Management of late-onset fetal growth restriction: pragmatic approach

OBJECTIVES: International guidelines recommend delivery from 37 weeks in small for gestational age (SGA) fetuses mostly because of stillbirth concerns. Differentiating SGA from late-onset fetal growth restriction (FGR) is challenged by the limited prospective evidence to guide management. We prospectively assessed a novel protocol that used ultrasound criteria to classify women with suspected late FGR into two groups: low-risk with expectant management until the expected date of delivery and high-risk with delivery soon after 37 weeks. Furthermore, we compared the outcome of this prospective cohort with a historical cohort of women similarly presenting with suspected late FGR, to evaluate the impact of implementation of the new protocol. METHODS: This was a prospective study in women with a singleton non-anomalous fetus at ≥32 weeks with any of the following inclusion criteria: estimated fetal weight (EFW) ≤10th centile, ≥50 centiles decrease of the abdominal circumference (AC) from previous scans, umbilical artery Doppler pulsatility index >95th centile or cerebroplacental ratio <5th centile. Women were stratified into low- or high-risk late FGR. Women in the low-risk group were delivered by 41 weeks unless meeting high-risk criteria for delivery later on, whereas women in the high-risk group (PAPP-A <0.4MoM, EFW <3rd centile, or EFW ≥3rd and ≤10th centile with AC drop or abnormal Dopplers) were delivered at 37 weeks. The primary outcome was adverse neonatal outcome including hypothermia, hypoglycemia, neonatal unit admission, jaundice requiring treatment, suspected infection, feeding difficulties, Apgar score <7 at 1 minute, hospital readmission and any of the severe adverse neonatal outcome (perinatal death, resuscitation using inotropes or mechanical ventilation, Apgar score <7 at 5 minutes, metabolic acidosis, sepsis, cerebral, cardiac or respiratory morbidity). Secondary outcomes were adverse maternal outcome (operative delivery for abnormal fetal heart rate) and severe adverse neonatal outcome. Women managed according with the new protocol were compared with a historical cohort where management was guided by individual clinician's expertise. RESULTS: Over 18 months (2018-2019), 321 women were included. Adverse neonatal outcome was significantly less common in low- (n=156) compared with high-risk fetus (n=165): 45 vs 57%; aOR, 0.6; 95% CI, 0.4-0.9; P=0.022. There was no significant difference in adverse maternal outcome (18% vs 24%; aOR, 0.7; 95% CI, 0.4-1.2; P=0.142) and severe adverse neonatal outcome (3.8% vs 8.5%; aOR: 0.5; 95% CI, 0.2-1.3; P=0.153) between low and high-risk group. Compared to women delivered prior to the implementation of the new protocol and classified retrospectively into low- and high-risk late FGR (n=323), there was a lower adverse neonatal outcome (45% vs 58%; aOR, 0.6; 95% CI, 0.4-0.9; P=0.026) in the low-risk late FGR clinic group. CONCLUSIONS: Appropriate risk classification to define management in low- and high-risk FGR groups was associated with reduced adverse neonatal outcome in the low-risk group. In clinical practice a policy of expectantly managing women with late-onset low-risk FGR pregnancies at term could improve neonatal and long-term development. Randomized controlled trials are needed to assess the effect of an evidence based conservative management protocol of late FGR on perinatal morbidity, mortality and long-term neurodevelopment

A multimodal iPSC platform for cystic fibrosis drug testing

Cystic fibrosis is a monogenic lung disease caused by dysfunction of the cystic fibrosis transmembrane conductance regulator anion channel, resulting in significant morbidity and mortality. The progress in elucidating the role of CFTR using established animal and cell-based models led to the recent discovery of effective modulators for most individuals with CF. However, a subset of individuals with CF do not respond to these modulators and there is an urgent need to develop novel therapeutic strategies. In this study, we generate a panel of airway epithelial cells using induced pluripotent stem cells from individuals with common or rare CFTR variants representative of three distinct classes of CFTR dysfunction. To measure CFTR function we adapt two established in vitro assays for use in induced pluripotent stem cell-derived airway cells. In both a 3-D spheroid assay using forskolin-induced swelling as well as planar cultures composed of polarized mucociliary airway epithelial cells, we detect genotype-specific differences in CFTR baseline function and response to CFTR modulators. These results demonstrate the potential of the human induced pluripotent stem cell platform as a research tool to study CF and in particular accelerate therapeutic development for CF caused by rare variants

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Combinations of strobilurin fungicides and acibenzolar (Bion) to reduce scab on passionfruit caused by Cladosporium oxysporum

Field applications of the strobilurin group of fungicides were shown to provide effective control of fruit scab and alternata spot of passionfruit cv. Supersweet 1. An anti-resistance program incorporating industry standard fungicides (copper oxychloride, mancozeb, iprodione), azoxystrobin and acibenzolar resulted in the most improved level of control, and significantly reduced the severity and incidence of scab by approximately 30% and 80%, respectively, compared with the industry standard fungicides. Tank-mixing acibenzolar with azoxystrobin or the industry standard fungicides, significantly improved scab but not control of alternata spot disease. In growth cabinet studies, acibenzolar was also shown to provide significant protection of seedling plants when applied on the same day or 4 days prior to challenge inoculation with the scab pathogen, Cladosporium oxysporum. This protection was shown to last at least 25 days

Thigh-length compression stockings and DVT after stroke

Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease

A double-blind randomized controlled trial of olanzapine plus sertraline vs olanzapine plus placebo for psychotic depression: The study of pharmacotherapy of psychotic depression (STOP-PD)

© 2009 American Medical Association. All rights reserved. Context: Evidence for the efficacy of combination pharmacotherapy has been limited and without positive trials in geriatric patients with major depression (MD) with psychotic features. Objectives: To compare remission rates ofMDwith psychotic features in those treated with a combination of atypical antipsychotic medication plus a serotonin reuptake inhibitorwith those treated with antipsychotic monotherapy; and to compare response by age. Design: Twelve-week, double-blind, randomized, controlled trial. Setting: Clinical services of 4 academic sites. Patients: Two hundred fifty-nine subjects withMDwith psychotic features randomized by age (\u3c60 or ≥60 years) (mean [standard deviation (SD)], 41.3 [10.8] years in 117 younger adults vs 71.7 [7.8] years in 142 geriatric participants). Intervention: Target doses of 15 to 20 mg of olanzapine per day plus masked sertraline or placebo at 150 to 200 mg per day. Main Outcome Measure: Remission rates of MD with psychotic features. Results: Treatment with olanzapine/sertraline was associated with higher remission rates during the trial than olanzapine/placebo (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.12-1.47; P\u3c.001); 41.9% of subjects who underwent combination therapy were in remission at their last assessment compared with 23.9% of subjects treated with monotherapy (χ21=9.53, P=.002). Combination therapy was comparably superior in both younger (OR, 1.25; 95% CI, 1.05-1.50; P=.02) and older (OR, 1.34; 95% CI, 1.09-1.66; P=.01) adults. Overall, tolerability was comparable across age groups. Both age groups had significant increases in cholesterol and triglyceride concentrations, but statistically significant increases in glucose occurred only in younger adults. Younger adults gained significantly more weight than older subjects (mean [SD], 6.5 [6.6] kg vs 3.3 [4.9] kg, P=.001). Conclusions: Combination pharmacotherapy is efficacious for the treatment of MD with psychotic features. Future research must determine the benefits vs risks of continuing atypical antipsychotic medications beyond 12 weeks