Summary Background Existing approaches for the screening and treatment of asymptomatic bacteriuria in pregnancy are based on trials that were done more than 30 years ago. In this study, we reassessed ...the consequences of treated and untreated asymptomatic bacteriuria in pregnancy. Methods In this multicentre prospective cohort study with an embedded randomised controlled trial, we screened women (aged ≥18 years) at eight hospitals and five ultrasound centres in the Netherlands with a singleton pregnancy between 16 and 22 weeks' gestation for asymptomatic bacteriuria. Screening was done with a single dipslide and two culture media. Dipslides were judged positive when the colony concentration was at least 1×105 colony-forming units (CFU) per mL of a single microorganism or when two different colony types were present but one had a concentration of at least 1×105 CFU per mL. Asymptomatic bacteriuria-positive women were eligible to participate in the randomised controlled trial comparing nitrofurantoin with placebo treatment. In this trial, participants were randomly assigned 1:1 to receive either nitrofurantoin 100 mg or identical placebo tablets, and were instructed to self-administer these tablets twice daily for 5 consecutive days. Randomisation was done by a web-based application with a computer-generated list with random block sizes of two, four, or six participants rendered by an independent data manager. 1 week after the end of treatment, they provided us with a follow-up dipslide. Women, treating physicians, and researchers all remained unaware of the bacteriuria status and treatment allocation. Women who refused to participate in the randomised controlled trial did not receive any antibiotics, but their outcomes were collected for analysis in the cohort study. We compared untreated and placebo-treated asymptomatic bacteriuria-positive women with asymptomatic bacteriuria-negative women and nitrofurantoin-treated asymptomatic bacteriuria-positive women. The primary endpoint was a composite of pyelonephritis with or without preterm birth at less than 34 weeks, analysed by intention to treat at 6 weeks post-partum. This trial is registered with the Dutch Trial Registry, number NTR3068. Findings Between Oct 11, 2011, and June 10, 2013, we enrolled 5621 women into our screening cohort, of whom 5132 were eligible for screening. After exclusions for contaminated dipslides and patients lost to follow-up, in our final cohort of 4283 women, 248 were asymptomatic bacteriuria positive, of whom 40 were randomly assigned to nitrofurantoin and 45 to placebo for the randomised controlled trial, whereas the other 163 asymptomatic bacteriuria-positive women were followed without treatment. The proportion of women with pyelonephritis, preterm birth, or both did not differ between untreated or placebo-treated asymptomatic bacteriuria-positive women and asymptomatic bacteriuria-negative women (6 2·9% of 208 vs 77 1·9% of 4035; adjusted odds ratio OR 1·5, 95% CI 0·6–3·5) nor between asymptomatic bacteriuria-positive women treated with nitrofurantoin versus those who were untreated or received placebo (1 2·5% of 40 vs 6 2·9% of 208; risk difference −0·4, 95% CI −3·6 to 9·4). Untreated or placebo-treated asymptomatic bacteriuria-positive women developed pyelonephritis in five 2·4% of 208 cases, compared with 24 0·6% of 4035 asymptomatic bacteriuria-negative women (adjusted OR 3·9, 95% CI 1·4–11·4). Interpretation In women with an uncomplicated singleton pregnancy, asymptomatic bacteriuria is not associated with preterm birth. Asymptomatic bacteriuria showed a significant association with pyelonephritis, but the absolute risk of pyelonephritis in untreated asymptomatic bacteriuria is low. These findings question a routine screen-treat-policy for asymptomatic bacteriuria in pregnancy. Funding ZonMw (the Netherlands Organisation for Health Research and Development).
Introduction
We investigated the predictive capacity of mid‐trimester cervical length (CL) measurement for spontaneous and iatrogenic preterm birth.
Material and methods
We performed a prospective ...observational cohort study in nulliparous women and low‐risk multiparous women with a singleton pregnancy between 16+0 and 21+6 weeks of gestation. We assessed the prognostic capacity of transvaginally measured mid‐trimester CL for spontaneous and iatrogenic preterm birth (<37 weeks) using likelihood ratios (LR) and receiver‐operating‐characteristic analysis. We calculated numbers needed to screen to prevent one preterm birth assuming different treatment effects. Main outcome measures were preterm birth <32, <34 and <37 weeks.
Results
We studied 11 943 women, of whom 666 (5.6%) delivered preterm: 464 (3.9%) spontaneous and 202 (1.7%) iatrogenic. Mean CL was 44.1 mm (SD 7.8 mm). In nulliparous women, the LRs for spontaneous preterm birth varied between 27 (95% CI 7.7–95) for a CL ≤ 20 mm, and 2.0 (95% CI 1.6–2.5) for a CL between 30 and 35 mm. For low‐risk multiparous women, these LRs were 37 (95% CI 7.5–182) and 1.5 (95% CI 0.97–2.2), respectively. Using a cut‐off for CL ≤ 30 mm, 28 (6.0%) of 464 women with spontaneous preterm birth were identified. The number needed to screen to prevent one case of preterm birth was 618 in nulliparous women and 1417 for low‐risk multiparous women (40% treatment effect, cut‐off 30 mm).
Conclusion
In women at low risk of preterm birth, CL predicts spontaneous preterm birth. However, its isolated use as a screening tool has limited value due to low sensitivity.
Objective
To determine if the verification of short cervical length with a repeated measurement improved the identification of patients with short cervical length at increased risk of preterm ...delivery.
Methods
The present secondary analysis analyzed prospective cohort study data from patients with singleton pregnancies without a history of preterm delivery who presented for obstetric care in the Netherlands and delivered between November 18, 2009, and January 1, 2013. Cervical length was measured during standard anomaly scan and a second measurement was performed if the cervical length was 30 mm of shorter. Logistic regression and Cox proportional hazards modeling were used to evaluate associations between cervical length measurements and spontaneous preterm delivery before 37 weeks of pregnancy.
Results
Cervical length measurements from 12 358 patients were included; 221 (1.8%) had an initial cervical length measurement of 30 mm or shorter. A second cervical length measurement was performed for 167 (75.6%) patients; no differences were identified in the odds of spontaneous preterm delivery when evaluated using the first, second, or a mean of both measurements, regardless of whether cervical length was analyzed as a continuous or dichotomous variable.
Conclusion
Among patients with singleton pregnancies, verification of short cervical length did not improve the identification of short cervical length.
A second cervical length measurement to verify short cervical length did not improve the identification of patients at risk of preterm delivery.
The prevalence of asymptomatic bacteriuria (ASB) in pregnancy is 2-10% and is associated with both maternal and neonatal adverse outcomes as pyelonephritis and preterm delivery. Antibiotic treatment ...is reported to decrease these adverse outcomes although the existing evidence is of poor quality.
We plan a combined screen and treat study in women with a singleton pregnancy. We will screen women between 16 and 22 weeks of gestation for ASB using the urine dipslide technique. The dipslide is considered positive when colony concentration ≥105 colony forming units (CFU)/mL of a single microorganism or two different colonies but one ≥105 CFU/mL is found, or when Group B Streptococcus bacteriuria is found in any colony concentration. Women with a positive dipslide will be randomly allocated to receive nitrofurantoin or placebo 100 mg twice a day for 5 consecutive days (double blind). Primary outcomes of this trial are maternal pyelonephritis and/or preterm delivery before 34 weeks. Secondary outcomes are neonatal and maternal morbidity, neonatal weight, time to delivery, preterm delivery rate before 32 and 37 weeks, days of admission in neonatal intensive care unit, maternal admission days and costs.
This trial will provide evidence for the benefit and cost-effectiveness of dipslide screening for ASB among low risk women at 16-22 weeks of pregnancy and subsequent nitrofurantoin treatment.
Dutch trial registry: NTR-3068.
This systematic review aims to get insight into the feasibility of cardiopulmonary exercise testing (CPET) in patients with cancer prior to a physical exercise programme. We will focus on quality ...(defined as the adherence to international guidelines for methods of CPET) and safety of CPET. Furthermore, we compare the peak oxygen uptake (·VO(2peak)) values of patients with cancer with reference values for healthy persons to put these values into a clinical perspective. A computer aided search with 'cardiopulmonary exercise testing' and 'cancer' using MEDLINE, EMBASE, Pedro, CINAHL® and SPORTDiscus™ was carried out. We included studies in which CPET with continuous gas exchange analysis has been performed prior to a physical exercise programme in adults with cancer. Twenty studies describing 1158 patients were eligible. Reported adherence to international recommendations for CPET varied per item. In most studies, the methods of CPET were not reported in detail. Adverse events occurred in 1% of patients. The percentage ·VO(2peak) of reference values for healthy persons varied between 65% and 89% for tests before treatment, between 74% and 96% for tests during treatment and between 52% and 117% for tests after treatment. Our results suggest that CPET is feasible and seems to be safe for patients with cancer prior to a physical exercise programme. We recommend that standard reporting and quality guidelines should be followed for CPET methods. The decreased ·VO(2peak) values of patients with cancer indicate that physical exercise should be implemented in their standard care.
Current risk assessments for treatment of children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are based on several clinical and biological criteria, including genomic alterations. ...Genomic profiling of BCP-ALL in the last few years has substantially extended the number of risk factors that can be used for risk stratification, including a novel entity known as BCR-ABL1 -like or Ph-like ALL. This subgroup of BCR-ABL1-like cases is characterized by the high recurrence of a diverse repertoire of novel gene fusions and mutations which frequently result in enhanced tyrosine kinase and cytokine receptor signaling Roberts et al., NEJM 2014;371:1005-15. Leukemia's with these alterations could potentially be targeted with appropriate tyrosine kinase inhibitors. Clinical trials with newly-diagnosed patients carrying these alterations are therefore required, but the large genomic diversity within this group of patients currently provides a major bottleneck.
Here, we describe the use of Targeted Locus Amplification (TLA), combined with deep-sequencing to detect fusion genes and sequence mutations relevant for stratification of BCP-ALL. TLA involves a strategy to selectively amplify and sequence regions >100 kb around a preselected primer pair by crosslinking of physically proximal genomic sequences de Vree et al., Nat Biotechnol. 2014;32:1019-25. Since TLA results in the amplification of all sequences at either end of the primer pair, TLA is highly effective in picking up structural variations including novel fusion partners. Furthermore, breakpoints can be identified from the TLA sequencing data from which targets for detection of minimal residual disease can be directly designed.
A total of 31 primer sets targeting 19 recurrently affected genes were designed and multiplexed, including the 'classical' players MLL, RUNX1, TCF3, and IKZF1, the tyrosine kinase genes ABL1, ABL2, PDGFRB, CSF1R, JAK1, JAK2, JAK3, FLT3, and TYK2, and the cytokine signaling genes CRLF2, EPOR, IL7R, TSLP, SH2B3, and IL2RB. Primer sets were chosen such that the most relevant regions were sufficiently covered. As a pilot, viable cells from 46 selected BCP-ALL samples were analysed, including 26 cases with a BCR-ABL1 -like expression profile Den Boer et al., Lancet Oncol. 2009;10:125-34, of which 6 had a known kinase fusion. 7 Gb of aligned sequence data was obtained for each patient sample. All 21 rearrangements known to be present in these samples were detected by TLA, including rearrangements in ETV6-RUNX1 (n=5), MLL (n=4), TCF3-PBX1 (n=3), CRLF2 (n=4), EBF1-PDGFRB (n=2), BCR-ABL1 (n=1), RCSD1-ABL2 (n=1), and SSBP2 -CSF1R (n=1). For 10 of the fusions sequencing depth was sufficient to extract breakpoint-spanning sequences directly. For two cases with known JAK2 fusions with an unknown partner, the fusion gene was identified (TERF2 and BCR), as was the case for an unknown ABL1 fusion (FOXP1). New fusions were identified in 9 cases, including previously described IGH@-EPOR and TCF3-ZNF384 fusions, and novel kinase activating fusions of MAP3K19-TSLP and HDAC9-FLT3. In addition we identified deletion breakpoint fusions in IKZF1, and sequence mutations in JAK1, JAK3,and IL7R. In total, we detected gene fusions or sequence mutations affecting tyrosine kinase or cytokine receptor signaling in 16 of the 26 cases with a BCR-ABL1 -like expression profile. We conclude that TLA is an effective method for the reliable detection of sequence mutations and structural variations that are relevant for disease prognosis and/or could be targeted by approved kinase inhibiton.
Simonis:Cergentis BV: Employment. Klous:Cergentis BV: Employment. Yilmaz:Cergentis BV: Employment. Splinter:Cergentis BV: Employment.
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