Heimdallr, Baldr, and Solarstein: designing the next generation of VLTI instruments in the Asgard suite.

High angular resolution imaging is an increasingly important capability in contemporary astrophysics. Of particular relevance to emerging fields such as the characterization of exoplanetary systems, imaging at the required spatial scales and contrast levels results in forbidding challenges in the correction of atmospheric phase errors, which in turn drives demanding requirements for precise wavefront sensing. Asgard is the next-generation instrument suite at the European Southern Observatory's Very Large Telescope Interferometer (VLTI), targeting advances in sensitivity, spectral resolution, and nulling interferometry. In this paper, we describe the requirements and designs of three core modules: Heimdallr, a beam combiner for fringe tracking, low order wavefront correction, and visibility science; Baldr, a Zernike wavefront sensor to correct high order atmospheric aberrations; and Solarstein, an alignment and calibration unit. In addition, we draw generalizable insights for designing such system and discuss integration plans.

Sensitivity of ocean circulation to warming during the Early Eocene greenhouse.

Multiple abrupt warming events ("hyperthermals") punctuated the Early Eocene and were associated with deep-sea temperature increases of 2 to 4 °C, seafloor carbonate dissolution, and negative carbon isotope (δ13C) excursions. Whether hyperthermals were associated with changes in the global ocean overturning circulation is important for understanding their driving mechanisms and feedbacks and for gaining insight into the circulation's sensitivity to climatic warming. Here, we present high-resolution benthic foraminiferal stable isotope records (δ13C and δ18O) throughout the Early Eocene Climate Optimum (~53.26 to 49.14 Ma) from the deep equatorial and North Atlantic. Combined with existing records from the South Atlantic and Pacific, these indicate consistently amplified δ13C excursion sizes during hyperthermals in the deep equatorial Atlantic. We compare these observations with results from an intermediate complexity Earth system model to demonstrate that this spatial pattern of δ13C excursion size is a predictable consequence of global warming-induced changes in ocean overturning circulation. In our model, transient warming drives the weakening of Southern Ocean-sourced overturning circulation, strengthens Atlantic meridional water mass aging gradients, and amplifies the magnitude of negative δ13C excursions in the equatorial to North Atlantic. Based on model-data consistency, we conclude that Eocene hyperthermals coincided with repeated weakening of the global overturning circulation. Not accounting for ocean circulation impacts on δ13C excursions will lead to incorrect estimates of the magnitude of carbon release driving hyperthermals. Our finding of weakening overturning in response to past transient climatic warming is consistent with predictions of declining Atlantic Ocean overturning strength in our warm future.

Proactive Coping in Early Pregnancy and Adverse Pregnancy Outcomes.

Objective: Outside of pregnancy, proactive coping has been associated with both mental and physical well-being and with improved quality of life in chronic disease, but its effects in pregnancy are understudied. Our objective was to evaluate whether early pregnancy proactive coping was associated with adverse perinatal outcomes. Study Design: This was a planned secondary analysis of nulliparous pregnant people recruited from a tertiary care center. Participants completed a validated assessment of proactive coping (Proactive Coping Scale) at 8-20 weeks and were followed longitudinally through delivery. Detailed pregnancy and delivery data were collected by trained research personnel. The primary outcome was a composite of adverse perinatal outcomes including unplanned cesarean delivery, gestational diabetes, and hypertensive disorders of pregnancy. Secondary analyses included individual perinatal composite components and a neonatal morbidity composite measure. Multivariate regression compared adverse perinatal outcomes by Proactive Coping Scale quartile, controlling for a priori confounders. Results: Of the 281 parturients, the median Proactive Coping Scale score was 45.0 (range 25-55), and 47% experienced an adverse perinatal outcome. After adjusting for confounders, those in the lowest Proactive Coping Scale quartile had 2.2 times higher odds of experiencing an adverse perinatal outcome compared to those in the highest Proactive Coping Scale quartile. There were no differences in odds of the individual composite components or the adverse neonatal outcome. Conclusion: Lower early pregnancy proactive coping scores are associated with significant increase in adverse perinatal outcomes. Interventions that target improving proactive coping may be a novel mechanism for reducing perinatal morbidity.

Proactive coping is the process of preparing for a stressor or goal, which has been studied in the context of chronic disease. We sought to understand how proactive coping relates to pregnancy outcomes. Our results indicated that higher proactive coping scores were associated with lower risk of adverse pregnancy outcomes. Therefore, interventions to increase proactive coping may have a role in reducing adverse pregnancy outcomes.

The relationship between hair cortisol concentration and autism diagnosis.

BACKGROUND: Autistic children are prone to experience heightened levels of distress and physiological reactivity to a range of sensory, social, and emotional stimuli. In line with this, multiple studies have demonstrated that autistic children have higher acute cortisol stress responses to adverse or threatening stimuli and altered cortisol awakening responses. However, few studies have examined whether this sensitivity may relate to heightened levels of chronic stress and persistently elevated hypothalamic-pituitary-adrenal (HPA) axis activity. The measurement of cortisol accumulation in hair is considered a non-invasive biomarker of chronic stress and has been associated with several childhood diseases. Here, we investigated whether hair cortisol concentration in a large sample of autistic children differed from non-autistic children, and after accounting for a range of child, parental and family-level characteristics. METHODS: Hair cortisol concentration was measured in 307 autistic children and 282 non-autistic controls aged between 2 and 17 years recruited from four Australian states who participated in providing hair samples and demographic data to the Australian Autism Biobank. Independent samples t-test or one-way analysis of variance (ANOVA) were conducted to determine significant differences in the mean hair cortisol concentration (pg/mg) between potential covariates. Primary analysis included multivariable regression modelling of the collapsed sample to identify variables that were significantly associated with hair cortisol concentration after controlling for covariates. We also accounted for the potential interaction of multiple biological (e.g., age, sex, BMI) and psychosocial characteristics at the level of the child, the mother and the father, and the family unit. RESULTS: Our findings suggest that the diagnosis of autism was not a significant predictor of chronic stress, as measured by hair cortisol concentration. However, findings of the multivariable regression analysis showed that key factors such as area of residence (Queensland vs Victorian state of residence) and decrease in child's age were significantly associated with higher hair cortisol concentration whereas lower family income was significantly associated with higher hair cortisol concentration. CONCLUSION: To our knowledge, this is the first study to show that socioeconomic factors such as family annual income affect hair cortisol status in autistic children, indicating that the psychosocial environment may be a potential mediator for chronic stress in autistic children just as it has been demonstrated in non-autistic children.

Association Between Hispanic Ethnicity and Engagement in a Remote Postpartum Blood Pressure Monitoring Programs: Secondary Analysis of a Pilot Randomized Trial.

OBJECTIVE: Remote self-measured blood pressure (SMBP) programs improve racial health equity among postpartum people with hypertensive disorders of pregnancy (HDP) who receive recommended blood pressure ascertainment after hospital discharge.1-3 However, as prior studies have been conducted within racially diverse but ethnically homogeneous populations,1-3 the effect of SMBP programs on ethnicity-based inequities is less understood.4 We examined whether SMBP rates differed among Hispanic versus non-Hispanic participants in remote SMBP programs. STUDY DESIGN: This is a planned secondary analysis of a RCT conducted among postpartum patients with HDP who were enrolled into our remote SMBP program, in which they obtain SMBP and then manually enter the SMBP value into a patient portal for individual provider response. In the parent trial, consenting patients were randomized to continued manual blood pressure entry of SMBP or use of a Bluetooth-enabled blood pressure cuff synched to a smartphone application utilizing artificial intelligence to respond to each obtained blood pressure or symptom for six weeks and to flag abnormalities for providers. Both SMBP programs were available in Spanish and English. For this study, women who self-reported their ethnicity were stratified into two ethnic groups - Hispanic and non-Hispanic - regardless of randomization group. Those who did not self-report ethnicity but completed all study procedures in Spanish were also categorized as Hispanic. Outcomes were the same in the parent study and this secondary analysis. The primary outcome was ≥1 SMBP assessment within 10 days postpartum. Secondary outcomes included number of blood pressure assessments and healthcare utilization outcomes (remote antihypertensive medication initiation or dose-increase and presentation to the Emergency Department or readmission for hypertension within 30 days of discharge). Participants rated their experience with SMBP via a scale from 0 (worst possible) to 10 (best possible) and the Decision Regret Scale, which assessed their regret in SMBP program participation (0=no regret; 100=high regret)).5 Outcomes were compared between groups. Risk differences (RD) were calculated for categorical and regression coefficients for continuous outcomes. The parent RCT was IRB-approved and published on clinicaltrials.gov (NCT05595629) before enrollment. RESULTS: Among 119 women in the parent study, 83 (70%) self-reported ethnicity and the proportion of Hispanic people was similar in both treatment groups. This study compared 23 Hispanic (19% monolingual in Spanish) to 62 non-Hispanic women. Rates of SMBP assessment within 10 days postpartum was similar (Hispanic 64% vs non-Hispanic 79%; RD -0.1 (95% Confidence Interval (CI) -0.4, 0.1). There were no differences in mean number of remote SMBP assessments or rates of remote antihypertensive medication initiation or dose titration. The rates of hypertension-related presentations to the Emergency Department or hospital readmission were also similar between groups. Lastly, regardless of ethnicity, participants had low scores on the Decision Regret Scale and rated their experience with their remote SMBP program highly favorably. (See Table 1.) Conclusion: Hispanic and non-Hispanic postpartum patients with HDP had similar outcomes and favorable patient perceptions. The small sample size in this study may have produced inadequate power to detect a difference between study groups, thereby leading to Type II error. Thus, more research on Hispanic participants in remote SMBP programs is needed. However, the effect of remote SMBP programs on perinatal equity may not be limited to race-based disparities.

An endogenous retrovirus regulates tumor-specific expression of the immune transcriptional regulator SP140.

Speckled Protein 140 (SP140) is a chromatin reader with critical roles regulating immune cell transcriptional programs, and SP140 splice variants are associated with immune diseases including Crohn's disease, multiple sclerosis, and chronic lymphocytic leukemia. SP140 expression is currently thought to be restricted to immune cells. However, by analyzing human transcriptomic datasets from a wide range of normal and cancer cell types, we found recurrent cancer-specific expression of SP140, driven by an alternative intronic promoter derived from an intronic endogenous retrovirus (ERV). The ERV belongs to the primate-specific LTR8B family and is regulated by oncogenic mitogen-activated protein kinase (MAPK) signaling. The ERV drives expression of multiple cancer-specific isoforms, including a nearly full-length isoform that retains all the functional domains of the full-length canonical isoform and is also localized within the nucleus, consistent with a role in chromatin regulation. In a fibrosarcoma cell line, silencing the cancer-specific ERV promoter of SP140 resulted in increased sensitivity to interferon-mediated cytotoxicity and dysregulation of multiple genes. Our findings implicate aberrant ERV-mediated SP140 expression as a novel mechanism contributing to immune gene dysregulation in a wide range of cancer cells.

Integrating Explicit and Implicit Fullerene Models into UNRES Force Field for Protein Interaction Studies.

Fullerenes, particularly C60, exhibit unique properties that make them promising candidates for various applications, including drug delivery and nanomedicine. However, their interactions with biomolecules, especially proteins, remain not fully understood. This study implements both explicit and implicit C60 models into the UNRES coarse-grained force field, enabling the investigation of fullerene-protein interactions without the need for restraints to stabilize protein structures. The UNRES force field offers computational efficiency, allowing for longer timescale simulations while maintaining accuracy. Five model proteins were studied: FK506 binding protein, HIV-1 protease, intestinal fatty acid binding protein, PCB-binding protein, and hen egg-white lysozyme. Molecular dynamics simulations were performed with and without C60 to assess protein stability and investigate the impact of fullerene interactions. Analysis of contact probabilities reveals distinct interaction patterns for each protein. FK506 binding protein (1FKF) shows specific binding sites, while intestinal fatty acid binding protein (1ICN) and uteroglobin (1UTR) exhibit more generalized interactions. The explicit C60 model shows good agreement with all-atom simulations in predicting protein flexibility, the position of C60 in the binding pocket, and the estimation of effective binding energies. The integration of explicit and implicit C60 models into the UNRES force field, coupled with recent advances in coarse-grained modeling and multiscale approaches, provides a powerful framework for investigating protein-nanoparticle interactions at biologically relevant scales without the need to use restraints stabilizing the protein, thus allowing for large conformational changes to occur. These computational tools, in synergy with experimental techniques, can aid in understanding the mechanisms and consequences of nanoparticle-biomolecule interactions, guiding the design of nanomaterials for biomedical applications.

Internal Adaptation of Composite Fillings Made Using Universal Adhesives-A Micro-Computed Tomography Analysis.

This study aimed to evaluate internal tooth-filling interfaces of composite fillings made using universal adhesives using micro-computed tomography (µCT). Sixty class V cavities were randomly assigned into six groups: Peak Universal etch and rinse (PER), Peak Universal self-etch (PSE), Adhese Universal etch and rinse (AER), and Adhese Universal self-etch (ASE). Two further adhesives considered gold standards were used as control groups: OptiBond FL (OER) for the etch and rinse technique and Clearfil SE for the self-etch technique (CSE). All teeth were subjected to thermomechanical loading and four-year water storage. Next, they were analyzed using µCT to investigate the internal tooth-filling interfaces. The proportions between the gap volume (GV) at the tooth-filling interface and the volume of applied composite filling (FV), between the gap and cavity volumes (CV), and between the gap volumes at the tooth-filling interface of the external (EGV) and internal (IGV) parts were calculated. Adhese Universal achieved the significantly lowest gap-to-filling- and gap-to-cavity-volume ratios for both types of etching techniques comparing to those of the Peak Universal and control groups. Significant differences between the gaps in external and internal parts of the tooth-filling interface were only noted in the control groups. Internal gap formation and development at the tooth-filling interface depend on the material as well as the type of its application.

Arrhythmias and cardiac MRI associations in patients with established cardiac dystrophinopathy.

AIMS: Some patients with cardiac dystrophinopathy die suddenly. Whether such deaths are preventable by specific antiarrhythmic management or simply indicate heart failure overwhelming medical therapies is uncertain. The aim of this prospective, cohort study was to describe the occurrence and nature of cardiac arrhythmias recorded during prolonged continuous ECG rhythm surveillance in patients with established cardiac dystrophinopathy and relate them to abnormalities on cardiac MRI. METHODS AND RESULTS: A cohort of 10 patients (36.3 years; 3 female) with LVEF<40% due to Duchenne (3) or Becker muscular (4) dystrophy or Duchenne muscular dystrophy-gene carrying effects in females (3) were recruited, had cardiac MRI, ECG signal-averaging and ECG loop-recorder implants. All were on standard of care heart medications and none had prior history of arrhythmias.No deaths or brady arrhythmias occurred during median follow-up 30 months (range 13-35). Self-limiting episodes of asymptomatic tachyarrhythmia (range 1-29) were confirmed in 8 (80%) patients (ventricular only 2; ventricular and atrial 6). Higher ventricular arrhythmia burden correlated with extent of myocardial fibrosis (extracellular volume%, p=0.029; native T1, p=0.49; late gadolinium enhancement, p=0.49), but not with LVEF% (p=1.0) on MRI and atrial arrhythmias with left atrial dilatation. Features of VT episodes suggested various underlying arrhythmia mechanisms. CONCLUSIONS: The overall prevalence of arrhythmias was low. Even in such a small sample size, higher arrhythmia counts occurred in those with larger scar burden and greater ventricular volume, suggesting key roles for myocardial stretch as well as disease progression in arrhythmogenesis. These features overlap with the stage of left ventricular dysfunction when heart failure also becomes overt. The findings of this pilot study should help inform the design of a definitive study of specific antiarrhythmic management in dystrophinopathy. TRIAL REGISTRATION NUMBER: ISRCTN15622536.

Abatacept increases T cell exhaustion in early RA individuals who carry HLA risk alleles.

Exhausted CD8 T cells (TEX) are associated with worse outcome in cancer yet better outcome in autoimmunity. Building on our past findings of increased TIGIT+KLRG1+ TEX with teplizumab therapy in type 1 diabetes (T1D), in the absence of treatment we found that the frequency of TIGIT+KLRG1+ TEX is stable within an individual but differs across individuals in both T1D and healthy control (HC) cohorts. This TIGIT+KLRG1+ CD8 TEX population shares an exhaustion-associated EOMES gene signature in HC, T1D, rheumatoid arthritis (RA), and cancer subjects, expresses multiple inhibitory receptors, and is hyporesponsive in vitro, together suggesting co-expression of TIGIT and KLRG1 may broadly define human peripheral exhausted cells. In HC and RA subjects, lower levels of EOMES transcriptional modules and frequency of TIGIT+KLRG1+ TEX were associated with RA HLA risk alleles (DR0401, 0404, 0405, 0408, 1001) even when considering disease status and cytomegalovirus (CMV) seropositivity. Moreover, the frequency of TIGIT+KLRG1+ TEX was significantly increased in RA HLA risk but not non-risk subjects treated with abatacept (CTLA4Ig). The DR4 association and selective modulation with abatacept suggests that therapeutic modulation of TEX may be more effective in DR4 subjects and TEX may be indirectly influenced by cellular interactions that are blocked by abatacept.

Trends in Income Inequities in Cardiovascular Health Among US Adults, 1988-2018.

BACKGROUND: Mean cardiovascular health has improved over the past several decades in the United States, but it is unclear whether the benefit is shared equitably. This study examined 30-year trends in cardiovascular health using a suite of income equity metrics to provide a comprehensive picture of cardiovascular income equity. METHODS: The study evaluated data from the 1988-2018 National Health and Nutrition Examination Survey. Survey groupings were stratified by poverty-to-income ratio (PIR) category, and the mean predicted 10-year risk of a major cardiovascular event or death based on the pooled cohort equations (PCE) was calculated (10-year PCE risk). Equity metrics including the relative and absolute concentration indices and the achievement index-metrics that assess both the prevalence and the distribution of a health measure across different socioeconomic categories-were calculated. RESULTS: A total of 26 633 participants aged 40 to 75 years were included (mean age, 53.0-55.5 years; women, 51.9%-53.0%). From 1988-1994 to 2015-2018, the mean 10-year PCE risk improved from 7.8% to 6.4% (P<0.05). The improvement was limited to the 2 highest income categories (10-year PCE risk for PIR 5: 7.7%-5.1%, P<0.05; PIR 3-4.99: 7.6%-6.1%, P<0.05). The 10-year PCE risk for the lowest income category (PIR <1) did not significantly change (8.1%-8.7%). In 1988-1994, the 10-year PCE risk for PIR <1 was 6% higher than PIR 5; by 2015-2018, this relative inequity increased to 70% (P<0.05). When using metrics that account for all income categories, the achievement index improved (8.0%-7.1%, P<0.05); however, the achievement index was consistently higher than the mean 10-year PCE risk, indicating the poor persistently had a greater share of adverse health. CONCLUSIONS: In this serial cross-sectional survey of US adults spanning 30 years, the population's mean 10-year PCE risk improved, but the improvement was not felt equally across the income spectrum.

Investigation of the Hydrolytic Degradation Kinetics of 3D-Printed PLA Structures under a Thermally Accelerated Regime.

The application of biobased and biodegradable polymers, such as polylactide (PLA), in fused deposition modeling (FDM) 3D-printing technology creates a new prospect for rapid prototyping and other applications in the context of ecology. The popularity of the FDM method and its significance in material engineering not only creates new prospects for the development of technical sciences on an industrial scale, but also introduces new technologies into households. In this study, the kinetics of the hydrolytic degradation of samples obtained by the FDM method from commercially available PLA filaments under a thermally accelerated regime were analyzed. The investigation was conducted at the microstructural, supramolecular, and molecular levels by using methods such as micro-computed tomography (micro-CT), wide-angle X-ray diffraction (WAXD), viscosimetry, and mass erosion measurements. The obtained results clearly present the rapid structural changes in 3D-printed materials during degradation due to their amorphous initial structure. The complementary studies carried out at different scale levels allowed us to demonstrate the relationship between the observed structural changes in the samples and the hydrolytic decomposition of the polymer chains, which made it possible to scientifically understand the process and expand the knowledge on biodegradation.

Assessment of Impact of the Surface Modification Techniques on Structural, Biophysical, and Electrically Conductive Properties of Different Fabrics.

This article presents studies on the evaluation of the impact of surface modification of cotton, viscose, and polyester fabrics using three techniques (flocking, layer by layer, and screen printing) with materials with electrically conductive properties on their structural, biophysical, and conductive properties. Each tested fabric is characterized by specific biophysical properties. which can be disturbed by various modification methods, therefore, the following tests were carried out in the article: optical microscopy, micro-computed tomography, guarded perspiration heating plate, air permeability, sorption and electrical conductivity tester. The use of screen printing increased the thermal resistance of the cotton woven fabric by 119%, the polyester woven fabric by 156%, and the viscose fabric by 261%. The smallest changes in thermal resistance compared to unmodified textiles were observed in layer by layer modified fabrics and are as follows: -15% (cotton woven fabric), +77% (PES woven fabric), and +80% (viscose woven fabric).

Optimal Timing of Tracheostomy in the Setting of COVID-19 and Associated Pneumothorax.

Introduction At the beginning of the 2020 pandemic, no criteria were in place regarding the timing of tracheostomy placement in intubated COVID-19 patients, nor were there any data pertaining to pneumothorax incidence in this population. This study examines the timing of tracheostomy placement and its correlation with patient outcomes, along with pneumothorax incidence in COVID-19 patients who underwent a tracheostomy.  Methods We performed a multi-institutional retrospective study of intubated COVID-19 patients admitted to intensive care units (ICUs) in North and South Dakota between April 2020 and December 2020. The timing of the tracheostomy was assessed, with primary outcomes being mortality, successful ventilator weaning, discharge to a long-term care facility, and overall length of stay. Patients were grouped by age, gender, ethnicity, and comorbidities. Pre- and post-tracheostomy pneumothorax was extracted from this dataset. Results We identified 85 patients who were intubated with COVID-19 and underwent a tracheostomy. The timing of tracheostomy varied widely, ranging from five to 53 days with an average time to tracheostomy being 17.3 days. Thirty-four of the patients expired, 32 patients were discharged to a long-term care hospital (LTCH), and 11 patients were discharged to an inpatient rehabilitation facility. Only three patients were discharged home. Regression analysis did not reveal statistically significant differences between patients who survived (N = 51) and patients who expired (N = 34) for almost all variables analyzed. Sixteen of the 85 patients were diagnosed with pneumothorax during their hospital stay. Half of these patients were diagnosed after a tracheostomy was placed. Conclusion This study did not demonstrate statistically significant differences in overall mortality or incidence of pneumothorax when it pertains to the timing of placement of tracheostomy. Variation in mortality was identified, in which younger patients were more likely to survive than older patients, a finding that was echoed in other studies. Considering this evidence, we cannot conclude that an association between the timing of tracheostomy and mortality from COVID-19; therefore, tracheostomy in the setting of COVID-19 can be performed at the provider's discretion.

Immunoglobulin G genetic variation can confound assessment of antibody levels via altered binding to detection reagents.

Objectives: Amino acid variations across more than 30 immunoglobulin (Ig) allotypes may introduce structural changes that influence recognition by anti-Ig detection reagents, consequently confounding interpretation of antibody responses, particularly in genetically diverse cohorts. Here, we assessed a panel of commercial monoclonal anti-IgG1 clones for capacity to universally recognise two dominant IgG1 haplotypes (G1m-1,3 and G1m1,17). Methods: Four commercial monoclonal anti-human IgG1 clones were assessed via ELISAs and multiplex bead-based assays for their ability to bind G1m-1,3 and G1m1,17 IgG1 variants. Detection antibodies were validated against monoclonal IgG1 allotype standards and tested for capacity to recognise antigen-specific plasma IgG1 from G1m-1,3 and G1m1,17 homozygous and heterozygous SARS-CoV-2 BNT162b2 vaccinated (n = 28) and COVID-19 convalescent (n = 44) individuals. An Fc-specific pan-IgG detection antibody corroborated differences between hinge- and Fc-specific anti-IgG1 responses. Results: Hinge-specific anti-IgG1 clone 4E3 preferentially bound G1m1,17 compared to G1m-1,3 IgG1. Consequently, SARS-CoV-2 Spike-specific IgG1 levels detected in G1m1,17/G1m1,17 BNT162b2 vaccinees appeared 9- to 17-fold higher than in G1m-1,3/G1m-1,3 vaccinees. Fc-specific IgG1 and pan-IgG detection antibodies equivalently bound G1m-1,3 and G1m1,17 IgG1 variants, and detected comparable Spike-specific IgG1 levels between haplotypes. IgG1 responses against other human coronaviruses and influenza were similarly poorly detected by 4E3 anti-IgG1 in G1m-1,3/G1m-1,3 subjects. Conclusion: Anti-IgG1 clone 4E3 confounds assessment of antibody responses in clinical cohorts owing to bias towards detection of G1m1,17 IgG1 variants. Validation of anti-Ig clones should include evaluation of binding to relevant antibody variants, particularly as the role of immunogenetics upon humoral immunity is increasingly explored in diverse populations.

Peptide-based inhibitors targeting the PD-1/PD-L1 axis: potential immunotherapeutics for cancer.

The PD-1/PD-L1 complex belongs to the group of inhibitory immune checkpoints and plays a critical role in immune regulation. The PD-1/PD-L1 axis is also responsible for immune evasion of cancer cells, and this complex is one of the main targets of immunotherapies used in oncology. Treatment using immune checkpoint inhibitors is mainly based on antibodies. This approach has great therapeutic potential; however, it also has major drawbacks and can induce immune-related adverse events. Thus, there is a strong need for alternative, non-antibody-based therapies using small molecules, peptides, or peptidomimetics. In the present study, we designed, synthesized, and evaluated a set of PD-1-targeting peptides based on the sequence and structure of PD-L1. The binding of these peptides to PD-1 was investigated using SPR and ELISA. We also assessed their ability to compete with PD-L1 for binding to PD-1 and their inhibitory properties against the PD-1/PD-L1 complex at the cellular level. The best results were obtained for the peptide PD-L1(111-127)(Y112C-I126C), named (L11), which displaced PD-L1 from binding to PD-1 in the competitive assay and inhibited the formation of the PD-1/PD-L1 complex. The (L11) peptide also exhibited strong affinity for PD-1. NMR studies revealed that (L11) does not form a well-defined secondary structure; however, MD simulation indicated that (L11) binds to PD-1 at the same place as PD-L1. After further optimization of the structure, the peptide inhibitor obtained in this study could also be used as a potential therapeutic compound targeting the PD-1/PD-L1 axis.

Neonatal Outcomes are Similar between Patients with Resolved and Those with Persistent Oligohydramnios.

OBJECTIVE: Oligohydramnios (defined as amniotic fluid volume < 5 cm or deepest vertical pocket < 2 cm) is regarded as an ominous finding on prenatal ultrasound. Amniotic fluid, however, is not static, and to date, there have been no studies comparing perinatal outcomes in patients who are diagnosed with oligohydramnios that resolves and those who have persistent oligohydramnios. STUDY DESIGN: This is a secondary analysis of a National Institutes of Health-funded retrospective cohort study of singleton gestations delivered at a tertiary care hospital between 2002 and 2013 with mild hypertensive disorders and/or fetal growth restriction (FGR). Maternal characteristics, delivery, and neonatal information were abstracted by trained research nurses. Patients with a diagnosis of oligohydramnios were identified, and those with resolved versus persistent oligohydramnios at the time of delivery were compared. The primary outcome was a composite of neonatal resuscitation at delivery: administration of oxygen, bag-mask ventilation, continuous positive airway pressure, intubation, chest compression, or cardiac medication administration. Secondary outcomes included FGR, timing, and mode of delivery. RESULTS: Of 527 women meeting study criteria, 42 had oligohydramnios that resolved prior to delivery, whereas 485 had persistent oligohydramnios. There were no significant differences in patient demographics between groups. The gestational age at diagnosis was significantly lower for patients with resolved versus persistent oligohydramnios (median: 33.0 [interquartile range, IQR: 29.1-35.9] vs. 38.0 [IQR: 36.4-39.3], p < 0.001). There was not a substantial difference in rate of neonatal resuscitation (41 vs. 32%, p = 0.31). Patients with resolved oligohydramnios were more likely to have developed FGR than those with persistent oligohydramnios (55 vs. 36%, p < 0.02). There were no significant differences for gestational age at delivery, birth weight, or neonatal intensive care unit admission. CONCLUSION: Patients whose oligohydramnios resolved were diagnosed earlier yet had similar rates of neonatal resuscitation but higher rates of FGR than those who had persistent oligohydramnios. KEY POINTS: · When diagnosed earlier in pregnancy, oligohydramnios was more likely to resolve prenatally.. · Patients who were diagnosed with oligohydramnios earlier in pregnancy had higher rates of FGR.. · There were no differences in the rates of the composite outcome of need for neonatal resuscitation when comparing those with resolved versus those with persistent oligohydramnios. No differences in composite neonatal morbidity were noted between those with resolved versus persistent oligohydramnios..