Pregnancy loss in major fetal congenital heart disease: incidence, risk factors and timing.

OBJECTIVE: Fetuses with congenital heart disease (CHD) are at increased risk of pregnancy loss compared with the general population. We aimed to assess the incidence, timing and risk factors of pregnancy loss in cases with major fetal CHD, overall and according to cardiac diagnosis. METHODS: This was a retrospective, population-level cohort study of fetuses and infants diagnosed with major CHD between 1997 and 2018 identified by the Utah Birth Defect Network (UBDN), excluding cases with termination of pregnancy and minor cardiovascular diagnoses (e.g. isolated aortic/pulmonary pathology and isolated septal defects). The incidence and timing of pregnancy loss were recorded, overall and according to CHD diagnosis, with further stratification based on presence of isolated CHD vs additional fetal diagnosis (genetic diagnosis and/or extracardiac malformation). Adjusted risk of pregnancy loss was calculated and risk factors were assessed using multivariable models for the overall cohort and prenatal diagnosis subgroup. RESULTS: Of 9351 UBDN cases with a cardiovascular code, 3251 cases with major CHD were identified, resulting in a study cohort of 3120 following exclusion of cases with pregnancy termination (n = 131). There were 2956 (94.7%) live births and 164 (5.3%) cases of pregnancy loss, which occurred at a median gestational age of 27.3 weeks. Of study cases, 1848 (59.2%) had isolated CHD and 1272 (40.8%) had an additional fetal diagnosis, including 736 (57.9%) with a genetic diagnosis and 536 (42.1%) with an extracardiac malformation. The observed incidence of pregnancy loss was highest in the presence of mitral stenosis (< 13.5%), hypoplastic left heart syndrome (HLHS) (10.7%), double-outlet right ventricle with normally related great vessels or not otherwise specified (10.5%) and Ebstein's anomaly (9.9%). The adjusted risk of pregnancy loss was 5.3% (95% CI, 3.7-7.6%) in the overall CHD population and 1.4% (95% CI, 0.9-2.3%) in cases with isolated CHD (adjusted risk ratio, 9.0 (95% CI, 6.0-13.0) and 2.0 (95% CI, 1.0-6.0), respectively, based on the general population risk of 0.6%). On multivariable analysis, variables associated with pregnancy loss in the overall CHD population included female fetal sex (adjusted odds ratio (aOR), 1.6 (95% CI, 1.1-2.3)), Hispanic ethnicity (aOR, 1.6 (95% CI, 1.0-2.5)), hydrops (aOR, 6.7 (95% CI, 4.3-10.5)) and additional fetal diagnosis (aOR, 6.3 (95% CI, 4.1-10)). On multivariable analysis of the prenatal diagnosis subgroup, years of maternal education (aOR, 1.2 (95% CI, 1.0-1.4)), presence of an additional fetal diagnosis (aOR, 2.7 (95% CI, 1.4-5.6)), atrioventricular valve regurgitation ≥ moderate (aOR, 3.6 (95% CI, 1.3-8.8)) and ventricular dysfunction (aOR, 3.8 (95% CI, 1.2-11.1)) were associated with pregnancy loss. Diagnostic groups associated with pregnancy loss were HLHS and variants (aOR, 3.0 (95% CI, 1.7-5.3)), other single ventricles (aOR, 2.4 (95% CI, 1.1-4.9)) and other (aOR, 0.1 (95% CI, 0-0.97)). Time-to-pregnancy-loss analysis demonstrated a steeper survival curve for cases with an additional fetal diagnosis, indicating a higher rate of pregnancy loss compared to cases with isolated CHD (P < 0.0001). CONCLUSIONS: The risk of pregnancy loss is higher in cases with major fetal CHD compared with the general population and varies according to CHD type and presence of additional fetal diagnoses. Improved understanding of the incidence, risk factors and timing of pregnancy loss in CHD cases should inform patient counseling, antenatal surveillance and delivery planning. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Correction: Sub-Doppler infrared spectroscopy of resonance-stabilized hydrocarbon intermediates: ν3/ν4 CH stretch modes and CH2 internal rotor dynamics of benzyl radical.

Correction for 'Sub-Doppler infrared spectroscopy of resonance-stabilized hydrocarbon intermediates: ν3/ν4 CH stretch modes and CH2 internal rotor dynamics of benzyl radical' by A. Kortyna et al., Phys. Chem. Chem. Phys., 2017, 19, 29812-29821.

Sub-Doppler infrared spectroscopy of resonance-stabilized hydrocarbon intermediates: ν3/ν4 CH stretch modes and CH2 internal rotor dynamics of benzyl radical.

Highly reactive benzyl radicals are generated by electron dissociative attachment to benzyl chloride doped into a neon-hydrogen-helium discharge and immediately cooled to Trot = 15 K in a high density, supersonic slit expansion environment. The sub-Doppler spectra are fit to an asymmetric-top rotational Hamiltonian, thereby yielding spectroscopic constants for the ground (v = 0) and first excited (v = 1, ν3, ν4) vibrational levels of the ground electronic state. The rotational constants obtained for the ground state are in good agreement with previous laser induced fluorescence measurements (LIF), with vibrational band origins (ν3 = 3073.2350 ± 0.0006 cm-1, ν4 = 3067.0576 ± 0.0006 cm-1) in agreement with anharmonically corrected density functional theory calculations. To assist in detection of benzyl radical in the interstellar medium, we have also significantly improved the precision of the ground state rotational constants through combined analysis of the ground state IR and LIF combination differences. Of dynamical interest, there is no evidence in the sub-Doppler spectra for tunneling splittings due to internal rotation of the CH2 methylene subunit, which implies a significant rotational barrier consistent with partial double bond character in the CC bond. This is further confirmed with high level ab initio calculations at the CCSD(T)-f12b/ccpVdZ-f12 level, which predict a zero-point energy corrected barrier to internal rotation of ΔEtun ≈ 11.45 kcal mol-1 or 4005 cm-1. In summary, the high-resolution infrared spectra are in excellent agreement with simple physical organic chemistry pictures of a strongly resonance-stabilized benzyl radical with a nearly rigid planar structure due to electron delocalization around the aromatic ring.

Operational Head-on Beam-Beam Compensation with Electron Lenses in the Relativistic Heavy Ion Collider.

Head-on beam-beam compensation has been implemented in the Relativistic Heavy Ion Collider in order to increase the luminosity delivered to the experiments. We discuss the principle of combining a lattice for resonance driving term compensation and an electron lens for tune spread compensation. We describe the electron lens technology and its operational use. To date, the implemented compensation scheme approximately doubled the peak and average luminosities.

The diagnosis and management of Piriformis Syndrome: myths and facts.

Piriformis Syndrome (PS) is an uncommon, controversial neuromuscular disorder that is presumed to be a compression neuropathy of the sciatic nerve at the level of the piriformis muscle (PM). The diagnosis is hampered by a lack of agreed upon clinical criteria and a lack of definitive investigations such as imaging or electrodiagnostic testing. Treatment has focused on stretching, physical therapies, local injections, including botulinum toxin, and surgical management. This article explores the various sources of controversy surrounding piriformis syndrome including diagnosis, investigation and management. We conclude with a proposal for diagnostic criteria which include signs and symptoms, imaging, and response to therapeutic injections.

Value and Applicability of Large Administrative Healthcare Databases in Prosthetics and Orthotics Outcomes Research.

The goal of health economics and outcomes research is to improve healthcare decision making. In the absence of high-value clinical data, the availability and quality of administrative healthcare data could be vital in the generation of evidence for orthotics and prosthetics services. The purpose of this article is to provide a stronger understanding of administrative healthcare data analysis, an area that has been scarcely examined within prosthetics and orthotics despite the wealth of information available within such data. Examples of common datasets in this arena currently available are provided, as well as an overview of the limitations and advantages of studies utilizing such datasets.

The Value of Health Economics and Outcomes Research in Prosthetics and Orthotics.

The demand has increased for evidence regarding the effectiveness and value of prosthetic and orthotic rehabilitation interventions. Clinicians and managers are under pressure to provide treatment recommendations and demonstrate effectiveness through outcomes. It is often assumed that rehabilitation interventions, including the provision of custom-made and custom-fit orthotic and prosthetic devices, are beneficial to patients. Assessing the value of orthotic and prosthetic services has become more critical to continue to ensure equitable access to needed services. Health economics and outcomes research methods serve as tools to gauge the value of prosthetic and orthotic rehabilitation interventions. The purpose of this article is to provide an overview of the current need of health economics and outcomes research in orthotics and prosthetics, to introduce common economic methods that assist to generate real-world evidence, and to discusses the potential value of economic methods for clinicians and clinical practice.

piggyBac-like elements in the pink bollworm, Pectinophora gossypiella.

A transgenic line of the pink bollworm, Pectinophora gossypiella, a key lepidopteran cotton pest, was generated previously using the piggyBac transposon IFP2 from Trichoplusia ni. Here we identified an endogenous piggyBac-like element (PLE), designated as PgPLE1, in the pink bollworm. A putatively intact copy of PgPLE1 (PgPLE1.1) presents the canonical features of PLE: inverted terminal repeats with three C/G residues at the extreme ends, inverted subterminal repeats, TTAA target site and an open reading frame encoding transposase with 68% similarity to IFP2. Vectorette PCR revealed large variation in the insertion sites of PgPLE1 amongst worldwide populations, indicating the potential mobility of PgPLE1. The PgPLE1 was undetectable in the genome of Pectinophora endema, implying the recent invasion of PgPLE1 after the divergence of these two closely related species.

Recovery of human motoneurons during rotation.

During prolonged contractions, few studies have reported rotation among low threshold motoneurons. The question arises whether a motoneuron stops firing due to an increase in firing threshold or whether it is due to regional switching of activity among muscle fascicles. We postulated that if the rest period resulted from an increase in firing threshold, a progressive recovery in the excitability of the motoneuron would be observed during the rest period. The excitability of soleus or tibialis anterior motoneurons was tested during the rest periods. The results showed that a previously tonic motoneuron that had dropped off during rotation, rarely responded to Ia or TMS inputs in the initial parts of the rest period; however, its response probability increased significantly in the second half. Based on these data, we suggest that the observed rotation is due to changes in firing thresholds of motoneurons during prolonged firing.

Chemistry and chemical intermediates in supersonic free jet expansions.

Short-lived intermediates often play key roles in determining the course of chemical reactions. Recently the combination of sophisticated laser techniques and supersonic free jet expansions has offered new insight into the structure and reactivity of such intermediates. Because of their extremely reactive nature the intermediates are produced in situ in the expansion. The free jet expansion provides cooling of the intermediates to very low temperatures, so that even complex organic free radicals and molecular ions can be identified and characterized. Radical-radical reactions and ionic cluster formation likewise proceed in the expansion and can be monitored by laser spectroscopy.

Flame synthesis and in vitro biocompatibility assessment of superparamagnetic iron oxide nanoparticles: cellular uptake, toxicity and proliferation studies.

Superparamagnetic iron oxide nanoparticles are used in diverse applications, such as targeted drug delivery, magnetic resonance imaging and hyperthermic malignant cell therapy. In the current work, superparamagnetic iron oxide nanoparticles were produced by flame synthesis, which has improved nanoparticle property control and is capable of commercial production rates with minimal post-processing. The iron oxide nanoparticle material characteristics were analyzed by electron microscopy and Raman spectroscopy. Finally, flame synthesized iron oxide nanoparticle interaction with endothelial cells was compared to commercially available iron oxide nanoparticles. Flame synthesis produced a heterogeneous mixture of 6-12 nm diameter hematite and magnetite nanoparticles with superparamagnetic properties. Endothelial cell scanning electron microscopy, confirmed by energy dispersive spectroscopy, demonstrated that flame synthesized nanoparticles are ingested into cells in a similar manner to commercially available nanoparticles. The flame synthesized particles showed no statistically significant toxicity difference from commercially available nanoparticles, as measured by Live/Dead assay, Alamar blue, and lactase dehydrogenase release. Neither type of nanoparticle affected cell proliferation induced by fibroblast growth factor-2. These data suggest that combustion synthesized iron oxide nanoparticles are comparable to commercially available nanoparticles for biological applications, yet flame synthesis is a simpler process with higher purity products and lower manufacturing costs. Future work will include functionalizing nanoparticles for specific cell targeting and bioactive factor delivery.

piggyBac-like elements in cotton bollworm, Helicoverpa armigera (Hübner).

Two piggyBac-like elements (PLEs) were identified in the cotton bollworm, Helicoverpa armigera, and were designated as HaPLE1 and HaPLE2. HaPLE1 is flanked by 16 bp inverted terminal repeats (ITRs) and the duplicated TTAA tetranucleotide, and contains an open reading frame (ORF) of 1794 bp with the presumed DDD domain, indicating that this element may be an active autonomously mobile element. HaPLE2 was found with the same ITRs, but lacks the majority of an ORF-encoding transposase. Thus, this element was thought to be a non-autonomous element. Transposable element displays and distribution of the two PLEs in individuals from three different H. armigera populations suggest that transmobilization of HaPLE2 by the transposase of HaPLE1 may be likely, and mobilization of HaPLE1 might occur not only within the same individual, but also among different individuals. In addition, horizontal transfer was probably involved in the evolution of PLEs between H. armigera and Trichoplusia ni.

Hypericum perforatum L. extract - novel photosensitizer against human bladder cancer cells.

The polar methanolic fraction (PMF) of the Hypericum perforatum L. extract has recently been developed and tested as a novel, natural photosensitizer for use in the photodynamic therapy (PDT), and photodynamic diagnosis (PDD). PMF has been tested on HL-60 leukemic cells and cord blood hemopoietic progenitors. In the present study, the efficacy of PMF as a phototoxic agent against urinary bladder carcinoma has been studied using the T24 (high grade metastatic cancer), and RT4 (primary low grade papillary transitional cell carcinoma) human bladder cancer cells. Following cell culture incubation, PMF was excited using 630 nm laser light. The photosensitizer exhibited significant photocytotoxicity in both cell lines at a concentration of 60microg/ml, with 4-8 J/cm(2) light dose, resulting in cell destruction from 80% to 86%. At the concentration of 20microg/ml PMF was not active in either cell line. These results were compared with the results obtained in the same cell lines, under the same conditions with a clinically approved photosensitizer, Photofrin. Photofrin was used in the maximum clinically tolerable dose of 4microg/ml, and it was also excited with 630 nm laser light. In the T24 cell Photofrin exhibited slightly less photocytotocixity, compared with PMF, resulting in 77% cell death with 8J/cm(2) light dose. However, against the RT4 cells Photofrin resulted in minimal cell death (9%) with even 8J/cm(2) light dose. Finally, the type of cell death induced by PMF photoactivation was studied using flow cytometry and DNA laddering. Cell death by PMF photodynamic action in these two bladder cell lines is caused predominently by apoptosis. The reported significant photocytotoxicity, selective localization, natural abundance, easy, and inexpensive preparation, underscore that the PMF extract hold the promise of being a novel, effective PDT photosensitizer.

Bone morphogenetic protein-2 (BMP-2) and transforming growth factor-beta1 (TGF-beta1) alter connexin 43 phosphorylation in MC3T3-E1 Cells.

BACKGROUND: Bone morphogenetic proteins (BMPs) and transforming growth factor-betas (TGF-betas) are important regulators of bone repair and regeneration. BMP-2 and TGF-beta1 have been shown to inhibit gap junctional intercellular communication (GJIC) in MC3T3-E1 cells. Connexin 43 (Cx43) has been shown to mediate GJIC in osteoblasts and it is the predominant gap junctional protein expressed in these murine osteoblast-like cells. We examined the expression, phosphorylation, and subcellular localization of Cx43 after treatment with BMP-2 or TGF-beta1 to investigate a possible mechanism for the inhibition of GJIC. RESULTS: Northern blot analysis revealed no detectable change in the expression of Cx43 mRNA. Western blot analysis demonstrated no significant change in the expression of total Cx43 protein. However, significantly higher ratios of unphosphorylated vs. phosphorylated forms of Cx43 were detected after BMP-2 or TGF-beta1 treatment. Immunofluorescence and cell protein fractionation revealed no detectable change in the localization of Cx43 between the cytosol and plasma membrane. CONCLUSIONS: BMP-2 and TGF-beta1 do not alter expression of Cx43 at the mRNA or protein level. BMP-2 and TGF-beta1 may inhibit GJIC by decreasing the phosphorylated form of Cx43 in MC3T3-E1 cells.

Mechanisms of stress-related mucosal damage.

During the last 15 years, there has been a dramatic decline in the incidence of bleeding from stress-related mucosal damage. This decrease probably relates to an increased understanding of those mechanisms responsible for the pathogenesis of stress-related mucosal damage and the application of this knowledge to prophylaxis and treatment. Stress-related bleeding has become less of a clinical problem, in part, because of the development of improved techniques for the treatment of shock and its accompanying gastric mucosal hypoperfusion. The nearly routine use of prophylactic antacid and/or histamine (H2)-receptor antagonist therapy to adequately buffer intragastric acidity is another factor that has minimized the development of stress-related damage. As continued understanding of the mechanisms responsible for stress damage is obtained and therapy applied appropriately, this disease should become a disorder of only historical interest in years to come.

Synthesis and structure-activity profiles of A-homoestranes, the estratropones.

2-Methoxyestradiol, a mammalian metabolite of estradiol, has reported antiangiogenic activity which has been proposed to be mediated through interaction at the colchicine binding site on the tubulin monomer. Subsequent structure-activity studies of 2-methoxyestradiol have yielded highly potent steroidal inhibitors of tubulin polymerization. In an effort to probe the scope of binding at the colchicine binding site and the nature of the relationship between 2-methoxyestradiol and colchicine, a series of colchicine/2-methoxyestradiol hybrids was synthesized. These A-homoestrane hybrid systems, collectively termed estratropones, possessed an A-ring tropone system with the keto functionality at either the C-2, C-3, or C-4 position of the steroid nucleus. The estratropones were evaluated for their ability to inhibit the polymerization of tubulin using an in vitro purified bovine brain assay. Most of these hybrids inhibit polymerization with greater potency than either of the natural products. The most potent of these congeners possessed an approximate 5-fold enhancement of the activity of colchicine for the inhibition of tubulin polymerization. alpha-Substituents on the tropone ring showed varied effects on the activities for the two classes of estratropones studied in this regard, the C-3 oxo and the C-4 oxo species. The 3-substituted 4-oxoestratropones exhibited antitubulin activity according to Cl approximately Br > OCH3, whereas the 4-substituted 3-oxoestratropones exhibited activity according to OCH3 > Br approximately Cl. It is unclear if these substituent factors are purely electronic or steric effects or if the substituent operates indirectly by altering the conformation of the nonplanar troponoid ring. The estratropones represent a new class of tubulin binding agents with potential antiangiogenic utility.

Electromechanical microinjection of pink bollworm Pectinophora gossypiella embryos increases survival.

We report and compare methods and apparatus for injection of pink bollworm, Pectinophora gossypiella (Saunders), embryos. Injection with an electromechanical device resulted in 59% survival of embryos. Previous techniques relying on a mechanical manipulator resulted in 8% survival. Pink bollworm (PBW) embryo injection technology is based in part on methods developed for injection and genetic transformation of Caenorhabditis elegans ([Maupas] Dougherty) and Drosophila melanogaster (Meigen) with substantial alterations in both method and apparatus to accommodate special conditions of PBW biology, behavior and morphology. The microinjection methodology described here has direct application to other difficult-to-inject insects and invertebrates.

Comparison of adaptations to a 12-month exercise program and late outcome in patients with healed myocardial infarction and ejection fraction <45% and >50%.

To characterize the differences in adaptations to endurance exercise training and prognosis between patients with depressed and normal left ventricular (LV) function, 20 patients with coronary artery disease were studied and followed for 7 years. Patients with normal LV function had enhancement of LV systolic function, but the group with LV dysfunction did not exhibit cardiac adaptations and had more cardiac events than those with normal LV function.

Hemorrhagic shock increases gut macromolecular permeability in the rat.

The effect of hemorrhagic shock on gut permeability to macromolecules was investigated using fluorescein isothiocyanate dextrans (4,300 or 73,100 daltons). These were given orally, then measured in systemic blood during hemorrhage (mean arterial pressure of 30 mmHg) and reperfusion; sham-shocked animals served as controls. Hemorrhage lasting 2 h resulted in a 5-fold increase in concentration of both tracers relative to that found in control groups. Reperfusion reduced these differences, with values approximately threefold greater than those of controls after 2 h. On a molar basis, the smaller molecule was more permeant than the larger one. This study provides evidence that hemorrhagic shock physically perturbs the normal barrier function of the mucosa, permitting very large substances in the gut lumen access to the circulation. It may further explain, at least in part, previous observations that hypovolemic shock results in bacterial translocation and endotoxemia.

Protective effect of a 21-aminosteroid against hemorrhage-induced ischemia-reperfusion injury in the rat stomach: role of lipid peroxidation.

We investigated the role that lipid peroxidation plays in a hemorrhage-induced ischemia-reperfusion model of gastric injury. Rats were pretreated with an inhibitor of this process, a 21-aminosteroid (U-74389G, 10 mg/kg), or an appropriate control solution intravenously 15 min prior to 20 min of ischemia, followed by 20 min of reperfusion. Results indicated that U-74389G pretreatment significantly attenuated gastric damage compared with corresponding control animals (19.8 vs. 176.8 mm2, p < .001). Enaldehyde levels (picomoles/mg protein), a biochemical index of lipid peroxidation, paralleled these injury findings (12 vs 960, p < .001). Histologically, U-74389G pretreatment almost completely prevented gastric injury compared to control stomachs. Additional studies revealed that lipid peroxidation preceded the formation of gastric damage, and injury occurred predominantly during reperfusion, because animals subjected to ischemia alone without reperfusion failed to develop appreciable injury or enhanced enaldehyde formation. Further, if U-74389G was given intravenously after ischemia, but prior to reperfusion, gastric injury and enaldehyde formation were similarly attenuated. Our findings are consistent with the hypothesis that lipid peroxidation likely plays an important role in hemorrhage-induced ischemia-reperfusion injury to the stomach.