Decision-to-delivery interval and neonatal outcomes for category-1 caesarean sections during the COVID-19 pandemic.

General anaesthesia is known to achieve the shortest decision-to-delivery interval for category-1 caesarean section. We investigated whether the COVID-19 pandemic affected the decision-to delivery interval and influenced neonatal outcomes in patients who underwent category-1 caesarean section. Records of 562 patients who underwent emergency caesarean section between 1 April 2019 and 1 July 2019 in seven UK hospitals (pre-COVID-19 group) were compared with 577 emergency caesarean sections performed during the same period during the COVID-19 pandemic (1 April 2020-1 July 2020) (post-COVID-19 group). Primary outcome measures were: decision-to-delivery interval; number of caesarean sections achieving decision-to-delivery interval < 30 min; and a composite of adverse neonatal outcomes (Apgar 5-min score < 7, umbilical arterial pH < 7.10, neonatal intensive care unit admission and stillbirth). The use of general anaesthesia decreased significantly between the pre- and post-COVID-19 groups (risk ratio 0.48 (95%CI 0.37-0.62); p < 0.0001). Compared with the pre-COVID-19 group, the post-COVID-19 group had an increase in median (IQR [range]) decision-to-delivery interval (26 (18-32 [4-124]) min vs. 27 (20-33 [3-102]) min; p = 0.043) and a decrease in the number of caesarean sections meeting the decision-to-delivery interval target of < 30 min (374/562 (66.5%) vs. 349/577 (60.5%); p = 0.02). The incidence of adverse neonatal outcomes was similar in the pre- and post-COVID-19 groups (140/568 (24.6%) vs. 140/583 (24.0%), respectively; p = 0.85). The small increase in decision-to-delivery interval observed during the COVID-19 pandemic did not adversely affect neonatal outcomes.

Modelling population processes with random initial conditions.

Population dynamics are almost inevitably associated with two predominant sources of variation: the first, demographic variability, a consequence of chance in progenitive and deleterious events; the second, initial state uncertainty, a consequence of partial observability and reporting delays and errors. Here we outline a general method for incorporating random initial conditions in population models where a deterministic model is sufficient to describe the dynamics of the population. Additionally, we show that for a large class of stochastic models the overall variation is the sum of variation due to random initial conditions and variation due to random dynamics, and thus we are able to quantify the variation not accounted for when random dynamics are ignored. Our results are illustrated with reference to both simulated and real data.

Nitric oxide synthase expression and activity in the tight-skin mouse model of fibrosis.

OBJECTIVES: Nitric oxide (*NO) is an important physiological signalling molecule and a potent vasodilator. We have previously demonstrated abnormal *NO metabolism in the plasma of patients with systemic sclerosis (SSc; scleroderma), a disease that features vascular dysfunction as well as collagen overproduction and fibrosis. The aim of the present study was to examine nitric oxide synthase (NOS) expression and activity and assess the potential role of antioxidants in the scleroderma-like syndrome of the tight-skin 1 (TSK-1/+) mouse, an experimental animal model for fibrosis. METHODS: Skin, lung or plasma was taken from TSK-1/+ (n = 15) and wild-type (WT; n = 12) littermate mice. Type 1 collagen, endothelial NOS (eNOS), haemoxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) protein and gene expression were determined by western blot and reverse transcriptase-polymerase chain reaction. eNOS expression was further determined by immunohistochemistry. NOS activity was evaluated by conversion of [14C] L-arginine to [14C] L-citrulline. Levels of circulating plasma nitrite/nitrate (NO(x)) were also measured. Total antioxidant activity was evaluated by ABTS+ production (ABTS = 2,2'-azino-bis-[3-ethylbenz-thiazoline-6-sulphonic acid). RESULTS: In the skin, eNOS was present in the epidermal layer, hair follicles and also in the endothelial cells lining the blood vessels. Expression of both the eNOS protein and gene was significantly reduced in TSK-1/+ skin tissue, while type 1 collagen protein was elevated compared with WT. Furthermore, there was decreased NOS activity in TSK-1/+ skin tissue; however, there was no measurable difference in plasma NO(x). Correspondingly, the protective antioxidant enzyme HO-1 and the associated transcription factor Nrf2 showed reduced protein and gene expression levels in TSK-1/+ skin, while there was also less total antioxidant activity. In TSK-1/+ lung tissue, however, we observed no difference in collagen protein expression, *NO metabolism or HO-1 expression and total antioxidant activity compared with WT. CONCLUSIONS: The findings suggest that there is also abnormal *NO metabolism in the TSK-1/+ mouse model of fibrosis, particularly in the skin, while expression and activity of protective antioxidants are reduced. The TSK-1/+ mouse may also be useful for testing treatments that target vascular endothelial cell function in patients with SSc.

Abnormal nitric oxide metabolism in systemic sclerosis: increased levels of nitrated proteins and asymmetric dimethylarginine.

OBJECTIVES: Endothelial dysfunction is a primary event in systemic sclerosis; however, the aetiology of events and the role of nitric oxide (NO) is still unclear. The aim of the present study is to investigate whether there are abnormalities in NO metabolism in plasma from patients with primary Raynaud's phenomenon (RP) and in the pathogenesis of systemic sclerosis (SSc): limited SSc (lSSc) and diffuse (dSSc). We also wanted to investigate the effect of factors within patients' SSc serum on NO metabolism in human microvascular endothelial cells (HMECs). METHODS: Plasma (n=89) or serum (n=80) was assayed for total nitrate and nitrite (NOx), nitration of proteins and the NO inhibitor asymmetric dimethylarginine (ADMA). HMECs were treated with patients' SSc serum and assayed for indicators of NO metabolism. RESULTS: Plasma NOx was elevated in patients with RP or lSSc (P<0.002), but not in patients with dSSc, compared with controls. Nitrated proteins in plasma, however, were found to be very high in dSSc patients (P<0.03), compared with RP, lSSc or controls. Patients with dSSc also showed increased levels of serum ADMA (P<0.05). The high level of nitrated proteins in dSSc was strongly associated with the severity and duration of dSSc disease. Skin biopsy sections from dSSc patients also showed enhanced nitrotyrosine staining compared with controls. In HMECs, pre-incubation with SSc serum impaired the activity of nitric oxide synthase (NOS) but not the expression of inducible or endothelial NOS. SSc serum also induced a reduction in intracellular cGMP synthesis, and NOx production in the cell culture medium, but was not associated with increased cell cytotoxicity. CONCLUSIONS: NO formation is increased in patients with primary RP or lSSc, but nitration of proteins and elevated ADMA is a particular feature of dSSc and may reflect abnormal NO regulation and/or contribute to endothelial dysfunction in SSc.

Relativistic effects and two-body currents in (H)((-->)e(')p)n using out-of-plane detection.

Measurements of the (2)H((-->)e,e(')p)n reaction were performed with the out-of-plane magnetic spectrometers (OOPS) at the MIT-Bates Linear Accelerator. The longitudinal-transverse, f(LT) and f(')(LT), and the transverse-transverse, f(TT), interference responses at a missing momentum of 210 MeV/c were simultaneously extracted in the dip region at Q2 = 0.15 (GeV/c)(2). In comparison to models of deuteron electrodisintegration, the data clearly reveal strong effects of relativity and final-state interactions and the importance of two-body meson-exchange currents and isobar configurations. We demonstrate that such effects can be disentangled by extracting these responses using the novel out-of-plane technique.

Adenoviral delivery of a leukocyte-type 12 lipoxygenase ribozyme inhibits effects of glucose and platelet-derived growth factor in vascular endothelial and smooth muscle cells.

The lipoxygenase (LO) pathway has been implicated as an important mediator of chronic glucose and platelet-derived growth factor (PDGF)-induced effects in the vascular system. Endothelial cells treated with 12LO products or cultured in high glucose showed enhanced monocyte adhesion, an important step in atherogenesis. We have previously reported that PDGF increased HETE levels in porcine aortic smooth muscle cells. Although several pharmacological inhibitors to the LO pathway are available, most lack specificity and may harbor undesirable side effects. Therefore, we developed a recombinant adenovirus expressing a hammerhead ribozyme (AdRZ) targeted against the porcine leukocyte-type 12LO mRNA to investigate the involvement of LO in glucose- and PDGF-mediated effects in vascular cells. Infection of porcine aortic endothelial cells with AdRZ reduced the level of glucose-enhanced 12LO mRNA expression as determined by quantitative, real-time reverse transcriptase-polymerase chain reaction. Reverse-phase HPLC and RIA analysis also revealed a corresponding decrease in glucose-stimulated 12HETE production in both the cellular and supernatant fractions. In the ribozyme-treated porcine aortic endothelial cells, there was marked inhibition of high glucose-stimulated monocyte adhesion. Infection with AdRZ also reduced PDGF-induced porcine aortic smooth muscle cell migration by approximately 50%. These studies demonstrate the efficacy of recombinant adenovirus expressing 12LO ribozyme in studying the effects of 12LO in vascular wall cells. They document an important role for the 12LO pathway in regulating inflammatory changes in endothelial cells and smooth muscle cells.

Short-term feeding of atherogenic diet to mice results in reduction of HDL and paraoxonase that may be mediated by an immune mechanism.

Short-term feeding (up to 7 days) of an atherogenic diet to C57BL/6 low density lipoprotein receptor-deficient mice did not result in decreased hepatic paraoxonase (PON) mRNA but caused a dramatic decrease in plasma PON activity and mass. The decreased activity and mass were temporally related to an increase in plasma and high density lipoprotein (HDL) lipid hydroperoxides and to a decrease in HDL cholesterol and native apolipoprotein A-I (apoA-I) and apolipoprotein A-II (apoA-II). As the native apoA-I protein disappeared from the circulation, higher molecular weight forms of apoA-I appeared, some of which contained epitopes recognized by an antibody (EO6) that recognizes oxidized phospholipids. After mice consumed an atherogenic diet for 1 or 3 days, switching the mice to a low fat chow diet for 3 days resulted in a return to baseline levels of lipid hydroperoxides but only a small return toward baseline for HDL cholesterol, with no significant increase in apoA-I mass or PON activity and mass. After mice consumed an atherogenic diet for 3 days, switching to the chow diet for 3 days did not significantly alter the high molecular weight forms of apoA-I or the signal generated by EO6. In marked contrast, after mice consumed an atherogenic diet for 7 days, switching to the chow diet for 3 days resulted in a dramatic increase in native apoA-I to baseline levels, with virtual disappearance of the high molecular weight forms of apoA-I, including the form recognized by EO6. After mice consumed an atherogenic diet for 7 days, switching to the chow diet for 3 days also resulted in significant increases in HDL cholesterol and PON mass and activity, although baseline levels were not reached. IgG and IgM antibodies were found to be associated with apoA-I in control animals, were minimally decreased after the 3-day atherogenic diet, were dramatically decreased after the 7-day atherogenic diet, and returned to near or above baseline levels after a return to the chow diet for 3 days. We conclude that the atherogenic diet rapidly induces lipid hydroperoxide formation and apoA-I oxidation with the formation of high molecular weight forms of apoA-I. Concomitant with these changes in apoA-I levels, HDL cholesterol and PON activity and mass declined without changes in mRNA levels for apoA-I or PON, suggesting increased clearance of these altered HDL particles. We further conclude that between the third and seventh day of the atherogenic diet, an as-yet-unidentified mechanism for clearing the high molecular weight forms of apoA-I is induced and that this mechanism may be related to the clearance of immune complexes.

Serotonin promotes the survival of cortical glutamatergic neurons in vitro.

The appearance of 5-hydroxytryptamine (serotonin; 5-HT) in the cerebral cortex coincides with developmental events such as cell proliferation, survival, and differentiation. We tested the hypothesis that 5-HT plays a role in these events by examining rat cortical progenitor cells in vitro. Using bromodeoxyuridine incorporation we found that 5-HT did not affect the proliferation of these cells, but a cell survival assay indicated that it promoted their survival. The observed survival effect was mimicked by the 5-HT2a/2c receptor agonist alpha-methyl-5-HT and blocked by the 5-HT2a receptor antagonist cinanserin. Consistent with increased survival was the finding, using the terminal transferase nick end labeling method, of reduced cell death in cultures exposed to 5-HT. Immunohistochemical analysis with cell-specific markers revealed that the effect of 5-HT was directed specifically to the glutamate-containing neuronal population and not to any other cortical cell types. These results indicate that 5-HT does not exert its effects on dividing neuroepithelial cells in the developing cortex, but rather on postmitotic neurons.

Effects on cardiac performance of atrioventricular node catheter ablation using radiofrequency current for drug-refractory atrial arrhythmias.

Patients with atrial fibrillation or atrial flutter (AF) are candidates for radiofrequency (RF) catheter ablation of the atrioventricular (AV) node with the aim being to control heart rate. As patients with AF can have markedly impaired ventricular function, information concerning the hemodynamic effects of AV node ablation using RF current would be valuable. Fourteen consecutive patients (mean age 65 +/- 3 years) with drug-resistant AF underwent AV node catheter ablation with RF current and had permanent pacemaker implantation. The mean left ventricular ejection fraction (EF) by two-dimensional echocardiography immediately before ablation was 42 +/- 3% (range 14%-54%) and their mean exercise time was 4.4 +/- 0.4 minutes. Complete AV block was achieved in all 14 patients with 6 +/- 2 RF applications (range 1-18). There was no evidence of any acute cardiodepressant effect associated with delivery of RF current, and EF 3 days after ablation was 44 +/- 4%. By 6 weeks after ablation, the left ventricular EF was significantly improved compared to baseline (47 +/- 4% postablation vs 42 +/- 3% preablation; P < 0.05), and this modest increase in EF was accompanied by an improvement in exercise time (5.4 +/- 0.4 min). In conclusion, delivery of RF current for AV node catheter ablation in patients with AF and reduced ventricular function is not associated with any acute cardiodepressant effect. On the contrary, improved control of rapid heart rate following successful AV node ablation is associated with a modest and progressive improvement in cardiac performance.

The evaluation of emergency care. Development of a quantitative criterion.

A method based on comparing proportions of immediate and later deaths has been used in a retrospective study of fatal road traffic accidents occurring in North Yorkshire from January 1974 to July 1976. The method enables comparative data to be expressed in terms of a care index based on morbidity distribution as indicated by the ratio of immediate to later deaths. Using this method the general practitioner scheme in operation in North Yorkshire appears to give a higher standard of emergency care than elsewhere in the county.