Safety and feasibility pilot study of continuous low-dose maternal supplemental oxygen in fetal single ventricle heart disease.

OBJECTIVES: Fetuses with single ventricle physiology (SVP) exhibit reductions in fetal cerebral oxygenation with associated delays in fetal brain growth and neurodevelopmental outcomes. Maternal supplemental oxygen (MSO) has been proposed to improve fetal brain growth but current evidence on dosing, candidacy, and outcomes are limited. In this pilot study, we evaluated the safety and feasibility of continuous low-dose MSO in the setting of SVP. METHODS: This single-centre, open-label, pilot phase 1 safety and feasibility clinical trial included 25 pregnant individuals with a fetal diagnosis of SVP. Participants self-administered continuous supplemental oxygen using medical-grade oxygen concentrators for up to 24 hours per day from the second half of gestation until delivery. The primary aim was the evaluation of the safety profile and feasibility of MSO. A secondary preliminary analysis was performed to assess the impact of MSO on the fetal circulation by echocardiography and late-gestational cardiovascular magnetic resonance, early outcomes including brain growth and pre-operative brain injury, and 18-month neurodevelopmental outcomes by the Bayley Scales of Infant and Toddler Development 3rd Edition compared to a contemporary fetal SVP cohort that received standard of care (SOC). RESULTS: Among 25 participants, the average maternal age at conception was 35 years, and fetal SVP diagnoses included 16 right ventricle dominant, 8 left ventricle dominant, and 1 indeterminant ventricular morphology. Participants started the trial at approximately 29.3 gestational weeks and took MSO for a median 16.1 hours per day for 63 days, cumulating a median 1029 hours of oxygen intake from enrollment until delivery. The only treatment-associated adverse events were nasal complications that were typically resolved by attaching a humidifier unit to the oxygen concentrator. No premature closure of the ductus arteriosus or unexpected fetal demise was observed. In the secondary analysis, MSO was not associated with any changes in fetal growth, middle cerebral artery pulsatility index, cerebroplacental ratio, nor head circumference to abdominal circumference ratio Z-scores over gestation compared to SOC. Although MSO was associated with changes in umbilical artery pulsatility index Z-score over gestation compared to SOC (p=0.02), this was likely due to initial baseline differences in placental resistance. At late-gestational cardiovascular magnetic resonance, MSO was not associated with any significant increase in umbilical vein oxygen saturation, fetal oxygen delivery, or fetal cerebral oxygen delivery. Similarly, we observed no differences in newborn outcomes including brain volume and pre-operative brain injury, nor mortality by 18 months of age, nor neurodevelopmental outcomes at 18 months of age. CONCLUSIONS: This pilot phase 1 clinical trial indicates low-dose maternal supplemental oxygen therapy is safe and well tolerated in pregnancies diagnosed with fetal SVP. However, our protocol was not associated with any significant changes in fetal circulatory physiology or improvements in early neurologic or neurodevelopmental outcomes. This article is protected by copyright. All rights reserved.

Peripheral cord insertion is associated with adverse pregnancy outcome only when accompanied by clinically significant placental pathology.

OBJECTIVE: To examine the relationship between umbilical cord insertion site, placental pathology and adverse pregnancy outcome in a cohort of normal and complicated pregnancies. METHODS: Sonographic measurement of the cord insertion and detailed placental pathology were performed in 309 participants. Associations between cord insertion site, placental pathology and adverse pregnancy outcome (pre-eclampsia, preterm birth, small-for-gestational age) were examined. RESULTS: A total of 93 (30%) participants were identified by pathological examination to have a peripheral cord insertion site. Only 41 of the 93 (44%) peripheral cords were detected by prenatal ultrasound. Peripherally inserted cords were associated significantly (P < 0.0001) with diagnostic placental pathology (most commonly with maternal vascular malperfusion (MVM)); of which 85% had an adverse pregnancy outcome. In cases of isolated peripheral cords, without placental pathology, the incidence of adverse outcome was not statistically different when compared to those with central cord insertion and no placental pathology (31% vs 18%; P = 0.3). A peripheral cord with an abnormal umbilical artery (UA) pulsatility index (PI) corresponded to an adverse outcome in 96% of cases compared to 29% when the UA-PI was normal. CONCLUSIONS: This study demonstrates that peripheral cord insertion is often part of the spectrum of findings of MVM disease and is associated with adverse pregnancy outcome. However, adverse outcome was uncommon when there was an isolated peripheral cord insertion and no placental pathology. Therefore, additional sonographic and biochemical features of MVM should be sought when a peripheral cord is observed. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Determination of fetal heart rate short-term variation from umbilical artery Doppler waveforms.

OBJECTIVE: To evaluate the feasibility of using umbilical artery (UA) Doppler waveforms to measure fetal heart rate (FHR) short-term variation (STV) across gestation. METHODS: This was a prospective longitudinal study, conducted at two study sites, of 195 pregnancies considered low risk. Pulsed-wave Doppler of the UAs was performed at 4-weekly intervals, between 14 and 40 weeks of gestation, using a standardized imaging protocol. Up to 12 consecutive UA Doppler waveforms were analyzed using offline processing software. FHR STV was calculated using average R-R intervals extracted from the waveforms and baseline corrected for FHR. RESULTS: Baseline-corrected FHR STV increased significantly with gestational age (conditional R2 = 0.37; P < 0.0001) and was correlated inversely with FHR (conditional R2 = 0.54; P < 0.0001). The STV ranged (median (interquartile range)) from 3.5 (2.9-4.1) ms at 14-20 weeks' gestation to 6.3 (4.8-7.7) ms at 34-40 weeks' gestation. The change in heart rate STV did not differ between study sites or individual sonographers. CONCLUSIONS: UA Doppler waveforms offer a robust and feasible method to derive STV of the FHR. It should be emphasized that the UA Doppler-derived STV is not interchangeable with measurements derived with computerized cardiotocography. Accordingly, further investigations are needed to validate associations with outcome, in order to determine the value of concurrent fetal cardiovascular and heart rate evaluations that are possible with the technique described here. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Female-mediated causes and consequences of status change in a social fish.

In highly social species, dominant individuals often monopolize reproduction, resulting in reproductive investment that is status dependent. Yet, for subordinates, who typically invest less in reproduction, social status can change and opportunities to ascend to dominant social positions are presented suddenly, requiring abrupt changes in behaviour and physiology. In this study, we examined male reproductive anatomy, physiology and behaviour following experimental manipulations of social status in the cooperatively breeding cichlid fish, Neolamprologus pulcher. This unusual fish species lives in permanent social groups composed of a dominant breeding pair and 1-20 subordinates that form a linear social dominance hierarchy. By removing male breeders, we created 18 breeding vacancies and thus provided an opportunity for subordinate males to ascend in status. Dominant females play an important role in regulating status change, as males successfully ascended to breeder status only when they were slightly larger than the female breeder in their social group. Ascending males rapidly assumed behavioural dominance, demonstrated elevated gonadal investment and androgen concentrations compared with males remaining socially subordinate. Interestingly, to increase gonadal investment ascending males appeared to temporarily restrain somatic growth. These results highlight the complex interactions between social status, reproductive physiology and group dynamics, and underscore a convergent pattern of reproductive investment among highly social, cooperative species.

Consistent individual differences in the social phenotypes of wild great tits, Parus major.

Despite growing interest in animal social networks, surprisingly little is known about whether individuals are consistent in their social network characteristics. Networks are rarely repeatedly sampled; yet an assumption of individual consistency in social behaviour is often made when drawing conclusions about the consequences of social processes and structure. A characterization of such social phenotypes is therefore vital to understanding the significance of social network structure for individual fitness outcomes, and for understanding the evolution and ecology of individual variation in social behaviour more broadly. Here, we measured foraging associations over three winters in a large PIT-tagged population of great tits, and used a range of social network metrics to quantify individual variation in social behaviour. We then examined repeatability in social behaviour over both short (week to week) and long (year to year) timescales, and investigated variation in repeatability across age and sex classes. Social behaviours were significantly repeatable across all timescales, with the highest repeatability observed in group size choice and unweighted degree, a measure of gregariousness. By conducting randomizations to control for the spatial and temporal distribution of individuals, we further show that differences in social phenotypes were not solely explained by within-population variation in local densities, but also reflected fine-scale variation in social decision making. Our results provide rare evidence of stable social phenotypes in a wild population of animals. Such stable social phenotypes can be targets of selection and may have important fitness consequences, both for individuals and for their social-foraging associates.

Treatment of post-herpetic neuralgia. A review of 77 consecutive cases.

The treatment of 77 consecutive cases of post-herpetic neuralgia is reviewed. Stellate blockade proved helpful in 75% of patients with pain of less than 1 year's duration; 40% became virtually pain free. Drug treatment and electrical counterirritation methods gave improvement in 60% of cases but only 15% became pain free. Stellate block carried out after 1 year of pain proved helpful in only 44% of patients, and only 22% became pain free. Stellate blockade carried out within 1 year of the onset of symptoms would appear to be one of the treatments of choice for post-herpetic neuralgia. It would be of interest to see the results of a controlled randomised trial.

A comparison of the acute effect of single doses of vigabatrin and sodium valproate on photosensitivity in epileptic patients.

The acute effect of oral administration of a single dose of vigabatrin, a new antiepileptic drug which acts by irreversible enzyme-activated inhibition of the brain enzyme, GABA-aminotransferase, on the photoconvulsive response in patients with photosensitive epilepsy, was compared with that of the established antiepileptic drug, sodium valproate. Both drugs significantly suppressed the photoconvulsive response in 3 out of 6 subjects. This result was interpreted as further evidence of vigabatrin's potential value in the future treatment of patients with epilepsy.

Using a 6-minute walk test to predict outcomes in patients with left ventricular dysfunction.

Maximal oxygen consumption (VO2MAX) is an independent variable that predicts outcomes in patients suffering from left ventricular dysfunction (LVD). Determining VO2MAX in a rehabilitation setting is not only costly and time-consuming but it would also be beyond many patients' physical abilities. This study's goal was to show that a simpler and less costly 6-minute walk test can predict mortality in patients with LVD. Sixty-six Phase 1 cardiac rehabilitation patients with LVD performed the 6-minute walk test upon admission and at discharge from a rehabilitation hospital. Upon discharge, the group that was able to walk significantly longer distances upon discharge had a higher survival rate 3 months after discharge. The 6-minute walk test can predict longer survival in patients with LVD and can provide valuable information for determining treatment plans, future prognosis, and home disposition of deconditioned LVD patients in a rehabilitation setting.

Pathologic basis of improving the screening utility of 2-dimensional placental morphology ultrasound.

OBJECTIVE: To determine the utility of measuring maximum placental length in the second trimester to predict a small for gestational age placenta by weight at delivery in clinically high-risk women. STUDY DESIGN: Placental dimensions determined by 2-dimensional (2-D) real-time ultrasound at 19-23 weeks' gestation were compared to post-natal placental weights and pathology in 95 high-risk patients with singleton pregnancies. RESULTS: Maximum placental length <10.0 cm performed poorly (false positive rate 25.5%) for the detection of a small placenta by weight at delivery. Placental pathology examination revealed eccentric cord insertion to be an important explanation for poor screening test result, since this finding was significantly more common in the false negative group (length ≥ 10.0 cm, weight <10th percentile) compared with the true negative group (length ≥ 10.0 cm, weight ≥ 10 th percentile) (15/28 vs. 9/38, Fisher's exact test, p = 0.005). CONCLUSIONS: Prediction of reduced placental weight by 2-D ultrasound determination of maximum placental length in clinically high-risk pregnancies confounded by the phenomenon of asymmetric chorion regression. Refinement of 2-D ultrasound methods to include orthogonal plane measurements, or replacement by 3-D techniques is predicted to significantly improve the effectiveness of diagnosing small placentas in-utero.

Reproductive-tactic-specific variation in sperm swimming speeds in a shell-brooding cichlid.

Theory predicts that males experiencing elevated levels of sperm competition will invest more in gonads and produce faster-swimming sperm. Although there is ample evidence in support of the first prediction, few studies have examined sperm swimming speed in relation to sperm competition. In this study, we tested these predictions from sperm competition theory by examining sperm characteristics in Telmatochromis vittatus, a small shell-brooding cichlid fish endemic to Lake Tanganyika. Males exhibit four different reproductive tactics: pirate, territorial, satellite, and sneaker. Pirate males temporarily displace all other competing males from a shell nest, whereas sneaker males always release sperm in the presence of territorial and satellite males. Due to the fact that sneakers spawn in the presence of another male, sneakers face the highest levels of sperm competition and pirates the lowest, whereas satellites and territorials experience intermediate levels. In accordance with predictions, sperm from sneakers swam faster than sperm from males adopting the other reproductive tactics, whereas sperm from pirates was slowest. Interestingly, we were unable to detect any variation in sperm tail length among these reproductive tactics. Thus, sperm competition appears to have influenced sperm energetics in this species without having any influence on sperm size.

Conjugal disharmony: a hitherto unrecognised cause of strokes.

Two women of reproductive age suffered strokes. Neither was taking oral contraceptives, and investigations showed no other causal factors. The radiological findings were characteristic of traumatic internal carotid artery occlusion, but neither patient gave a history of trauma. Only after further inquiry into the patients' social circumstances did it emerge that each had survived an attempt at strangulation by her husband. Such a cause of stroke in young women should be considered when other causes of carotid artery occlusion cannot be identified.

Methods of assessment of antiepileptic drugs.

Epilepsy is a symptom with protean manifestations and as such it is a difficult disease in which to carry out a therapeutic trial. The methods available to research workers for the assessment of new antiepileptic drugs are hampered by the fact that epilepsy is a fluctuant condition. Although it is a chronic disorder open to study using cross-over trials and within-patient comparisons, accurate assessment cannot be easily made at any one point in time. Research workers are therefore automatically placed at a time factor disadvantage and this is especially so for those searching for quick methods of evaluating new compounds. The need for a quick and reliable method of assessing a new antiepileptic drug has long been appreciated. This article will discuss the methods currently available and we will begin by considering the most commonly used method of assessment with particular reference to some of the problems involved in conducting a controlled clinical trial in epilepsy.

Acute effects of intravenous phenytoin on the frequency of inter-ictal spikes in man.

Phenytoin was administered intravenously to six adult epileptic patients in doses ranging from 500--1000 mg (equivalent to 5.6 mg/kg--20 mg/kg body weight). A significant decrease in the frequency of inter-ictal spikes in the EEG was seen and this effect was most marked 10--20 min after the infusion, when the mean spike count was reduced to 27% (s.d. 17%) of the control (P less than 0.05). In one subject the decrease in inter-ictal spikes coincided with a decrease in fit frequency. Adverse reactions affecting the vestibular system occurred in three patients at doses of 15--20 mg/kg. No cardiovascular complications were observed in any subject. The overall results suggest that doses of 7.5--10 mg/kg would be sufficient to significantly reduce the frequency of inter-ictal spikes in the EEG.

A double-blind controlled trial of high dose methylprednisolone in patients with multiple sclerosis: 1. Clinical effects.

A randomised double-blind, placebo-controlled trial of high-dose, pulsed intravenous methylprednisolone was carried out in 50 individuals with multiple sclerosis; 22 patients were in acute relapse and 28 had chronic progressive disease. After a baseline assessment using the Kurtzke functional and expanded disability status scales each patient was randomly allocated to intravenous treatment with methylprednisolone (500 mg) or a saline placebo administered as a single daily dose for 5 days. Clinical assessments were repeated at 1 and 4 weeks after starting treatment. The results from all 50 patients showed a highly significant effect in favour of methylprednisolone treatment (p less than 0.001). In patients with relapse, there was a significant decrease in clinical disability scores at 1 and 4 weeks in the methylprednisolone treated group compared with controls (p less than 0.05 for each comparison). In the chronic progressive group, disability scores at 4 weeks only were significantly lower after treatment with methylprednisolone (p less than 0.01), mainly attributable to improvement in pyramidal function.

A placebo-controlled trial of isoprinosine in patients with multiple sclerosis.

Isoprinosine was used under double-blind, randomised, and placebo-controlled conditions in 52 patients with relapsing/remitting or progressive multiple sclerosis. All patients received pulsed treatment with methylprednisolone. There was no significant effect of treatment on clinical disability or the accumulation of MRI abnormalities, after correction of results for multiple comparisons. It is concluded that isoprinosine is not effective therapy for multiple sclerosis.

Rectal diazepam in the treatment of absence status: a pharmacodynamic study.

Rectal administration of diazepam is highly effective in terminating absence status as judged by reduction of spike-wave activity in the EEG. Pharmacokinetic studies indicate that diazepam can have antiepileptic properties at serum levels well below those previously reported as being necessary to achieve a therapeutic effect.

Absorption of diazepam from the rectum and its effect on interictal spikes in the EEG.

Rectal administration of several different preparations of diazepam to a group of adult volunteer patients with epilepsy produced variable rates of absorption. Peak serum concentrations following 10 mg, 20 mg, and 30 mg of diazepam solution were achieved between 13-60 min, 10-120 min, and 30-90 min respectively. An experimental diazepam "solid solution" suppository was found to have significantly better absorption characteristics compared with the commercially available Valium suppository. Diazepam solution 20 mg was administered rectally in 10 adult epileptic patients with frequent spontaneous interictal spikes in their EEGs. A highly significant reduction in spike frequency was seen compared with placebo. The effect was most marked 10-20 min after administration of diazepam, when the mean spike count fell to 39 +/- 35 SD percent of the control value (p less than 0.01), and this corresponded with a mean serum diazepam level of 210 +2- 125 ng/ml.

Acute cervical cord injuries in patients with epilepsy.

Seven cases with acute cervical cord lesions associated with a fit and fall, were found in approximately 500 patients with epilepsy over a period of 7 years. In all patients the epilepsy was refractory to drug therapy and six suffered tonic fits which resulted in falls and frequent head injuries. Notable radiological changes were found in the cervical spine; there was ankylosis in five, hyperostosis in four and the minimum sagittal diameter of the bony canal was less than 11mm in three cases. The findings indicate that repetitive trauma may be a factor in producing bony changes in the cervical spine which put the patient at risk of cervical cord injury, especially when the spinal canal is developmentally narrow.

A clinical trial of single dose rectal and oral administration of diazepam for the prevention of serial seizures in adult epileptic patients.

The clinical anticonvulsant efficacy of single dose rectal and oral administration of diazepam 20 mg was examined in two double-blind placebo-controlled trials in adult epileptic patients. All subjects suffered from drug resistant epilepsy and frequently experienced serial seizures. Diazepam was administered rectally as a new experimental suppository formulation immediately after a seizure and was highly effective in preventing recurrent fits within a 24 h observation period (p less than 0.001). Pharmacokinetic studies revealed a wide range of serum diazepam concentrations 60 min after administration of the suppository (mean serum diazepam level 190 +/- 73 (SD ng/ml). In a similar study oral administration of diazepam 20 mg significantly reduced the incidence of serial seizures compared with a placebo (p less than 0.01) and the mean 60 min serum diazepam level was 273 +/- 190 (SD) ng/ml.