHCA, were based in the US, and presented results in US Dollars. No studies reported results or used model inputs from low-income settings. Progressive realization of the chain of survival could likely begin with investments in termination of resuscitation protocols, professional prehospital defibrillator use, and CPR training followed by the distribution of AEDs in high-density public locations. Finally, other interventions such as indiscriminate defibrillator placement or adrenaline use, would be the lowest priority for early investment. CONCLUSION: Our review found no high-quality evidence on the cost-effectiveness of treating OHCA in low-resource settings. Existing evidence can be utilized to develop a roadmap for the development of a cost-effective approach to OHCA care, however further economic evaluations using context-specific data are crucial to accurately inform prioritization of scarce resources within emergency care in these settings.

Aberrant overexpression of the autoantigen protein vimentin promotes Th17 cell differentiation and autoimmune arthritis via activation of STAT3 signaling.

Vimentin contributes to the positioning and function of organelles, cell migration, adhesion, and division. However, secreted vimentin accumulates on the cell surface (Mor-Vaknin et al., 2003; Ramos et al., 2020 [1,2]) where it acts as a coreceptor for viral infection and as an autoantigen in inflammatory and autoimmune diseases. The roles of vimentin in Th17 cells were examined in mice with knockdown of vimentin. We also examined whether STAT3 is required for vimentin expression. Vimentin expression was significantly increased in Th17 cells through STAT3 activation, and vimentin+ IL-17+ T cells were markedly increased in the joint and spleen tissues of CIA mice. The arthritis score and expression levels of proinflammatory cytokines were significantly decreased in CIA mice treated with vimentin shRNA vector. In this study, we demonstrated that vimentin is significantly expressed in Th17 cells through STAT3 activation. Our results provide new insights into the role of vimentin in Th17 cells and the complex pathogenesis of RA.

Progranulin derivative attenuates lung neutrophilic infiltration from diesel exhaust particle exposure.

BACKGROUND: Air pollutants, such as diesel exhaust particles (DEPs), induce respiratory disease exacerbation with neutrophilic infiltration. Progranulin (PGRN), an epithelial cell and macrophage-derived secretory protein, is associated with neutrophilic inflammation. PGRN is digested into various derivatives at inflammatory sites and is involved in several inflammatory processes. PGRN and its derivatives likely regulate responses to DEP exposure in allergic airway inflammation. AIM: To investigate the role of PGRN and its derivatives in the regulation of responses to DEP exposure in allergic airway inflammation. METHODS: A murine model of allergic airway inflammation was generated in PGRN-deficient mice, and they were simultaneously exposed to DEP followed by intranasal administration of full-length recombinant PGRN (PGRN-FL) and a PGRN-derived fragment (FBAC). Inflammatory status was evaluated by bronchoalveolar lavage fluid and histopathologic analyses. Human bronchial epithelial cells were stimulated with DEPs and house dust mites (HDMs), and the effect of FBAC treatment was evaluated by assessing various intracellular signaling molecules, autophagy markers, inflammatory cytokines, and intracellular oxidative stress. RESULTS: DEP exposure exaggerated neutrophilic inflammation, enhanced IL-6 and CXCL15 secretions, and increased oxidative stress in the murine model; this effect was greater in PGRN-deficient mice than in wild-type mice. The DEP-exposed mice with PGRN-FL treatment revealed no change in neutrophil infiltration and higher oxidative stress status in the lungs. On the contrary, FBAC administration inhibited neutrophilic infiltration and reduced oxidative stress. In human bronchial epithelial cells, DEP and HDM exposure increased intracellular oxidative stress and IL-6 and IL-8 secretion. Decreased nuclear factor erythroid 2-related factor 2 (Nrf2) expression and increased phosphor-p62 and LC3B expression were also observed. FBAC treatment attenuated oxidative stress from DEP and HDM exposure. CONCLUSIONS: FBAC reduced neutrophilic inflammation exaggerated by DEP exposure in a mouse model of allergic airway inflammation by reducing oxidative stress. PGRN and PGRN-derived proteins may be novel therapeutic agents in attenuating asthma exacerbation induced by air pollutant exposure.

Association between Left Ventricular Geometry, Systolic Ejection Time, and Estimated Glomerular Filtration Rate in Ambulatory Patients with Preserved Left Ventricular Ejection Fraction.

INTRODUCTION: Cardiac function is important to quantify for risk stratification. Although left ventricular ejection fraction (LVEF) is commonly used, and identifies patients with poor systolic function, other easily acquired measures of cardiac function are needed, particularly to stratify patients with relatively preserved LVEF. LV relative wall thickness (RWT) has been associated with adverse clinical outcomes in patients with preserved LVEF, but the clinical relevance of this observation is not known. The purpose of this study was to assess whether increased RWT is a marker of subclinical cardiac dysfunction as measured by a surrogate of LV dysfunction and left ventricular ejection time (LVET) and if increased RWT is independently associated with chronic kidney disease (CKD), an important clinical outcome and cardiovascular disease risk equivalent. METHODS: This retrospective cohort study enrolled ambulatory patients 18 years and older undergoing routine transthoracic echocardiography (TTE) at Johns Hopkins Hospital from January 2017 to January 2018. Patients with LVEF <50%, severe valvular disease, or liver failure were excluded. Multivariable regression evaluated the relationship between RWT, LVET, and CKD adjusted for demographics, comorbidities, and vital signs. RESULTS: We analyzed data from 375 patients with mean age (±SD) 52.2 ± 15.3 years of whom 58% were female. Mean ± SD of RWT was 0.45 ± 0.10, while mean ± SD of LVET was 270 ms ± 33. In multivariable linear regression adjusted for demographics, comorbidities, vital signs, and left ventricular mass, each 0.1 increase in RWT was associated with a decrease of 4.6 ms in LVET, indicating worse cardiac function (ß, ± 95% CI) (-4.60, -7.37 to -1.48, p = 0.004). Of those with serum creatinine available 1 month before or after TTE, 20% (50/247) had stage 3 or greater CKD. In logistic regression (adjusted for sex, comorbidities, and medications), each 0.1 unit increase in RWT was associated with an 61% increased odds of CKD (aOR = 1.61, 1.03-2.53, p = 0.037). In multivariable ordinal regression adjusted for the same covariates, each 0.1 unit increase in RWT was associated with a 44% increased odds of higher CKD stage (aOR = 1.44, 1.03-2.02, p = 0.035). There was a trend but no statistically significant relationship between RWT and change in estimated glomerular filtration rate at 1 year. CONCLUSION: In an outpatient cohort undergoing TTE, increased RWT was independently associated with a surrogate of subclinical systolic dysfunction (LVET) and CKD. This suggests that RWT, an easily derived measure of LV geometry on TTE, may identify clinically relevant subclinical systolic dysfunction and patients with worse kidney function. Additional investigation to further clarify the relationships between RWT, systolic function, and kidney dysfunction over time and how this information may guide clinical intervention are warranted.

Fingolimod, an antagonist of sphingosine 1-phosphate, ameliorates Sjögren's syndrome by reducing the number of STAT3-induced germinal center B cells and increasing the number of Breg cells.

BACKGROUND: Sjögren's syndrome (SS) is an autoimmune disease caused by infiltrating lymphocytes. FTY720 affects the S1P signaling pathway, which plays a role in T and B cell migration from secondary lymphoid tissues to target organs. In this study, we investigate the regulatory mechanism of FTY720 in the context of SS. METHOD: FTY720 was given orally every day to NOD mice. The salivary flow rate (SFR) and blood glucose level were assayed every 3 weeks. Histopathological features were investigated at the end of the study. In vitro, FTY720 was added to mouse splenocytes, and changes in the lymphocyte subsets were assessed. RESULTS: In vivo, FTY720 increased the SFR and reduced the blood glucose level. The salivary gland histological score and infiltration of the salivary glands by B and T cells were dramatically decreased. Furthermore, STAT expression in the salivary gland was decreased. In vitro, FTY720 inhibited Th17 cells, while increasing regulatory T (Treg) cells, respectively. Also, FTY720 decreased and increased the numbers of germinal center (GC) B cells and regulatory B cells (Breg cells), respectively. FTY720 decreased the IgG level in culture supernatants. Also, STAT3 activation was decreased by FTY720. CONCLUSION: Our results show the therapeutic potential of FTY720 in the context of SS; FTY720 prevents lymphocyte migration from secondary lymphoid organs to target organs.

CVN424, a GPR6 inverse agonist, for Parkinson's disease and motor fluctuations: a double-blind, randomized, phase 2 trial.

Background: CVN424 is a GPR6 inverse agonist that provides selective pharmacological control of the indirect striatopallidal pathway. We assessed the safety and efficacy of CVN424 as an adjunctive treatment to levodopa for reducing OFF-time in individuals with Parkinson's disease (PD) experiencing motor-fluctuations. Methods: This was a randomised, double-blind, placebo-controlled study conducted at 21 sites across the United States to evaluate two doses of CVN424 (NCT04191577). Patients with PD (Hoehn and Yahr stages 2-4) who were on a stable dose of levodopa and experiencing ≥2 h of daily OFF-time were randomised (1:1:1) to receive either once-daily CVN424 (50 mg or 150 mg) or placebo for a 28-day treatment period. The primary endpoints were safety and tolerability. The key secondary endpoint was the change from baseline to Day 27 in OFF-time. Findings: The study was conducted from December 23, 2019, to October 14, 2021. Out of 198 participants screened, 141 eligible participants were randomised to one of the three treatment groups (n = 47 per group), and 127 participants completed the 28-day treatment period. The most common treatment emergent adverse events (TEAEs) were headache (2% with CVN424 50 mg, 9% with CVN424 150 mg, and 2% with placebo) and nausea (4% with CVN424 50 mg, 6% with CVN424 150 mg and 2% with placebo). No serious treatment-related adverse events were reported. On Day 27, the mean ± standard deviation (SD) change from baseline in daily OFF-time was -1.3 ± 3.0 h in the CVN424 50 mg group, -1.6 ± 2.5 h in the CVN424 150 mg group, and -0.5 ± 2.9 h in the placebo group. The placebo-adjusted LS mean ± standard error (SE) treatment difference was significant for the CVN424 150 mg dose (1.3 ± 0.56 h, [95 CI% -2.41 to -0.19], nominal p = 0.02). Interpretation: Treatment with CVN424 was safe and well-tolerated. Despite the short study duration and small sample size, the 150 mg CVN424 dose provided a clinically meaningful reduction in daily OFF-time. This study supports the development of CVN424 for the treatment of PD. Funding: Cerevance.

Genuine Multipartite Entanglement Detection with Imperfect Measurements: Concept and Experiment.

Standard procedures for entanglement detection assume that experimenters can exactly implement specific quantum measurements. Here, we depart from such idealizations and investigate, in both theory and experiment, the detection of genuine multipartite entanglement when measurements are subject to small imperfections. For arbitrary qubits number n, we construct multipartite entanglement witnesses where the detrimental influence of the imperfection is independent of n. In a tabletop four-partite photonic experiment, we demonstrate first how a small amount of alignment error can undermine the conclusions drawn from standard entanglement witnesses and then perform the correction analysis. Furthermore, since we consider quantum devices that are trusted but not perfectly controlled, we showcase advantages in terms of noise resilience as compared to device-independent models.

Peptide PET Imaging: A Review of Recent Developments and a Look at the Future of Radiometal-Labeled Peptides in Medicine.

The development of peptide-based, radiometal-labeled PET imaging agents has seen an increase in attention due to the favorable properties the peptide backbone exhibits. These include high selectivity and affinity to proteins and cells directly linked to various types of cancers. In addition, rapid clearance from circulation and low toxicity allow for unique approaches to engineering a viable peptide-based imaging agent. Utilizing peptides as the backbone allows for various modifications to improve metabolic stability, target cell affinity, and image quality and imaging capabilities and reduce toxicity. Select radiolabeled peptides have already been FDA approved, with many more in late-stage trials. This review summarizes the current state of the radiometal-labeled PET peptide imaging field as well as explores methods used by researchers to modify peptides, concluding with a look at the future of peptide-based therapy and diagnostics.

Time Since Prior NSTEMI and Major Adverse Cardiovascular and Cerebrovascular Events After Noncardiac Surgery.

Importance: Delaying elective noncardiac surgery after a recent acute myocardial infarction is associated with better outcomes, but current American Heart Association recommendations are based on data that are more than 20 years old. Objective: To examine the association between the time since a non-ST-segment elevation myocardial infarction (NSTEMI) and the risk of postoperative major adverse cardiovascular and cerebrovascular events (MACCE). Design, Setting, and Participants: This cross-sectional study examined Medicare claims data between 2015 and 2020 for patients 67 years or older who had major noncardiac surgery. Data were analyzed from September 21, 2023, to February 1, 2024. Exposure: Time elapsed between a prior NSTEMI and surgery. Main Outcomes and Measures: MACCE (30-day mortality, in-hospital myocardial infarction, heart failure, or stroke) and all-cause 30-day mortality. Multivariable logistic regression was used to estimate the association between outcomes and time since a prior NSTEMI. Results: The sample included 5 227 473 surgeries. The mean (SD) age was 75.7 (6.6) years; 2 981 239 (57.0%) were female, and 2 246 234 (43%) were male. There were 42 278 patients (0.81%) with a previous NSTEMI. Compared with patients without a prior NSTEMI, patients with an NSTEMI within 30 days of elective surgery had higher odds of MACCE, regardless of whether they had undergone coronary revascularization (adjusted odds ratio [aOR], 2.15; 95% CI, 1.09-4.23; P = .03) or not (aOR, 2.04; 95% CI, 1.31-3.16; P = .001). The odds of postoperative MACCE leveled off after 30 days in patients who had undergone any coronary revascularization procedure (and after 90 days in patients with drug-eluting stents) and then increased after 180 days (any revascularization at 181-365 days: aOR, 1.46; 95% CI, 1.25-1.71; P < .001; patients with drug-eluting stents at 181-365 days: aOR, 1.73; 95% CI, 1.42-2.12; P < .001). The odds of MACCE did not level off for patients who did not have revascularization. Findings for all-cause 30-day mortality were similar to those for MACCE, except that the odds of mortality in patients with previous NSTEMI who had revascularization leveled off after 60 days in elective surgeries and 90 days for nonelective surgeries (elective 30-day: aOR, 2.88; 95% CI, 1.30-6.36; P = .009; elective 61- to 90-day: aOR, 1.03; 95% CI, 0.57-1.86; P = .92; nonelective 30-day: aOR, 1.91; 95% CI, 1.52-2.40; P < .001; nonelective 91- to 120-day: aOR, 1.00; 95% CI, 0.73-1.37; P = .99). Conclusions and Relevance: This study found that among older patients undergoing noncardiac surgery who had revascularization, the odds of postoperative MACCE and mortality leveled off between 30 and 90 days and then increased after 180 days. The odds did not level off for patients who did not have revascularization. Delaying elective noncardiac surgery to occur between 90 and 180 days after an NSTEMI may be reasonable for patients who have had revascularization.

An Estimation of the Requirements of the Standardized Ileal Digestible Tryptophan, Valine, Isoleucine and Methionine on Young Pigs' (Up to 50 kg) Feed Efficiency: A Meta-Regression Analysis.

Currently, the NRC amino acid (AA) requirements for pigs published in 2012 are used as a reference in variable swine industries. However, recent results in several articles suggest that the standardized ileal digestible (SID) AA-lysine (Lys) ratio significantly evolved over the last two decades, while some publications report inconsistent outcomes. Therefore, the present study used a meta-regression analysis to assess the relative ratio to lysine to maximize the feed efficiency of four essential amino acids (tryptophan, valine, isoleucine, and methionine) in pig diets. According to the PRISMA guidelines, articles examining the target AA requirement using a basal diet supplemented with varying levels of crystalline AA (tryptophan, valine, isoleucine, or methionine) were identified across Scopus, PubMed, and Science Direct. As a result, 23, 22, 16, and 9 articles using tryptophan, valine, isoleucine, and methionine were selected and categorized into experiments for inclusion in our meta-analysis. The results suggested that the requirements of tryptophan, valine, isoleucine, and methionine in our meta-regression analysis were superior to NRC recommendations, regardless of the regression models and the growth phases with significant RSQ values (RSQ ≈ 1). Also, the QUAD and CLP regression models emphasized higher requirements than the LP model for the great majority of amino acids and growth phases. The results of the QUAD and CLP models were selected as estimations of the amino acid requirements for pigs under challenged conditions, whereas the LP model was chosen to estimate the amino acid requirements of genetically improved pigs under a modern housing system. The results of this meta-regression analysis could be used to refresh the information on the NRC amino acids (AA) requirements for swine.

Quantitative Modeling to Characterize Maternal Inflammatory Response of Histologic Chorioamnionitis in Placental Membranes.

PROBLEM: The placental membranes are a key barrier to fetal and uterine infection. Inflammation of the membranes, diagnosed as maternal inflammatory response (MIR) or alternatively as acute chorioamnionitis, is associated with adverse maternal-fetal outcomes. MIR is staged 1-3, with higher stages indicating more hazardous inflammation. However, the diagnosis relies upon subjective evaluation and has not been deeply characterized. The goal of this work is to develop a cell classifier for eight placental membrane cells and quantitatively characterize MIR1-2. METHOD OF STUDY: Hematoxylin and eosin (H&E)-stained placental membrane slides were digitized. A convolutional neural network was trained on a dataset of hand-annotated and machine learning-identified cells. Overall cell class-level metrics were calculated. The model was applied to 20 control, 20 MIR1, and 23 MIR2 placental membrane cases. MIR cell composition and neutrophil distribution were assessed via density and Ripley's cross K-function. Clinical data were compared to neutrophil density and distribution. RESULTS: The classification model achieved a test-set accuracy of 0.845, with high precision and recall for amniocytes, decidual cells, endothelial cells, and trophoblasts. Using this model to classify 53 073 cells from healthy and MIR1-2 placental membranes, we found that (1) MIR1-2 have higher neutrophil density and fewer decidual cells and trophoblasts, (2) Neutrophils colocalize heavily around decidual cells in healthy placental membranes and around trophoblasts in MIR1, (3) Neutrophil density impacts distribution in MIR, and (4) Neutrophil metrics correlate with features of clinical chorioamnionitis. CONCLUSIONS: This paper introduces cell classification into the placental membranes and quantifies cell composition and neutrophil spatial distributions in MIR.

Investigating the Formation of Polymer-Nanoparticle Complex Coacervate Hydrogels Using Polymerization-Induced Self-Assembly-Derived Nanogels with a Succinate-Functional Core.

This paper reports polymer-nanoparticle-based complex coacervate (PNCC) hydrogels prepared by mixing anionic nanogels synthesized by polymerization-induced self-assembly (PISA) and cationic branched poly(ethylenimine) (bPEI). Specifically, poly(3-sulfopropyl methacrylate)58-b-poly(2-(methacryloyloxy)ethyl succinate)500 (PKSPMA58-PMES500) nanogels were prepared by reversible addition-fragmentation chain-transfer (RAFT)-mediated PISA. These nanogels swell on increasing the solution pH and form free-standing hydrogels at 20% w/w and pH ≥ 7.5. However, the addition of bPEI significantly improves the gel properties through the formation of PNCCs. Diluted bPEI/nanoparticle mixtures were analyzed by dynamic light scattering (DLS) and aqueous electrophoresis to examine the mechanism of PNCC formation. The influence of pH and the bPEI-to-nanogel mass ratio (MR) on the formation of these PNCC hydrogels was subsequently investigated. A maximum gel strength of 1300 Pa was obtained for 20% w/w bPEI/PKSPMA58-PMES500 PNCC hydrogels prepared at pH 9 with an MR of 0.1, and shear-thinning behavior was observed in all cases. After the removal of shear, these PNCC gels recovered rapidly, with the recovery efficiency being pH-dependent.

SARS-CoV-2 spike aggravates lupus nephritis and lung fibrosis in systemic lupus erythematosus.

OBJECTIVE: COVID-19 induces the development of autoimmune diseases, including SLE, which are characterised by inflammation, autoantibodies and thrombosis. However, the effects of COVID-19 on SLE remain unclear. METHODS: We investigated the effects of COVID-19 on SLE development and progression in three animal models. Plasmids encoding SARS-CoV-2 spike protein and ACE2 receptor were injected into R848-induced BALB/C lupus mice, R848-induced IL-1 receptor antagonist knockout (KO) lupus mice and MRL/lpr mice. Serum levels of albumin and autoantibodies, lymphocyte phenotypes and tissue histology were evaluated. RESULTS: In R848-induced BALB/C lupus mice, the SARS-CoV-2 spike protein increased autoantibody and albumin levels compared with vehicle and mock treatments. These mice also exhibited splenomegaly, which was further exacerbated by the spike protein. Flow cytometric analysis revealed elevated T helper 1 cell counts, and histological analysis indicated increased levels of the fibrosis marker protein α-smooth muscle actin. In KO mice, the spike protein induced splenomegaly, severe kidney damage and pronounced lung fibrosis. In the MRL/lpr group, spike protein increased the serum levels of autoantibodies, albumin and the thrombosis marker chemokine (C-X-C motif) ligand 4. CONCLUSION: COVID-19 accelerated the development and progression of lupus by inducing autoantibody production, fibrosis and thrombosis.