Risk factors for and pregnancy outcomes after SARS-CoV-2 in pregnancy according to disease severity: A nationwide cohort study with validation of the SARS-CoV-2 diagnosis.

INTRODUCTION: We identified risk factors and outcomes associated with SARS-CoV-2 infection in pregnancy in a universally tested population according to disease severity and validated information on SARS-CoV-2 during pregnancy in national health registers in Denmark. MATERIAL AND METHODS: Cohort study using data from national registers and medical records including all pregnancies between March 1, 2020 and February 28, 2021. We compared women with a validated positive SARS-CoV-2 test during pregnancy with non-infected pregnant women. Risk factors and pregnancy outcomes were assessed by Poisson and Cox regression models and stratified according to disease severity defined by hospital admission status and admission reason (COVID-19 symptoms or other). Using medical record data on actual period of pregnancy, we calculated predictive values of the SARS-CoV-2 diagnosis in pregnancy in the registers. RESULTS: SARS-CoV-2 infection was detected in 1819 (1.6%) of 111 185 pregnancies. Asthma was associated with infection (relative risk [RR] 1.63, 95% confidence interval [CI] 1.28-2.07). Risk factors for severe COVID-19 disease requiring hospital admission were high body mass index (median ratio 1.06, 95% CI 1.04-1.09), asthma (RR 7.47, 95% CI 3.51-15.90) and gestational age at the time of infection (gestational age 28-36 vs < 22: RR 3.53, 95% CI 1.75-7.10). SARS-CoV-2-infected women more frequently had hypertensive disorders in pregnancy (adjusted hazard ratio [aHR] 1.31, 95% CI 1.04-1.64), early pregnancy loss (aHR 1.37, 95% CI 1.00-1.88), preterm delivery before gestational age 28 (aHR 2.31, 95% CI 1.01-5.26), iatrogenically preterm delivery before gestational age 37 (aHR 1.49, 95% CI 1.01-2.19) and small-for-gestational age children (aHR 1.28, 95% CI 1.05-1.54). The associations were stronger among women admitted to hospital for any reason. The validity of the SARS-CoV-2 diagnosis in relation to pregnancy in the registers compared with medical records showed a negative predictive value of 99.9 (95% CI 99.9-100.0) and a positive predictive value of 82.1 (95% CI 80.4-83.7). CONCLUSIONS: Women infected with SARS-CoV-2 during pregnancy were at increased risk of hypertensive disorders in pregnancy, early pregnancy loss, preterm delivery and having children small for gestational age. The validity of Danish national registers was acceptable for identification of SARS-CoV-2 infection during pregnancy.

Transdermal Drug Delivery of Tazarotene: Determining Tazarotene's Potential in Local Transdermal Therapy.

Retinoid-based drugs, while effective, are associated with systemic toxicity. Topical alternatives offer a safer option, and tazarotene, a third-generation synthetic retinoid, holds promise. This study investigates tazarotene's transdermal delivery potential, focusing on its application for joint-related conditions. The aim of this study was to investigate the suitability of tazarotene as a candidate for transdermal delivery into joints. In vitro permeation studies, using porcine skin, assessed tazarotene's transdermal drug delivery from solution and gel formulations. A tape-stripping analysis determined stratum corneum retention and a pilot study using porcine joints assessed tazarotene's ability to reach articular cartilage. Ultra Performance Liquid Chromatography coupled with a mass detector method was used to quantify tazarotene and tazarotenic acid permeation. The results validate that tazarotene can permeate porcine skin and accumulate in articular cartilage in detectable amounts. The detection of tazarotene and tazarotenic acid in both the in vitro permeation studies and the pilot study on porcine joints validate the drug's potential therapeutic use for hand osteoarthritis. This study lays the groundwork for future research, contributing insights into tazarotene's potential for transdermal drug delivery and guiding further exploration in topical retinoid applications.

Transdermal Drug Delivery: Determining Permeation Parameters Using Tape Stripping and Numerical Modeling.

The function of transdermal drug delivery (TDD) systems is complex due to the multiple layers necessary for controlling the rate of drug release and the interaction with the patient's skin. In this work, we study a particular aspect of a TDD system, that is, the parameters that describe the drug permeation through the skin layers. Studies of the diffusion of two compounds were carried out and supported by tape stripping and numerical modeling. The experimental studies are carried out for porcine skin in a Franz diffusion cell and tape stripping is used to quantify the concentration of drug in the stratum corneum. A multi-layered numerical model, based on Fickian diffusion, is used to determine the unknown parameters that define the skin's permeability, such as the partition between layers and the mass transfer coefficients due to the surface barrier. A significant correlation was found between the numerical modeling and experimental results, indicating that the partition and mass transfer effects at the interlayer boundary are accurately represented in the numerical model. We find that numerical modeling is essential to fully describe the diffusion characteristics.

Multi-region finite element modelling of drug release from hydrogel based ophthalmic lenses.

Understanding the way in which drug is released from drug carrying hydrogel based ophthalmic lenses aids in the development of efficient ophthalmic drug delivery. Various solute-polymer interactions affect solute diffusion within hydrogels as well as hydrogel-bulk partitioning. Additionally, surface modifications or coatings may add to resistance of mass transfer across the hydrogel interface. It is necessary to consider both interfacial resistances as well as the appropriate driving force when characterizing interface flux. Such a driving force is induced by a difference in concentration which deviates from equilibrium conditions. We present a Galerkin finite element approach for solute transport in hydrogels which accounts for diffusion within the gel, storage effects due to polymer-solute interaction, as well as partitioning and mass transfer resistance effects at the interface. The approach is formulated using a rotational symmetric model to account for realistic geometry. We show that although the resulting global system is not symmetric in the case of partitioning, it is similar to a symmetric negative semidefinite system. Thus, it has non-positive real eigenvalues and is coercive, ensuring the validity of the finite element formulation as well as the numerical stability of the implicit backward Euler time integration method employed. Two models demonstrating this approach are presented and verified with release experimental data. The first is the release of moxifloxacin from intraocular lenses (IOLs) plasma grafted with different polyacrylates. The second accounts for both loading as well as the release of diclofenac from disc shaped IOL material loaded for varied time periods and temperature.

Speed Adaptable Prosthetic Foot: Concept Description, Prototyping and Initial User Testing.

This article presents a novel design of a prosthetic foot that features adaptable stiffness that changes according to the speed of ankle motion. The motivation is the natural graduation in stiffness of a biological ankle over a range of ambulation tasks. The device stiffness depends on rate of movement, ranging from a dissipating support at very slow walking speed, to efficient energy storage and return at normal walking speed. The objective here is to design a prosthetic foot that provides a compliant support for slow ambulation, without sacrificing the spring-like energy return beneficial in normal walking. The design is a modification of a commercially available foot and employs material properties to provide a change in stiffness. The velocity dependent properties of a non-Newtonian working fluid provide the rate adaptability. Material properties of components allow for a geometry shift that results in a coupling action, affecting the stiffness of the overall system. The function of an adaptive coupling was tested in linear motion. A prototype prosthetic foot was built, and the speed dependent stiffness measured mechanically. Furthermore, the prototype was tested by a user and body kinematics measured in gait analysis for varying walking speed, comparing the prototype to the original foot model (non-modified). Mechanical evaluation of stiffness shows increase in stiffness of about 60% over the test range and 10% increase between slow and normal walking speed in user testing.

A numerical framework for drug transport in a multi-layer system with discontinuous interlayer condition.

Discontinuous boundary conditions arise naturally when describing various physical phenomena and numerically modelling such conditions can prove difficult. In the field of pharmaceutical sciences, two such cases are the partitioning of a compound between different materials and a flux rate membrane controlling mass transfer between materials which both result in a discontinuous jump in concentration across adjacent materials. In this study, we introduce a general one-dimensional finite element drug delivery framework, which along with diffusion, reversible binding and dissolution within material layers, incorporates the partitioning and mass transfer conditions between layers of material. We apply the framework to construct models of experiments, which along with experimental data, allow us to infer pharmacokinetic properties of potential material for drug delivery. Understanding such material properties is the key to optimising the therepeutic effect of a targeted drug delivery system.

Obstetrical complications in dichorionic twin pregnancies in women with polycystic ovary syndrome.

INTRODUCTION: Both women with polycystic ovary syndrome (PCOS) and women with twin pregnancies have increased risk of adverse pregnancy outcome. The aim of this study was to investigate the impact of PCOS and maternal androgen levels on the outcome of dichorionic twin pregnancy. MATERIAL AND METHODS: A retrospective study of 360 women with dichorionic twin pregnancies: 72 women with PCOS from a fertility clinic (years 1997-2010) and 288 women without PCOS from a hospital cohort (years 2005-2007). The obstetrical outcome was extracted from Danish National registers and supplemented by patient file data. In all, 65% of the PCOS group had a registered prepregnancy androgen level and these were stratified into normoandrogenic and hyperandrogenic women. The groups were compared by multiple regression analysis adjusting for mode of conception and prepregnancy body mass index. RESULTS: We found no overall impact of PCOS on the pregnancy outcome; the risks of preeclampsia, gestational diabetes and preterm delivery were comparable within the groups. However, five deliveries in the PCOS group compared with two in the control group occurred before gestational week 28. No difference in the obstetrical outcome between hyperandrogenic and normoandrogenic women was found. The body mass index in the PCOS population was lower than in the non-PCOS, possibly reflecting a higher socioeconomic status and a healthier lifestyle, which may underestimate the impact of a PCOS diagnosis. CONCLUSION: Neither PCOS nor maternal androgen levels confer additional risks to the outcome of dichorionic twin pregnancies of normal weight women.

Comparable risk of childhood asthma after vaginal delivery and emergency caesarean section.

INTRODUCTION: Caesarean section is thought to be a risk factor for childhood asthma, but this association may be caused by confounding from, for instance, familial factors. To address this problem, we used twin pairs to assess the risk of childhood asthma after emergency caesarean section. METHODS: The study was a register-based nation-wide matched cohort study using twin pairs to minimise residual confounding. Included were twin pairs in which the first twin was delivered vaginally and the second by emergency caesarean section during the study period from January 1997 through December 2012. RESULTS: In total, 464 twin pairs (928 twins) were included. In 30 pairs, the first twin (vaginal delivery) was diagnosed with asthma, but the second twin (emergency caesarean section) was not. In 20 pairs, the second twin (emergency caesarean section) was diagnosed with asthma, but the first twin (vaginal delivery) was not. In 11 pairs, both twins developed asthma. In the unadjusted analysis, emergency caesarean section did not affect the risk of asthma (odds ratio = 0.67 (95% confidence interval: 0.38-1.17); p = 0.16). After adjusting for birth weight, gender, umbilical cord pH, Apgar score at 5 min. and neonatal respiratory morbidity, the risk of childhood asthma following emergency caesarean section remained unchanged. CONCLUSION: Emergency caesarean section was not associated with childhood asthma. FUNDING: none. TRIAL REGISTRATION: not relevant.

[Complications in pregnant women with polycystic ovary syndrome]. / Komplikationer hos gravide med polycystisk ovariesyndrom

Pregnant women with polycystic ovary syndrome (PCOS) are at increased risk of pregnancy-related disorders such as gestational diabetes (GDM), gestational hypertension and preeclampsia in the 2nd and 3rd trimester. In addition, the risk of preterm birth, children who are small and large for gestational age, caesarean section and poorer neonatal outcome seem to be elevated, however with less clear evidence. Except for the screening for GDM, there is no evidence of a benefit of increased surveillance during pregnancy for women with PCOS.

Does internal podalic version of the non-vertex second twin still have a place in obstetrics? A Danish national retrospective cohort study.

OBJECTIVE: Investigate the rate of internal podalic version followed by breech extraction for a second non-vertex twin with the first delivered vaginally, and compare neonatal outcome with emergency cesarean section. DESIGN: Cohort study. SETTING: National Danish Registers. POPULATION: Twin pregnancies (1997-2012) with gestational age ≥34 weeks; first twin delivered vaginally, second by internal podalic version and breech extraction or cesarean section. METHODS: Data were collected from the Danish National Patient Register and the Danish National Birth Register. MAIN OUTCOME MEASURES: Rates of delivery mode, 5-min Apgar score, asphyxia, umbilical cord pH, admission to neonatal intensive care unit, treatment by mechanical ventilation, and experience level of obstetricians performing internal podalic version. RESULTS: 457 births were available for analysis: 39 cases of internal podalic version and breech extraction and 418 cesarean section cases for second twin. Compared with the cesarean section group, the internal podalic version group had lower rates of asphyxia. Apgar scores and umbilical cord pH levels were not significantly different, although with a tendency to be higher in the internal version than the cesarean section group, however, fewer cases needed mechanical ventilation. Thirty internal versions and breech extractions were performed by obstetricians with >5 years clinical experience and three by trainees. CONCLUSION: Cesarean sections for a second twin seem to have been frequent during the last 15 years while internal podalic version is a vanishing procedure. A slight tendency for better neonatal outcome was found in the internal podalic version and extraction group than cesarean section.

[A pregnant woman with spontaneous rupture of the uterine artery].

Pregnant women with acute abdominal pain are a clinical challenge. We present a rare but potential life-threatening condition of a pregnant woman with acute abdominal pain. The woman was in gestational week 37 with severe abdominal pain and was admitted to the labour ward. She became haemo-dynamic instable 24 hours after vaginal delivery, and emergency laparotomi revealed a spontaneous rupture of the right uterine artery. Spontaneous rupture of the uterine artery is rare but should be considered as a possible cause of acute abdominal pain in pregnant women.

Numerical modelling of transdermal delivery from matrix systems: parametric study and experimental validation with silicone matrices.

A model is presented for transdermal drug delivery from single-layered silicone matrix systems. The work is based on our previous results that, in particular, extend the well-known Higuchi model. Recently, we have introduced a numerical transient model describing matrix systems where the drug dissolution can be non-instantaneous. Furthermore, our model can describe complex interactions within a multi-layered matrix and the matrix to skin boundary. The power of the modelling approach presented here is further illustrated by allowing the possibility of a donor solution. The model is validated by a comparison with experimental data, as well as validating the parameter values against each other, using various configurations with donor solution, silicone matrix and skin. Our results show that the model is a good approximation to real multi-layered delivery systems. The model offers the ability of comparing drug release for ibuprofen and diclofenac, which cannot be analysed by the Higuchi model because the dissolution in the latter case turns out to be limited. The experiments and numerical model outlined in this study could also be adjusted to more general formulations, which enhances the utility of the numerical model as a design tool for the development of drug-loaded matrices for trans-membrane and transdermal delivery.

Numerical modelling and experimental investigation of drug release from layered silicone matrix systems.

Medical devices and polymeric matrix systems that release drugs or other bioactive compounds are of interest for a variety of applications. The release of the drug can be dependent on a number of factors such as the solubility, diffusivity, dissolution rate and distribution of the solid drug in the matrix. Achieving the goal of an optimal release profile can be challenging when relying solely on traditional experimental work. Accurate modelling complementing experimentation is therefore desirable. Numerical modelling is increasingly becoming an integral part of research and development due to the significant advances in computer simulation technology. This work focuses on numerical modelling and investigation of multi-layered silicone matrix systems. A numerical model that can be used to model multi-layered systems was constructed and validated by comparison with experimental data. The model could account for the limited dissolution rate and effect of the drug distribution on the release profiles. Parametric study showed how different factors affect the characteristics of drug release. Multi-layered medical silicone matrices were prepared in special moulds, where the quantity of drug in each layer could be varied, and release was investigated with Franz-diffusion cell setup. Data for long-term release was fitted to the model and the full depletion of the system predicted. The numerical model constructed for this study, whose input parameters are the diffusion, effective dissolution rate and dimensional solubility coefficients, does not require any type of steady-state approximation. These results indicate that numerical model can be used as a design tool for development of controlled release systems such as drug-loaded medical devices.