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).

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.

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.

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 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.

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.

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.

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.

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.

A Comparison of Outcomes in Patients with Infrapopliteal Disease Randomised to Vein Bypass or Plain Balloon Angioplasty in the Bypass vs. Angioplasty in Severe Ischaemia of the Leg (BASIL) Trial.

OBJECTIVE: The aim was to compare outcomes in a subgroup of patients with infrapopliteal (IP) disease randomised to infrapopliteal vein bypass (VB) or plain balloon angioplasty (PBA) in the original BASIL trial. METHODS: A comparison of outcomes from patients randomised to VB or PBA undergoing revascularisation for severe limb ischaemia (SLI) because of IP disease with or without femoropopliteal disease. Data were extracted from case report forms from the BASIL trial. The primary outcome was amputation free survival (AFS); secondary outcomes included overall survival (OS), 30 day mortality and morbidity, freedom from arterial re-intervention, immediate technical success, repeat and crossover interventions, length of hospital stay, and quality of revascularisation. RESULTS: A total of 104 patients were identified in the BASIL study with IP disease, 56 randomised to IP VB, and 48 to IP PBA. Groups were similar at baseline except for more chronic kidney disease and non-steroidal anti-inflammatory drug use in the VB group, and more previous surgical arterial intervention and antihypertensive use in the PBA group. There were no statistically significant differences in AFS or OS; however, clinically important trends were apparent in favour of a VB first strategy. Patients allocated to VB demonstrated significantly quicker relief of rest pain when compared with PBA (p = .005), but no significant differences in improved tissue healing. Median length of index hospital admission was significantly greater in the VB than in the PBA group (18 vs. 10 days, p < .0001) but there was no difference between the two groups in median total hospital stay between randomisation and the primary endpoint (VB 43.5 vs. PBA 42 days). CONCLUSIONS: Further randomised trials, like BASIL-2 and BEST-CLI, are required to determine whether patients with severe limb ischaemia who require IP revascularisation and who are suitable for VB should have bypass or endovascular intervention as their primary revascularisation procedure.

Diagnostic accuracy of individual antenatal tools for prediction of small-for-gestational age at birth.

OBJECTIVE: To determine the accuracy of fetal and newborn growth charts for the prediction of small-for-gestational age (SGA) at birth (birth weight < 10th centile). METHODS: This was a prospective cohort study performed within a UK specialist fetal growth clinic. A total of 105 consecutive pregnant women referred for a suspected SGA fetus were included. All pregnancies were managed according to a standard protocol using estimated fetal weight (EFW) plotted on customized Gestation Related Optimal Weight (GROW) charts. The last antenatal estimates of EFW (according to charts of GROW, Hadlock et al. and Mikolajczyk et al.), abdominal circumference (AC) (according to charts of Hadlock et al., INTERGROWTH-21st Project and Chitty et al.) or change in AC over time (calculated according to Pregnancy Outcome Prediction (POP) study) were compared against four birth-weight charts (GROW, INTERGROWTH-21st , Mikolajczyk et al. and World Health Organization (WHO)). The ability of each antenatal test to predict adverse perinatal outcome (APO) was assessed. RESULTS: Birth weight < 10th centile was assigned in 62 (59%) neonates using the GROW chart, 57 (54%) using the Mikolajczyk et al. chart, 55 (52%) using the INTERGROWTH-21st chart and 51 (49%) using the WHO chart. AC-Hadlock had the best negative likelihood ratio (range, 0.3-0.4) and sensitivity (range, 74%-82%) for predicting SGA as defined by all four postnatal birth-weight charts. AC-INTERGROWTH-21st had the best positive likelihood ratio (range, 5.9-10.9) and specificity (94%-96%). For prediction of APO, AC-Hadlock and EFW-GROW had the best sensitivities (57% and 52%, respectively), whereas AC-POP had the best positive likelihood ratio (2.2) and specificity (88%). Antenatal prediction of APO increased to a sensitivity of 61% when AC-POP and EFW-GROW were combined; however, specificity was only 56%. CONCLUSIONS: We have identified wide variation in the diagnostic accuracy of various antenatal tools for the prediction of both SGA and APO, dependent on the choice of chart. Suboptimal diagnostic accuracy of commonly used antenatal tests may lead to increasing medicalization without prevention of APO. Researchers should focus their attention on a combination of fetal biometry and biomarkers for better prediction of SGA and prevention of APO. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Serum total hCGß level is an independent prognostic factor in transitional cell carcinoma of the urothelial tract.

BACKGROUND: Serum total human chorionic gonadotrophin ß subunit (hCGß) level might have prognostic value in urothelial transitional cell carcinoma (TCC) but has not been investigated for independence from other prognostic variables. METHODS: We utilised a clinical database of patients receiving chemotherapy between 2005 and 2011 for urothelial TCC and an independent cohort of radical cystectomy patients for validation purposes. Prognostic variables were tested by univariate Kaplan-Meier analyses and log-rank tests. Statistically significant variables were then assessed by multivariate Cox regression. Total hCGß level was dichotomised at < vs ≥2 IU l(-1). RESULTS: A total of 235 chemotherapy patients were eligible. For neoadjuvant chemotherapy, established prognostic factors including low ECOG performance status, normal haemoglobin, lower T stage and suitability for cisplatin-based chemotherapy were associated with favourable survival in univariate analyses. In addition, low hCGß level was favourable when assessed either before (median survival not reached vs 1.86 years, P=0.001) or on completion of chemotherapy (4.27 vs 0.42 years, P=0.000002). This was confirmed in multivariate analyses and in patients receiving first- and second-line palliative chemotherapy, and in a radical cystectomy validation set. CONCLUSIONS: Serum total hCGß level is an independent prognostic factor in patients receiving chemotherapy for urothelial TCC in both curative and palliative settings.

Provision and practice of specialist preterm labour clinics: a UK survey of practice.

OBJECTIVE: To identify the current status of specialist preterm labour (PTL) clinic provision and management within the UK. DESIGN: Postal survey of clinical practice. SETTING UK POPULATION: All consultant-led obstetric units within the UK. METHODS: A questionnaire was sent by post to all 210 NHS consultant-led obstetric units within the UK. Units that had a specialist PTL clinic were asked to complete a further 20 questions defining their protocol for risk stratification and management. MAIN OUTCOME MEASURES: Current practice in specialist preterm labour clinics. RESULTS: We have identified 23 specialist clinics; the most common indications for attendance were previous PTL (100%), preterm prelabour rupture of membranes (95%), two large loop excisions of the transformation zone (95%) or cone biopsy (95%). There was significant heterogeneity in the indications for and method of primary treatment for short cervix, with cervical cerclage used in 45% of units, progesterone in 18% of units and Arabin cervical pessary in 5%. A further 23% used multiple treatment modalities in combination. CONCLUSIONS: A significant heterogeneity in all topics surveyed suggests an urgent need for networking, more evidence-based guidelines and prospective comparative audits to ascertain the real impact of specialist PTL clinics on the reduction in preterm birth and its sequelae.

Predicting preterm birth in women with previous preterm birth and cervical length ≥ 25 mm.

OBJECTIVE: To identify risk factors predicting subsequent spontaneous preterm birth or preterm prelabor rupture of membranes (PPROM) in a cohort of women with a history of spontaneous preterm birth and a cervical length of ≥ 25 mm at 20-24 weeks' gestation. METHODS: We identified all pregnant women who attended our preterm labor clinic between January 2010 and December 2012 because of previous spontaneous preterm birth or PPROM before 34 weeks. Women with a normal cervical length (defined as ≥ 25 mm) between 20 and 24 weeks' gestation were identified and included in the analysis. Maternal characteristics, obstetric history, shortest cervical length and gestational age at shortest cervical length of women who delivered preterm (before 37 weeks) were compared with those who delivered at or after 37 weeks in the index pregnancy. Multiple regression analysis was planned to examine the relationship between significant clinical and cervical-length variables to identify significant clinical predictors of spontaneous preterm birth among high-risk patients with a normal cervix between 20 and 24 weeks' gestation. RESULTS: Of 134 women with a normal cervix at 20-24 weeks, 28 (20.9%) delivered spontaneously or had PPROM before 37 weeks; of these 12 (9.0%) delivered before 34 weeks. None of the selected explanatory variables was predictive of recurrent preterm birth in this cohort. No correlation between absolute cervical length and gestational age at delivery was found (R = 0.01). CONCLUSION: In high-risk women with a cervical length of ≥ 25 mm at 20-24 weeks' gestation, demographic characteristics and absolute cervical length are not useful in predicting subsequent spontaneous preterm birth.

TRGT-denovo: accurate detection of de novo tandem repeat mutations.

Motivation: Identifying de novo tandem repeat (TR) mutations on a genome-wide scale is essential for understanding genetic variability and its implications in rare diseases. While PacBio HiFi sequencing data enhances the accessibility of the genome's TR regions for genotyping, simple de novo calling strategies often generate an excess of likely false positives, which can obscure true positive findings, particularly as the number of surveyed genomic regions increases. Results: We developed TRGT-denovo, a computational method designed to accurately identify all types of de novo TR mutations-including expansions, contractions, and compositional changes-within family trios. TRGT-denovo directly interrogates read evidence, allowing for the detection of subtle variations often overlooked in variant call format (VCF) files. TRGT-denovo improves the precision and specificity of de novo mutation (DNM) identification, reducing the number of de novo candidates by an order of magnitude compared to genotype-based approaches. In our experiments involving eight rare disease trios previously studiedTRGT-denovo correctly reclassified all false positive DNM candidates as true negatives. Using an expanded repeat catalog, it identified new candidates, of which 95% (19/20) were experimentally validated, demonstrating its effectiveness in minimizing likely false positives while maintaining high sensitivity for true discoveries. Availability and implementation: Built in Rust, TRGT-denovo is available as source code and a pre-compiled Linux binary along with a user guide at: https://github.com/PacificBiosciences/trgt-denovo.

Electrical design of the flexible imaging diffraction diagnostic for laser experiments (FIDDLE) at the National Ignition Facility (NIF)-Requirements, design, and performance.

The Flexible Imaging Diffraction Diagnostic for Laser Experiments (FIDDLE) is a newly developed diagnostic for imaging time resolved diffraction in experiments at the National Ignition Facility (NIF). It builds on the successes of its predecessor, the Gated Diffraction Development Diagnostic (G3D). The FIDDLE was designed to support eight Daedalus version 2 sensors (six more hCMOS sensors than any other hCMOS-based diagnostic in NIF to date) and an integrated streak camera. We will review the electrical requirements, design, and performance of the electrical subsystems that were created to support this large number of cameras in the FIDDLE. The analysis of the data that the FIDDLE is intended to collect relies heavily on the accurate and well-understood timing of each sensor. We report camera-to-camera timing jitter of less than 100 ps rms and sensor integration times of 2.2 ns FWHM in 2-2 timing mode. Additionally, diffraction experiments on the NIF produce electric fields (EMI) on the order of 1 kV/m, which have been observed to negatively impact the performance of some electrical components of the FIDDLE. We report on the results of testing hCMOS camera electronics in a similar EMI environment generated in an offline lab. We also summarize the use of a novel approach to using a vector network analyzer as an EMI leak detector to understand and reduce the negative impacts of EMI on the FIDDLE.

Mitigation strategies for time-resolved x-ray diagnostic data degradation due to high neutron yield of ICF experiments at the NIF.

Inertial confinement fusion experiments taking place at the National Ignition Facility are generating ever increasing amounts of fusion energy, with the deuterium tritium fusion neutron yield growing a hundredfold over the past ten years. Strategies must be developed to mitigate this harsh environment's deleterious effects on the operation and the performance of the time-resolved x-ray imagers deployed in the National Ignition Facility target bay to record the dynamics of the implosions. We review the evolution of these imagers in recent years and detail some of the past and present efforts undertaken to maintain or improve the quality of the experimental data collected on high neutron yield experiments. These include the use of a dump-and-read electronic backend, the selection of photographic film with a low background sensitivity, and the optical filtering of Cherenkov radiation.