Quantification of Cervical Elasticity During Pregnancy Based on Transvaginal Ultrasound Imaging and Stress Measurement.

Strain elastography and shear wave elastography are commonly used to quantify cervical elasticity. However, the absence of stress information in strain elastography causes difficulty in inter-session elasticity comparison, and the robustness of shear wave elastography is compromised by cervical tissue's high inhomogeneity. OBJECTIVE: To overcome these limitations, we develop a quantitative cervical elastography system by adding a stress sensor to a clinically used transvaginal ultrasound imaging system. METHODS: We record the cervical deformation in B-mode images and measure the probe-surface stress through the sensor. Then we quantify the strain using a customized algorithm and estimate the cervical Young's modulus through stress-strain linear regression. RESULTS: In phantom experiments, we demonstrate the system's high accuracy (alignment with the quasi-static compression method, p-value = 0.369 > 0.05), robustness (alignment between 60°- and 90°-contact measurements, p-value = 0.638 > 0.05), repeatability (consistency of single sonographers' measurements, coefficient of variation < 0.06), and reproducibility (alignment between two sonographers' measurements, Pearson correlation coefficient = 0.981). Applying it to pregnant participants, we observe significant cervical softening (p-value < 0.001): Young's modulus decreases 3.95% weekly and its geometric mean value during the first (11 to 13 weeks), second, and third trimesters are 13.07 kPa, 7.59 kPa, and 4.40 kPa, respectively. CONCLUSION: The proposed system is accurate, robust, and safe, and enables longitudinal and inter-examiner comparisons. SIGNIFICANCE: The system applies to different ultrasound machines with minor software updates, which allows for studies of cervical softening patterns in pregnancy for larger populations, facilitating insights into conditions such as preterm birth.

The Association between Mode of Transportation Support and Research Study Visit Attendance among Pregnant Patients.

OBJECTIVE: This study aimed to examine the association between transportation assistance and study visits, and explore differences by transportation modality. STUDY DESIGN: This was a secondary analysis of prospective cohort study. We identified patients requesting transportation support for research ultrasound visits and identified controls (1:2 ratio) who did not request support matched for age, race, and insurance type. Conditional logistic regression examined the association between transportation support and mode of transportation with study visit attendance. RESULTS: Transportation support was requested by 57/1,184 (4.8%) participants. Participants that requested transportation support were three times more likely to attend visits than their matched controls (adjusted odds ratio [aOR] = 3.16, 95% confidence interval [CI]: 1.76-5.68). Among visits with transportation support, those supported by a ridesharing service had five-fold higher odds of attendance than visits supported with taxi service (aOR = 5.06, 95% CI: 1.50-16.98). CONCLUSION: Transportation support, especially a ridesharing service, is associated with improved attendance at research study visits in a sample of predominantly low-income, Black, pregnant participants. Implementing transportation support may be a promising strategy to improve engagement in research studies. KEY POINTS: · Participants utilizing transportation assistance were more likely to attend study appointments.. · Participants using ridesharing had higher likelihood of attendance than those using taxi service.. · Transportation assistance may improve research engagement for historically marginalized people..

A multidisciplinary Prematurity Research Cohort Study.

BACKGROUND: Worldwide, 10% of babies are born preterm, defined as a live birth before 37 weeks of gestation. Preterm birth is the leading cause of neonatal death, and survivors face lifelong risks of adverse outcomes. New approaches with large sample sizes are needed to identify strategies to predict and prevent preterm birth. The primary aims of the Washington University Prematurity Research Cohort Study were to conduct three prospective projects addressing possible causes of preterm birth and provide data and samples for future research. STUDY DESIGN: Pregnant patients were recruited into the cohort between January 2017 and January 2020. Consenting patients were enrolled into the study before 20 weeks' gestation and followed through delivery. Participants completed demographic and lifestyle surveys; provided maternal blood, placenta samples, and cord blood; and participated in up to three projects focused on underlying physiology of preterm birth: cervical imaging (Project 1), circadian rhythms (Project 2), and uterine magnetic resonance imaging and electromyometrial imaging (Project 3). RESULTS: A total of 1260 participants were enrolled and delivered during the study period. Of the participants, 706 (56%) were Black/African American, 494 (39%) were nulliparous, and 185 (15%) had a previous preterm birth. Of the 1260 participants, 1220 (97%) delivered a live infant. Of the 1220 with a live birth, 163 (14.1%) had preterm birth, of which 74 (6.1%) were spontaneous preterm birth. Of the 1220 participants with a live birth, 841 participated in cervical imaging, 1047 contributed data and/or samples on circadian rhythms, and 39 underwent uterine magnetic resonance imaging. Of the 39, 25 underwent electromyometrial imaging. CONCLUSION: We demonstrate feasibility of recruiting and retaining a diverse cohort in a complex prospective, longitudinal study throughout pregnancy. The extensive clinical, imaging, survey, and biologic data obtained will be used to explore cervical, uterine, and endocrine physiology of preterm birth and can be used to develop novel approaches to predict and prevent preterm birth.

Sleep behavior and chronotype before and throughout pregnancy.

STUDY OBJECTIVE: To compare sleep behavior before and during pregnancy. METHODS: In this prospective cohort study, healthy women were followed from pre-pregnancy until delivery. At pre-pregnancy and each trimester, participants completed validated questionnaires of chronotype and sleep quality and timing, including the Munich ChronoType Questionnaire, Epworth Sleepiness Scale, and Pittsburgh Sleep Quality Index. The primary outcomes were sleep period start and end times, sleep duration, sleep midpoint, and social jetlag, compared between pre-pregnancy and each trimester. Wrist actigraphy was used to measure the same outcomes in a subset of participants. RESULTS: Eighty-six women were included in analysis of questionnaires. Of these, 37 provided complete actigraphy data. Questionnaire and actigraphy data indicate that participants had less social jetlag during pregnancy than before pregnancy. Sleep period start times were earlier on both work and free days in the first and second trimesters than pre-pregnancy, and returned to pre-pregnancy times by the third trimester. Actigraphy data revealed that, compared to pre-pregnancy, participants had longer sleep periods in all trimesters on work days and in the first trimester on free days. Sleep surveys revealed that participants had poorer sleep quality in the first and third trimesters and more sleepiness in the first trimester than pre-pregnancy. CONCLUSION: The first trimester of pregnancy is characterized by earlier sleep period start time, longer sleep duration, and poorer sleep quality than pre-pregnancy. Sleep quality temporarily improves in the second trimester, and sleep period start time returns to pre-pregnancy time by the third trimester. STUDY RATIONALE: Multiple parameters of sleep have been studied in the context of pregnancy and pregnancy outcomes, but rarely in comparison to pre-pregnancy or longitudinally through pregnancy. STUDY IMPACT: Actigraphy and questionnaire data reveal sleep timing and quality change throughout pregnancy. These data on sleep changes in healthy pregnancy can be used as a baseline to identify sleep-related risk factors throughout pregnancy.

Evolving cervical imaging technologies to predict preterm birth.

Preterm birth, defined as delivery at less than 37 weeks' gestation, increases maternal-fetal morbidity and mortality and places heavy financial and emotional burdens on families and society. Although premature cervical remodeling is a major factor in many preterm deliveries, how and why this occurs is poorly understood. This review describes existing and emerging imaging techniques and their advantages and disadvantages in assessing cervical remodeling. Brightness mode (B-mode) ultrasound is used to measure the cervical length, currently the gold standard for determining risk of preterm birth. Several new B-mode ultrasound techniques are being developed, including measuring attenuation, cervical gland area, and the cervical consistency index. Shear wave speed can differentiate between soft (ripe) and firm (unripe) cervices by measuring the speed of ultrasound through a tissue. Elastography provides qualitative information regarding cervical stiffness by compressing the tissue with the ultrasound probe. Raman spectroscopy uses a fiber optic probe to assess the biochemical composition of the cervix throughout pregnancy. Second harmonic generation microscopy uses light to quantify changes in collagen fiber structure and size during cervical maturation. Finally, photoacoustic endoscopy records light-induced sound to determine optical characteristics of cervical tissue. In the long term, a combination of several imaging approaches, combined with consideration of clinical epidemiologic characteristics, will likely be required to accurately predict preterm birth.

Breast cancer risk, worry, and anxiety: Effect on patient perceptions of false-positive screening results.

OBJECTIVE: The impact of mammography screening recall on quality-of-life (QOL) has been studied in women at average risk for breast cancer, but it is unknown whether these effects differ by breast cancer risk level. We used a vignette-based survey to evaluate how women across the spectrum of breast cancer risk perceive the experience of screening recall. METHODS: Women participating in mammography or breast MRI screening were recruited to complete a vignette-based survey. Using a numerical rating scale (0-100), women rated QOL for hypothetical scenarios of screening recall, both before and after benign results were known. Lifetime breast cancer risk was calculated using Gail and BRCAPRO risk models. Risk perception, trait anxiety, and breast cancer worry were assessed using validated instruments. RESULTS: The final study cohort included 162 women at low (n = 43, 26%), intermediate (n = 66, 41%), and high-risk (n = 53, 33%). Actual breast cancer risk was not a predictor of QOL for any of the presented scenarios. Across all risk levels, QOL ratings were significantly lower for the period during diagnostic uncertainty compared to after benign results were known (p < 0.05). In multivariable regression analyses, breast cancer worry was a significant predictor of decreased QoL for all screening scenarios while awaiting results, including scenarios with non-invasive imaging alone or with biopsy. High trait anxiety and family history predicted lower QOL scores after receipt of benign test results (p < 0.05). CONCLUSIONS: Women with high trait anxiety and family history may particularly benefit from discussions about the risk of recall when choosing a screening regimen.

Author Correction: Enabling precision medicine in neonatology, an integrated repository for preterm birth research.

The original version of the Data Descriptor contained errors in the author list and affiliations. Rita Leite's first name was misspelled as "Rite" and affiliations 4 and 5 were incorrectly swapped. In addition, members of the March of Dimes Prematurity Research Center consortium were not listed in the agreed positions within the author list. These errors have now been corrected in the HTML and PDF versions.

In vivo characterization of connective tissue remodeling using infrared photoacoustic spectra.

Premature cervical remodeling is a critical precursor of spontaneous preterm birth, and the remodeling process is characterized by an increase in tissue hydration. Nevertheless, current clinical measurements of cervical remodeling are subjective and detect only late events, such as cervical effacement and dilation. Here, we present a photoacoustic endoscope that can quantify tissue hydration by measuring near-infrared cervical spectra. We quantify the water contents of tissue-mimicking hydrogel phantoms as an analog of cervical connective tissue. Applying this method to pregnant women in vivo, we observed an increase in the water content of the cervix throughout pregnancy. The application of this technique in maternal healthcare may advance our understanding of cervical remodeling and provide a sensitive method for predicting preterm birth.

Transvaginal fast-scanning optical-resolution photoacoustic endoscopy.

Photoacoustic endoscopy offers in vivo examination of the visceral tissue using endogenous contrast, but its typical B-scan rate is ∼10 Hz, restricted by the speed of the scanning unit and the laser pulse repetition rate. Here, we present a transvaginal fast-scanning optical-resolution photoacoustic endoscope with a 250-Hz B-scan rate over a 3-mm scanning range. Using this modality, we not only illustrated the morphological differences of vasculatures among the human ectocervix, uterine body, and sublingual mucosa but also showed the longitudinal and cross-sectional differences of cervical vasculatures in pregnant women. This technology is promising for screening the visceral pathological changes associated with angiogenesis.

Enabling precision medicine in neonatology, an integrated repository for preterm birth research.

Preterm birth, or the delivery of an infant prior to 37 weeks of gestation, is a significant cause of infant morbidity and mortality. In the last decade, the advent and continued development of molecular profiling technologies has enabled researchers to generate vast amount of 'omics' data, which together with integrative computational approaches, can help refine the current knowledge about disease mechanisms, diagnostics, and therapeutics. Here we describe the March of Dimes' Database for Preterm Birth Research (http://www.immport.org/resources/mod), a unique resource that contains a variety of 'omics' datasets related to preterm birth. The database is open publicly, and as of January 2018, links 13 molecular studies with data across tens of thousands of patients from 6 measurement modalities. The data in the repository are highly diverse and include genomic, transcriptomic, immunological, and microbiome data. Relevant datasets are augmented with additional molecular characterizations of almost 25,000 biological samples from public databases. We believe our data-sharing efforts will lead to enhanced research collaborations and coordination accelerating the overall pace of discovery in preterm birth research.

HilE Regulates HilD by Blocking DNA Binding in Salmonella enterica Serovar Typhimurium.

The Salmonella type three secretion system (T3SS), encoded in the Salmonella pathogenicity island 1 (SPI1) locus, mediates the invasion of the host intestinal epithelium. SPI1 expression is dependent upon three AraC-like regulators: HilD, HilC, and RtsA. These regulators act in a complex feed-forward loop to activate each other and hilA, which encodes the activator of the T3SS structural genes. HilD has been shown to be the major integration point of most signals known to activate the expression of the SPI1 T3SS, acting as a switch to control induction of the system. HilE is a negative regulator that acts upon HilD. Here we provide genetic and biochemical data showing that HilE specifically binds to HilD but not to HilC or RtsA. This protein-protein interaction blocks the ability of HilD to bind DNA as shown by both an in vivo reporter system and an in vitro gel shift assay. HilE does not affect HilD dimerization, nor does it control the stability of the HilD protein. We also investigated the role of HilE during the infection of mice using competition assays. Although deletion of hilE does not confer a phenotype, the hilE mutation does suppress the invasion defect conferred by loss of FliZ, which acts as a positive signal controlling HilD protein activity. Together, these data suggest that HilE functions to restrict low-level HilD activity, preventing premature activation of SPI1 until positive inputs reach a threshold required to fully induce the system.IMPORTANCESalmonella is a leading cause of gastrointestinal and systemic disease throughout the world. The SPI1 T3SS is required for Salmonella to induce inflammatory diarrhea and to gain access to underlying tissue. A complex regulatory network controls expression of SPI1 in response to numerous physiological inputs. Most of these signals impinge primarily on HilD translation or activity. The system is triggered when HilD activity crosses a threshold that allows efficient activation of its own promoter. This threshold is set by HilE, which binds to HilD to prevent the inevitable minor fluctuations in HilD activity from inappropriately activating the system. The circuit also serves as a paradigm for systems that must integrate numerous environmental parameters to control regulatory output.

Intestinal Long-Chain Fatty Acids Act as a Direct Signal To Modulate Expression of the Salmonella Pathogenicity Island 1 Type III Secretion System.

UNLABELLED: Salmonella enterica serovar Typhimurium uses the Salmonella pathogenicity island 1 (SPI1) type III secretion system (T3SS) to induce inflammatory diarrhea and bacterial uptake into intestinal epithelial cells. The expression of hilA, encoding the transcriptional activator of the T3SS structural genes, is directly controlled by three AraC-like regulators, HilD, HilC, and RtsA, each of which can activate hilD, hilC, rtsA, and hilA genes, forming a complex feed-forward regulatory loop. Expression of the SPI1 genes is tightly controlled by numerous regulatory inputs to ensure proper timing in production of the T3SS apparatus. Loss of FadD, an acyl coenzyme A (acyl-CoA) synthetase required for degradation of long-chain fatty acids (LCFAs), was known to decrease hilA expression. We show that free external LCFAs repress expression of hilA independently of FadD and the LCFA degradation pathway. Genetic and biochemical evidence suggests that LCFAs act directly to block primarily HilD activity. Further analyses show that in the absence of FadD, hilA expression is downregulated due to endogenous production of free LCFAs, which are excreted into the culture medium via TolC and then transported back into the bacterial cell via FadL. A fadL mutant is more virulent than the wild-type strain in mouse oral competition assays independently of LCFA degradation, showing that, in the host, dietary LCFAs serve as a signal for proper regulation of SPI1 expression, rather than an energy source. IMPORTANCE: To cause disease, Salmonella must respond to diverse environmental cues to express its invasion machinery at the appropriate location in the host intestine. We show that host intestinal free long-chain fatty acids (LCFAs) affect Salmonella invasion by reducing expression of the SPI1 type III secretion system, acting primarily via the AraC-like activator HilD. Degradation of LCFAs is not required for this regulation, showing that free LCFAs serve as a cue to proper intestinal localization to invade host epithelial cells and not as a nutrient source.

Auditing a breast MRI practice: performance measures for screening and diagnostic breast MRI.

PURPOSE: Breast MRI is increasingly used for both screening and diagnostic purposes. Although performance benchmarks for screening and diagnostic mammography have been published, performance benchmarks for breast MRI have yet to be established. The purpose of this study was to comprehensively evaluate breast MRI performance measures, stratified by screening and diagnostic indications, from a single academic institution. METHODS: Institutional review board approval was acquired for this HIPAA-compliant study. Informed consent was not required. Retrospective review of the institutional database identified all breast MRI examinations performed from April 1, 2007, to March 31, 2008. After application of exclusion criteria, the following performance measures for screening and diagnostic indications were calculated: cancer detection rate, positive predictive value (PPV), and abnormal interpretation rates. RESULTS: The study included 2,444 examinations, 1,313 for screening and 1,131 for diagnostic indications. The cancer detection rates were 14 per 1,000 screening breast MRI examinations and 47 per 1,000 diagnostic examinations (P < .00001). The abnormal interpretation rate was 12% (152 of 1,313) for screening and 17% (194 of 1,131) for diagnostic indications (P = .00008). The PPVs of MRI were lower for screening [PPV1 (abnormal findings) = 12%, PPV2 (biopsy recommended) = 24%, PPV3 (biopsy performed) = 27%] compared with diagnostic indications (PPV1 (abnormal findings) = 28%, PPV2 (biopsy recommended) = 36%, PPV3 (biopsy performed) = 38%]. CONCLUSIONS: Breast MRI performance measures differ significantly between screening and diagnostic MRI indications. Medical audits for breast MRI should calculate performance measures for screening and diagnostic breast MRI separately, as recommended for mammography.

Cost-effectiveness of alternating magnetic resonance imaging and digital mammography screening in BRCA1 and BRCA2 gene mutation carriers.

BACKGROUND: Current clinical guidelines recommend earlier, more intensive breast cancer screening with both magnetic resonance imaging (MRI) and mammography for women with breast cancer susceptibility gene (BRCA) mutations. Unspecified details of screening schedules are a challenge for implementing guidelines. METHODS: A Markov Monte Carlo computer model was used to simulate screening in asymptomatic women who were BRCA1 and BRCA2 mutation carriers. Three dual-modality strategies were compared with digital mammography (DM) alone: 1) DM and MRI alternating at 6-month intervals beginning at age 25 years (Alt25), 2) annual MRI beginning at age 25 years with alternating DM added at age 30 years (MRI25/Alt30), and 3) DM and MRI alternating at 6-month intervals beginning at age 30 years (Alt30). Primary outcomes were quality-adjusted life years (QALYs), lifetime costs (in 2010 US dollars), and incremental cost-effectiveness (dollars per QALY gained). Additional outcomes included potential harms of screening, and lifetime costs stratified into component categories (screening and diagnosis, treatment, mortality, and patient time costs). RESULTS: All 3 dual-modality screening strategies increased QALYs and costs. Alt30 screening had the lowest incremental costs per additional QALY gained (BRCA1, $74,200 per QALY; BRCA2, $215,700 per QALY). False-positive test results increased substantially with dual-modality screening and occurred more frequently in BRCA2 carriers. Downstream savings in both breast cancer treatment and mortality costs were outweighed by increases in up-front screening and diagnosis costs. The results were influenced most by estimates of breast cancer risk and MRI costs. CONCLUSIONS: Alternating MRI and DM screening at 6-month intervals beginning at age 30 years was identified as a clinically effective approach to applying current guidelines, and was more cost-effective in BRCA1 gene mutation carriers compared with BRCA2 gene mutation carriers.

Annual screening strategies in BRCA1 and BRCA2 gene mutation carriers: a comparative effectiveness analysis.

BACKGROUND: Although breast cancer screening with mammography and magnetic resonance imaging (MRI) is recommended for breast cancer-susceptibility gene (BRCA) mutation carriers, there is no current consensus on the optimal screening regimen. METHODS: The authors used a computer simulation model to compare 6 annual screening strategies (film mammography [FM], digital mammography [DM], FM and magnetic resonance imaging [MRI] or DM and MRI contemporaneously, and alternating FM/MRI or DM/MRI at 6-month intervals) beginning at ages 25 years, 30 years, 35 years, and 40 years, and 2 strategies of annual MRI with delayed alternating DM/FM versus clinical surveillance alone. Strategies were evaluated without and with mammography-induced breast cancer risk using 2 models of excess relative risk. Input parameters were obtained from the medical literature, publicly available databases, and calibration. RESULTS: Without radiation risk effects, alternating DM/MRI starting at age 25 years provided the highest life expectancy (BRCA1, 72.52 years, BRCA2, 77.63 years). When radiation risk was included, a small proportion of diagnosed cancers was attributable to radiation exposure (BRCA1, <2%; BRCA2, <4%). With radiation risk, alternating DM/MRI at age 25 years or annual MRI at age 25 years/delayed alternating DM at age 30 years was the most effective, depending on the radiation risk model used. Alternating DM/MRI starting at age 25 years also produced the highest number of false-positive screens per woman (BRCA1, 4.5 BRCA2, 8.1). CONCLUSIONS: Annual MRI at age 25 years/delayed alternating DM at age 30 years is probably the most effective screening strategy in BRCA mutation carriers. Screening benefits, associated risks, and personal acceptance of false-positive results should be considered in choosing the optimal screening strategy for individual women.

FliZ regulates expression of the Salmonella pathogenicity island 1 invasion locus by controlling HilD protein activity in Salmonella enterica serovar typhimurium.

A prerequisite for Salmonella enterica to cause both intestinal and systemic disease is the direct injection of effector proteins into host intestinal epithelial cells via a type three secretion system (T3SS); the T3SS genes are carried on Salmonella pathogenicity island 1 (SPI1). These effector proteins induce inflammatory diarrhea and bacterial invasion. Expression of the SPI1 T3SS is tightly regulated in response to environmental signals through a variety of global regulatory systems. We have previously shown that three AraC-like regulators, HilD, HilC, and RtsA, act in a complex feed-forward regulatory loop to control the expression of the hilA gene, which encodes the direct regulator of the SPI1 structural genes. In this work, we characterize a major positive regulator of this system, the flagellar protein FliZ. Through genetic and biochemical analyses, we show that FliZ posttranslationally controls HilD to positively regulate hilA expression. This mechanism is independent of other flagellar components and is not mediated through the negative regulator HilE or through FliZ-mediated RpoS regulation. We demonstrate that FliZ controls HilD protein activity and not stability. FliZ regulates HilD in the absence of Lon protease, previously shown to degrade HilD. Indeed, it appears that FliZ, rather than HilD, is the most relevant target of Lon as it relates to SPI1 expression. Mutants lacking FliZ are significantly attenuated in their ability to colonize the intestine but are unaffected during systemic infection. The intestinal attenuation is partially dependent on SPI1, but FliZ has additional pleiotropic effects.