Value of cervical electrical impedance spectroscopy to predict spontaneous preterm delivery in asymptomatic women: the ECCLIPPx prospective cohort study.

OBJECTIVES: Preterm birth (PTB) accounts for two-thirds of deaths of structurally normal babies and is associated with substantial lifetime healthcare costs. Prevention of PTB remains limited by the modest accuracy of prediction methods, namely transvaginal ultrasound (TVS) cervical length (CL) measurement and quantitative cervicovaginal fetal fibronectin (FFN) estimation. We report the first substantive study detailing the predictive performance of a cervical probe device based on electrical impedance spectroscopy (EIS) for PTB - the EleCtriCaL Impedance Prediction of Preterm birth by spectroscopy of the cervix (ECCLIPPx) study. We aimed to compare the accuracy of cervical EIS-based prediction of spontaneous PTB with that of prediction using TVS-CL and FFN in asymptomatic women in the mid-trimester. METHODS: We studied asymptomatic women with a singleton pregnancy at 20-22 weeks' and 26-28 weeks' gestation. EIS was performed using a Sheffield Mark 5.0 device that makes measurements in the frequency range 76 Hz to 625 kHz using a small probe housing tetrapolar electrodes. TVS-CL and FFN were also measured. The associations of cervical EIS, TVS-CL and FFN with spontaneous delivery before 37 weeks and before 32 weeks were determined by multivariate linear and non-linear logistic regression analysis. Areas under the receiver-operating-characteristics curves (AUC) plots of sensitivity against specificity were used to compare the predictive performance of all parameters, both in isolation and in combination. RESULTS: Of the 365 asymptomatic women studied at 20-22 weeks who were not receiving treatment, 29 had spontaneous PTB, 14 had indicated PTB and 322 had term birth. At the higher frequencies assessed, cervical EIS predicted spontaneous PTB before 37 weeks with an AUC of 0.76 (95% CI, 0.71-0.81), compared with AUCs of 0.72 (95% CI, 0.66-0.76) for TVS-CL and 0.62 (95% CI, 0.56-0.72) for FFN. Combining all three assessments improved the prediction of spontaneous PTB before 37 weeks (AUC, 0.79 (95% CI, 0.74-0.83)) compared with TVS-CL and FFN alone. Incorporating a history of spontaneous PTB (defined as previous mid-trimester miscarriage or spontaneous PTB (14 to < 37 weeks)) into the cervical EIS prediction model improved the accuracy of prediction of spontaneous PTB before 37 weeks (AUC, 0.83 (95% CI, 0.78-0.87)) and before 32 weeks (AUC, 0.86 (95% CI, 0.82-0.90)). CONCLUSIONS: Mid-trimester cervical EIS assessment predicts spontaneous PTB. Larger confirmatory studies investigating its potential clinical utility and to inform effective preventive interventions are required. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Prognostic Value of Electrical Impedance Spectroscopy (EIS) When Used as an Adjunct to Colposcopy - A Longitudinal Study.

OBJECTIVE: Colposcopy can be used with Electrical Impedance Spectroscopy (EIS) as an adjunct, to assess the presence of High Grade Cervical Intra-epithelial Neoplasia (CIN2+). This analysis of longitudinal data has used the results from women with a negative colposcopy, in order to see if the initial (index) EIS results were able to predict the women who subsequently developed CIN2+. A further objective was to investigate what tissue structural changes might be reflected in the electrical impedance spectra. METHODS: 847 patients were referred with low grade cytologly. EIS measurements were made around the transformation zone of the cervix during colposcopy. Every EIS spectrum was matched to a template representing CIN2+ and the result was positive if the match exceeded a probability index threshold. The colposcopic impression was also recorded. All the women who developed biopsy proven CIN2+ within three years of the index colposcopy were identified. RESULTS: The median follow-up was 30.5 months. Where both CI and EIS were initially positive, there was an increased prevalence (8.13%) of CIN2+ developing as opposed to 3.45% in the remaining patients (p=0.0159). In addition, if three or more EIS spectra were positive there was a higher prevalence (9.62% as opposed to 3.56% p=0.0132) of CIN2+ at three years. The index spectra recorded from the women who developed CIN2+ showed EIS changes consistent with increases in the extracellular volume and in cell size inhomogeneity. CONCLUSION: EIS does offer prognostic information on the risk of CIN2+ developing over the three-year period following the EIS measurements. The changes in EIS spectra are consistent with an increase in cell size diversity as pre-malignancy develops. These changes may be a consequence of increased genetic diversity as neoplasia develops.

Accuracy of detection of high-grade cervical intraepithelial neoplasia using electrical impedance spectroscopy with colposcopy.

OBJECTIVE: To determine if electrical impedance spectroscopy (EIS) improves the diagnostic accuracy of colposcopy when used as an adjunct. DESIGN: Prospective, comparative, multi-centre clinical study. SETTING: Three colposcopy clinics: two in England and one in Ireland. POPULATION: Women referred with abnormal cytology. METHODS: In phase 1, EIS was assessed against colposcopic impression and histopathology of the biopsies taken. In phase 2, a probability index and cut-off value for the detection of high-grade cervical intraepithelial neoplasia (HG-CIN, i.e. grade CIN2+) was derived to indicate sites for biopsy. EIS data collection and analyses were performed in real time and blinded to the clinician. The phase-2 data were analysed using different cut-off values to assess performance of EIS as an adjunct. MAIN OUTCOME MEASURE: Histologically confirmed HG-CIN (CIN2+). RESULTS: A total of 474 women were recruited: 214 were eligible for analysis in phase 1, and 215 were eligible in phase 2. The average age was 33.2 years (median age 30.3 years, range 20-64 years) and 48.5% (208/429) had high-grade cytology. Using the cut-off from phase 1 the accuracy of colposcopic impression to detect HG-CIN when using EIS as an adjunct at the time of examination improved the positive predictive value (PPV) from 78.1% (95% CI 67.5-86.4) to 91.5%. Specificity was also increased from 83.5% (95% CI 75.2-89.9) to 95.4%, but sensitivity was significantly reduced from 73.6% (95% CI 63.0-82.5) to 62.1%, and the negative predictive value (NPV) was unchanged. The positive likelihood ratio for colposcopic impression alone was 4.46. This increased to 13.5 when EIS was used as an adjunct. The overall accuracy of colposcopy when used with EIS as an adjunct was assessed by varying the cut-off applied to a combined test index. Using a cut-off set to give the same sensitivity as colposcopy in phase 2, EIS increased the PPV to detect HG-CIN from 53.5% (95% CI 45.0-61.8) to 67%, and specificity increased from 38.5% (95% CI 29.4-48.3) to 65.1%. NPV was not significantly increased. Alternatively, applying a cut-off to give the same specificity as colposcopy alone increased EIS sensitivity from 88.5% (95% CI 79.9-94.4) to 96.6%, and NPV from 80.8% (95% CI 67.5-90.4) to 93.3%. PPV was not significantly increased. The receiver operator characteristic (ROC) to detect HG-CIN had an area under the curve (AUC) of 0.887 (95% CI 0.840-0.934). CONCLUSIONS: EIS used as an adjunct to colposcopy improves colposcopic performance. The addition of EIS could lead to more appropriate patient management with lower intervention rates.

Role of adiponectin in the development of high fat diet-induced metabolic abnormalities in mice.

The adipokine adiponectin is decreased in severe obesity and is inversely associated with adipose mass. Adiponectin is associated with insulin sensitivity and cardioprotection. Obesity frequently results in the development of a "cardiometabolic syndrome" characterized by increased circulating insulin and leptin, and cardiac hypertrophy and dysfunction. This study examined if adiponectin-deficiency affects the development of metabolic and cardiac abnormalities in response to modest obesity. Mice were studied under normal conditions and with mild cardiac pressure-overload induced by abdominal aortic banding. After surgery, wild type and adiponectin-deficient mice were fed a high-fat diet for 8 weeks (45% energy from fat vs. 10%). In wild type mice the high-fat diet increased fat and whole body mass, which corresponded with elevated circulating insulin and leptin and a decrease the glucose/insulin ratio. On the other hand, in adiponectin-deficient mice the high-fat diet had less impact on body mass and no effect on fat mass, insulin, leptin, or glucose/insulin. There was modest cardiac hypertrophy with aortic banding, but no cardiac dysfunction or effects of adiponectin deficiency or diet. The results suggest that the increase in adipose mass, leptin and insulin induced by a high fat diet is dependent on adiponectin. The lack of accelerated cardiac hypertrophy and dysfunction in the adiponectin-deficient mice subjected to aortic banding and the high-fat diet suggest that adiponectin may not play a major role in protecting the heart during the early stages of diet-induced obesity.

Impedimetric sensing of cells on polypyrrole-based conducting polymers.

Polypyrrole (PPy) is a conducting polymer that may be electrochemically generated with the incorporation of any anionic species, including net-negatively charged biological molecules such as proteins and polysaccharides. In this article, dermatan and chloride-loaded PPy films were prepared on gold sputter-coated coverslips and various skin derived cells were studied on them by electrochemical impedance spectroscopy. Impedance spectra in the frequency range 1-100 kHz were either determined at specific times or impedance was monitored continuously at specific frequencies. An equivalent impedance circuit was fitted to the recorded impedance spectra to obtain parameters whose contributions could be mapped to intracellular and intercellular current pathways, and the membrane properties of cells. Results show cell-induced impedance changes were detected over PPy modified electrodes and were dependent on cell density and type, monitoring frequency, material composition, and treatment. Lower cell densities were detected on PPy when compared with bare gold. Keratinocyte confluence, as determined by impedimetric analysis, was reached more rapidly on PPy than on gold. This was consistent with previous, more cumbersome, biochemical assays. Electrical equivalent circuit analysis provided evidence that the technique may be extended to discriminate cell type because of the intracellular and intercellular resistance, and cell membrane capacitance being related to cell morphology.

The use of electrical impedance spectroscopy in the detection of cervical intraepithelial neoplasia.

The objective of this study was to assess the performance of cervical impedance spectroscopy in the detection of cervical intraepithelial neoplasia (CIN) using the new MKIII impedance probe. A prospective observational study recruited women referred to colposcopy with an abnormal Papanicolaou smear. A pencil probe incorporating four gold electrodes was used to measure electrical impedance spectra from cervical epithelium. Colposcopy examinations, including probe positioning, were video recorded to allow for correlation between results obtained from colposcopic impression, histopathologic examination of colposcopic punch biopsies, and impedance measurements. Cervical impedance-derived parameters R, S, R/S, C, and Fc were assessed to see if significant difference in values obtained in CIN and normal epithelium existed. The performance of the probe in identifying women with CIN was also assessed. One hundred seventy-six women were recruited and 1168 points analyzed. Parameters R, S, and Fc showed significant separation of CIN or squamous intraepithelial lesion (SIL) from squamous, mature metaplastic, and columnar epithelium. Sensitivities of 74% and specificity of 53% can be achieved in identifying CIN 2/3 (High-grade SIL) in screened women. We conclude that cervical impedance spectrometry provides a potentially promising real-time screening tool for CIN with similar sensitivity and specificity to currently used screening tests. Further research is ongoing to develop the probe for potential clinical use.

Study of the optimum level of electrode placement for the evaluation of absolute lung resistivity with the Mk3.5 EIT system.

Inter-subject variability has caused the majority of previous electrical impedance tomography (EIT) techniques to focus on the derivation of relative or difference measures of in vivo tissue resistivity. Implicit in these techniques is the requirement for a reference or previously defined data set. This study assesses the accuracy and optimum electrode placement strategy for a recently developed method which estimates an absolute value of organ resistivity without recourse to a reference data set. Since this measurement of tissue resistivity is absolute, in Ohm metres, it should be possible to use EIT measurements for the objective diagnosis of lung diseases such as pulmonary oedema and emphysema. However, the stability and reproducibility of the method have not yet been investigated fully. To investigate these problems, this study used a Sheffield Mk3.5 system which was configured to operate with eight measurement electrodes. As a result of this study, the absolute resistivity measurement was found to be insensitive to the electrode level between 4 and 5 cm above the xiphoid process. The level of the electrode plane was varied between 2 cm and 7 cm above the xiphoid process. Absolute lung resistivity in 18 normal subjects (age 22.6 +/- 4.9, height 169.1 +/- 5.7 cm, weight 60.6 +/- 4.5 kg, body mass index 21.2 +/- 1.6: mean +/- standard deviation) was measured during both normal and deep breathing for 1 min. Three sets of measurements were made over a period of several days on each of nine of the normal male subjects. No significant differences in absolute lung resistivity were found, either during normal tidal breathing between the electrode levels of 4 and 5 cm (9.3 +/- 2.4 Omega m, 9.6 +/- 1.9 Omega m at 4 and 5 cm, respectively: mean +/- standard deviation) or during deep breathing between the electrode levels of 4 and 5 cm (10.9 +/- 2.9 Omega m and 11.1 +/- 2.3 Omega m, respectively: mean +/- standard deviation). However, the differences in absolute lung resistivity between normal and deep tidal breathing at the same electrode level are significant. No significant difference was found in the coefficient of variation between the electrode levels of 4 and 5 cm (9.5 +/- 3.6%, 8.5 +/- 3.2% at 4 and 5 cm, respectively: mean +/- standard deviation in individual subjects). Therefore, the electrode levels of 4 and 5 cm above the xiphoid process showed reasonable reliability in the measurement of absolute lung resistivity both among individuals and over time.

First case of septicemia due to a strain belonging to enteric group 58 (Enterobacteriaceae) and its designation as Averyella dalhousiensis gen. nov., sp. nov., based on analysis of strains from 20 additional cases.

When enteric group 58 was first described as a distinct new group of Enterobacteriaceae in 1985, there were only five known human isolates: four from wounds and one from feces. In 1996, we investigated the first blood isolate of enteric group 58, a case of sepsis in a 33-year-old woman receiving total parenteral nutrition. Fifteen additional clinical isolates have since been identified at CDC, including several recognized from a collection of "unidentified" strains dating back to 1973. All strains were characterized with a standard set of 49 biochemical tests used for Enterobacteriaceae, and the results were analyzed to determine phenotypic relatedness and best taxonomic fit. Antibiograms were determined as a taxonomic tool. Original identifications provided by submitting laboratories encompassed a wide variety of Enterobacteriaceae, including 14 species in eight genera, the most common being Enterobacter spp., Salmonella spp., Serratia spp., Kluyvera spp., or Escherichia spp. Enteric group 58 strains have been most frequently isolated from traumatic injuries, fractures, and wounds and rarely from feces. Defining its clinical significance and distinguishing infection from colonization requires further study, but our case report indicates that serious systemic infection can occur. The vernacular name enteric group 58 was used from 1985 to 2004. In this paper, we formally name it Averyella dalhousiensis gen. nov., sp. nov., on the basis of its unique phenotype and its unique 16S rRNA gene sequence. These data indicate that enteric group 58 is not closely related to any of the existing genera or species of Enterobacteriaceae. The type strain is designated CDC 9501--97, and a phenotypic definition is given based on all 21 strains.

Detection of emboli in vessels using electrical impedance measurements--phantom and electrodes.

A phantom was constructed to simulate the electrical properties of the neck. A range of possible electrode configurations was then examined in order to improve the sensitivity of the impedance measurement method for the in vivo detection of air emboli. The neck phantom consisted of simulated skin, fat and muscle layers made of agar and a conductive rubber tube mimicking the common carotid artery. The ring-shaped electrodes with a guard electrode showed the highest sensitivity to emboli at short distances.

Electrical bioimpedance readings increase with higher pressure applied to the measuring probe.

Electrical bioimpedance spectroscopy (EBIS) is a technique that uses a probe to calculate the transfer impedance from tissues. This transfer impedance can give information about the normal or pathological condition of the tissue. To take readings, pressure has to be applied to the probe in order to get a good contact between the electrodes and the tissue. We have been using EBIS to investigate the early diagnosis of dysplasia and cancer in the human cervix, oesophagus and bladder. We have found that, with increasing pressure (range used here was approximately 1 kPa to approximately 50 kPa), the resistivity readings increase in a consistent way up to 80%. In this paper, we show how this is a case in three different tissue types (oesophageal, gastric and vesical samples). These increases can be higher than those associated with the pathological changes that we are investigating (non-inflamed columnar tissue, for instance, shows values 50% higher than dysplastic columnar tissue). Finite-element modelling was also used to investigate the effect of volume reduction in the connective tissue or stroma. This simulation suggests no strong correlation between reduction of this structure and increase in resistivity. We hypothesize therefore that these changes may be mainly associated with the squeezing of water from the extracellular space. Finally, as pressure is difficult to control by hand, we raise the issue of the necessity of considering this variable when making EIS measurements.

Estimation of the size of air emboli detectable by electrical impedance measurement.

Non-invasive detection of air emboli in blood is investigated in vitro using a tetrapolar electrical impedance measurement. A cubic tank with a linear array of four electrodes, spaced approximately 1 cm apart down one side, was filled with 0.2 Sm(-1) saline. Bubbles were generated by carbon dioxide gas. Electrical transfer impedance was measured every 8.2 ms at 1.25 MHz. The movement of bubbles was recorded by a video camera, and their sizes and depths from the middle of the array were measured using captured video images. Changes in transfer impedance caused by passage of bubbles were clearly observed and almost identical with those calculated theoretically. Using lead field theory and experimental results, the fundamental limit on the detectable size of bubbles was estimated at the carotid artery, the great saphenous vein and the cephalic vein. The theoretical results showed that a 0.5 mm diameter bubble is detectable at a depth of 5.3 mm, similar to the depth of the great saphenous and the cephalic veins, and a 2.3 mm diameter bubble is detectable at a depth of 21 mm, similar to the depth of the common carotid artery.

Low frequency electrical bioimpedance for the detection of inflammation and dysplasia in Barrett's oesophagus.

Biological tissues undergoing inflammation and dysplasia seem to exhibit changes in the intercellular space that can be sensed using low frequency electrical impedance methods. Basically, low frequency electric current flows through this space and its widening as well as the disruption of the tight junction decrease the resistance, facilitating current flow. The electrical changes accompanying structural changes from columnar tissue to adenocarcinoma in Barrett's metaplastic mucosa and gastric tissue are illustrated using resected tissue from 32 patients. Two hundred and fifty-eight biopsies were analysed, correlating their electrical resistivity (R) at 9.6 kHz and their histopathological interpretation. Compared to non-inflamed non-dysplastic columnar tissue (R = 4.9 ohms m), the results suggest a small but statistically significant decrease of electrical impedance in columnar tissue showing inflammation (R = 4.2 ohms m, p = 0.016) and a larger decrease when dysplasia is present (R = 3.4 ohms m, p = 0.040). If this method is validated further, this technique could be used to obtain guided biopsies from patients undergoing surveillance programmes for Barrett's oesophagus. We aim to refine this technique using a new system with lower frequencies and, possibly, in vitro (cultured cells) and in vivo (rats) models of Barrett's oesophagus.

Modelling of epithelial tissue impedance measured using three different designs of probe.

Impedance measurement is a promising technique for detecting pre-malignant changes in epithelial tissue. This paper considers how the design of the impedance probe affects the ability to discriminate between tissue types. To do this, finite element models of the electrical properties of squamous and glandular columnar epithelia have been used. The glandular tissue model is described here for the first time. Glandular mucosa is found in many regions of the gastrointestinal tract, such as the stomach and intestine, and has a large effective surface area. Firstly, the electrical properties of a small section of gland, with epithelial cells and supportive tissue, are determined. These properties are then used to build up a three-dimensional model of a whole section of mucosa containing many thousands of glands. Measurements using different types of impedance probe were simulated by applying different boundary conditions to the models. Transepithelial impedance, and tetrapolar measurement with a probe placed on the tissue surface have been modelled. In the latter case, the impedance can be affected by conductive fluid, such as mucus, on the tissue surface. This effect has been investigated, and a new design of probe, which uses a guard electrode to counteract this potential source of variability, is proposed.

Electrical impedance tomography (EIT): a review.

Electrical impedance tomography (EIT) has been the subject of quite intensive research for about 20 years but has yet to become established as a routine tool in healthcare. None the less the volume of published research work in this area is still rising. This review takes a broad look at what has been achieved and attempts to give the reader sufficient information to form an opinion as to the likely future for this interesting area of research.

A study of the morphological parameters of cervical squamous epithelium.

Electrical impedance spectroscopy is a technique that has been investigated as a potential method for the diagnosis of epithelial carcinomas. Finite element modelling can provide an insight into the patterns of current flow in normal and pathological epithelium and hence aid in the process of probe design optimization. In order to develop a finite element model of the structure of normal and precancerous cervical squamous epithelium, it was first necessary to obtain the mean values and ranges of a number of morphological tissue parameters. The most important parameters in discriminating normal from neoplastic tissue were identified as being cell size and shape distribution, nuclear-to-cytoplasmic volume ratio and volume of extracellular space. A survey of the literature revealed an absence of reliable quantitative data for these parameters. We therefore present the results of our own basic image analysis on normal and pathological tissue sections, which we hope will be of use to other workers wishing to model cervical squamous epithelium, or other similar tissue structures.

Electrical impedance measurements: an objective measure of prelabor cervical change.

OBJECTIVE: To investigate the use of electrical impedance measurements of the pregnant cervix as an objective measure of cervical favorability (Bishop score > or = 5). METHODS: A prospective study of 86 women, investigating electrical impedance measurements of the pregnant cervix at the time of induction of labor. Transfer electrical impedance measurements were made by placing a tetrapolar pencil probe of 8 mm in diameter on the surface of the cervix. A Bishop score was determined simultaneously. RESULTS: A mean resistivity (standard error of the mean) of 7.03 (6.01-8.04) omega(m) was measured for the unfavorable group and 5.34 (4.61-6.07) omega(m) for the favorable group. This was a statistically significant difference (p = 0.016). CONCLUSION: We highlight the ability of this safe, painless technique to differentiate the favorable from the unfavorable cervix at induction of labor.

Neonatal lungs: maturational changes in lung resistivity spectra.

The electrical resistivity of lung tissue can be related to the structure and composition of the tissue and also to the air content. Electrical impedance tomographic measurements have been used on 155 normal children over the first three years of life and 25 pre-term infants, to determine the absolute resistivity of lung tissue as a function of frequency. The results show consistent changes with increasing age in both lung tissue resistivity (5.8 ohm m at birth to 20.9 ohm m at 3 years of age) and in the changes of resistivity with frequency (Cole parameter ratio R/S=0.41 at birth and 0.84 at 3 years of age). Comparison with a lung model showed that the measurements are consistent with maturational changes in the number and size of alveoli, the extracapillary blood volume and the size of the extracapillary vessels. However, the results show that the process of maturation is not complete at the age of three years.

Neonatal lungs--can absolute lung resistivity be determined non-invasively?

The electrical resistivity of lung tissue can be related to the structure and composition of the tissue and also to the air content. Conditions such as pulmonary oedema and emphysema have been shown to change lung resistivity. However, direct access to the lungs to enable resistivity to be measured is very difficult. We have developed a new method of using electrical impedance tomographic (EIT) measurements on a group of 142 normal neonates to determine the absolute resistivity of lung tissue. The methodology involves comparing the measured EIT data with that from a finite difference model of the thorax in which lung tissue resistivity can be changed. A mean value of 5.7 +/- 1.7 omega(m) was found over the frequency range 4 kHz to 813 kHz. This value is lower than that usually given for adult lung tissue but consistent with the literature on the composition of the neonatal lung and with structural modelling.

Modelled current distribution in cervical squamous tissue.

The electrical properties of cervical squamous epithelium have been modelled in the frequency range 100 Hz to 10 MHz. The hierarchical modelling process comprises a cellular level stage, which includes detailed models of cells typical of different depths within the epithelium and a tissue model, which utilizes electrical properties obtained from the cellular models. The fit between the modelled and measured impedance spectra and the distribution of current with depth depends on the macroscopic model structure. Both the properties of the basement membrane and the presence of a surface mucus layer are shown to have a significant effect. The best fit with measured data is obtained when a 10 microm thick, high-conductivity surface layer is included in the tissue model.