Obstetrical aspects in congenital ichtyosis

We present a case of congenital ichthyosis because obstetrical literature is scarce and most obstetricians could need a reminder and update. Congenital ichthyosis (CI) comprises a variety of skin disorders characterised by abnormal keratinization of the epidermis, which are mostly transmitted in an autosomal recessive manner. This condition is rare (seven per million people) with various clinical neonatal expressions and diversified prognosis, from self-healing to lethal. Even less severe phenotypes have significant associated morbidity and mortality. CI babies are often born prematurely and are at highest risk for complications during the postnatal period .CI, while fairly rare, is a condition well described in the literature, mainly from the neonatal point of view. We describe a case in which congenital ichthyosis was diagnosed after birth, and summarise the present literature with particular attention on obstetric implications as the prenatal diagnosis, genetic and ultrasound testing, perinatal complications and care for future pregnancies

Can the cerebroplacental ratio (CPR) predict intrapartum fetal compromise? : a prospective observational study

Objective: To investigate the potential clinical use of serial fetal CPR measurements during the last month of pregnancy for the prediction of adverse perinatal outcome in unselected low-risk pregnancies. Methods: A multicenter prospective observational cohort study in 315 consecutively recruited low-risk pregnancies. All eligible pregnancies underwent serial sonographic evaluation of fetal weight and Doppler indices at two week intervals, from 36 weeks gestation until delivery. Data were converted into centiles correcting for gestational age. These data were not available for the obstetrical team and hence, could not influence management decisions. Primary outcomes were operative delivery for presumed fetal compromise and a composite neonatal outcome (arterial cord Ph 90th centile). Results: Three hundred fifteen women were recruited in this study. We ecxluded 32 pregnancies because of small for gestational age babies (SGA), leaving 293 women and 583 CPR values for data-analysis. There were 85 (27%) adverse neonatal outcomes and 29 patients (9%) underwent operative delivery for presumed fetal compromise. Both primary and secondary outcomes were not significant different between the different CPR groups. Furthermore, we examined if individual serial CPR measurements could predict adverse outcome and found no linear correlation between repeated measurements of CPR and adverse outcomes. Conclusion: Our study shows that routine serial screening by CPR measurements provides poor prediction for adverse perinatal outcome in uncomplicated pregnancies

Large-scale surgical workflow segmentation for laparoscopic sacrocolpopexy

Purpose: Laparoscopic sacrocolpopexy is the gold standard procedure for the management of vaginal vault prolapse. Studying surgical skills and different approaches to this procedure requires an analysis at the level of each of its individual phases, thus motivating investigation of automated surgical workflow for expediting this research. Phase durations in this procedure are significantly larger and more variable than commonly available benchmarks such as Cholec80, and we assess these differences. / Methodology: We introduce sequence-to-sequence (seq2seq) models for coarse-level phase segmentation in order to deal with highly variable phase durations in Sacrocolpopexy. Multiple architectures (LSTM and transformer), configurations (time-shifted, time-synchronous), and training strategies are tested with this novel framework to explore its flexibility. / Results: We perform 7-fold cross-validation on a dataset with 14 complete videos of sacrocolpopexy. We perform both a frame-based (accuracy, F1-score) and an event-based (Ward metric) evaluation of our algorithms and show that different architectures present a trade-off between higher number of accurate frames (LSTM, Mode average) or more consistent ordering of phase transitions (Transformer). We compare the implementations on the widely used Cholec80 dataset and verify that relative performances are different to those in Sacrocolpopexy. / Conclusions: We show that workflow segmentation of Sacrocolpopexy videos has specific challenges that are different to the widely used benchmark Cholec80 and require dedicated approaches to deal with the significantly larger phase durations. We demonstrate the feasibility of seq2seq models in Sacrocolpopexy, a broad framework that can be further explored with new configurations. We show that an event-based evaluation metric is useful to evaluate workflow segmentation algorithms and provides complementary insight to the more commonly used metrics such as accuracy or F1-score

High-Fidelity Low-Cost Synthetic Training Model for Fetoscopic Spina Bifida Repair

BACKGROUND: Fetoscopic Spina Bifida repair (fSB-repair) is increasingly being practiced, but limited skill acquisition poses a barrier to widespread adoption. Extensive training in relevant models, including both ex- and in-vivo models may help. To address this, a synthetic training model that is affordable, realistic and allows skill analysis would be useful.OBJECTIVE: To create a high-fidelity model for training the essential neurosurgical steps of fetoscopic spina bifida repair using synthetic materials. Additionally, we aimed to obtain a cheap and easily reproducible model.STUDY DESIGN: We developed a three-layered silicon-based model resembling the anatomical layers of a typical myelomeningocele lesion. It allows for filling the cyst with fluid and conducting a water tightness test post-repair. A compliant silicon ball mimics the uterine cavity, and is fixed to a solid 3D printed base. The fetal back with the lesion (single-use) is placed inside the uterine ball, which is reusable and repairable to allow practicing port insertion and fixation multiple times. Following cannula insertion, the uterus is insufflated, and clinical fetoscopic, robotic or prototype instruments can be used. Three skilled endoscopic surgeons each did six simulated fetoscopic repairs following the surgical steps of an open repair. The primary outcome was surgical success, based on water tightness of the repair, operation time &lt;180 minutes and an Objective-Structured-Assessment-of-Technical-Skills (OSATS)-score of ≥ 18/25. Skill retention was measured using a competence commulative sum (C-CUSUM) analysis on composite binary outcome for surgical success. Secondary outcomes were cost and fabrication time of the model.RESULTS: We made a model for simulating spina bifida repair neurosurgical steps with anatomical details, port insertion, placode release and descent, undermining of skin and muscular layer, and endoscopic suturing. The model is made with reusable 3D-printed molds with easily accessible materials. The one-time startup cost was 211€, and each single-use simulated MMC-lesion costs 9.5€ in materials and 50 min working hours. Two skilled endoscopic surgeons performed six simulated three-port fetoscopic repairs, while a third used a Da-Vinci surgical robot. Operation times decreased over 30% from the first to last trial. Six experiments per surgeon did not show an obvious OSATS-score improvement. C-CUSUM analysis confirmed competency for each surgeon.CONCLUSION: This high-fidelity low-cost spina bifida model allows simulated dissection and closure of a myelomeningocele lesion.</p

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

The SANAD II study of the effectiveness and cost-effectiveness of levetiracetam, zonisamide, or lamotrigine for newly diagnosed focal epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial

Background: Levetiracetam and zonisamide are licensed as monotherapy for patients with focal epilepsy, but there is uncertainty as to whether they should be recommended as first-line treatments because of insufficient evidence of clinical effectiveness and cost-effectiveness. We aimed to assess the long-term clinical effectiveness and cost-effectiveness of levetiracetam and zonisamide compared with lamotrigine in people with newly diagnosed focal epilepsy. Methods: This randomised, open-label, controlled trial compared levetiracetam and zonisamide with lamotrigine as first-line treatment for patients with newly diagnosed focal epilepsy. Adult and paediatric neurology services across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked focal seizures. Participants were randomly allocated (1:1:1) using a minimisation programme with a random element utilising factor to receive lamotrigine, levetiracetam, or zonisamide. Participants and investigators were not masked and were aware of treatment allocation. SANAD II was designed to assess non-inferiority of both levetiracetam and zonisamide to lamotrigine for the primary outcome of time to 12-month remission. Anti-seizure medications were taken orally and for participants aged 12 years or older the initial advised maintenance doses were lamotrigine 50 mg (morning) and 100 mg (evening), levetiracetam 500 mg twice per day, and zonisamide 100 mg twice per day. For children aged between 5 and 12 years the initial daily maintenance doses advised were lamotrigine 1·5 mg/kg twice per day, levetiracetam 20 mg/kg twice per day, and zonisamide 2·5 mg/kg twice per day. All participants were included in the intention-to-treat (ITT) analysis. The per-protocol (PP) analysis excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analysis included all participants who received one dose of any study drug. The non-inferiority limit was a hazard ratio (HR) of 1·329, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on lamotrigine. The trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64). Findings: 990 participants were recruited between May 2, 2013, and June 20, 2017, and followed up for a further 2 years. Patients were randomly assigned to receive lamotrigine (n=330), levetiracetam (n=332), or zonisamide (n=328). The ITT analysis included all participants and the PP analysis included 324 participants randomly assigned to lamotrigine, 320 participants randomly assigned to levetiracetam, and 315 participants randomly assigned to zonisamide. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission versus lamotrigine (HR 1·18; 97·5% CI 0·95–1·47) but zonisamide did meet the criteria for non-inferiority in the ITT analysis versus lamotrigine (1·03; 0·83–1·28). The PP analysis showed that 12-month remission was superior with lamotrigine than both levetiracetam (HR 1·32 [97·5% CI 1·05 to 1·66]) and zonisamide (HR 1·37 [1·08–1·73]). There were 37 deaths during the trial. Adverse reactions were reported by 108 (33%) participants who started lamotrigine, 144 (44%) participants who started levetiracetam, and 146 (45%) participants who started zonisamide. Lamotrigine was superior in the cost-utility analysis, with a higher net health benefit of 1·403 QALYs (97·5% central range 1·319–1·458) compared with 1·222 (1·110–1·283) for levetiracetam and 1·232 (1·112, 1·307) for zonisamide at a cost-effectiveness threshold of £20 000 per QALY. Cost-effectiveness was based on differences between treatment groups in costs and QALYs. Interpretation: These findings do not support the use of levetiracetam or zonisamide as first-line treatments for patients with focal epilepsy. Lamotrigine should remain a first-line treatment for patients with focal epilepsy and should be the standard treatment in future trials. Funding: National Institute for Health Research Health Technology Assessment programme

The SANAD II study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial

Background: Valproate is a first-line treatment for patients with newly diagnosed idiopathic generalised or difficult to classify epilepsy, but not for women of child-bearing potential because of teratogenicity. Levetiracetam is increasingly prescribed for these patient populations despite scarcity of evidence of clinical effectiveness or cost-effectiveness. We aimed to compare the long-term clinical effectiveness and cost-effectiveness of levetiracetam compared with valproate in participants with newly diagnosed generalised or unclassifiable epilepsy. Methods: We did an open-label, randomised controlled trial to compare levetiracetam with valproate as first-line treatment for patients with generalised or unclassified epilepsy. Adult and paediatric neurology services (69 centres overall) across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked generalised or unclassifiable seizures. Participants were randomly allocated (1:1) to receive either levetiracetam or valproate, using a minimisation programme with a random element utilising factors. Participants and investigators were aware of treatment allocation. For participants aged 12 years or older, the initial advised maintenance doses were 500 mg twice per day for levetiracetam and valproate, and for children aged 5–12 years, the initial daily maintenance doses advised were 25 mg/kg for valproate and 40 mg/kg for levetiracetam. All drugs were administered orally. SANAD II was designed to assess the non-inferiority of levetiracetam compared with valproate for the primary outcome time to 12-month remission. The non-inferiority limit was a hazard ratio (HR) of 1·314, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on valproate. All participants were included in the intention-to-treat (ITT) analysis. Per-protocol (PP) analyses excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analyses included all participants who received one dose of any study drug. This trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64). Findings: 520 participants were recruited between April 30, 2013, and Aug 2, 2016, and followed up for a further 2 years. 260 participants were randomly allocated to receive levetiracetam and 260 participants to receive valproate. The ITT analysis included all participants and the PP analysis included 255 participants randomly allocated to valproate and 254 randomly allocated to levetiracetam. Median age of participants was 13·9 years (range 5·0–94·4), 65% were male and 35% were female, 397 participants had generalised epilepsy, and 123 unclassified epilepsy. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission (HR 1·19 [95% CI 0·96–1·47]); non-inferiority margin 1·314. The PP analysis showed that the 12-month remission was superior with valproate than with levetiracetam. There were two deaths, one in each group, that were unrelated to trial treatments. Adverse reactions were reported by 96 (37%) participants randomly assigned to valproate and 107 (42%) participants randomly assigned to levetiracetam. Levetiracetam was dominated by valproate in the cost-utility analysis, with a negative incremental net health benefit of −0·040 (95% central range −0·175 to 0·037) and a probability of 0·17 of being cost-effectiveness at a threshold of £20 000 per quality-adjusted life-year. Cost-effectiveness was based on differences between treatment groups in costs and quality-adjusted life-years. Interpretation: Compared with valproate, levetiracetam was found to be neither clinically effective nor cost-effective. For girls and women of child-bearing potential, these results inform discussions about benefit and harm of avoiding valproate. Funding: National Institute for Health Research Health Technology Assessment Programme

Exponential growth, high prevalence of SARS-CoV-2, and vaccine effectiveness associated with the Delta variant

SARS-CoV-2 infections were rising during early summer 2021 in many countries associated with the Delta variant. We assessed RT-PCR swab-positivity in the REal-time Assessment of Community Transmission-1 (REACT-1) study in England. We observed sustained exponential growth with average doubling time (June-July 2021) of 25 days driven by complete replacement of Alpha variant by Delta, and by high prevalence at younger less-vaccinated ages. Unvaccinated people were three times more likely than double-vaccinated people to test positive. However, after adjusting for age and other variables, vaccine effectiveness for double-vaccinated people was estimated at between ~50% and ~60% during this period in England. Increased social mixing in the presence of Delta had the potential to generate sustained growth in infections, even at high levels of vaccination

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant