Glucose Testing in an Index Pregnancy and Outcomes in a Subsequent Pregnancy: Implications for Screening and a Novel Risk Calculator.

OBJECTIVE: Our objective was to assess whether variables from an index pregnancy (PG1) can be used to guide testing for gestational diabetes mellitus (GDM) in a subsequent pregnancy (PG2) and to create a risk calculator for GDM in PG2. STUDY DESIGN: This was a retrospective cohort study of patients delivering ≥2 singleton gestations at >24 weeks' gestation from June 2009 to December 2018, for whom results of a 1-hour glucose challenge test (GCT) were available from PG1. Univariable and multivariable analyses were performed to evaluate factors associated with GDM in PG2. RESULTS: In total, 4,278 patients met the inclusion criteria. Among patients with a normal 1-hour GCT (<140 mg/dL) in PG1 (n = 3,719), 3.9% were diagnosed with GDM in PG2. In multivariable analysis of this group, GDM in PG2 was associated with higher GCT in PG1 (adjusted odds ratio [aOR]: 1.05, 95% confidence interval [CI]: 1.04-1.06), large for gestational age neonate in PG1 (aOR: 1.97, 95% CI: 1.24-3.13), and higher BMI (aOR: 1.08, 95% CI: 1.05-1.11). A novel risk calculator for GDM in PG2 was developed based on these associations. Using a risk cut-off of 15%, the calculator had a positive predictive value of 26% and a negative predictive value of 97%, with 3.2% of patients identified as "at risk". Among patients with abnormal 1-hour GCT in PG1, 38.3% (n = 214/559) had an abnormal 1-hour GCT in PG2 and 34.5% (n = 74/214) of these patients received a diagnosis of GDM. CONCLUSION: A normal 1-hour GCT in an PG1 is followed by GDM in a subsequent pregnancy in only 3.9% of cases. A novel calculator supports replacing universal screening with targeted testing in subsequent pregnancies in this population. Among patients with an abnormal 1-hour GCT in PG1, nearly 40% have an abnormal 1-hour GCT in a subsequent pregnancy. Direct diagnostic testing can be considered in such patients. KEY POINTS: · Normal GCT in a first pregnancy is associated with normal GCT in subsequent pregnancy.. · A risk calculator can target diabetes testing in a subsequent pregnancy.. · Abnormal GCT in a first pregnancy is associated with abnormal GCT in subsequent pregnancy..

The Association between Maternal Body Mass Index and the Risk of Perinatal Depression.

OBJECTIVE: The aim of this study was to evaluate whether the risk of perinatal depression is associated with body mass index (BMI) category. STUDY DESIGN: We performed a retrospective cohort study of women who completed an Edinburgh Postnatal Depression Scale (EPDS) questionnaire during the antepartum period at an integrated health system from January 2003 to May 2018. Risk of perinatal depression was defined as a score of ≥10 on the EPDS or an affirmative response to thoughts of self-harm. Risk of perinatal depression was compared by first trimester BMI category, defined as underweight (BMI: <18.5 kg/m2), normal weight (BMI: 18.5-24.9 kg/m2), overweight (BMI: 25.0-29.9 kg/m2), or obese (BMI: ≥30.0 kg/m2). Univariable analyses were performed using χ 2, Fisher's exact test, analysis of variance, Kruskal-Wallis, and Wilcoxon rank-sum tests as appropriate to evaluate the association between maternal BMI category, demographic and clinical characteristics, and risk of perinatal depression. Logistic multivariable regression models were performed to adjust for potential confounders identified as variables with p < 0.10 in univariable analysis. RESULTS: Our analysis included 3,420 obese women, 3,839 overweight women, 5,949 normal weight women, and 1,203 underweight women. The overall median gestational age at EPDS administration was 27 weeks (interquartile range: 23-29). Overweight and obese women were more likely to be non-Hispanic Black, Hispanic, multiparous, to have public insurance, prepregnancy diabetes, and chronic hypertension as compared with normal or underweight women (p < 0.001). In univariable analysis, the risk of perinatal depression was not significantly different among underweight (10.8%, odds ratio [OR]: 0.86, 95% confidence interval [CI]: 0.79-1.18) or overweight women (12%, OR: 0.96, 95% CI: 0.79-1.18); however, the risk was higher among obese women (14.7%, 95% CI: 1.21-1.55) compared with normal weight women (11.2%). In multivariable analysis, obesity remained associated with an increased risk of perinatal depression (adjusted OR: 1.19, 95% CI: 1.04-1.35). CONCLUSION: Obesity is associated with an increased risk of perinatal depression as compared with women of normal weight. KEY POINTS: · Maternal obesity is associated with an increased risk of perinatal depression.. · Maternal BMI is associated with increased risk of perinatal depression.. · Maternal obesity is an independent risk factor for perinatal depression..

Evaluation of carbon-11 labeled 5-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)nicotinamide as PET tracer for imaging of CSF-1R expression in the brain.

Pharmacological targeting of tumor associated macrophages and microglia in the tumor microenvironment is a novel therapeutic strategy in the treatment of glioblastoma multiforme. As such, the colony stimulating factor-1 receptor (CSF-1R) has been identified as a druggable target. However, no validated companion diagnostic marker for these therapies exists to date. Towards development of a CSF-1R PET tracer, a set of six compounds based on recently reported CSF-1R inhibitor 5-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)nicotinamide (Compound 5) was designed, synthesized and evaluated in vitro for potency and selectivity. The highest affinity for CSF-1R was found for compound 5 (IC50: 2.7 nM). Subsequent radiosynthesis of [11C]5 was achieved in 2.0 ± 0.2% yield (decay corrected to start of synthesis) by carbon-11 carbon monoxide aminocarbonylation in 40 min after end of bombardment. In vitro autoradiography with [11C]5 on rat brain sections demonstrated high specific binding, but also strong off-target binding. Ex vivo, only intact tracer was observed in blood plasma at 90 min post injection in healthy rats. PET scanning results demonstrated negligible brain uptake under baseline conditions and this brain uptake did not increase by blocking of efflux transporters using Tariquidar. To conclude, [11C]5 was successfully synthesized and evaluated in healthy rats. However, the inability of [11C]5 to cross the blood-brain-barrier excludes its use for imaging of CSF-1R expression in the brain.

Elevated Glucose Challenge Test in a Nondiabetic Index Pregnancy and Gestational Diabetes in a Subsequent Pregnancy.

OBJECTIVE: The aim of this study was to evaluate whether a 1-hour glucose challenge test (GCT) ≥140 mg/dL in a nondiabetic index pregnancy is associated with the development of gestational diabetes mellitus (GDM) in a subsequent pregnancy. STUDY DESIGN: We performed a retrospective cohort study from a single institution from June 2009 to December 2018. Women with a nondiabetic index singleton gestation who underwent a 1-hour GCT at 24 to 28 weeks and had a successive singleton delivery were included. GDM was defined by a 1-hour GCT of ≥ 200 mg/dL, ≥2 of 4 elevated values on a 3-hour GCT, or a diagnosis of GDM defined by International Classification of Disease codes in the electronic medical record. Univariable analyses were performed to evaluate the associations between an elevated 1-hour GCT result in the index pregnancy, maternal characteristics, and the development of GDM in the subsequent pregnancy. Variables found to be significant (p < 0.05) were included in multivariable analysis. RESULTS: A total of 2,423 women were included. Of these, 340 (14.0%) had an elevated 1-hour GCT in the index pregnancy. Women with an elevated 1-hour GCT in the index pregnancy compared with those without were significantly more likely to be older, married, privately insured, of Hispanic ethnicity or Asian race, chronically hypertensive, have a higher body mass index (BMI), have a shorter inter-pregnancy interval, and to develop GDM in the subsequent pregnancy (14.4 vs. 3.3%, p < 0.001). In multivariable analysis, an elevated 1-hour GCT (adjusted odds ratio [aOR]: 4.54, 95% confidence interval [CI]: 3.02-6.81), first-trimester BMI ≥30 kg/m2 in the index pregnancy (aOR: 3.10, 95% CI: 2.03-4.71), Asian race (aOR: 2.96, 95% CI: 1.70-5.12), Hispanic ethnicity (aOR: 2.11, 95% CI: 1.12-4.00), and increasing age (aOR: 1.07, 95% CI: 1.02-1.12) were significantly associated with an increased risk of GDM in the subsequent pregnancy. CONCLUSION: An elevated 1-hour GCT in a nondiabetic index pregnancy is associated with a fourfold increased risk of GDM in a subsequent pregnancy. KEY POINTS: · An abnormal 1 hour GCT in an index pregnancy is associated with GDM in a subsequent pregnancy.. · An abnormal 1 hour GCT may be an independent risk factor for GDM in a subsequent pregnancy.. · An abnormal 1 hour GCT is associated with a 4 fold increased risk of GDM in a subsequent pregnancy..

Single versus Double-Balloon Transcervical Catheter for Labor Induction: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate for difference in outcomes between single- and double-balloon catheters for labor induction. STUDY DESIGN: We searched CINAHL, Embase, Cochrane Register, MEDLINE, ISI Web of Sciences, LILACs, and Google Scholar and retrieved studies through May 2017. Selection criteria included randomized controlled trials comparing single- versus double-balloon catheters. The primary outcome was time from catheter insertion to delivery. Heterogeneity of the results among studies was tested with the quantity I2 . For I2 values ≥50%, a random effects model was used to pool data across studies. Summary measures were reported as adjusted odds ratios (aORs) or as a mean difference (MD) with 95% confidence interval (CI). RESULTS: Four trials including a total of 682 patients were included: 340 patients were randomized to induction with a single-balloon catheter and 342 to induction with a double-balloon catheter. There was no significant difference between groups with respect to time to delivery (18.8 vs. 19.6 hours; MD: 0.40; 95% CI: -1.56 to 0.76), vaginal delivery rate (65.3 vs. 62.3%; aOR: 1.04; 95% CI: 0.56-1.92), cesarean delivery rate (25.6 vs. 27.5%; aOR: 0.98; 95% CI: 0.55-1.73), or epidural use (58.4 vs. 62%; aOR: 0.81; 95% CI: 0.56-1.18). CONCLUSION: Double-balloon catheters have no apparent advantage over single-balloon catheters for labor induction.

Subcortical dopaminergic deficits in a DISC1 mutant model: a study in direct reference to human molecular brain imaging.

Imaging of the human brain has been an invaluable aid in understanding neuropsychopharmacology and, in particular, the role of dopamine in the striatum in mental illness. Here, we report a study in a genetic mouse model for major mental illness guided by results from human brain imaging: a systematic study using small animal positron emission tomography (PET), autoradiography, microdialysis and molecular biology in a putative dominant-negative mutant DISC1 transgenic model. This mouse model showed augmented binding of radioligands to the dopamine D2 receptor (D2R) in the striatum as well as neurochemical and behavioral changes to methamphetamine administration. Previously we reported that this model displayed deficits in the forced swim test, a representative indicator of antidepressant efficacy. By combining the results of our two studies, we propose a working hypothesis for future studies that this model might represent a mixed condition of depression and psychosis. We hope that this study will also help bridge a major gap in translational psychiatry between basic characterization of animal models and clinico-pharmacological assessment of patients mainly through PET imaging.

The association of insertion methods on immediate postpartum intrauterine device expulsion rates: A retrospective cohort study.

OBJECTIVE: To evaluate the method of immediate postpartum IUD (ppIUD) insertion (manual versus ring forceps) and expulsion rate within 6-week postpartum. STUDY DESIGN: We performed a retrospective cohort study of patients who had a singleton vaginal delivery and an immediate ppIUD inserted at Rush University from January 2014 to September 2023. The primary outcome was rate of expulsion within 6-week postpartum. We compared the rate of expulsion by method of insertion, either using a manual technique versus using ring forceps. We performed univariable analysis for the association between baseline maternal characteristics and the primary outcome and we performed multivariable logistic regression to determine the independent association of the method of insertion and the primary outcome. RESULTS: Two hundred nineteen patients met eligibility with 117 immediate ppIUDs inserted manually and 102 inserted with ring forceps. Baseline maternal demographics were similar across study groups. After adjusting for factors selected a priori (estimated blood loss, body mass index, gestational age at delivery, nulliparity, type of IUD), use of ring forceps was more likely to result in expulsion compared to manual insertion (30.4% vs 16.2% respectively; adjusted OR 2.49, 95% confidence interval 1.28-4.90). CONCLUSION: In this retrospective analysis, insertion of immediate ppIUD with ring forceps was independently associated with an increased rate of expulsion within 6 weeks postpartum when compared to manual insertion. IMPLICATIONS: In this setting, ring forceps was associated with high rates of immediate postpartum IUD expulsion compared to manual technique. Studies disagree, suggesting need for additional work.

Recurrent massive perivillous fibrin deposition treated with aspirin and enoxaparin: A case report.

Massive perivillous fibrin deposition (MPVFD) is a potentially devastating complication of pregnancy that occurs in 0.03-0.5% of deliveries and is associated with severe fetal growth restriction, stillbirth, and neurologic injury due to uteroplacental insufficiency. The management of patients with recurrent pregnancy loss secondary to MPVFD has not been widely studied. We describe the case of a healthy 19-year-old with a history of two prior intrauterine fetal demises at 35w6d and 36w6d secondary to MPVFD of the placenta who subsequently delivered a healthy infant at 33w6d after she had been treated in the prenatal period with aspirin and prophylactic enoxaparin. Antenatal treatment with daily aspirin and prophylactic enoxaparin as well as close antenatal follow-up may be an option for patients with recurrent pregnancy loss due to MPVFD.

The association between a single abnormal glucose and fetal c-peptide.

AIM: We aimed to evaluated if fetuses of subjects with one elevated value on the 3-h GTT had a measurable physiologic difference in fetal C-peptide levels as compared to those with no elevated values on the GTT. METHODS: We performed a prospective cohort study to evaluate insulin levels in singleton non-anomalous fetuses of subjects with one elevated value on the GTT as compared to subjects with no elevated values on their GTT. Fetal insulin levels were measured by fetal C-peptide in cord blood. Distribution of data was assessed and outliers representing values > the 99th and < the 1st percentiles were excluded. Data were log transformed to achieve normal distribution and univariable analyses were performed to compare fetal C-peptide levels, baseline maternal characteristics and perinatal outcomes in subjects with one elevated value as compared those with no elevated values. RESULTS: Our analysis included 99 subjects, with 49 subjects in the one elevated value group and 50 subjects in the no elevated values group. Fetal C-peptide levels (picomoles per liters, pmol/L), were significantly higher in the elevated value group as compared to the no elevated value group (mean ± SD; 4.6 ± 0.8 vs. 4.3 ± 0.7, P = 0.046, respectively). In univariable analysis, there was no significant difference in maternal characteristics or adverse composite perinatal outcomes. CONCLUSION: Fetuses of subjects who had one elevated value on their GTT had a measurable physiologic difference in C-peptide levels as compared to fetuses of subjects with no elevated values on the GTT.

Imaging CD19+ B Cells in an Experimental Autoimmune Encephalomyelitis Mouse Model using Positron Emission Tomography.

Multiple sclerosis (MS) is the most common demyelinating central nervous system (CNS) disease affecting young adults, often resulting in neurological deficits and disability as the disease progresses. B lymphocytes play a complex and critical role in MS pathology and are the target of several therapeutics in clinical trials. Currently, there is no way to accurately select patients for specific anti-B cell therapies or to non-invasively quantify the effects of these treatments on B cell load in the CNS and peripheral organs. Positron emission tomography (PET) imaging has enormous potential to provide highly specific, quantitative information regarding the in vivo spatiotemporal distribution and burden of B cells in living subjects. This paper reports methods to synthesize and employ a PET tracer specific for human CD19+ B cells in a well-established B cell-driven mouse model of MS, experimental autoimmune encephalomyelitis (EAE), which is induced with human recombinant myelin oligodendrocyte glycoprotein 1-125. Described here are optimized techniques to detect and quantify CD19+ B cells in the brain and spinal cord using in vivo PET imaging. Additionally, this paper reports streamlined methods for ex vivo gamma counting of disease-relevant organs, including bone marrow, spinal cord, and spleen, together with high-resolution autoradiography of CD19 tracer binding in CNS tissues.

Effectiveness of extended postpartum inpatient monitoring for hypertensive disorders of pregnancy to reduce the risk of readmission for preeclampsia with severe features.

BACKGROUND: Preeclampsia is an obstetrical disorder, which complicates 3% to 6% of pregnancies and contributes to 21.6% of readmissions in the postpartum period. The optimal strategy for inpatient monitoring of blood pressures to minimize readmissions for postpartum patients with hypertensive disorders is not known. We hypothesized that extended monitoring of postpartum patients with hypertensive disorders of pregnancy for at least 36 hours after the last blood pressure that was ≥150/100 mm Hg would result in decreased readmission rates for preeclampsia with severe features compared with those who were not observed by these blood pressure goals. OBJECTIVE: This study aimed to evaluate whether extended inpatient monitoring of postpartum patients with hypertensive disorders of pregnancy for at least 36 hours after their last blood pressure that was ≥150/100 mm Hg would improve readmission rates for preeclampsia with severe features within 6 weeks of delivery. STUDY DESIGN: This was a retrospective cohort study in patients with a singleton pregnancy and a diagnosis of a hypertensive disorder of pregnancy at their delivery admission or at any point during pregnancy who delivered 1 year before and 1 year after the implementation of extended inpatient monitoring of postpartum hypertension. The primary outcome was readmission for preeclampsia with severe features within 6 weeks of delivery. The secondary outcomes were length of stay during first admission, number of readmissions for any indication, intensive care unit admission, postpartum day at readmission, median systolic blood pressure in the 24-hour period before discharge, median diastolic blood pressure in the 24-hour period before discharge, intravenous antihypertensive medication required during first admission, and intravenous antihypertensive medication required during second admission. Univariable analysis was performed for the association between baseline maternal characteristics and the primary outcome. Multivariable analysis was performed, adjusting for baseline maternal characteristic differences between exposure groups. RESULTS: A total of 567 patients met the inclusion criteria of which 248 patients delivered before and 319 delivered after the implementation of extended monitoring. For baseline characteristics, the extended monitoring group had a significantly higher proportion of patients who were non-Hispanic Black and Hispanic, more diagnoses of hypertensive disorders and/or diabetes mellitus at the time of admission for delivery, a difference in the distribution of hypertensive diagnoses at the time of discharge from the first admission, and fewer discharged patients from their first admission on labetalol than the preintervention group. In a univariable analysis of the primary outcome, there was a significantly increased risk of readmission for preeclampsia with severe features in the extended monitoring group (62.5% vs 96.2% of total readmissions; P=.004). In multivariable analysis, patients in the extended monitoring group were more likely to be readmitted for preeclampsia with severe features than patients in the preintervention group (adjusted odds ratio, 3.45; 95% confidence interval, 1.03-11.5; P=.044). CONCLUSION: Extended monitoring with a strict blood pressure goal of <150/<100 mm Hg did not decrease readmissions for preeclampsia with severe features in patients with a previous diagnosis of a hypertensive disorder of pregnancy.

Development and Initial Assessment of [18F]OP-801: a Novel Hydroxyl Dendrimer PET Tracer for Preclinical Imaging of Innate Immune Activation in the Whole Body and Brain.

PURPOSE: Innate immune activation plays a critical role in the onset and progression of many diseases. While positron emission tomography (PET) imaging provides a non-invasive means to visualize and quantify such immune responses, most available tracers are not specific for innate immune cells. To address this need, we developed [18F]OP-801 by radiolabeling a novel hydroxyl dendrimer that is selectively taken up by reactive macrophages/microglia and evaluated its ability to detect innate immune activation in mice following lipopolysaccharide (LPS) challenge. PROCEDURES: OP-801 was radiolabeled in two steps: [18F]fluorination of a tosyl precursor to yield [18F]3-fluoropropylazide, followed by a copper-catalyzed click reaction. After purification and stability testing, [18F]OP-801 (150-250 µCi) was intravenously injected into female C57BL/6 mice 24 h after intraperitoneal administration of LPS (10 mg/kg, n=14) or saline (n=6). Upon completing dynamic PET/CT imaging, mice were perfused, and radioactivity was measured in tissues of interest via gamma counting or autoradiography. RESULTS: [18F]OP-801 was produced with >95% radiochemical purity, 12-52 µCi/µg specific activity, and 4.3±1.5% decay-corrected yield. Ex vivo metabolite analysis of plasma samples (n=4) demonstrated high stability in mice (97±3% intact tracer >120 min post-injection). PET/CT images of mice following LPS challenge revealed higher signal in organs known to be inflamed in this context, including the liver, lung, and spleen. Gamma counting confirmed PET findings, showing significantly elevated signal in the same tissues compared to saline-injected mice: the liver (p=0.009), lung (p=0.030), and spleen (p=0.004). Brain PET/CT images (summed 50-60 min) revealed linearly increasing [18F]OP-801 uptake in the whole brain that significantly correlated with murine sepsis score (r=0.85, p<0.0001). Specifically, tracer uptake was significantly higher in the brain stem, cortex, olfactory bulb, white matter, and ventricles of LPS-treated mice compared to saline-treated mice (p<0.05). CONCLUSION: [18F]OP-801 is a promising new PET tracer for sensitive and specific detection of activated macrophages and microglia that warrants further investigation.

Clinical Radiosynthesis and Translation of [18F]OP-801: A Novel Radiotracer for Imaging Reactive Microglia and Macrophages.

Positron emission tomography (PET) is a powerful tool for studying neuroinflammatory diseases; however, current PET biomarkers of neuroinflammation possess significant limitations. We recently reported a promising dendrimer PET tracer ([18F]OP-801), which is selectively taken up by reactive microglia and macrophages. Here, we describe further important characterization of [18F]OP-801 in addition to optimization and validation of a two-step clinical radiosynthesis. [18F]OP-801 was found to be stable in human plasma for 90 min post incubation, and human dose estimates were calculated for 24 organs of interest; kidneys and urinary bladder wall without bladder voiding were identified as receiving the highest absorbed dose. Following optimization detailed herein, automated radiosynthesis and quality control (QC) analyses of [18F]OP-801 were performed in triplicate in suitable radiochemical yield (6.89 ± 2.23% decay corrected), specific activity (37.49 ± 15.49 GBq/mg), and radiochemical purity for clinical imaging. Importantly, imaging mice with tracer (prepared using optimized methods) 24 h following the intraperitoneal injection of liposaccharide resulted in the robust brain PET signal. Cumulatively, these data enable clinical translation of [18F]OP-801 for imaging reactive microglia and macrophages in humans. Data from three validation runs of the clinical manufacturing and QC were submitted to the Food and Drug Administration (FDA) as part of a Drug Master File (DMF). Subsequent FDA approval to proceed was obtained, and a phase 1/2 clinical trial (NCT05395624) for first-in-human imaging in healthy controls and patients with amyotrophic lateral sclerosis is underway.

PET Imaging of Innate Immune Activation Using 11C Radiotracers Targeting GPR84.

Chronic innate immune activation is a key hallmark of many neurological diseases and is known to result in the upregulation of GPR84 in myeloid cells (macrophages, microglia, and monocytes). As such, GPR84 can potentially serve as a sensor of proinflammatory innate immune responses. To assess the utility of GPR84 as an imaging biomarker, we synthesized 11C-MGX-10S and 11C-MGX-11Svia carbon-11 alkylation for use as positron emission tomography (PET) tracers targeting this receptor. In vitro experiments demonstrated significantly higher binding of both radiotracers to hGPR84-HEK293 cells than that of parental control HEK293 cells. Co-incubation with the GPR84 antagonist GLPG1205 reduced the binding of both radiotracers by >90%, demonstrating their high specificity for GPR84 in vitro. In vivo assessment of each radiotracer via PET imaging of healthy mice illustrated the superior brain uptake and pharmacokinetics of 11C-MGX-10S compared to 11C-MGX-11S. Subsequent use of 11C-MGX-10S to image a well-established mouse model of systemic and neuro-inflammation revealed a high PET signal in affected tissues, including the brain, liver, lung, and spleen. In vivo specificity of 11C-MGX-10S for GPR84 was confirmed by the administration of GLPG1205 followed by radiotracer injection. When compared with 11C-DPA-713-an existing radiotracer used to image innate immune activation in clinical research studies-11C-MGX-10S has multiple advantages, including its higher binding signal in inflamed tissues in the CNS and periphery and low background signal in healthy saline-treated subjects. The pronounced uptake of 11C-MGX-10S during inflammation, its high specificity for GPR84, and suitable pharmacokinetics strongly support further investigation of 11C-MGX-10S for imaging GPR84-positive myeloid cells associated with innate immune activation in animal models of inflammatory diseases and human neuropathology.

The association of immediate postpartum glucose values with persistent insulin resistance in patients with gestational diabetes.

OBJECTIVE: Gestational diabetes (GDM) affects approximately 6% of pregnancies and has critical maternal and neonatal implications.1 About 20-33% of these patients have insulin resistance or type 2 diabetes when evaluated at 6 to 12 weeks postpartum, however only approximately half of the affected patients return for postpartum testing.2-5 Fasting glucose during delivery hospitalization is correlated with fasting glucose on oral glucose tolerance testing (OGTT) at 4 to 12 weeks postpartum, but there is limited data on the utility of this value to identify the patients at an increased risk for postpartum insulin resistance.3 We aimed to evaluate if higher fasting glucose values on postpartum day 1 (PPD1) are correlated with an increased risk of persistent insulin resistance at 4 to 12 weeks postpartum diagnosed on OGTT. STUDY DESIGN: We conducted a retrospective cohort study of patients with GDM who delivered from 2009 to 2019 at 2 suburban hospitals. Eligible patients had a singleton pregnancy affected by GDM with complete data on PPD1 fasting glucose and OGTT at 4 to 12 weeks postpartum. GDM was diagnosed by a 50 gram, 1-hour OGTT value of ≥200 mg/dL or a 3-hour glucose tolerance test with ≥2 values exceeding defined thresholds (Carpenter-Coustan criteria). Postpartum impaired fasting glucose was defined as a fasting glucose ≥100 mg/dL, and impaired glucose tolerance was defined as a 2-hour glucose ≥140 mg/dL on postpartum glucose tolerance testing. PPD1 fasting glucose values were divided into 3 categories (<95, ≥95 to 109, and ≥110 mg/dL) for analyses. Univariate analyses were performed using chi-squared, analysis of variance, and Wilcoxon rank-sum tests as appropriate to evaluate the association between an abnormal postpartum OGTT and demographic variables, clinical characteristics, and PPD1 glucose by glucose category. Logistic regression models were performed to adjust for variables that were determined a priori and those found to be significant (P<.05) in univariate analyses. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated using descriptive statistics. RESULTS: Our analysis included 367 patients (Figure), of which 69.5% (255/367) had a PPD1 glucose <95 mg/dL, 19.9% (73/367) had a PPD1 glucose of 95 to 109 mg/dL, and 10.6% (39/367) had a PPD1 glucose ≥110 mg/dL. In multivariate analysis, compared with PPD1 <95 mg/dL, there was no significant association between postpartum glucose categories and abnormal postpartum OGTT results (PPD1 glucose ≥95 to 109 mg/dL: aOR [adjusted odds ratio], 1.10; 95% CI [confidence interval], 0.58-2.07; P=.77; PPD1 glucose ≥110 mg/dL: aOR, 1.01; 95% CI, 0.44-2.30; P=.99, Table). Fasting glucose on PPD1 of 95 mg/dL had a sensitivity of 20.1% (95% CI, 13.8-27.8%), specificity of 81.2% (95% CI, 76.4-85.4%), positive predictive value of 32.2% (95% CI, 22.6-43.1%), and negative predictive value of 69.7% (95% CI, 64.7-74.3%) to identify patients with impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes postpartum. In identifying patients with type 2 diabetes at 4 to 12 weeks postpartum, fasting glucose of 95 mg/dL on PPD1 had a sensitivity of 1.79% (95% CI, 0.2-6.3%), specificity of 98.4% (95% CI, 96.0-99.6%), positive predictive value 33.3% (95% CI, 4.3-77.7%), and negative predictive value of 69.6% (95% CI, 64.6-74.3%). CONCLUSION: Fasting glucose on PPD1 was not associated with persistent insulin resistance at 4 to 12 weeks postpartum.

AWHONN postpartum discharge education: patient knowledge and sustainability.

OBJECTIVE: The objective is to evaluate whether the implementation of the Association of Women's Health, Obstetric and Neonatal Nurses (AWHONN) postpartum discharge educational initiative is associated with improved patient knowledge of warning signs of severe maternal morbidity (SMM) and if the initiative is self-sustaining. DESIGN: A pre-post design was used to evaluate patient knowledge of warning signs of SMM (Plan-Do-Study-Act, PDSA cycle 1) and if the quality improvement initiative was self-sustaining (PDSA cycle 2). Patient understanding of warning signs of SMM prior to initiation of the AWHONN education (Usual Discharge) was compared with understanding of those who were discharged after implementation (POST-BIRTH discharge). The initiative was designed to be self-sustaining. The POST-BIRTH flyer describes nine warning signs of SMM. Eligible participants were English-speaking patients discharged with a live newborn who were able to be contacted within 2 weeks. Participants completed a telephone administered nine-item survey to assess knowledge of SMM. The primary outcome was the percentage of correct answers. To evaluate sustainability, whether the POST-BIRTH fliers and discharge checklist were still being used at 19 months postinitiative was planned. RESULTS: For PDSA cycle 1, in the Usual Discharge group, 347 patients were discharged, 164 (44.7%) were eligible and 151 (92.1%) completed the survey. In the POST-BIRTH discharge group, 268 patients were discharged, 199 (74.3%) were eligible and 183 (92.0%) completed the survey. Compared with the Usual Discharge group, the POST-BIRTH group had significantly more correct responses (30% vs 60%, p<0.001). In PDSA cycle 2, POST-BIRTH flyers were still being used universally on one of the two floors from which postpartum patients are discharged, but not the other. CONCLUSION: The implementation of an educational initiative for postpartum patients is associated with improved knowledge of warning signs of SMM. The use of the education was self-sustaining on one discharge floor but not the other.

Discovery of a CSF-1R inhibitor and PET tracer for imaging of microglia and macrophages in the brain.

Colony stimulating factor 1 receptor (CSF-1R) is a kinase expressed on macrophages and microglia in the brain. It has been recognized as a potential drug and imaging target in treatment of neuroinflammatory diseases and glioblastoma. Despite several attempts, no validated CSF-1R PET tracer is currently available. The aim of this work was to develop a brain permeable CSF-1R PET tracer for non-invasive imaging of CSF-1R in vivo. Based on fragments of two potent and selective CSF-1R inhibitors, novel hybrid molecules were designed and synthesized. Affinity for human recombinant CSF-1R and selectivity over c-KIT and PDGFR-ß was determined using a FRET based in vitro assay. Radiosynthesis was performed by fully automated [11C]CH3I methylation of the corresponding des-methyl precursor. PET imaging was performed at baseline, efflux transporter blocking and CSF-1R blocking conditions. Moreover, tracer distribution and blood and plasma radiometabolites were determined following injection in healthy mice. The most promising CSF-1R inhibitor, compound 4, showed high selectivity and high affinity for CSF-1R (IC50: 12 ± 3 nM) and no affinity for kinase family members c-KIT and PDGFR-beta. [11C]4 was obtained in good yield (15 ± 0.2 % decay corrected yield, (2.0 ± 0.26 GBq at end of synthesis) and excellent purity. The compound demonstrated high brain penetration and good metabolic stability (>2 %ID/g at 60 min post injection and 79 ± 8 % intact [11C]4 in brain at 60 min post injection) and no strong efflux transporter substrate behavior. Blocking CSF-1R prior to imaging with [11C]4 resulted in significant decrease in brain uptake. In conclusion, [11C]4 shows good potential as a novel PET tracer for imaging of CSF-1R in the CNS and future experiments in relevant animal models are warranted.

Radiosynthesis and initial preclinical evaluation of [11C]AZD1283 as a potential P2Y12R PET radiotracer.

INTRO: Chronic neuroinflammation and microglial dysfunction are key features of many neurological diseases, including Alzheimer's Disease and multiple sclerosis. While there is unfortunately a dearth of highly selective molecular imaging biomarkers/probes for studying microglia in vivo, P2Y12R has emerged as an attractive candidate PET biomarker being explored for this purpose. Importantly, P2Y12R is selectively expressed on microglia in the CNS and undergoes dynamic changes in expression according to inflammatory context (e.g., toxic versus beneficial/healing states), thus having the potential to reveal functional information about microglia in living subjects. Herein, we identified a high affinity, small molecule P2Y12R antagonist (AZD1283) to radiolabel and assess as a candidate radiotracer through in vitro assays and in vivo positron emission tomography (PET) imaging of both wild-type and total knockout mice and a non-human primate. METHODS: First, we evaluated the metabolic stability and passive permeability of non-radioactive AZD1283 in vitro. Next, we radiolabeled [11C]AZD1283 with radioactive precursor [11C]NH4CN and determined stability in formulation and human plasma. Finally, we investigated the in vivo stability and kinetics of [11C]AZD1283 via dynamic PET imaging of naïve wild-type mice, P2Y12R knockout mouse, and a rhesus macaque. RESULTS: We determined the half-life of AZD1283 in mouse and human liver microsomes to be 37 and > 160 min, respectively, and predicted passive CNS uptake with a small amount of active efflux, using a Caco-2 assay. Our radiolabeling efforts afforded [11C]AZD1283 in an activity of 12.69 ± 10.64 mCi with high chemical and radiochemical purity (>99%) and molar activity of 1142.84 ± 504.73 mCi/µmol (average of n = 3). Of note, we found [11C]AZD1283 to be highly stable in vitro, with >99% intact tracer present after 90 min of incubation in formulation and 60 min of incubation in human serum. PET imaging revealed negligible brain signal in healthy wild-type mice (n = 3) and a P2Y12 knockout mouse (0.55 ± 0.37%ID/g at 5 min post injection). Strikingly, high signal was detected in the liver of all mice within the first 20 min of administration (peak uptake = 58.28 ± 18.75%ID/g at 5 min post injection) and persisted for the remaining duration of the scan. Ex vivo gamma counting of mouse tissues at 60 min post-injection mirrored in vivo data with a mean %ID/g of 0.9% ± 0.40, 0.02% ± 0.01, and 106 ± 29.70% in the blood, brain, and liver, respectively (n = 4). High performance liquid chromatography (HPLC) analysis of murine blood and liver metabolite samples revealed a single radioactive peak (relative area under peak: 100%), representing intact tracer. Finally, PET imaging of a rhesus macaque also revealed negligible CNS uptake/binding in monkey brain (peak uptake = 0.37 Standard Uptake Values (SUV)). CONCLUSION: Despite our initial encouraging liver microsome and Caco-2 monolayer data, in addition to the observed high stability of [11C]AZD1283 in formulation and human serum, in vivo brain uptake was negligible and rapid accumulation was observed in the liver of both naïve wildtype and P2Y12R knockout mice. Liver signal appeared to be independent of both metabolism and P2Y12R expression due to the confirmation of intact tracer in this tissue for both wildtype and P2Y12R knockout mice. In Rhesus Macaque, negligible uptake of [11C]AZD1283 brain indicates a lack of potential for translation or its further investigation in vivo. P2Y12R is an extremely promising potential PET biomarker, and the data presented here suggests encouraging metabolic stability for this scaffold; however, the mechanism of liver uptake in mice should be elucidated prior to further analogue development.

Multimodal imaging of capsid and cargo reveals differential brain targeting and liver detargeting of systemically-administered AAVs.

The development of gene delivery vehicles with high organ specificity when administered systemically is a critical goal for gene therapy. We combine optical and positron emission tomography (PET) imaging of 1) reporter genes and 2) capsid tags to assess the temporal and spatial distribution and transduction of adeno-associated viruses (AAVs). AAV9 and two engineered AAV vectors (PHP.eB and CAP-B10) that are noteworthy for maximizing blood-brain barrier transport were compared. CAP-B10 shares a modification in the 588 loop with PHP.eB, but also has a modification in the 455 loop, added with the goal of reducing off-target transduction. PET and optical imaging revealed that the additional modifications retained brain receptor affinity. In the liver, the accumulation of AAV9 and the engineered AAV capsids was similar (∼15% of the injected dose per cc and not significantly different between capsids at 21 h). However, the engineered capsids were primarily internalized by Kupffer cells rather than hepatocytes, and liver transduction was greatly reduced. PET reporter gene imaging after engineered AAV systemic injection provided a non-invasive method to monitor AAV-mediated protein expression over time. Through comparison with capsid tagging, differences between brain localization and transduction were revealed. In summary, AAV capsids bearing imaging tags and reporter gene payloads create a unique and powerful platform to assay the pharmacokinetics, cellular specificity and protein expression kinetics of AAV vectors in vivo, a key enabler for the field of gene therapy.