Analysis and mitigation of an oscillating background on hybrid complementary metal-oxide semiconductor (hCMOS) imaging sensors at the National Ignition Facility.

Nanosecond-gated hybrid complementary metal-oxide semiconductor imaging sensors are a powerful tool for temporally gated and spatially resolved measurements in high energy density science, including inertial confinement fusion, and in laser diagnostics. However, a significant oscillating background excited by photocurrent has been observed in image sequences during testing and in experiments at the National Ignition Facility (NIF). Characterization measurements and simulation results are used to explain the oscillations as the convolution of the pixel-level sensor response with a sensor-wide RLC circuit ringing. Data correction techniques are discussed for NIF diagnostics, and for diagnostics where these techniques cannot be used, a proof-of-principle image correction algorithm is presented.

Effectiveness of dinoprostone gel, misoprostol vaginal insert and dinoprostone vaginal insert for induction of labour in twin pregnancies.

OBJECTIVES: To compare the effectiveness and safety of Dinoprostone Gel (DG), Misoprostol Vaginal Insert (MVI) and Dinoprostone Vaginal Insert (DVI) for induction of labour (IOL) in twin pregnancies. STUDY DESIGN: Retrospective cohort study of twin pregnancies > 34 + 0 weeks gestation that underwent induction of labour (IOL) with DG, MVI or DVI between December 2016 and November 2019 in a Tertiary NHS hospital, North West England, UK. Delivery characteristics, maternal complications and neonatal outcomes were compared between the three groups. RESULTS: A total of 87 twin pregnancies were included for analysis. 27 women received DG, 34 received MVI and 26 DVI. The MVI cohort had a higher proportion of nulliparous women (55.9%) compared to the DG and DVI cohorts, 29.6% and 38.5% respectively. No other differences amongst demographic characteristics were considered clinically significant. DG demonstrated a significantly quicker time to delivery (minutes) compared to DVI (1021 ± 556 versus 1649 ± 852; P = 0.0026). Significantly fewer women required terbutaline for hyperstimulation/tachysystole in the DG group compared to MVI (0% vs 32%; RR 0.05; 95% CI 0.003-0.88). Both DG and MVI groups required significantly less oxytocin following artificial rupture of membranes compared to DVI (33% vs 65%; RR 0.51; 95% CI 0.28-0.93) and (29% vs 65%; RR 0.45; 95% CI 0.25-0.81). There were no significant differences in mode of delivery, maternal complications and neonatal outcomes. CONCLUSION: Our data suggests that for women with a twin pregnancy considering a planned labour that induction with DG, MVI and DVI appear to be equally safe and effective IOL methods. These results should be interpreted with caution due to the study being underpowered to detect significant adverse outcomes. In order to determine the optimal method of IOL in twins, direct randomised comparison is needed.

Comparison of international guidelines on the management of twin pregnancy.

OBJECTIVES: To review current international clinical guidelines on the antenatal and intrapartum management of twin pregnancies, examining areas of consensus and conflict. METHODS: We conducted a database search using Medline, Pubmed, Scopus, Academic Search Complete, CINAHL and ERCI Guidelines website. Guidelines were screened for eligibility using our inclusion and exclusion criteria. Those deemed eligible were quality assessed using the AGREE II tool and relevant data was extracted. RESULTS: We identified 21 relevant guidelines from 16 countries including two international society guidelines. There was consensus in determination of chorionicity and amnionicity within the first trimester, fetal anomaly scan between 18 and 22 weeks and the recommended screening for twin-to-twin transfusion syndrome (TTTS). For those that provided intrapartum guidance, there was agreement in recommending caesarean section to deliver monochorionic monoamniotic (MCMA) twins, epidural anaesthesia for intrapartum analgesia and the use of cardiotocography (CTG) for intrapartum fetal monitoring. The main areas of conflict included cervical length screening, frequency of ultrasound surveillance, timing of delivery of dichorionic twin pregnancies and circumstances for recommending vaginal delivery. There was a lack of advice on intrapartum management. CONCLUSIONS: This review has highlighted the need for unified international guidance on the management of twin pregnancy. Comparisons of current guidance demonstrates a lack of confidence in the management of labour in twin pregnancies. Further evidence on intrapartum care of twin pregnancies is needed to inform practice guidelines and improve both short and long term maternal and fetal outcomes.

Distribution of inadvertently excised parathyroid glands during thyroid surgery and the link with post-surgical hypoparathyroidism.

OBJECTIVES: To evaluate the incidence of inadvertent parathyroidectomy, identify risk factors, determine the location of inadvertently excised glands, review pathology reporting in inadvertent parathyroidectomy, and explore relationships between inadvertent parathyroidectomy and post-surgical hypoparathyroidism or hypocalcaemia. METHODS: A retrospective cohort study of 899 thyroidectomies between 2015 and 2020 was performed. Histopathology slides of patients who had an inadvertent parathyroidectomy and a random sample of patients without a reported inadvertent parathyroidectomy were reviewed. RESULTS: Inadvertent parathyroidectomy occurred in 18.5 per cent of thyroidectomy patients. Central neck dissection was an independent risk factor (inadvertent parathyroidectomy = 49.4 per cent with central neck dissection, 12.0 per cent without central neck dissection, p < 0.001). Most excised parathyroid glands were extracapsular (53.3 per cent), followed by subcapsular (29.1 per cent) and intrathyroidal (10.9 per cent). Parathyroid tissue was found in 10.2 per cent of specimens where no inadvertent parathyroidectomy was reported. Inadvertent parathyroidectomy was associated with a higher incidence of six-month post-surgical hypoparathyroidism or hypocalcaemia (19.8 per cent who had an inadvertent parathyroidectomy, 7.7 per cent without inadvertent parathyroidectomy). CONCLUSION: Inadvertent parathyroidectomy increases the risk of post-surgical hypoparathyroidism or hypocalcaemia. The proportion of extracapsular glands contributing to inadvertent parathyroidectomy highlights the need for preventative measures.

Hospital and community care costs for people newly diagnosed of living with HIV in London, UK.

This study of people newly diagnosed of living with HIV (ND-PLHIV) calculated the use, cost and outcome of HIV services at a London HIV centre. ND-PLHIV were followed July 2017-October 2018. Hospital data included inpatient days (IP), outpatient (OP), dayward (DW) visits, tests and procedures, and anti-retroviral drugs (ARVs). Community services were recorded in daily diaries. Mean per patient-year (MPPY) use was multiplied by unit costs. 13.6 MPPY (95%CI 12.4-14.9) OP visits, 0.4 MPPY (95%CI 0.1-0.7) IP days, 0.09 MPPY (95%CI 0.01-0.2) DW visits and 4.6 MPPY community services (95%CI 3.4-5.8). Total annual costs per patient-year (CPPY) was £11,483 (95%CI £10,369-12,597): ARVs comprised 63% and community services 2%. White participants used fewer hospital and more community services compared with minority ethnic community (MEC) participants. Costs for White ND-PLHIV was £10,778 CPPY (95%CI £9629-11,928); £13,214 (95%CI £10,656-15,772) for MEC ND-PLHIV (p < 0.06). Annual costs were inversely related to CD4 count at entry (r = -5.58, p = 0.02); mean CD4 count was 476 cells/mm3 (95%CI 422-531) versus 373 cells/mm3 (95%CI 320-425) for White and MEC participants respectively (p = 0.03). Annual costs for ND-PLHIV with CD4 ≤ 350 cells/mm3 was £2478 PPY higher compared with CD4 count >350 cells/mm3 (p = 0.04).

The frequency-following response to assess the neural representation of spectral speech cues in older adults.

Older adults often present difficulties understanding speech that cannot be explained by age-related changes in sound audibility. Psychoacoustic and electrophysiologic studies have linked these suprathreshold difficulties to age-related deficits in the auditory processing of temporal and spectral sound information. These studies suggest the existence of an age-related temporal processing deficit in the central auditory system, but the existence of such deficit in the spectral domain remains understudied. The FFR is an electrophysiological evoked response that assesses the ability of the neural auditory system to reproduce the spectral and temporal patterns of a sound. The main goal of this short review is to investigate if the FFR can identify and measure spectral processing deficits in the elderly compared to younger adults (for both, without hearing loss or competing noise). Furthermore, we want to determine what stimuli and analyses have been used in the literature to assess the neural encoding of spectral cues in older adults. Almost all reviewed articles showed an age-related decline in the auditory processing of spectral acoustic information. Even when using different speech and non-speech stimuli, studies reported an age-related decline at the fundamental frequency, at the first formant, and at other harmonic components using different metrics, such as the response's amplitude, inter-trial phase coherence, signal-to-response correlation, and signal-to-noise ratio. These results suggest that older adults may present age-related spectral processing difficulties, but further FFR studies are needed to clarify the effect of advancing age on the neural encoding of spectral speech cues. Spectral processing research on aging would benefit from using a broader variety of stimuli and from rigorously controlling for hearing thresholds even in the absence of disabling hearing loss. Advances in the understanding of the effect of age on FFR measures of spectral encoding could lead to the development of new clinical tools, with possible applications in the field of hearing aid fitting.

Vaginal bacterial load in the second trimester is associated with early preterm birth recurrence: a nested case-control study.

OBJECTIVE: To assess the association between vaginal microbiome (VMB) composition and recurrent early spontaneous preterm birth (sPTB)/preterm prelabour rupture of membranes (PPROM). DESIGN: Nested case-control study. SETTING: UK tertiary referral hospital. SAMPLE: High-risk women with previous sPTB/PPROM <34+0 weeks' gestation who had a recurrence (n = 22) or delivered at ≥37+0 weeks without PPROM (n = 87). METHODS: Vaginal swabs collected between 15 and 22 weeks' gestation were analysed by 16S rRNA gene sequencing and 16S quantitative PCR. MAIN OUTCOME MEASURE: Recurrent early sPTB/PPROM. RESULTS: Of the 109 high-risk women, 28 had anaerobic vaginal dysbiosis, with the remainder dominated by lactobacilli (Lactobacillus iners 36/109, Lactobacillus crispatus 23/109, or other 22/109). VMB type and diversity were not associated with recurrence. Women with a recurrence, compared to those without, had a higher median vaginal bacterial load (8.64 versus 7.89 log10 cells/mcl, adjusted odds ratio [aOR] 1.90, 95% CI 1.01-3.56, P = 0.047) and estimated Lactobacillus concentration (8.59 versus 7.48 log10 cells/mcl, aOR 2.35, (95% CI 1.20-4.61, P = 0.013). A higher recurrence risk was associated with higher median bacterial loads for each VMB type after stratification, although statistical significance was reached only for L. iners domination (aOR 3.44, 95% CI 1.06-11.15, P = 0.040). Women with anaerobic dysbiosis or L. iners domination had a higher median vaginal bacterial load than women with a VMB dominated by L. crispatus or other lactobacilli (8.54, 7.96, 7.63, and 7.53 log10 cells/mcl, respectively). CONCLUSIONS: Vaginal bacterial load is associated with early sPTB/PPROM recurrence. Domination by lactobacilli other than L. iners may protect women from developing high bacterial loads. Future PTB studies should quantify vaginal bacteria and yeasts. TWEETABLE ABSTRACT: Increased vaginal bacterial load in the second trimester may be associated with recurrent early spontaneous preterm birth.

The novel fungal CYP51 inhibitor VT-1598 displays classic dose-dependent antifungal activity in murine models of invasive aspergillosis.

Aspergillus spp. infections remain a global concern, with ∼30% attributable mortality of invasive aspergillosis (IA). VT-1598 is a novel fungal CYP51 inhibitor designed for exquisite selectivity versus human CYP enzymes to achieve a maximal therapeutic index and therefore maximal antifungal efficacy. Previously, its broad-spectrum in vitro antifungal activity was reported. We report here the pharmacokinetics (PK) and pharmacodynamics (PD) of VT-1598 in neutropenic mouse models of IA. The plasma area-under-the-curve (AUC) of VT-1598 increased nearly linearly between 5 and 40 mg/kg after 5 days of QD administration (155 and 1033 µg*h/ml, respectively), with a further increase with 40 mg/kg BID dosing (1354 µg*h/ml). When A. fumigatus isolates with in vitro susceptibilities of 0.25 and 1.0 µg/ml were used in a disseminated IA model, VT-1598 treatment produced no decrease in kidney fungal burden at QD 10 mg/kg, intermediate decreases at QD 20 mg/kg and maximum or near maximum decreases at 40 mg/kg QD and BID. The PK/PD relationships of AUCfree/MIC for 1-log killing for the two strains were 5.1 and 1.6 h, respectively, similar to values reported for approved CYP51 inhibitors. In a survival study where animals were observed for 12 days after the last treatment, survival was 100% at the doses tested (20 and 40 mg/kg QD), and fungal burden remained suppressed even though drug wash-out was complete. Similar dose-dependent reductions in lung fungal burden were observed in a pulmonary model of IA. These data strongly support further exploration of VT-1598 for the treatment of this lethal mold infection.

Treatment with abiraterone and enzalutamide does not overcome poor outcome from metastatic castration-resistant prostate cancer in men with the germline homozygous HSD3B1 c.1245C genotype.

BACKGROUND: In men with castration-sensitive prostate cancer (CSPC), the HSD3B1 c.1245A>C variant has been reported to be associated with shorter responses to first-line androgen-deprivation therapy (ADT). Here, we evaluated the association between the inherited HSD3B1 c.1245A>C variant and outcomes from metastatic castration-resistant prostate cancer (mCRPC) after first-line treatment with abiraterone (Abi) or enzalutamide (Enza). PATIENTS AND METHODS: Patients with mCRPC (n = 266) were enrolled from two centers at the time of starting first-line Abi/Enza. Outcomes after Abi/Enza included best prostate-specific antigen (PSA) response, treatment duration, and overall survival (OS). Outcomes after first-line ADT were determined retrospectively, and included treatment duration and OS. As was prespecified, we compared patients with the homozygous variant HSD3B1 genotype (CC genotype) versus the combined group with the heterozygous (AC) and homozygous wild-type (AA) genotypes. RESULTS: Among the 266 patients, 22 (8.3%) were homozygous for the HSD3B1 variant (CC). The CC genotype had no association with PSA response rate; the median Abi/Enza treatment duration was 7.1 months for the CC group and 10.3 months for the AA/AC group (log rank P = 0.34). Patients with the CC genotype had significantly worse OS, with median survival at 23.6 months for the CC group and 30.7 months for the AA/AC group (log rank P = 0.02). In multivariable analysis adjusting for age, Gleason score, PSA, prior chemotherapy, and M1 disease, the association between the CC genotype and OS remained significant (hazard ratio 1.78, 95% confidence interval 1.03-3.07, P = 0.04). Poor outcome after first-line ADT in the CC group was also observed when evaluating retrospective ADT duration data for the same combined cohort. CONCLUSIONS: In this large two-center study evaluating the HSD3B1 c.1245 genotype and outcomes after first-line Abi/Enza, homozygous variant (CC) HSD3B1 genotype was associated with worse outcomes. Novel therapeutic strategies are needed to enable treatment selection based on this genetic marker.

A phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 (capivasertib) in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: Activation of the PI3K/AKT/mTOR pathway through loss of phosphatase and tensin homolog (PTEN) occurs in approximately 50% of patients with metastatic castration-resistant prostate cancer (mCRPC). Recent evidence suggests that combined inhibition of the androgen receptor (AR) and AKT may be beneficial in mCRPC with PTEN loss. PATIENTS AND METHODS: mCRPC patients who previously failed abiraterone and/or enzalutamide, received escalating doses of AZD5363 (capivasertib) starting at 320 mg twice daily (b.i.d.) given 4 days on and 3 days off, in combination with enzalutamide 160 mg daily. The co-primary endpoints were safety/tolerability and determining the maximum tolerated dose and recommended phase II dose; pharmacokinetics, antitumour activity, and exploratory biomarker analysis were also evaluated. RESULTS: Sixteen patients were enrolled, 15 received study treatment and 13 were assessable for dose-limiting toxicities (DLTs). Patients were treated at 320, 400, and 480 mg b.i.d. dose levels of capivasertib. The recommended phase II dose identified for capivasertib was 400 mg b.i.d. with 1/6 patients experiencing a DLT (maculopapular rash) at this level. The most common grade ≥3 adverse events were hyperglycemia (26.7%) and rash (20%). Concomitant administration of enzalutamide significantly decreased plasma exposure of capivasertib, though this did not appear to impact pharmacodynamics. Three patients met the criteria for response (defined as prostate-specific antigen decline ≥50%, circulating tumour cell conversion, and/or radiological response). Responses were seen in patients with PTEN loss or activating mutations in AKT, low or absent AR-V7 expression, as well as those with an increase in phosphorylated extracellular signal-regulated kinase (pERK) in post-exposure samples. CONCLUSIONS: The combination of capivasertib and enzalutamide is tolerable and has antitumour activity, with all responding patients harbouring aberrations in the PI3K/AKT/mTOR pathway. CLINICAL TRIAL NUMBER: NCT02525068.

Effect of sildenafil on maternal hemodynamics in pregnancies complicated by severe early-onset fetal growth restriction: planned subgroup analysis from a multicenter randomized placebo-controlled double-blind trial.

OBJECTIVES: Fetal growth restriction (FGR) is associated with maternal cardiovascular changes. Sildenafil, a phosphodiesterase type-5 inhibitor, potentiates the actions of nitric oxide, and it has been suggested that it alters maternal hemodynamics, potentially improving placental perfusion. Recently, the Dutch STRIDER trial was stopped prematurely owing to excess neonatal mortality secondary to pulmonary hypertension. The main aim of this study was to investigate the effect of sildenafil on maternal hemodynamics in pregnancies with severe early-onset FGR. METHODS: This was a cardiovascular substudy within a UK multicenter, placebo-controlled trial, in which 135 women with a singleton pregnancy and severe early-onset FGR (defined as a combination of estimated fetal weight or abdominal circumference below the 10th centile and absent/reversed end-diastolic flow in the umbilical artery on Doppler velocimetry, diagnosed between 22 + 0 and 29 + 6 weeks' gestation) were assigned randomly to receive either 25 mg sildenafil three times daily or placebo until 32 + 0 weeks' gestation or delivery. Maternal blood pressure (BP), heart rate (HR), augmentation index, pulse wave velocity (PWV), cardiac output, stroke volume (SV) and total peripheral resistance were recorded before randomization, 1-2 h and 48-72 h post-randomization, and 24-48 h postnatally. For continuous data, analysis was performed using repeated measures ANOVA methods including terms for timepoint, treatment allocation and their interaction. RESULTS: Included were 134 women assigned randomly to sildenafil (n = 69) or placebo (n = 65) who had maternal BP and HR recorded at baseline. At 1-2 h post-randomization, compared with baseline values, sildenafil increased maternal HR by 4 bpm more than did placebo (mean difference, 5.00 bpm (95% CI, 1.00-12.00 bpm) vs 1.25 bpm (95% CI, -5.38 to 7.88 bpm); P = 0.004) and reduced systolic BP by 1 mmHg more (mean difference, -4.13 mmHg (95% CI, -9.94 to 1.44 mmHg) vs -2.75 mmHg (95% CI, -7.50 to 5.25 mmHg); P = 0.048). Even after adjusting for maternal mean arterial pressure, sildenafil reduced aortic PWV by 0.60 m/s more than did placebo (mean difference, -0.90 m/s (95% CI, -1.31 to -0.51 m/s) vs -0.26 m/s (95% CI, -0.75 to 0.59 m/s); P = 0.001). Sildenafil was associated with a non-significantly greater decrease in SV index after 1-2 h post-randomization than was placebo (mean difference, -5.50 mL/m2 (95% CI, -11.00 to -0.50 mL/m2 ) vs 0.00 mL/m2 (95% CI, -5.00 to 4.00 mL/m2 ); P = 0.056). CONCLUSIONS: Sildenafil in a dose of 25 mg three times daily increases HR, reduces BP and reduces arterial stiffness in pregnancies complicated by severe early-onset FGR. These changes are short term, modest and consistent with the anticipated vasodilatory effect. They have no short- or long-term clinical impact on the mother. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Effect of QUiPP prediction algorithm on treatment decisions in women with a previous preterm birth: a prospective cohort study.

OBJECTIVE: The QUiPP algorithm combines cervical length, quantitative fetal fibronectin (qfFN) and medical history to quantify risk of preterm birth. We assessed the utility of QUiPP to inform preterm birth prevention treatment decisions. DESIGN: A prospective cohort study with a subsequent impact assessment using the QUiPP risk of birth before 34 weeks' gestation. SETTING: A UK tertiary referral hospital. SAMPLE: In all, 119 women with previous spontaneous preterm birth (sPTB) or preterm premature rupture of membranes (PPROM) before 34 weeks' gestation. METHODS: Cervical length and qfFN were measured at 19+0 to 23+0  weeks' gestation. Clinical management was based on history and cervical length. After birth, clinicians were unblinded to qfFN results and QUiPP analysis was undertaken. MAIN OUTCOME MEASURES: Predictive statistics of QUiPP algorithm using 10% risk of sPTB before 34+0  weeks as treatment threshold. RESULTS: Fifteen of 119 women (13%) had PPROM or sPTB before 34 weeks. Of these, 53% (8/15) had QUiPP risk of sPTB before 34+0  weeks above 10%. Applying this treatment threshold in practice would have doubled our treatment rate (20 versus 42%). QUIPP threshold of 10% had positive likelihood ratio (LR) of 1.3 (95% CI 0.76-2.18), and negative LR of 0.8 (95% CI 0.45-1.40) for predicting sPTB before 34+0  weeks. CONCLUSIONS: Use of the QUiPP algorithm in this population may lead to substantial increase in interventions without evidence that currently available treatment options are beneficial for this particular group. TWEETABLE ABSTRACT: Independent study finds that the QUiPP algorithm could lead to substantial increases in treatment without evidence of benefit.

Misoprostol vaginal insert (Mysodelle) versus Dinoprostone intravaginal gel (Prostin) for induction of labour.

OBJECTIVE: The aim of this study is the compare the effectiveness and safety of Misoprostol Vaginal Insert (Mysodelle) versus Dinoprostone intravaginal gel (Prostin) for induction of labour. STUDY DESIGN: We performed a prospective cohort study of the use of misoprostol vaginal inserts (Mysodelle) in the induction of pregnancy and compared it to a historical cohort of women induced with the Dinoprostone intravaginal gel (Prostin) at the Liverpool Women's Hospital, a large UK teaching hospital. RESULTS: A total of 4102 women were induced between December 2016 and September 2018 of whom 2540 were induced with dinoprostone gel until September 2017. Since October 2017 1562 were induced using misoprostol vaginal inserts (MVI). The MVI demonstrated a significantly quicker median time to delivery compared with dinoprostone gel (18.2 h versus 21.8 h; p < 0.0001). There was a 32% reduced risk of Caesarean section with MVI (7.5% vs 10.9%; RR 0.62 95%CI 0.56-0.84) There was no significant difference in any of the key maternal or neonatal adverse outcomes. CONCLUSIONS: The results of this study suggest that misoprostol vaginal inserts, compared with dinoprostone intravaginal gel, achieve quicker delivery times, and a reduction in caesarean sections with no increased rate of adverse maternal or neonatal outcomes.

ORE identifies extreme expression effects enriched for rare variants.

MOTIVATION: Non-coding rare variants (RVs) may contribute to Mendelian disorders but have been challenging to study due to small sample sizes, genetic heterogeneity and uncertainty about relevant non-coding features. Previous studies identified RVs associated with expression outliers, but varying outlier definitions were employed and no comprehensive open-source software was developed. RESULTS: We developed Outlier-RV Enrichment (ORE) to identify biologically-meaningful non-coding RVs. We implemented ORE combining whole-genome sequencing and cardiac RNAseq from congenital heart defect patients from the Pediatric Cardiac Genomics Consortium and deceased adults from Genotype-Tissue Expression. Use of rank-based outliers maximized sensitivity while a most extreme outlier approach maximized specificity. Rarer variants had stronger associations, suggesting they are under negative selective pressure and providing a basis for investigating their contribution to Mendelian disorders. AVAILABILITY AND IMPLEMENTATION: ORE, source code, and documentation are available at https://pypi.python.org/pypi/ore under the MIT license. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The influence of the introduction of national guidelines on preterm birth prevention practice: UK experience.

OBJECTIVE: To identify the current status of specialist preterm labour (PTL) clinics and identify changes in management trends over the last 5 years following release of the NICE preterm birth (PTB) guidance. DESIGN: Postal Survey of Clinical Practice. SETTING: UK. POPULATION: All consultant-led obstetric units. METHODS: A questionnaire was sent by post to all 187 NHS consultant-led obstetric units. Units with a specialist PTL clinic were asked to answer a further six questions defining their protocol for risk stratification and management. MAIN OUTCOME MEASURES: Current practice in specialist PTL clinics. Changes in treatment trends over 5 years. RESULTS: Thirty-three PTL prevention clinics were identified, with 73% running weekly. NHS staff (84%) have replaced university staff as the lead clinicians (from 69% in 2012 to 21% in 2017), suggesting this clinic has become increasingly integrated with standard care for women at the highest risk of PTB. There has been a large shift from nearly half of clinics offering cerclage as primary treatment for short cervix to offering more choice (30%) between at least two of cerclage, vaginal progesterone or pessary and combinations of primary treatments (18%), demonstrating more equipoise among clinicians regarding therapies for short cervix. CONCLUSIONS: Over 5 years, there has been a 44% increase in the number of specialist PTL clinics in the UK. Although there is a better consensus over the target high-risk population, there is increasing heterogeneity among first-line treatments for short cervix. TWEETABLE ABSTRACT: UK PTB prevention clinics have increased by 44% over 5 years, with increasing clinical equipoise to best Rx for short cervix.

Screening and management of the small for gestational age fetus in the UK: A survey of practice.

BACKGROUND: Antenatal detection of the small for gestational (SGA) fetus has become an important indicator of quality of antenatal care in the UK. This has been driven by a desire to reduce stillbirth in this at risk group. METHODS: We conducted a postal survey of 187 NHS consultant units within the UK to determine what the current practice for the detection and subsequent management of the suspected SGA fetus was following the guidance from the Royal College of Obstetricians and Gynaecologists (RCOG) in 2013. RESULTS: The survey was performed in 3 rounds between 2016 and 2017 with a response rate of 65%. 85% of units assessed risk factors for SGA at booking. 81% of units used a customized symphysis fundal height (SFH) chart to screen for SGA with 95% of them using a cut off of <10th centile to refer for ultrasound assessment. When ultrasound is used to detect SGA, 80% of units used estimated fetal weight (EFW), with 89% of these using a cut off of <10th centile to diagnose SGA. Umbilical artery (UA) Doppler monitoring was undertaken in 97% of management and 94% delivered after 37 weeks. Only 24% of units had a dedicated fetal growth clinic, whilst 48% of units were able to offer computerised CTG to monitor the SGA fetus. CONCLUSIONS: Overall there is consistency in the screening methods for SGA (customised SFH charts) and identification of suspected SGA (SFH <10th centile, EFW <10th centile, UA monitoring and induction of labour at term). There was a low uptake of computerized CTG to monitor SGA babies and a low number of specialised fetal growth clinics.

The novel fungal CYP51 inhibitor VT-1598 is efficacious alone and in combination with liposomal amphotericin B in a murine model of cryptococcal meningitis.

Objectives: Annual global deaths from cryptococcal meningitis (CM) are estimated at 180 000 and mortality is as high as 30%, even with optimal therapy. VT-1598 is a novel fungal CYP51 inhibitor with potent intrinsic antifungal activity against Cryptococcus. We report here VT-1598's in vivo antifungal activity in a murine model of CM. Methods: Single-dose plasma and brain pharmacokinetics in mice and MIC for Cryptococcus neoformans H99 were determined prior to efficacy studies. Short-course monotherapy and combination doses were explored with the endpoint of brain fungal burden. A survival study was also conducted using monotherapy treatment with fungal burden measured after a 6 day drug washout. Results: Oral doses of VT-1598 had good plasma and brain exposure and resulted in significant (P < 0.0001) and dose-dependent reductions in brain fungal burden, reaching a 6 log10 reduction. Unlike either positive drug control (fluconazole or liposomal amphotericin B), both mid and high doses of VT-1598 reduced fungal burden to below levels measured at the start of treatment. When VT-1598 was dosed in the survival study, no VT-1598-treated animal succumbed to the infection. Whereas fluconazole showed a 2.5 log10 increase in fungal burden after the 6 day washout, the VT-1598 mid- and high-dose animals showed almost no regrowth (<0.5 log10). In a separate fungal burden study using suboptimal doses of VT-1598 and liposomal amphotericin B to probe for combination effects, each combination had a positive effect relative to corresponding monotherapies. Conclusions: These pre-clinical in vivo data strongly support clinical investigation of VT-1598 as a novel therapy for this lethal infection.