Nonpregnant Subjects Research Articles

Exhaled Breath Volatile Organic Compounds in Pregnancy: A Pilot Study.

This study aimed to assess the volatile organic compounds (VOC)s in breath samples collected non-invasively from pregnant women during pregnancy and postpartum and compare it to non-pregnant controls. This pilot study included 50 subjects: ten pregnant patients in their first trimester, ten in second trimester, ten in third trimester, ten in the first postpartum week, and ten non-pregnant subjects as a control. We collected exhaled breath from subjects who reported to be healthy and free of any respiratory symptoms. Clinical and demographic data were collected. The samples were analyzed for VOCs using a selected-ion flow-tube mass spectrometer (SIFT-MS). The VOCs monitored were twenty-two compounds selected for their common presence in exhaled breath. During pregnancy and postpartum period, there were differences in five compounds mainly: 2-propanol, acrylonitrile, 1-nonene, 2-nonene, and hydrogen sulfide. Significant differences in VOCs were identified during each trimester compared to controls. Volatile organic compounds could be measured safely and noninvasively in pregnant women. VOCs differed significantly among non-pregnant, pregnant women and postpartum period. The utilization of this novel assay to identify fetal conditions or identifying women at risk premature delivery should be further investigated in future studies.

Optical coherence tomography angiography evaluation of retinal and choroidal microvascular changes in pregnant women with a history of unexplained recurrent spontaneous abortions.

To study retinal and choroidal microcirculation by optical coherence tomography angiography (OCTA) in pregnant women with unexplained recurrent spontaneous abortion (RSA) and to compare them with healthy pregnant and nonpregnant subjects. Pregnant women with an unexplained history of RSA (group 1), healthy pregnant (group 2), and healthy non-pregnant women (group 3) were included in the study. After a thorough ophthalmologic examination:best-corrected visual acuity, intraocular pressure,slit-lamp biomicroscopy, fundus examination,autorefractometer, biometry, and axial length measurement; OCT and OCTA measurements were performed with Swept Source OCT-Angiography (Topcon Co, Japan). The nonpregnant group had higher values for central foveal superficial capillary plexus (SCP) and deep capillary plexus (DCP) vessel density (VD) and lower values for superior, inferior, and mean VD compared with pregnant groups (p < 0.001). Choriocapillaris values (CC) VD were higher in groups 1 and 2 than in group 3 (p < 0.001). The group with unexplained RSA had a relatively smaller FAZ (foveal avascular zone) area than the group of healthy pregnant women (p:0.047). There were no statistically significant differences between groups in the retina, retinal nerve fiber layer, ganglion cell layer, and choroidal thickness (p > 0.05). Although our study did not identify any etiology in pregnant women with RSA, we observed detectable differences in FAZ area and vessel density values using OCTA, when comparing them with healthy pregnant women and healthy nonpregnant controls. We believe that OCTA, as used in many pathologies such as diabetic and hypertensive retinopathy and retinal vascular occlusion, can also be extended to unexplained RSA both to detect etiology and to monitor treatment in studies with a larger number of patients.

Optical Coherence Tomography Angiography Evaluation of Retinochoroidal Microvascular Circulation Differences in Pregnant Women with Pregestational and Gestational Diabetes Mellitus.

In this study, the changes in microvascular circulation caused by pregestational and gestational diabetes were observed, without focusing on retinal findings, to reveal the effect of diabetes regulation. A total of 135 subjects were included: 30 with gestational diabetes (GDM), 30 pregestational diabetes (PGDM), 30 healthy pregnant normoglycemic subjects, and 45 healthy non-pregnant subjects. All subjects were examined by optical coherence tomography (OCT) and angiography. The retina, retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), choroidal thickness (CT), superficial capillary plexus (SCP), deep capillary plexus (DCP), choriocapillaris (CC), vascular density (VD), and foveal avascular zone (FAZ) areas were measured. The foveal VD of SCP and DCP was significantly lower in the PGDM and GDM groups compared to the control groups (p:0.006 and p:0.001, respectively). CC VD was significantly higher in all pregnant groups compared to non-pregnant controls (p<0.001). The choroidal thickness values were highest in the healthy pregnant group and lowest in the PGDM group. There was no significant difference in FAZ area, retina, RNFL and GCL thickness between the groups. In the PGDM group, a negative correlation was observed between the FAZ area and the HbA1c level (r:- 0.417, p:0.043). There was a decrease in vascular density in pregnant women with diabetes compared to healthy pregnant women and controls. In the pregnant group with PGDM, a narrowing of the FAZ area was observed with increasing worsening of diabetes control. Diabetes type and glycemic control could influence the microvascular changes even in the absence of clinical or retinal findings.

Angiopoietin-like protein 4 induces growth hormone variant secretion and aggravates insulin resistance during pregnancy, linking obesity to gestational diabetes mellitus.

Angiopoietin-like protein 4 (ANGPTL4) is a secretory glycoprotein involved in regulating glucose homeostasis in non-pregnant subjects. However, its role in glucose metabolism during pregnancy and the pathophysiology of gestational diabetes mellitus (GDM) remains elusive. Thus, this study aimed to clarify the relationship between ANGPTL4 and GDM and investigate the pathophysiology of placental ANGPTL4 in glucose metabolism. We investigated this issue using blood and placenta samples in 957 pregnant women, the human 3A-sub-E trophoblast cell line, and the L6 skeletal muscle cell line. We found that ANGPTL4 expression in the placenta was higher in obese pregnant women than in lean controls. Palmitic acid significantly induced ANGPTL4 expression in trophoblast cells in a dose-response manner. ANGPTL4 overexpression in trophoblast cells resulted in endoplasmic reticulum (ER) stress, which stimulated the expression and secretion of growth hormone-variant (GH2) but not human placental lactogen. In L6 skeletal muscle cells, soluble ANGPTL4 suppressed insulin-mediated glucose uptake through the epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinases 1/2 (ERK 1/2) pathways. In pregnant women, plasma ANGPTL4 concentrations in the first trimester predicted the incidence of GDM and were positively associated with BMI, plasma triglyceride, and plasma GH2 in the first trimester. However, they were negatively associated with insulin sensitivity index ISI0,120 in the second trimester. Overall, placental ANGPTL4 is induced by obesity and is involved in the pathophysiology of GDM via the induction of ER stress and GH2 secretion. Soluble ANGPTL4 can lead to insulin resistance in skeletal muscle cells and is an early biomarker for predicting GDM.

Assessment of CD4, CD8 and White Cell Parameters Amongst HIV Seronegative Pregnant Subjects in Port Harcourt, Nigeria

Pregnancy involves maternal immunological adjustments to accommodate the fetus and maintain a strong immune defense against potential pathogens. The present study evaluated the changes in CD4, CD8, white blood cell (WBC) and total lymphocyte count (TLC) amongst HIV seronegative pregnant subjects in Port Harcourt, Nigeria. A total of 302 female subjects (18-39 years) were recruited for the study. They consisted of 205 pregnant subjects and 97 non-pregnant subjects which served as the control. All subjects were screened for HIV type 1 and type 2 using standard test kits. Total and differential white blood cell counts were determined using a haematology auto analyzer while the total lymphocyte count (TLC) was obtained by multiplying total white blood cell count (TWC) with percentage lymphocyte count. The CD4 and CD8 cell counts were analyzed using the automated flow cytometry analyzer while the CD4:CD8 cell count ratio was obtained by dividing the CD4 cell count value by that of CD8. The result of the study shows a statistically significant decrease in CD4 and CD8 cell counts, lymphocyte and total lymphocyte counts and an increase in neutrophil count in all the trimesters of pregnancy when compared to the non-pregnant control (p&amp;lt;0.05). Also, there was a significant increase in WBC during the third trimester and a similar decrease in monocyte count in the first and third trimesters of pregnancy. The evidence from the present study concludes that pregnancy modifies the maternal immune response to ensure fetal survival and the protection of the mother from invading pathogens as reported in the increase in total WBC, neutrophil and monocyte counts and a reduction in TLC, CD4 and CD8 counts. The study recommends routine assessments of these crucial cellular immune markers for pregnant women during antenatal visits.

An Application of a Physiologically Based Pharmacokinetic Approach to Predict Ceftazidime Pharmacokinetics in a Pregnant Population.

Physiological changes during pregnancy can alter maternal and fetal drug exposure. The objective of this work was to predict maternal and umbilical ceftazidime pharmacokinetics during pregnancy. Ceftazidime transplacental permeability was predicted from its physicochemical properties and incorporated into the model. Predicted concentrations and parameters from the PBPK model were compared to the observed data. PBPK predicted ceftazidime concentrations in non-pregnant and pregnant subjects of different gestational weeks were within 2-fold of the observations, and the observed concentrations fell within the 5th-95th prediction interval from the PBPK simulations. The calculated transplacental clearance (0.00137 L/h/mL of placenta volume) predicted an average umbilical cord-to-maternal plasma ratio of 0.7 after the first dose, increasing to about 1.0 at a steady state, which also agrees well with clinical observations. The developed maternal PBPK model adequately predicted the observed exposure and kinetics of ceftazidime in the pregnant population. Using a verified population-based PBPK model provides valuable insights into the disposition of drug concentrations in special individuals that are otherwise difficult to study and, in addition, offers the possibility of supplementing sparse samples obtained in vulnerable populations with additional knowledge, informing the dosing adjustment and study design, and improving the efficacy and safety of drugs in target populations.

Optical coherence tomography angiography assessment of retinochoroidal microcirculation differences in preeclampsia

BackgroundTo investigate microvascular changes in pregnant women with preeclampsia using optical coherence tomography angiography (OCTA) and compare the results with healthy pregnant and non-pregnant subjects. MethodsSuperficial capillary plexus (SCP), deep capillary plexus (DCP) choriocapillaris (CC) vessel density (VD) and foveal avascular zone area (FAZ), retina, retinal nerve fiber layer (RNFL), the ganglion cell layer (GCL) and the choroidal thickness were examined and compared in preeclamptic pregnant (group 1), healthy pregnant women (group 2) and non-pregnant, age-matched female controls (group 3). The correlations of the parameters with each other and with blood pressure were evaluated. ResultsNo significant difference was found between the groups when retinal, RNFL and GCL thickness values (p> 0.05). The choroidal thickness values were significantly lower in group 1 than in group 2 (p = 0.029). The central foveal VD of the SCP and DCP was significantly lower in group 1 compared to groups 2 and 3 (p = 0.03, p< 0.01 respectively). The mean VD of the SCP was significantly higher in groups 1 and 2 than in group 3 (p = 0.01). The FAZ area was statistically significantly lower in group 3 than in group 2 (p = 0.032). The CC VD was lower in group 3 compared to the other groups in all measurements (p < 0.01).The FAZ area was positively correlated with systolic blood pressure in group 1. ConclusionThe use of OCTA, a non-invasive imaging technique, to assess the retinal microcirculation appears to have the potential to in the early diagnosis or follow up in preeclampsia before signs of hypertensive retinopathy.

Relationship between maternal obesity and first-trimester TSH in women with negative anti-TPO antibodies.

Obesity is associated with increased thyroid-stimulating hormone (TSH) in non-pregnant subjects, but this phenomenon has not been fully characterized during pregnancy. Our aim was to evaluate the impact of BMI on first-trimester TSH in a wide cohort of pregnant women with negative anti-thyroperoxidase antibodies (AbTPO) and its implications on uterine artery pulsatility index (UtA-PI), a marker of early placentation. The study included 2268 AbTPO-negative pregnant women at their first antenatal visit. Anamnestic data, BMI, TSH, anti-nuclear antibody (ANA) and extractable nuclear antigen (ENA) positivity and mean UtA-PI were collected. A total of 1693 women had normal weight, 435 were overweight and 140 were obese. Maternal age, ANA/ENA positivity, history of autoimmune diseases and familiar history of thyroid diseases were similar in the three groups. TSH was significantly higher in obese women (1.8 (IQR: 1.4-2.4) mU/L) when compared to normal weight (1.6 (IQR: 1.2-2.2) mU/L) and overweight (median: 1.6 (IQR: 1.2-2.2) mU/L) ones (P < 0.001). BMI was significantly related with the risk of having a TSH level ≥4 mU/L at logistic regression, independently from non-thyroid autoimmunity, smoking or familiar predisposition for thyroid diseases (OR: 1.125, 95% CI: 1.080-1.172, P < 0.001). A restricted cubic splines regression showed a non-linear relationship between BMI and TSH. Women with a TSH ≥4 mU/L had a higher UtA-PI, independently from BMI. Overweight/obesity is significantly related with TSH serum levels in AbTPO-negative pregnant women, independently from the other risk factors for hypothyroidism during pregnancy. The increase of TSH levels could be clinically relevant, as suggested by its association with abnormal UtA-PI, a surrogate marker of abnormal placentation.

Should the non-canonical pathway of nitric oxide generation be targeted in hypertensive pregnancies?

Hypertension in pregnancy is prevalent, affecting around 10% of pregnancies worldwide, and significantly increases the risk of adverse outcomes for both mothers and their babies. Current treatment strategies for pregnant women with hypertension are limited, and new approaches for the management of hypertension in pregnancy are urgently needed. Substantial evidence from non-pregnant subjects has demonstrated the potential for dietary nitrate supplementation to increase nitric oxide (NO) bioavailability and lower blood pressure, following bioactivation via the non-canonical NO pathway. Emerging data suggest this approach may also be of benefit in pregnant women, although studies are limited. This review aims to summarise the current evidence from preclinical and clinical studies of nitrate supplementation in pregnancy, drawing on data from non-pregnant populations where appropriate and highlighting key gaps in knowledge that remain to be addressed in future trials.

Midkine can not be accepted as a new biomarker for unexplained female infertility

Abstract Objectives This study aimed to investigate whether a growth factor and a cytokine midkine (MK) can be a new biomarker for the diagnosis and treatment of unexplained female infertility (UFI) cases. Methods Serum (S), follicle fluid (FF), and cumulus cells (CCs) of the patients aged 20–42 years, diagnosed with male factor (MF) and UFI were used. Patients underwent Intracytoplasmic Sperm Injection (ICSI). The anti-Müllerian hormone (AMH) and MK levels with other hormone levels (FSH, LH, E2, PRL, INHB, TSH), the oocyte and embryo qualities, the fertilization and pregnancy rates, and cumulus cells (Cell number and ultrastructure, apoptosis rate) were evaluated. Student-T-test was performed and p&lt;0.05 was considered statistically significant. Results The lowest numbers of CCs were found at UFI (p&lt;0.05). The lowest apoptosis rate with the highest CC viability rate was evaluated at MF (p&lt;0.05). The lowest AMH and MK levels (S, FF) were detected at UFI in comparison to MF (p&lt;0.05). MK and AMH levels of non-pregnant subjects were much lower than pregnant subjects (p&lt;0.05). In addition, these levels were lower in the subjects above 35 age (p&lt;0.05). Structural analysis of CCs showed that the number of lytic cells with cell remnants and apoptotic bodies was higher in non-pregnant subjects. It seems that MK did not show any resistance to both AMH and apoptosis. Conclusions MK can not be accepted as a new biomarker for the diagnosis and treatment monitoring of UFI cases.

Characterization of extracellular vesicles in COVID-19 infection during pregnancy.

Introduction: SARS-CoV-2 infection may cause a severe inflammatory response, inflicting severe morbidity and mortality. This risk is modestly increased in pregnant patients. Despite the hypercoagulability and immunosuppression associated with pregnancy, most pregnant women experience a mild COVID-19 infection. Maternal extracellular vesicles (EVs) may interact with endothelial and immune components to facilitate a favorable disease course. This pilot study aimed to explore the characteristics of EVs released during COVID-19 infection occurring during the third trimester of pregnancy. Methods: In this prospective study, blood samples were obtained from 16 healthy non-pregnant (NP), 18 healthy-pregnant (HP), and 22 COVID-19 positive pregnant subjects (CoV-P). Disease course and pregnancy outcomes were assessed and EVs were characterized. Of note, limited volumes of sample acquired from the subjects made it necessary to use smaller and different subsets of samples for each analysis. Results: The majority (91%) of the COVID-19-pregnant subjects (18 mild and 2 moderate disease) experienced good pregnancy-related outcomes. EV concentrations were higher in healthy-pregnant subjects compared to non-pregnant subjects (p = 0.0041) and lower in COVID-19-pregnant subjects compared to healthy-pregnant subjects (p = 0.0150). CD63 exosome marker expression was higher in EVs of healthy-pregnant subjects and COVID-19-pregnant subjects compared to EVs of non-pregnant subjects (p = 0.0149, p = 0.0028, respectively). Similar levels of SARS-CoV-2 entry proteins (ACE-2 and TMPRSS2) were found in all three groups. Cytokine content increased in healthy-pregnant subject-EVs compared to non-pregnant EVs, while IL-2 and IL-6 levels were decreased in COVID-19-pregnant subject-EVs compared to healthy-pregnant subject-EVs (p = 0.043, p = 0.0390, respectively). CD8+, cytotoxic T-cell marker, was lower in non-pregnant EVs compared to healthy-pregnant subject-EVs and to COVID-19-pregnant subjects (p = 0.0108, p < 0.0001, respectively). COVID-19- pregnant subject-EVs demonstrated higher levels of platelet activation marker (CD62P) than non-pregnant (p = 0.0327) and healthy-pregnant subjects (p = 0.0365). Endothelial marker EV-CD144+ was lower in healthy-pregnant subjects versus non-pregnant subjects (p = 0.0093), but similar in COVID-19-pregnant and non-pregnant subjects. Other EVs' coagulation markers/activity, D-Dimer and fibrinogen levels were similar in healthy-pregnant subjects and COVID-19 positive pregnant subjects. Conclusion: COVID-19 positive pregnant subjects' EVs demonstrated an attenuated inflammatory response, with no additional activation of the coagulation system.

Pharmacokinetics of antibodies during Pregnancy: Impact of pregnancy on the pharmacokinetics of antibodies (Part 2).

In Part 1, we provided a general description of macromolecules, pharmacokinetics (PK) characteristics in non-pregnant subjects, and the physiological changes during pregnancy. Here we further elaborate on the impact of pregnancy on the PK of antibodies through illustrative case studies (immunoglobulins, infliximab, adalimumab and eculizumab). Using published data from nonclinical and clinical studies, we present measured or calculated PK parameters from pregnant subjects comparing with data from non-pregnant subjects, if available. Due to the paucity of PK data evaluating PK of antibodies during pregnancy, we also provide examples of PK studies for small molecules. Finally, we draw conclusions on the nature and direction of PK changes for both antibodies and small molecules as well as provide recommendations for areas that would benefit from further studies.

Mechanistic Modeling of the Drug‐Drug Interaction Between Efavirenz and Dolutegravir: Is This Interaction Clinically Relevant When Switching From Efavirenz to Dolutegravir During Pregnancy?

AbstractFollowing the 2021 World Health Organization's updated recommendations on the management of HIV infection, millions of people living with HIV are currently switched from efavirenz‐based antiretroviral therapy to dolutegravir‐based antiretroviral therapy. Pregnant individuals transitioning from efavirenz to dolutegravir might be at increased risk of insufficient viral suppression in the immediate postswitch period because both efavirenz‐ and pregnancy‐related increases in hormone levels induce enzymes involved in dolutegravir metabolism, namely, cytochrome P450 3A4 and uridine 5′‐diphospho‐glucuronosyltransferase 1A1. This study aimed at developing physiologically based pharmacokinetic models to simulate the switch from efavirenz to dolutegravir in the late second and third trimester. To this end, the drug‐drug interaction between efavirenz and the uridine 5′‐diphospho‐glucuronosyltransferase 1A1 substrates dolutegravir and raltegravir was first simulated in nonpregnant subjects. After successful validation, the physiologically based pharmacokinetic models were translated to pregnancy and dolutegravir pharmacokinetics following efavirenz discontinuation were predicted. Modeling results indicated that, at the end of the second trimester, both efavirenz concentrations and dolutegravir trough concentrations fell below respective pharmacokinetic target thresholds (defined as reported thresholds producing 90%‐95% of the maximum effect) during the time interval from 9.75 to 11 days after dolutegravir initiation. At the end of the third trimester, this time interval spanned from 10.3 days to &gt;4 weeks after dolutegravir initiation. These findings suggest that dolutegravir exposure in the immediate post‐efavirenz switch period during pregnancy may be suboptimal, leading to HIV viremia and, potentially, resistance. The clinical implications of these findings remain to be substantiated by future studies.

Pharmacokinetics of antibodies during pregnancy: General pharmacokinetics and pregnancy related physiological changes (Part 1).

Pharmacokinetics (PK) studies are important to determine a safe and effective dose of both small and large molecule drugs. Intrinsic factors such as pregnancy can substantially alter the PK of a drug. Several PK studies have been published for small molecules administered during pregnancy, but such investigations are scarce for macromolecules including monoclonal and polyclonal antibodies. In this part 1 of 2 reviews, we first provide a general description of macromolecule drugs, the PK differences with small molecules, and current knowledge on their absorption, distribution, metabolism and elimination in non-pregnant subjects. We then review in detail the physiological changes during pregnancy. While some of the physiologic adaptions of pregnancy, for example increased plasma volume and cardiac output, are expected to impact PK of antibody therapeutics, the effects of others, such as increased GFR and altered immune responses are not fully understood. We conclude that further investigations are needed to fully elucidate how pregnancy can impact PK properties of macromolecules.

The association between denture use and cardiovascular diseases. The United States National Health and Nutrition Examination Survey 2009-2018.

Poor dental health is associated with cardiovascular diseases (CVD). However, the relationship between CVD and denture use is currently unknown. This study aimed to investigate whether denture use is associated with CVD among American adults. 10,246 non-pregnant subjects aged 30-59 years from five cycles (2009-2018) of the United States National Health and Nutrition Examination Survey (NHANES) were included in this study. Participants who were observed by a dental examiner wearing denture/partial denture/plates were defined as denture users. CVD was defined as self-reported coronary heart disease, myocardial infarction, angina pectoris, stroke, and congestive heart failure. The association between denture use and CVD was analyzed using logistic regression with adjustment for potential cofounders. 4.4% (95% CI, 3.9-5.0) participants had CVD, and 3.5% (95% CI, 2.8-4.5) participants were denture users. Denture use was associated with CVD [OR = 4.26, 95% CI (2.90-6.28), P < 0.01], which remained significant [adjusted OR = 1.82, 95% CI (1.15-2.88), P < 0.01] after adjustments for sociodemographic characteristics, smoking, alcohol use, drug addiction, body mass index (BMI), and abnormal medical conditions including gum problem, hypertension, diabetes, and hyperlipidemia. Women with dentures had significantly higher odds of CVD [adjusted OR = 2.13, 95% CI (1.10-4.11), P = 0.025]. In this nationally representative survey, denture use was associated with CVD. Denture use may be an unconventional risk factor for assessing CVD risks, especially in women. Future studies are required to investigate whether CVD and denture use is causally related.

Reference Intervals of Thyroid Hormones During Pregnancy Established by Three Statistical Methods.

Monitoring the thyroid hormones during pregnancy is of great importance for fetal growth and development. Throughout the whole pregnancy, there is constant fluctuation in the thyroid hormone reference intervals (RIs). The purpose of this study is to determine method- and trimester-specific RIs for thyroid-stimulating hormone, free thyroxine, and free triiodothyronine in pregnant women in China. In this study, 2,167 women with normal pregnancies (first trimester, n = 299; second trimester, n = 1,032; third trimester, n = 836) and 4,231 healthy nonpregnant women subjects were recruited. Serum thyroid-stimulating hormone (TSH), free thyroxine (fT4), and free triiodothyronine (fT3) concentrations were measured using electrochemiluminescence immunoassays in Abbott Alinity i analyzer. Following the exclusion of outliers, the RIs were determined using three statistical techniques: the non-parametric method, the Hoffmann method, and the Q-Q plot method. Pregnant women's levels of these three thyroid hormones differ markedly from those of healthy non-pregnant women. In addition, the concentrations of these three hormones change considerably over the course of the three phases of pregnancy. The Q-Q plot method offered more comparable RIs with the non-parametric method in healthy non-pregnant women than the Hoffmann method. Three statistical techniques were used to construct the trimester-specific RIs of thyroid hormones in pregnant women, and there was little difference between them all. The RIs by the non-parametric and Q-Q plot methods indicated closer RIs, and the RIs by the Hoffmann approach were higher and wider than those by the other two methods. For thyroid hormones, trimester-specific RIs are required. The RIs determined by non-parametric and Q⁃Q plot indirect calculation could be used as the alternative method.

Atenativ, a Plasma-Derived Antithrombin Concentrate, Used in Patients with Congenital Antithrombin Deficiency Undergoing Surgery or Parturition: Study Description (NCT04918173)

Background: Antithrombin is an endogenous anticoagulant inhibiting the activity of thrombin, FXa, and other serine proteases. Persons with heterozygous variants are at increased risk for thrombosis and are often insensitive to heparin therapy. Type I homozygous variants are lethal embryologically attesting to antithrombin's indispensability. Current clinical wisdom is to use on-demand anticoagulation with or without antithrombin concentrate for high-risk periods and secondary prophylaxis (prophylaxis after a thrombotic event) for those persons experiencing a thrombus. Two high-risk periods are perioperative and peripartum. Methods: This is a multinational, prospective, open-label, uncontrolled phase 3 study to assess efficacy, safety, and single-dose pharmacokinetics of Atenativ in patients with congenital antithrombin deficiency undergoing surgery or delivery (NCT04918173). Atenativ is a lyophilized, highly pure antithrombin concentrate free of denatured antithrombin prepared from human plasma. The primary objective of the study is to determine the incidence of thrombotic and thromboembolic events after antithrombin replacement therapy in the high risk perioperative and peripartum scenarios. The secondary objectives are to determine single-dose pharmacokinetics (PK), assess coagulation parameters (activated partial thromboplastin time [aPTT], prothrombin time [PT], international normalized ratio [INR] and fibrinogen), and safety and tolerability of Atenativ. We will enroll 18 non-pregnant adult subjects older than 18 and younger than 80 years (4 of which will be 12-16 years of age from the US) to the pharmacokinetics phase and 20 subjects to the treatment phase of the study. Subjects may participate in both phases of the study, but only 1 surgery or delivery per subject is eligible. Salient inclusion criteria are: congenital antithrombin deficiency, defined by plasma activity of antithrombin ≤60%; personal or family history of thrombotic or thromboembolic events; and written informed consent from subject or legal guardian. Salient exclusion criteria are: emergency surgery, precipitous parturition or recent surgery; prior diagnosis of heparin-induced thrombocytopenia; and recent thrombotic or thromboembolic event. Lower extremity venous Doppler examination will be performed for patients entering the treatment phase. Subjects in the PK phase will receive a single dose of 60IU/kg with blood draws at baseline, 20 minutes, 1, 3, and 8 hours, and 2-8, 10, 12, and 14 days after the end of Atenativ infusion. The table illustrates Atenativ dosing schedule for surgical subjects and parturients. Statistics is confined to descriptive analyses without the need for a sample size estimation. Results: Site initiation has begun (8 countries and 15 sites), and subject enrollment has commenced and is planned to continue until Q4 of 2024. Conclusion: This study will endeavor to determine and decrease the incidence of thrombotic and thromboembolic events in subjects with congenital antithrombin deficiency during high-risk periods. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Aspirin Inhibits the Inflammatory Response of Protease-Activated Receptor 1 in Pregnancy Neutrophils: Implications for Treating Women with Preeclampsia.

Neutrophils expressing cyclooxygenase-2 (COX-2) extensively infiltrate maternal blood vessels in preeclampsia, associated with vascular inflammation. Because pregnancy neutrophils also express protease-activated receptor 1 (PAR-1, F2R thrombin receptor), which they do not in non-pregnant subjects, they can be activated by proteases. We tested the hypothesis that aspirin at a dose sufficient to inhibit COX-2 would reduce inflammatory responses in preeclampsia neutrophils. Neutrophils were isolated from normal pregnant and preeclamptic women at approximately 30 weeks' gestation. Normal pregnancy neutrophils were treated with elastase, a protease elevated in preeclampsia, or elastase plus aspirin to inhibit COX-2, or elastase plus pinane thromboxane, a biologically active structural analog of thromboxane and a thromboxane synthase inhibitor. Preeclamptic pregnancy neutrophils were treated with the same doses of aspirin or pinane thromboxane. Confocal microscopy with immunofluorescence staining was used to determine the cellular localization of the p65 subunit of nuclear factor-kappa B (NF-κB) and media concentrations of thromboxane were measured to evaluate the inflammatory response. In untreated neutrophils of normal pregnant women, p65 was localized to the cytosol. Upon stimulation with elastase, p65 translocated from the cytosol to the nucleus coincident with increased thromboxane production. When neutrophils were co-treated with aspirin or pinane thromboxane, elastase was not able to cause nuclear translocation of p65 or increase thromboxane. In untreated neutrophils of preeclamptic women, the p65 subunit was present in the nucleus and thromboxane production was elevated, but when preeclamptic neutrophils were treated with aspirin or pinane thromboxane, p65 was cleared from the nucleus and returned to the cytosol along with decreased thromboxane production. These findings suggest that COX-2 is a downstream mediator of PAR-1 and demonstrate that PAR-1- mediated inflammation can be inhibited by aspirin. Given the extensive and ubiquitous expression of PAR-1 and COX-2 in preeclamptic women, consideration should be given to treating women with preeclampsia using a dose of aspirin sufficient to inhibit COX-2.

Airway Complications in Pregnant Patients Undergoing Electroconvulsive Therapy: A Retrospective Case-Control Study.

Electroconvulsive therapy (ECT) is an evidence-based treatment for severe depression and bipolar disorder in pregnant women. Electroconvulsive therapy involves induction of general anesthesia, muscle relaxation, and positive-pressure ventilation. Airway manipulation may lead to complications such as vocal cord injury, aspiration, inability to ventilate, and death. The purpose of this study was to determine whether there were differences in the incidence of airway complications in pregnant patients who underwent mask ventilation (MV) versus endotracheal intubation (ETI) compared with nonpregnant control subjects. We conducted a single-center retrospective chart review of all adult pregnant patients who underwent anesthesia for ECT from June 1, 2011, to June 30, 2020. Each ECT treatment delivered to a pregnant patient was matched with 2 ECT treatments delivered to a nonpregnant female control subject. Charts were queried for airway management (MV vs ETI), gestational age, and airway complications. Each ECT treatment was considered an independent event. Seventy-six ECT treatments from 11 pregnant patients were matched with 154 ECT treatments from 13 nonpregnant patients. In pregnant patients, airway management consisted of MV in 57 of the 76 treatments: 12 of 12 in the first trimester, 33 of 44 in the second trimester, and 12 of 20 in the third trimester. All 154 ECT treatments in the control group used MV. No airway complications were experienced in pregnant or nonpregnant patients with MV or ETI. No airway complications were observed in pregnant patients undergoing MV or ETI regardless of gestational age.

Serum Zinc Level and Glycemic Status in Newly Diagnosed Type 2 Diabetes Mellitus Patients in a Tertiary Care Hospital of Bangladesh

Background: Reduced level of serum zinc has been observed in patients with type 2 diabetes mellitus (T2DM). Objectives: Estimation of serum zinc level and HbA1c in newly detected T2DM. Materials and methods: This cross-sectional study encompassed 100 newly detected non-pregnant T2DM subjects diagnosed on basis of ADA 2015 criteria (n=100; age: 44.74±11.34 years, mean+SD; Sex: 56/44, M/F) from the department of Endocrinology, BSMMU consecutively. Study period was March, 2015 to April, 2016. Blood sample was collected for measurement of zinc and HbA1c. Height, weight, waist circumference, hypertension, dyslipidaemia, ischemic heart disease (IHD), cerebrovascular disease (CVD), retinopathy, neuropathy, nephropathy, serum creatinine were recorded as confounding variables. HbA1c was measured using the NGSP certified Bio-Rad D-10TM Hemoglobin A1C Program while Zinc by using Atomic Absorption Spectrometric Analysis. Result: There was no statistically significant difference for zinc level in gender groups (M vs. F: 0.91±0.02 vs. 0.88±0.02 mg/L, p= 0.580; M±SEM), age groups (age &lt;25 years: 0.89±0.82, 25 – 34 years: 0.90±0.03, 35 – 44 years: 0.90±0.32, 45 – 54 years: 0.91±0.03, and 55 years: 85±0.03 mg/L, M±SEM; F= 0.379, p= 0.823), body mass index (BMI) groups (BMI &lt;25 vs. 25 kg/m2: 0.92±0.02vs. 87±0.02, p= 0.107), socioeconomic groups (low vs. middle vs. high socioeconomic status: 0.90±0.02 vs. 0.91±0.02 vs. 0.86±0.03 mg/L, M±SEM; F= 0.548, p= 0.580) as well as with and without family history of diabetes (0.90±0.01 vs. 0.89±0.02 mg/L, M±SEM; p= 0.705). Also zinc level was statistically similar among glycemic status groups (HbA1c &lt; 6.5% vs. 6.5-9% vs. &gt; 9%: 0.89±0.40 vs. 0.87±0.02 vs. 0.91±0.02 mg/L, F= 0.568, p= 0.569). Comparisons between groups with or without risk factors like: smoking (0.93±0.10 vs. 0.89±0.10 mg/L, p=0.724), hypertension (0.87±0.02 vs. 0.91±0.02 mg/L, p= 0.237), dyslipidemia (0.87±0.02 vs. 0.90±0.02 mg/L, p=0.393) and also co morbidities like: .......