Finally, a physical experiment is performed. When no human is present, we compare the results from the Type LP-2000 measured with Narda EFA-300 and the simulated value to verify the accuracy of the Type LP-2000. For the case of an approaching human body, the correction coefficient kb* = 1.9094 is obtained by comparing the data measured with the Type LP-2000 to the simulated value. The correction coefficient obtained from the experiment  is highly consistent with that obtained from the simulation . Two experimental programs are set; under these programs, the excitation voltages and distance measuring points are regulated to produce different electric field intensities. Using kb = 1.9094, the corrected measurement of electric field intensity can accurately reflect the original environmental electric field intensity, and the maximal error is less than 6% in all the data comparisons. These results verify the effectiveness of our proposed method.According to the operating specifications of existing electric field measuring instruments, measuring technicians must be located far from the instruments to eliminate the influence of the human body occupancy on a spatial electric field. Nevertheless, in order to develop a portable safety protection instrument with an effective electric field warning function for working staff in a high-voltage environment, it is necessary to study the influence of an approaching human body on the measurement of an electric field and to correct the measurement results. A single-shaft electric field measuring instrument called the Type LP-2000, which was developed by our research team, is used as the research object in this study. First, we explain the principle of electric field measurement and describe the capacitance effect produced by the human body. Through a theoretical analysis, we show that the measured electric field value decreases as a human body approaches. Their relationship is linearly proportional. Then, the ratio is identified as a correction coefficient to correct for the influence of human body proximity. The conclusion drawn from the theoretical analysis is proved via simulation. The correction coefficient  Strong electric fields exist around high-voltage electrical equipment. Existing research shows that strong power-frequency electric fields have potential harmful effects on human health and safety . TherefoHowever, power system practitioners are likely to be exposed to strong electric fields in a short amount of time because of their handling of high-voltage electrical equipment. Excessively strong electric field intensities result in discomfort and panic for practitioners, and such effects are harmful to personal safety and can lead to disoperation ,8,9. If Several power-frequency electric field measuring instruments are available for commercial purposes ; they inThe influence of the human body on electric field measurement has attracted increasing attention in recent decades. In , the exiIn the present work, we build an equivalent circuit that explains the principle of electric field measurement on the basis of a single-shaft electric field measuring instrument called a Type LP-2000 , which wD is the distance between two polar plates and The core of Type LP-2000 comprises a couple of metal polar plates that can be seen as a capacitor. Inductive charges with the same frequency appear on the metal plates when the measuring sensor is put into the alternating electric field. Then, the induced voltage can be measured. The relation between the induced voltage and the electric field intensity at the measuring point is linearly proportional when the physical dimension of the planar plate capacitor is sufficiently small .(1)U˙C=The equivalent circuit of the measuring system for obtaining the induced voltage is shown in C is the inherent capacitance of the plate capacitor, MC is the capacitance of the measuring capacitor, Ri is the input resistance of the measuring circuit, and In irmsU of crmsU of By further processing the circuit, the RMS value Erms of the electric field, that is,By combined Equations (1) and (3), we obtain the RMS value i.e., MC >> C; thus, Equation (4) can be simplified toK is a ratio coefficient written asIn the measurement circuit, the measuring capacitance is at the nF-level and is much larger than the inherent capacitance of the sensor, i, C, CMR, and D are all fixed values; thus, K is a constant. When the parameters of the measuring circuit are all fixed, the electric field intensity in the location of the parallel-plate capacitive sensor is proportional to the output voltage of the sensor. The electric field intensity Erms of the observation point can be obtained by measuring Uirms.In Equation (5), ω, 5–106, and the conductivity is about 0.1 S/m [In practical measurements, when an individual approaches the sensors, the measured electric field intensity changes because the human body possesses complex tissues. The relative dielectric constant of living tissue in a power—frequency environment is about 10 0.1 S/m . The hum 0.1 S/m .The relationship between the human body and the measuring sensor of the plate capacitor is shown in A and PolarB are the two polar plates of the capacitor, and D is the distance between the two plates, with the gap filled with epoxy resin. The distance between the human body and PolarB is d1, with an air medium in the middle. The body with PolarA and body with PolarB form the equivalent capacitors, C1 and C2, respectively. The equivalent circuit of the measuring system in the case of an approaching human body is shown in In MC is much larger than C and C1; therefore,bK is also a ratio coefficient written asAccording to bK is a constant, and the output voltage of the sensor remains proportional to the electric field at the measuring point.Equation (7) shows that when the measuring parameters are fixed, MC + C2 > MC and (C1C)/(C1 + C) < C1, bK > K. Moreover, we note that iU*rms < Uirms if Erms is constant. In other words, the measured induced voltage decreases when a human body approaches the electric field measuring sensor. Without correction, the measured electric field intensity becomes smaller than the physical truth.By comparing Equations (5) and (7), we observe that bk can be defined asIn sum, the correction coefficient bk.Thus, the spatial electric field intensity in the absence of a human body can be obtained by using the electric field intensity measured with the portable Type LP-2000 in real time multiplied by the correction coefficient The simulation model is set up with the software Ansoft/Maxwell, and most of the simulation parameters are set on the basis of the physical experiment condition shown in Different electric field intensities are produced when different levels of sinusoidal voltage with power-frequency are applied to the power transmission line. In the simulation model, the power transmission line is a copper conductor with a diameter of 14 mm and a distance of 122 cm from the ground. Observation point P is at the same level as the conductor and at 53 cm from the conductor in the horizontal distance.The simulation model of the plate capacitor is shown in In addition, the condition of the bottom boundary is set as grounding, and the boundary conditions of the other five surfaces are set as the balloon boundary with the electrical potential set to zero at infinity during the simulating.P is evenly distributed. After the placement of the sensor, the electric field at the four corners of the sensor become significantly distorted and enhanced, whereas the surface electric field outside of the polar plates is slightly enhanced [enhanced ,22. The E0 and electric field Erms after placing the measuring sensor at point P when different levers of excitation voltage are generated.The data in Erms and E0. Their relation can be expressed mathematically as0 is the correction coefficient between E0 and Erms. Here, k0 = 3.2464.We assume that the height of the approaching individual is 176 cm. Given that the individual’s shoes are isolated, the thickness of the insulating materials is assumed to be 2 mm during the simulation so that the person does not directly come into contact with the ground. The measuring sensor is fixed on the person’s arm, and its center is located at point P, similar to that shown in As shown in i.e., Erms and E*rms respectively) at point P when different levels of excitation voltage are generated.The data in Erms and E*rms can be expressed asbk is the correction coefficient regarding the influence of the human body on measurement; it is the same as that in Equation (9). Here, kb = 1.8010.Considering the dual influence of the measuring sensor and human body, we can correct the electric field intensity measured with the portable Type LP-2000 twice on the basis of Equations (10) and (11) to reflect accurately the original environmental electric field.The experimental platform composed of a voltage regulator, step-up transformer, conductor and insulator is shown in ELP-2000 of Type LP-2000, the measured result EEFA-300 of Narda EFA-300, and the original electric field E0 obtained via stimulation. The measuring errors are defined asIn the absence of a human body, the comparisons are conducted among the measured result The statistical data and error analyses are shown in Given the interference produced by other electric equipment in the laboratory, certain errors emerge between the measured electric field intensity and the stimulation results. However, the value measured by Type LP-2000, in general, is relatively close to the stimulation value and the value measured by Narda EFA-300. Therefore, the accuracy of Type LP-2000 is verified.LP-2000 of Type LP-2000 and the original electric field E0 in the stimulation are listed in i.e., kb* = 1.9094, which is close to kb = 1.8010 as obtained in the stimulation. The error results from the electromagnetic interference in the experimental environment.E*LP-2000 by using the correction coefficient kb* = 1.9094. The comparison between the corrected measured data E*LP-2000 and the original electric field E0 is shown in The measured result is corrected to obtain the corresponding E*LP-2000 are obtained by using the correction coefficient kb* = 1.9094. The original electric field E0 in the simulation and the corresponding error values are listed in As most of the experimental conditions are kept identical to those in the previous experiment and the excitation voltage of the conductor is set to 12 kV, different electric field intensities can be obtained at different measuring points by regulating the distances between the measuring point and the conductor, as shown in b obtained in the simulation was 1.8010, and the correction coefficient kb* obtained in the experiment was 1.9094; the two values can be considered approximately equal. Two experimental programs were established; under these programs, the excitation voltages and the distance measuring points were regulated to produce different electric field intensities. Using kb* = 1.9094, the corrected measured electric field intensity accurately reflected the original environmental electric field intensity, and the maximal error was less than 6% in all the data comparisons. These results verify the effectiveness of our proposed correction method.The influence of the human body on electric field measurement was investigated by using the Type LP-2000 single-shaft electric field measuring sensor developed by our research team. The results obtained from the principal model, simulation, and physical experiment showed that as an individual approached the sensor, the measured electric field intensity became less than the original environmental electric field intensity in the absence of a human body; however, both of them were proportional. The original environmental electric field intensity was obtained by using the electric field intensity measured with the portable Type LP-2000 in real time and multiplying its value by the defined correction coefficient. The correction coefficient kAdditionally, the single-shaft sensor proposed in this study may be more suitable for the electric field generated by transmission lines than for that generated in substation. Therefore, the 3D measurement sensor will be explored in our future research.


Benzodiazepines are one of the most frequently prescribed psychotropic drugs during pregnancy. Despite the fact that these drugs have been in use for a long time, there is still debate about the safety for the developing fetus and neonate. We present a case of a newborn with an apparent life-threatening event shortly after birth following maternal temazepam use during labour and advise to be reserved in prescribing any dose of any kind of benzodiazepine during labour. Benzodiazepines are one of the most frequently prescribed psychotropic drugs during pregnancy . However2 of 31 mmHg, HCO3− of 16.9 mmol/L, and base excess of −7.4. Investigation for inborn errors of metabolism did not show any abnormalities. Blood culture was taken and antimicrobial therapy was started empirically. Culture did not show any microorganisms and microbial therapy was stopped 48 hours after treatment initiation. Brain ultrasound did not show any abnormalities. Initially cerebral function monitoring (CFM) showed burst suppression and changed to continuous low voltage without signs of epileptic activity in 2-hour time (μg/L (20–100 μg/L) was found six hours since maternal temazepam intake. Three days later the neonate was fully recovered and could be discharged from the NICU.A 38-week-old female neonate, born via a spontaneous vaginal delivery guided by a midwife at home, was presented to our Neonatal Intensive Care Unit (NICU) after an episode of apnea, bradycardia, and hypotonia one hour postpartum. The mother, a healthy 30-year-old gravida 3 para 1 had an uneventful pregnancy during which she did not use any medication. Cervix dilation progressed slowly and the midwife was prescribed temazepam 20 mg to prevent maternal exhaustion in the first stage of labour. However, in contrary to what was expected, labour progressed quickly and three and a half hours since temazepam ingestion mother gave birth to a female infant newborn. Apgar Scores 1 and 5 minutes after birth were both 10 out of 10. Birth weight was 3650 gram (+1 SD), length was 34 cm (+1 SD), and head circumference was 34 cm (−1 SD). Breastfeeding was initiated immediately after birth. One hour later the baby was found nonbreathing, pale, and hypotonic on mothers breast. The attending midwife initiated neonatal resuscitation. Chest compressions were started in combination with ventilation because of persisting bradycardia after inflation breaths. Heart frequency normalized and spontaneous breathing returned. She was intubated and transported by the mobile medical team to our hospital in stable condition. Neurologic examination at arrival at the NICU showed a normal muscle tone and symmetric movements of all limbs. Pupils were isocore and reactive to light. Sucking reflex was present, while grasp reflex was absent. Initial blood workup showed normal values for glucose and electrolytes but a venous serum lactate of 8.6 mmol/L. Capillary blood gas showed a pH of 7.35, pCOour time . Supportγ-aminobutyric acid (GABA) at the GABAA receptor causing an inhibitory effect on neurotransmission by diminishing the chance of a successful action potential resulting in the pharmacodynamic effects described before. Temazepam is metabolized by the liver through glucuronidation by uridine diphosphate glucuronosyltransferase (UGT) and excreted through the kidneys [Benzodiazepines have hypnotic, anxiolytic, anticonvulsive, and muscle relaxant abilities. They are mainly used for sleeping and anxiety disorders. In addition, they are used as anticonvulsant and as hypnotic drug during medical treatment . Benzodi kidneys . In newbWhen benzodiazepines are used during the last trimester of pregnancy a floppy infant syndrome and withdrawal syndrome have been described . Floppy This case presents a newborn with an apparent life-threatening event shortly after birth most probably caused by maternal temazepam use during labour. A single dose of 20 mg temazepam resulted in a supratherapeutic plasma level in the newborn. Since 20 mg temazepam is considered a small dose, we advise to be reserved in prescribing any dose of any kind of benzodiazepine during labour.


Infant growth is defined as a positive change in body size over a period of time, and is a sensitive predictor of social health. The most effective way to determine child growth is by measuring birth weight and constructing a weight growth trajectory. Many studies were conducted on the effects of different factors on birth weight, but investigations of these effects on growth trajectory are really sparse. This study analyzes longitudinal data to determine factors affecting growth trajectory and used LMS chart for comparing children.In a cohort study, 256 neonates born in 2004 in Maku, Iran, were recruited and were followed until 2009.The weight of the neonates were measured at 12 occasions from birth, until the age of 5 years. A growth curve model was used to determine the affecting factors. The parametric LMS method was used to construct the reference centiles curve of the weight .The findings show that while controlling the other factors, birth region, breast feeding duration, mother’s education and infants’ gender significantly influenced the longitudinal weight rate. However, other variables did not reveal any significant association with growth. The growth charts increased rapidly from birth to 5 years of age for both sexes. It was observed that male children grew faster than females, through the first year of age up to 5 years.Although every child has a growth potential, this capacity could be influenced by various factors and can be compared with other infants through a growth chart. We used longitudinal data to obtain the risk factor of growth trajectory. LMS method was also used for description of growth. Thereafter, the weight chart of Shiraz, southern Iran’s corresponding infants, was compared. Infant growth is defined as a positive change in body size over a period of time, and it is a sensitive predictor of an individuals’ health . An inapConversely, many researchers have performed cross-sectional studies to evaluate the birth weight of infants and growth, but longitudinal studies are very limited even in the developed world . LongituTherefore, the aim of this study was to investigate the effect of different factors on the weight growth trajectory of preschool children of Maku birth cohort, who were followed longitudinally from birth to 5 years of age, using growth curve modeling. We also intended to present the growth weight of the birth cohort, and compare the relevant measures with that of Shiraz’s study.Maku, a city in West Azerbaijan, is located in the northwest of Iran and borders Turkey. It enjoys a semi-arid and cold climate with a population of about 200,000 including 8.1% of the total population of the province. A birth cohort of 256 neonates (124 boys and 132 girls) without apparent congenital anomaly born in Maku and its village in 2004, were recruited randomly using a multi-stage random sampling procedure from all existing maternity clinics. The subjects were followed for five years until 2009 and visited at the health centers periodically. A questionnaire on demographic and health status of the neonates and their parents including anthropometric measurements was completed. The subjects’ weights were measured by a trained auxologists at birth*; one, two, four, six, nine months and 1, 1.5, 2, 3, 4 and 5 years of age. Weight was measured in light clothing to the nearest 10 g until the second year of age, using baby scale and onwards to 0.1 kg.The effect of parents’ age, education and occupation, child rank, age of using supplement food, breast feeding duration, gender and region (city or village) was studied in this survey.However, the result of this study was compared with 317 Shirazi infants (164 girls and 152 boys) who were selected randomly among those born at the 14 maternity clinics of Shiraz in 1996 and followed for two years. Their weights were measured at birth, 1. 5, 3, 4.5, 6, 8, 10, 12, 15, 18, 21 and 24 months , x is a matrix of fixed effect variables ), z denotes matrix of random effects variable (intercept and Infants’ age), while β and u are parameters of fixed and random effects, respectively. Parameters were estimated using restricted maximum likelihood .Furthermore, the LMS method  was applSPSS version 16  was used to analyze the general aspects of the data. Growth curve model was performed using SAS 9.2 and was used to determine the influential factors. LMS chart maker and Excel softwares were used for construction of centileAlmost all mothers were housewives [247 (96.5%)], of whom about three fourth delivered their babies normally [189 (73.8%)] and the rest by cesarean section [67(26.2%)]. Over four fifth of the mothers stated that they had planned pregnancy [221(86.3%)]. Illiteracy rate in fathers and mothers were 12.9 and 26.6%, respectively. As shown in The intercept variance and the age slope variance are significant (p<0.0001), suggesting that a model that allowed age as random, would be better than the model considering age as fixed. In this study, we also compared the weight curve of Maku with Shirazi infants  by LMS mWe used growth curve model analysis of growth data from a large prospective birth cohort and observed the marked effects of sex, mother education, birth region and birth feeding duration. In most of the previous studies, the identification of factors was carried out via repeated measures and centile statistics. But growth curve modeling allows analysis of unbalanced repeated measures and longitudinal data for this purpose .In this study, gender had a significant effect on weight growth trend, such that boys were significantly weightier than girls from birth up to 5years of age. In the studies of Mother education had a significant effect on weight growth trend, such that infants of educated mothers were heavier than their counterparts. In Hosseini et al.’s study, the birth weight of low educated mothers was significantly lower than the children of mothers with higher education , mother’s age had no significant effect on child obesity risk in 6-year-old children  to assess the association between various environmental factors and response variables was performed in this study but growth could be affected by genetic, nutritional, hormonal and other environmental factors . The authors suggest that these factors be analyzed in future studies. Future studies can also report weight for height or weight for length instead of weight for age because this also is an appropriate measure during infancy. It is suggested that one should be cautious about the much needed samples, in order to report LMS chart in subgroups of the interested factors.In conclusion, we presented growth weight chart in North East Iranian infants by analyzing longitudinal data with the parametric LMS method. Also, the factors affecting growth weight that is useful in policy making for the development of individual health in the society were determined.


Diffusion tensor imaging (DTI) has been shown  to be exb = 770 smm-2 (+b0) with 1 mm isotropic resolution.3D DTI of a whole human heart was performed on a 3T Siemens Skyra using a monopolar spin echo sequence with 30 diffusion directions at ky-kz plane of the 3D Cartesian acquisition was applied retrospectively to the fully-sampled DTI dataset with sampling ratios 50, 33, 25, and 20% .Efficient variable-density under-sampling of the Diffusion tensor data was reconstructed and the left-ventricular wall was analyzed. Maps of fractional anisotropy (FA), mean diffusivity (MD), and helix angles (HA) were computed for the fully-sampled and reconstructed under-sampled datasets. To evaluate the accuracy of FCSA CS, root mean square errors (RMSEs) of FA, MD, and HA were estimated between the full-sampled and the accelerated data-sets. All computations were performed using custom-made software in Matlab.Figure We have demonstrated that CS using FCSA has potential to shorten acquisition times of cardiac DTI without compromising accuracy. These results can be used to minimize patient discomfort and mitigate growing healthcare costs through increasing contemporary scanner throughput.This work was supported by the National Institute of Health Research Cardiovascular Biomedical Research Unit at the Royal Brompton Hospital and Imperial College, London.


Congenital vallecular cyst is a rare entity and may present with acute airway obstruction. This is a case of congenital vallecular cyst presenting with airway compromise requiring immediate management. The epidemiology, pathogenesis, and clinical presentation of vallecular cysts are discussed as well as the diagnosis and management. Vallecular cysts present in neonates or infants . The patA 2-month-old girl was referred from the general practitioner to the Ear, Nose, and Throat Clinic with the preliminary diagnosis of laryngomalacia. She is a full term, normal delivered baby with a birth weight of 2.8 kg. She is on both breast and bottle feeds. She presented with a history of noisy breathing for 15 days which worsened during feeding. On examination, her weight was 3.5 kg, which falls below the 3rd percentile on the growth chart. She was afebrile and the rest of the vitals were normal. She was able to maintain an oxygen saturation of 96% at room air. She had inspiratory stridor with suprasternal and intercostal retraction. Flexible upper endoscopy showed a cystic lesion in the vallecula, about 1 cm in size. The cyst was pushing the epiglottis backward over the glottis and compromising the airway .CT scan imaging was done on the same day and reported a retroglossal fairly defined rounded nonenhancing hypodense cystic lesion measuring about 9 mm, seen projecting into oropharynx. No soft tissue component was noted. A differential diagnosis of thyroglossal or retention cyst was suggested and clinical correlation was advised Figures , and 4.Thyroid function test was done and showed normal results.The patient was taken to the operating theater and a diagnostic direct laryngoscopy under general anesthesia demonstrated a cystic mass in the vallecula. The cyst originated from the lingual surface of the epiglottis and partially obscured the laryngeal inlet. The aryepiglottic folds, vocal cords, and subglottic region were normal, excluding other associated laryngeal pathologies. Laryngeal intubation was possible and tracheostomy was not needed. A microscope was used to magnify the surgical field and optimize visualization. The cyst was aspirated and contained a clear, transparent fluid. Aspiration was followed by partial cyst excision using microlaryngeal instruments. The cyst was grasped using a cups forceps and partially excised using micro laryngeal scissors. There was minimal bleeding from the excision margins. This was controlled by applying mild pressure using absorbent cotton gauze balls. The remaining cyst margins were then cauterized using electrocautery.Histopathology showed a benign cyst underneath the stratified squamous epithelium and underlying edematous stroma. The cyst is lined by flattened squamous epithelium, devoid of contents. There was no inflammation or malignancy and a final diagnosis of benign supraglottic cyst was given. Staphylococcus aureus. The organisms were resistant to penicillin, cloxacillin, and erythromycin and sensitive to trimethoprim sulfamethoxazole, tetracycline, and cephalexin. The patient was started on the appropriate antibiotic treatment according to the sensitivity results.Microbiology culture of the aspirated fluid grew coagulase negativePostoperative follow-up showed complete recovery and at 3 months of follow-up the patient had no stridor and was thriving well. A flexible upper endoscopy showed no evidence of cyst recurrence and the laryngeal inlet was clearly visualized .Vallecular cysts have been described as retention cysts which form due to ductal obstruction of the mucous glands or minor salivary glands in the vallecula and tongue base .The lingual surface of the epiglottis has been described as the most common location . This isVallecular cyst is a rare entity and accounts for 10.5% to 20.1% of all laryngeal cysts  and ProwThe usual presenting symptoms include stridor, feeding difficulty, failure to thrive, dysphonia, or respiratory distress , 10. AltIn comparison, the patient in this report presented with stridor which worsened during feeding. She had poor weight gain and her weight fell below the 3rd percentile.The clinical presentation of vallecular cyst may be further complicated by the presence of coexistent laryngomalacia which will influence the surgical plan of management for the patient . In thisIn one case report, there was total absence of any functioning thyroid tissue which was detected by the thyroid scan . ThyroidThyroid function test was done for the patient in this report and was found to be normal.Other differential diagnosis included cystic hygroma, lymphangioma, haemangioma, teratoma, hamartoma, dermoid cyst, thyroid remnant cyst, and thyroglossal duct cyst –13.Histologically, vallecular cyst is lined with squamous epithelium and contains respiratory epithelium with mucous glands . SimilarThe initial radiologic investigation may include the neck ultrasound which will confirm the cystic nature of the lesion. However, to more accurately delineate the size and extent of the cyst, CT scan and MRI are necessary . On CT sIn cases where fetal vallecular cyst is suspected on antenatal ultrasound, a fetal MRI may be done. This will conclude the diagnosis and plan for perinatal intervention and parental counseling , 15.Direct laryngoscopy remains as the gold standard for definitive diagnoses of laryngeal cysts . Direct 2 laser, coblation, tonsillar snare, microdebrider, or microlaryngoscopic instruments [Various surgical techniques have been described for the management of vallecular cysts; these include aspiration, marsupialization, and excision , 17. Martruments , 18, 19.Vallecular cyst is rare; yet it may present as an acute life threatening emergency due to sudden airway obstruction. Otolaryngologist and general practitioners as well as other health care providers must be aware of this potentially fatal pathology so that timely lifesaving measures are initiated.


Lactobacillus was decreased at birth in infants with chorioamnionitis and in preterm infants who subsequently went on to develop lung disease. Our results, taken together with previous literature indicating a placental and amniotic fluid microbiome, suggest fetal acquisition of an airway microbiome. We speculate that the early airway microbiome may prime the developing pulmonary immune system, and dysbiosis in its development may set the stage for subsequent lung disease.Alterations of pulmonary microbiome have been recognized in multiple respiratory disorders. It is critically important to ascertain if an airway microbiome exists at birth and if so, whether it is associated with subsequent lung disease. We found an established diverse and similar airway microbiome at birth in both preterm and term infants, which was more diverse and different from that of older preterm infants with established chronic lung disease (bronchopulmonary dysplasia). Consistent temporal dysbiotic changes in the airway microbiome were seen from birth to the development of bronchopulmonary dysplasia in extremely preterm infants. Genus  Microbiome analysis based on sequencing of 16S ribosomal RNA genes characterizes bacterial species present both in terms of their identities and relative abundance in contrast to traditional microbiological approaches that are restricted to analyzing species that are readily cultured13567The demographics and clinical characteristics of enrolled patients in the Discovery Cohort are shown in The validation cohort was also categorized based on their pulmonary outcomes, into infants who did not go on to develop BPD  or the ones who later developed BPD . The demographics and clinical characteristics of enrolled ELBW patients for the validation cohort are shown in To determine the temporal changes in airway microbiome, we collected serial tracheal aspirates (TA) at various time points from birth until the development of BPD in 5 infants from the discovery cohort.We were able to detect and characterize bacterial DNA in tracheal aspirates of all ELBW and FT infants soon after birth  and 2. AFirmicutes and Proteobacteria on the first day of life, in addition to the presence of Actinobacteria, Bacteroidetes, Tenericutes, Fusobacterium, Cyanobacteria, and Verrucomicrobia  was collected on day 1 in 4 of the 5 patients , whereas in the 5th patient the first sample was collected on day 5. The demographics of these infants are given in Firmicutes and increase in abundance of Proteobacteria over time  . The firver time .Of the 23 ELBW infants in the discovery cohort, 15 (65%) were born by CS and 8 (35%) by vaginal delivery. There were no statistical differences between the airway microbiota of ELBW infants born by CS compared to the ones born by vaginal delivery .Lactobacillus was seen in infants exposed to chorioamnionitis as compared to infants not exposed to chorioamnionitis  had histological chorioamnionitis. The microbiome of infants with versus without histological chorioamnionitis differed at the genus level but not at the phylum level. A decreased abundance of genus ELBW infants from both our discovery cohort and validation cohort were subdivided into two groups based on their pulmonary outcomes into either BPD Resistant or BPD Predisposed.Lactobacillus was less abundant in BPD Predisposed infants at birth, compared to the BPD Resistant infants  and BPD Predisposed (7 infants). Both groups were similar in demographic characteristics . ConsistLactobacillus, in both discovery and validation cohorts.Using a highly specific limulus amebocyte lysate (LAL) endotoxin assay we determined endotoxin  concentrations in TA. Endotoxin expression was significant increased in infants with established BPD compared to infants at birth , p = 0.1In this study, we evaluated the airway microbiome of extremely preterm and term infants soon after birth and in preterm infants with established BPD. A major novel finding was that the airways have a diverse microbiome even at birth regardless of gestational age. To date, it has been considered that infant mucosal surfaces are populated by skin, vaginal, and intestinal microbes derived from the motheret al.Staphylococcus, Ureaplasma parvum, and Ureaplasma urealyticum were the most frequently identified dominant organisms, among other identified organisms like Pseudomonas, Enterococcus, and Escherichia. Lohmann et al.In the absence of direct access to the newborn lung tissue and due to the inability to obtain broncheoalveolar lavage fluid in newborn infants, tracheal aspirates are a surrogate for evaluation of the processes in the lower airways and distal lungs. To date, two studies have utilized culture independent methods to detect airway organisms in preterm infants. In a study of 10 infants, Mourani Proteobacteria in infants established BPD was marked by a corresponding increase in endotoxin levels, which adds validity to our microbiome analysis.A strength of our study was the sterile collection of tracheal aspirate samples from intubated ELBW and FT infants at or within six hours of birth, thus reducing the chances of contamination or postnatal colonization. Only samples with >1000 sequence reads were utilized for the qualitative analysis, thus further reducing the chances of erroneous results. Samples with low bacterial biomass were discarded. The increase in Lactobacillus abundance in airway microbiome of infants born to mothers with chorioamnionitis. Gritz and BhandariLactobacillus spp. in preterm infants. Also, as chorioamnionitis is an independently associated risk factor for BPDLactobacillus abundance at birth in the airways of BPD-Predisposed ELBW infants as compared to BPD-Resistant infants. This finding is congruent with findings of Lynch et al.1516Lactobacillus spp. into germ-free mice, which responded by improvement in alveolar developmentLactobacillus abundance at birth in airway microbiome was found to be predictive of BPD in the validation cohort as well. Our results indicate that the respiratory microbiome at birth could potentially be used for prognosis, and may potentially be modulated perhaps using “respiratory probiotics” for therapeutic interventions in preterm lung disease. Although it is known that mode of delivery can shape the acquisition and structure of the skin microbiota in newbornset al.et al.10222324In this study we employed genomic approaches rather than culture, and utilized separate development and validation cohorts to explore the predictive role of airway microbiome at birth for the future development of BPD. A central finding was the decreased Staphylococcus abundance at birth in the airways of BPD - Predisposed ELBW infants in our discovery cohort, which was not validated in the samples from our second site. Also, TAs might not represent the true microbiome of the distal lungs and could contain oral microbiota or aspirated gastric microbiota in addition to airway microbiota. Hence we employed our research strategy of very early (at birth or within 6 hours) collection of TA samples, when none of the infants were feeding. In addition we used samples with only >1000 sequence reads. A limitation of our study is the absence of “normal” full term controls to compare with diseased group, as normal infants do not get intubated. Although our FT infant cohort might not be the perfect controls, they were the only and the closest available options. Another limitation is the qualitative nature of our study, as we have not performed individual bacterial quantifications.Although all attempts were made to collect TA specimens in a sterile fashion, there is a possibility that contamination could have occurred as inhaled microbiota could contribute to the airway microbiomeProteobacteria and decreased Firmicutes in airway microbiome over time, despite multiple courses of antibiotics at different time points. Genus Lactobacillus has been known to have strong anti-inflammatory properties2829303132Proteobacteria and decrease in Firmicutes such as Lactobacillus may contribute to the airway inflammation associated with BPD and resulting impairment in lung development. The serial tracheal sample findings in our study do show that the initial lung microbiome in infants tends to evolve over time. It is likely that the postnatal changes in the airway microbiome are driven by exposure to environmental microbes, and is modulated by antimicrobial therapy to the infant.Serial microbiome analysis from the same patient may yield useful information on temporal changes leading to BPD. Hence we collected TA samples from extremely preterm infants in a serial fashion, and found consistent temporal changes in the airway microbiome from birth until the development of BPD. These infants were of the smallest viable gestational ages from 22–24 weeks, and hence were the most prone to develop BPD. All five infants had similar temporal changes in the airway microbiota – that of increasing abundance of Further understanding of the role of the complex airway microbiome in preterm infants requires investigation of the interactions among genes of the microbiota and host. There is a possibility that the microbiome may have beneficial cross-talk with the host preterm lung and the reduced diversity of microbes resulting from intensive care interventions makes the host lung more susceptible for injury and inflammation. The lung microbiome, similar that of other compartments, may be manipulated to correct dysbiosis and restore “healthy” microbial communities via use of probiotics, prebiotics or antibiotics. Early life gut microbial alterations include changes in the production of microbial-derived metabolites, and a similar phenomenon may happen in the lungsWe conducted a prospective observational cohort study between October 2014 and March 2015 at the University of Alabama at Birmingham (UAB) Regional Neonatal Intensive Care Unit. The Institutional Review Board of University of Alabama at Birmingham approved the human subject protocol and granted waiver of consent status as samples were obtained from routine clinical care and were handled in a completely de-identified manner. The methods were carried out in accordance with the approved guidelines. Further details are in the online data supplement.Inborn and outborn ELBW and FT infants who underwent endotracheal intubation and mechanical ventilation at birth (in the first 6 hours of life) were included. In addition, infants diagnosed with moderate or severe BPD at 36 weeks’ PMA defined using the physiologic definitionNo specific exclusions were made. Chorioamnionitis was determined by placental histopathology and all mothers with chorioamnionitis were administered antibiotics prenatally.We utilized patient samples from Philadelphia as a validation cohort to confirm our data. TA samples from Inborn and outborn ELBW infants who underwent endotracheal intubation and mechanical ventilation at birth were included. These samples were collected as part of ongoing studies3637oC until further processing. A similar protocol was employed at both study sites.Tracheal aspirate (TA) specimens were obtained from patients at the time of intubation in the first hours of life and thereafter whenever tracheal suctioning was clinically indicated, per unit protocol. Samples were obtained after ensuring that the infant was adequately oxygenated. The protocol for TA collection involved instillation of 1 mL sterile isotonic saline into the infant’s endotracheal tube, manual bagging through the endotracheal tube for three breaths, and suctioning of the fluid into a sterile mucus trap. Samples were stored frozen in −80Microbial genomic DNA was isolated and PCR was used with unique bar coded primers to amplify the V4 region of the 16S rRNA gene to create an “amplicon library” from individual samples39Data collection was performed via electronic medical record review at time of enrollment and during remainder of hospitalization. Chorioamnionitis was determined by histopathology, BPD at 36 weeks’ post-menstrual age was defined by the physiologic definitionHow to cite this article: Lal, C. V. et al. The Airway Microbiome at Birth. Sci. Rep.6, 31023; doi: 10.1038/srep31023 (2016).


Birth defects or congenital anomalies are one of the major causes of disability in developed and developing countries. Data on birth defects from population-based studies originating from developing countries are lacking. Increasingly, there is a shift to genetic testing and genomics study of birth defects. However, the translation from bench findings to bedside medicine has been muted. There is a need to address this imbalance where congenital anomalies remained the top etiology for neonatal mortality in developing countries. To build capacity in low resource countries, there is a need for accurate collection and ascertainment of birth defects in developing countries. The systematic collection and analysis of data on major birth defects using birth defects registries (BDRs) are an integral part of all clinical genetic services. Healthcare planners in developing countries must be aware of the advantages and limitations of BDRs. Despite the advent of the genomics era, BDRs are essential to the planning and developing care and prevention services at local and national levels, particularly in low resource or developing countries. Birth defects or congenital anomalies are one of the major causes of disability in developed and developing countries , 2. DataThe systematic collection and analysis of data on major birth defects using a birth defect register (BDR) has traditionally being an integral part of a clinical genetic service , 12. ThiThe functions of a BDR are manifold. It helps to establish local prevalence rates for birth defects in the local population as well as to facilitate and determine accurate baseline incidence and detection of trends of birth defects. This will be essential to the planning of health care facilities, allocation of appropriate health resources required for the design, and implementation of various preventative programs, training of medical, and paramedical staff to provide the skills to recognize major birth defects within the framework of public health  and faciIt is to be expected that there are a number of difficulties and limitations arising from the planning and maintenance of a BDR. Many medical practitioners are bewildered by the various terms used in a BDR. For example, the terms “congenital abnormalities,” “congenital disorders,” “congenital anomalies or malformations,” and “birth defects” have been used interchangeably in some centers although specific definitions are available for the above. The March of Dimes used “birth defects” and these include abnormalities in structure or function, including metabolism, which are present from birth. The World Health Organization (WHO) Human Genetics Programme (HGN) prefers “congenital disorder,” which is defined as any potential pathological condition arising before birth, including all disorders caused by environmental, genetic, or unknown factors, whether they are evident at birth or become manifest later in life. The WHO Burden of Disease Unit uses “congenital anomalies” defined as macroscopic morphological anomalies present from birth. This excludes functional birth defects, disability, common single gene disorders such as cystic fibrosis and glucose-6-phosphate dehydrogenase deficiency and inborn errors of metabolism. In a report of a joint WHO-March of Dimes meeting in 2006, it was decided that the term “birth defect” is synonymous with the term “congenital disorder” as defined and used by the HGN .Another difficult issue has been ascertainment of infants with multiple birth defects. This may require the assessment of a clinical geneticist to make a syndromic diagnosis or to perform the appropriate investigations. Increasingly, pre-natal diagnosis and termination of pregnancies are performed in many communities. This may reduce the births of newborns with birth defects but the true prevalence remains the same. Hence, many BDR include termination of pregnancies in the data collection. The timing of the case ascertainment may also cause variations in the data collection. Increasingly, there are many databases established to register patients with some specific disorders and the main objective is to study the phenotype–genotype correlations or genomic variations within the disorder . These dThere have been few studies in developing countries on the cost-effectiveness of BDR and long-term benefits are uncertain . Many meThe setting up of a Birth Defects Register requires careful and detailed planning with extensive consultation with various experts and open collaboration with many professional groups and healthcare services. The staff of the BDR may consists of clinical geneticist, pediatrician, obstetrician, representative from the maternal and child health service, epidemiologist and biostatistician, data manager, nursing staff, and clerical assistants. It also requires assured sources of funding as the health returns from a BDR may not be evident for many years. Frequently, experts from the public health and community genetics work closely together to design a program that will be the most suitable for the local situation. A BDR may be population-based or hospital-based.A BDR may need to decide whether to include all major birth defects or just sentinel birth defects. Ideally, all major birth defects should be included in a BDR. Some BDR have advocated sentinel defects only and these are usually birth defects that are evident at birth on inspection. The disadvantage of this is that major birth defects arising in certain population or following a teratogenic effect may be missed if reporting is based on sentinel findings that are not involved. Due to logistical difficulties, some BDR may opt to report birth defects in certain regions or localities only, rather than cover the entire population. Another important aspect is that the BDR must operate within the framework of the current health system and services. A BDR is usually governmental in origin although non-governmental organizations may be an active participant in the program. An important factor for a BDR to consider is to provide timely and up-to-date feedback to stakeholders of the program. This may include the members of the medical profession, health care planners, and hospitals and services that contributed to the BDR.In South-East Asia, only Singapore has a National BDR, which was established in 1992. It is population-based and funded by the government. It collects all major and minor birth defects but not inborn errors of metabolism. The common birth defects are congenital heart defects, cleft lip and palate, gastrointestinal defects, neural tube defects, and limb defects . More thThe systematic collection and analysis of data on major birth defects using BDRs are an integral part of all clinical genetic services. Healthcare planners in developing countries must be aware of the advantages and limitations of BDRs. Despite the advent of the genomics era, BDRs are essential to the planning and developing care and prevention services at local and national levels, particularly in low resource or developing countries.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Aspiration sclerotherapy is an effective therapeutic option for large symptomatic hepatic cysts. However, incomplete cyst reduction following aspiration sclerotherapy is frequently reported. Strong post-procedural cyst fluid secretion by cholangiocytes, which line the epithelium of the hepatic cyst, seems to be associated with lower reduction rates. Previous studies showed that somatostatin analogues curtail hepatic cyst fluid production. This trial will evaluate the effect of aspiration sclerotherapy combined with the somatostatin analogue pasireotide on cyst reduction. By combining treatment modalities we aim to improve cyst reduction leading to greater symptomatic relief and reduced rates of cyst recurrence.This single center, randomized, double-blind, placebo-controlled clinical trial evaluates the additional effect of pasireotide when combined with aspiration sclerotherapy in patients with a large (>5 cm) symptomatic hepatic cyst. A total of 34 participants will be randomized in a 1:1 ratio. In the active arm, patients will receive pasireotide  two weeks prior to and two weeks following aspiration sclerotherapy. Patients in the control arm will receive placebo injections at corresponding intervals. The primary outcome is proportional cyst diameter reduction four weeks after aspiration sclerotherapy compared to baseline measurements, obtained by ultrasonography. As secondary outcomes, proportional volume reduction, recurrence, symptomatic relief and improvement of health-related quality of life will be assessed. Furthermore, safety and tolerability of the combination of pasireotide and aspiration sclerotherapy will be evaluated.This trial aims to improve efficacy of aspiration sclerotherapy by a combined approach of two treatment modalities. We hypothesize that pasireotide will decrease fluid re-accumulation after aspiration sclerotherapy, leading to effective hepatic cyst reduction and symptomatic relief.NCT02048319; registered on 6 January 2014) and EudraCT .This trial is registered with ClinicalTrials.gov (identifier:  Hepatic cysts are fluid-filled cavities originating from congenital malformations of biliary duct cells. Isolated cysts occur at a prevalence of 2.5 to 18%, while polycystic liver disease (PLD) is infrequent . Large oSomatostatin analogues inhibit cyst fluid production . SeveralThe primary objective of the SCLEROCYST trial is to evaluate the combined effect of AS and pasireotide on cyst diameter reduction. Secondary objectives are to determine symptomatic relief and cyst recurrence.We hypothesize that administrating pasireotide curtails fluid re-accumulation following AS and thereby increases cyst diameter reduction.The SCLEROCYST trial is a randomized, double-blind, placebo-controlled clinical trial. This single-center study is performed at the Radboud University Medical Center, Nijmegen, the Netherlands. Trial duration will be 30 weeks, consisting of a screening period of four weeks and a treatment period of 26 weeks Figure .Figure 1A total of 34 patients will be randomized in a 1:1 ratio to receive either pasireotide or placebo. All patients will be subjected to AS. Randomization will be performed using block randomization with a block size of four. Included patients will be assigned a randomization number, corresponding to a treatment arm, concealed in a closed envelope. Access to treatment allocation will be restricted to research nurses who prepare and administer the injections. Both patients and treatment allocators will be unaware of the allocated treatment.All patients who are diagnosed with a symptomatic, hepatic cyst that meet the following eligibility criteria will be suitable for participation in this study.Aged between 18 and 70 years,Indication for treatment with AS, made upon diagnosis of a symptomatic, simple hepatic cyst exceeding 5 cm in diameter,The treated hepatic cyst must be solitary or dominant by nature; a dominant hepatic cyst is the largest cyst surrounded by multiple smaller cysts in patients with PLD andProvision of informed consent to participate.The inclusion criteria for this study are as follows:Suspicion of a complicated hepatic cyst ,9/l) orCoagulopathy  >2 or platelet count <80 × 10Severe co-morbidity contraindicating anesthesia (ASA 4 classification).The aspiration sclerotherapy-related exclusion criteria are as follows:Known long QT syndrome and/or corrected QT interval (QTc) at screening >470 ms;Family history of long QT syndrome or idiopathic sudden death;Uncontrolled or significant cardiac disease including a recent myocardial infarction, congestive heart failure, unstable angina or sustained and/or clinically significant cardiac arrhythmias;Risk factors for torsades de pointes: hypokalemia, hypomagnesemia, hypocalcaemia, clinically significant bradycardia or high grade atrioventricular block;Concomitant disease that could prolong QT interval such as autonomic neuropathy, HIV, cirrhosis, uncontrolled hypothyroidism or cardiac failure;Use of anti-arrhythmic medicinal products or other substances known to lead to QT interval prolongation;Symptomatic cholecystolithiasis;Uncontrolled diabetes, defined as glycated hemoglobin (HbA1C) level >64 mmol/ml despite adequate therapy;Moderate to severe hepatic impairment defined by a Child-Pugh classification of more than six points;History of acute pancreatitis;Hypersensitivity to somatostatin analogues or any component of pasireotide orNon-malignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with the study therapy.The pasireotide treatment-related exclusion criteria are as follows:Pregnant or nursing women,Use of oral contraception or estrogen supplementation,Intervention  within six months prior to baseline,Treatment with somatostatin analogues within six months prior to baseline orAny current or prior medical condition that may interfere with the conduct of the study or the evaluation of its results in the opinion of the investigator.Further exclusion criteria are as follows:All included patients will undergo AS of a single hepatic cyst following standard of care. This single session procedure will be performed by one of our five interventional radiologists, experienced in performing AS. Patients will be admitted the day of AS and will receive intravenous antibiotic prophylaxis  or clindamycin 600 mg  as an alternative in case of allergies). The procedure will be carried out with conscious sedation. Briefly, the cyst will be localized by ultrasonography. Following disinfection and local anaesthesia of the skin, a 5 French pigtail catheter  attached to a three-way tap will be inserted in the hepatic cyst to perform complete fluid evacuation (aspiration). Cyst leakage or communication with vessels or bile ducts will be examined by instillation of contrast medium  into the cyst cavity. Contrast medium will then be aspirated from the cyst followed by an injection of 100% ethanol (sclerotherapy). The amount of instilled ethanol consists of 10% of the aspirated cyst volume (up to a maximum of 50 ml). After 10 minutes, ethanol is aspirated and the drain will be removed.Subjects in the active treatment arm will receive two intragluteal injections of 60 mg pasireotide  long-acting release (LAR). The first injection will be administered two weeks prior to AS, the second injection will be administered two weeks following AS. Pasireotide LAR, powder for suspension for injection, is a one-month depot microparticle formulation for intramuscular administration. No dose adjustment is required for race, age, gender, body weight, mild hepatic impairment or renal impairment. The most common adverse events are gastrointestinal by nature and include mild diarrhea, nausea and abdominal pain . These ePatients in the placebo arm will receive two intragluteal injections of 2 ml sodium chloride solution 0.9% . The first injection will be administered two weeks prior to AS and the second injection will be administered two weeks following AS.The primary outcome of the SCLEROCYST trial is the mean proportional change (%) in cyst diameter of the treated hepatic cyst four weeks after AS, as measured by ultrasound.Secondary outcomes are mean proportional change (%) in cyst diameter two, 12 and 24 weeks after AS. Moreover, proportional change (%) in volume, absolute diameter reduction (cm) and rate of cyst recurrence  at follow-up visits will be assessed. In addition, symptoms and health-related quality of life will be measured at baseline, four, 12 and 24 weeks after AS. Finally, any complications or adverse events reported during procedure or follow-up visits will be recorded.The blinded primary investigator will perform cyst diameter measurements by ultrasonography. The treated hepatic cyst will be visualized in two planes to measure each maximal orthogonal diameter  three times. As a secondary endpoint, cyst volume will be estimated by multiplying the maximum of each orthogonal diameter by 0.523 . The meaAbdominal symptoms and health-related quality of life will be assessed at screening and during follow-up visits. The standardized gastrointestinal symptom questionnaire (GIS) assesses 11 abdominal symptoms using a seven-point Likert scale ranging from 0 (‘none’) to six (‘severe’) . The MedThis study consists of seven visits including one screening visit, three treatment visits and three follow-up visits.obtain written informed consent;extensive medical history and physical examination;laboratory markers: potassium, calcium, magnesium, estimated glomerular filtration rate calculated by the Modification of Diet in Renal Diseases (MDRD) formula, platelets, INR, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), total bilirubin (TB), albumin and fasting blood sugar (FBS);urine pregnancy test in female patients with childbearing potential;electrocardiogram: frequency, QTc and atrioventricular conduction;ultrasonography: cyst diameter and volume measurement andquestionnaires: GIS-, PLD- and SF-36 questionnaire.Potential subjects with an indication for AS will be asked to participate. Informed consent will be obtained from all participants. Upon providing informed consent, each subject will be screened for eligibility during a separate screening visit performed within 28 days prior to the start of the trial. During this screening visit the following assessments will be made:The first injection will be administered 14 days prior to AS and indicates the start of this trial. Patients in the treatment arm will receive the first injection of pasireotide LAR 60 mg, while patients in the placebo arm will receive an injection of the sodium chloride solution. The injections will be administered by an independent unblinded health professional who is not involved in the design, execution or analysis of the trial.Patients will be admitted the day of AS. Prior to the intervention, adverse events in the previous two weeks will be assessed. Moreover, blood will be drawn to evaluate safety laboratory markers . AS will be performed following standard procedure in both arms. Aspirated cyst fluid will be stored in our laboratory for future analyses.FBS >9.9 mmol/l;AST or ALT >5 × upper limit of normal (ULN);AST or ALT >3 × ULN with TB >2 × ULN oramylase >10 × ULN.Two weeks following AS (four weeks following the first injection) the patient will visit the outpatient clinic to receive the second injection. Cyst diameter will be assessed. All adverse events will be documented and blood will be obtained. If the following laboratory parameter levels are found, the second injection will not be administered:If the parameters fall within the margin of safety, the second injection will be administered.Three follow-up visits will be planned at six, 14 and 26 weeks following the first injection . The researcher will document adverse events and blood will be drawn to assess safety laboratory markers . The diameter of the treated cyst will be captured and cyst volume will be calculated. The primary endpoint of this study, mean proportional change (%) in cyst diameter at four weeks after AS, will be obtained during the first follow-up visit. Furthermore, abdominal symptoms and health-related quality of life will be measured using the GIS-, PLD- and SF-36 questionnaires.Subjects can withdraw informed consent and leave the study at any time. The investigator will withdraw a subject from the study for any of the following reasons: pregnancy, consistent failure to adhere to protocol requirements, unacceptable toxicity of study medication, surgical interventions during the study or any other reason if in the best interest of the patient. All data generated up to the time of discontinuation from the study will be analyzed and the reason(s) for discontinuation will be recorded.Recent data showed that patients treated by AS have a mean diameter reduction of 29.7 ± 19.76% after four weeks . By addiIntention-to-treat (ITT) analyses will be used for all clinical outcome variables. The ITT sample includes all patients who received at least one dose of study medication. In addition, we will carry out a parallel analysis on the per-protocol treated population. This sample is defined as all patients who have received both injections, AS and all ultrasound measurements. The primary outcome of this study is the proportional (%) change in cyst diameter of the treated hepatic cyst four weeks after AS, as measured by ultrasound. The mean diameter of each orthogonal diameter measured by the blinded primary investigator will be used for analysis. Subsequently, we will calculate a mean diameter from the three mean orthogonal diameters. Proportional change will be calculated by dividing the reduction of mean cyst diameter at four weeks by mean cyst diameter at baseline, multiplied by 100. Depending on distribution, values will be presented as mean ± SD or as median ± interquartile range. Consequently, differences between the treatment and placebo arm will be calculated using the independent student’s t-test or the Mann-Whitney U test, respectively. Absolute reduction and volume reduction will be presented and analyzed similar to data for the primary endpoint. Cyst recurrence will be compared between both groups using Fisher’s exact test. The cyst diameter measurements from the second blinded investigator will be used as a control to evaluate intra- and interobserver variability by performing a Bland-Altman analysis. Symptoms of the GIS-questionnaire will be dichotomized (0 to oneversus two to six) and compared between the treatment and placebo arm using the chi-square test. Health-related quality of life domain scores and component scores (SF-36) will be compared between both arms using the Mann-Whitney U test. Frequency tables will be compiled for (serious) adverse events classified according to the standard World Health Organization - Adverse Reaction Terminology (WHO-ART) Body System Dictionary and preferred terms. All statistical analyses will be two-sided, with a critical significance level of 5%.Ethical approval of the study protocol was given by the Central Committee on Research Involving Human Subjects and by the local accredited Medical Research Ethics Committee of the region Arnhem-Nijmegen, the Netherlands (reference number: 2013/354). This study is to be conducted in accordance with the International Conferences of Harmonization Good Clinical Practice Guidelines, the principles of the Declaration of Helsinki 1964 as modified by the 52nd WMA General Assembly, Edinburgh, Scotland, October 2000 including two notes of clarification on paragraph 29 and 30, and the local national laws governing the conduct of clinical research studies. An independent data and safety monitoring board has been formed to monitor patient safety and treatment efficacy during the trial.The SCLEROCYST trial is designed to evaluate the additional effect of pasireotide on hepatic cyst diameter reduction in patients treated by AS. We hypothesize that complementary pasireotide treatment results in an augmented treatment efficacy. Multiple studies have shown that AS is an effective and safe method to reduce hepatic cyst volume ,23,24. Htmax) around 20 days following administration [In the context of this study we want to evaluate whether these inhibitory mechanisms of somatostatin analogues can halt cyst fluid re-accumulation following AS. We have chosen to apply the multi-receptor-targeted, long-acting somatostatin analogue pasireotide (SOM230) . This cystration . TherefoThe strength of this study is its design: a randomized, double-blind, placebo-controlled trial. This will minimize confounding of results. Further, this study is powered on a clinical relevant difference of 50% in the pasireotide arm compared to the expected 30% cyst diameter reduction in the control arm. We believe that a statistical significant finding will have direct implications for future AS treatment. Smaller differences between arms will not be detected in view of power issues. Nevertheless, given the additional costs and potential side effects of pasireotide, we believe that a strong improvement over conventional AS is needed to justify the implementation of this combination treatment. Finally, with this study we hope to achieve a better understanding in the pathological mechanisms behind hepatic cyst development and fluid re-accumulation following AS.This study has several limitations. First, the effect of treatment will be measured by ultrasonography. Since we will perform cyst measurements within short intervals we have selected ultrasonography as the most appropriate imaging modality to avoid exposure to radiation (from computed tomography scans) and high costs (from magnetic resonance imaging). However, ultrasound measurements are operator-dependent and are therefore susceptible to bias. To minimize biased results, we have added several safety measures. All measurements will be performed according to standard operating procedures and will be executed in triplicate. Moreover, all measurements will be performed by the same investigator who is blinded for treatment allocation. In addition, a second, blinded independent investigator will repeat all measurements. Second, in this study sclerotherapy will be performed with 100% ethanol. Multiple sclerosing agents are in use for AS ranging from ethanol to tetracycline antibiotics, polidocanol, ethanolamine oleate or hypertonic saline ,28-32. TTo summarize, the SCLEROCYST trial is designed to evaluate the additional effect of a somatostatin analogue combined with AS. We aim to reduce fluid re-accumulation following treatment leading to increased cyst diameter reduction and symptomatic relief.The trial is currently ongoing. Recruitment and inclusion of patients started in April 2014.


To determine whether the benefits of universal newborn hearing screening (UNHS) seen at age 8 years persist through the second decade.Prospective cohort study of a population sample of children with permanent childhood hearing impairment (PCHI) followed up for 17 years since birth in periods with (or without) UNHS.Birth cohort of 100 000 in southern England.114 teenagers aged 13–19 years, 76 with PCHI and 38 with normal hearing. All had previously their reading assessed aged 6–10 years.Birth in periods with and without UNHS; confirmation of PCHI before and after age 9 months.Reading comprehension ability. Regression modelling took account of severity of hearing loss, non-verbal ability, maternal education and main language.Confirmation of PCHI by age 9 months was associated with significantly higher mean z-scores for reading comprehension  although birth during periods with UNHS was not . The gap between the reading comprehension z-scores of teenagers with early compared with late confirmed PCHI had widened at an adjusted mean rate of 0.06 per year (95% CI −0.02 to 0.13) during the 9.2-year mean interval since the previous assessment.The benefit to reading comprehension of confirmation of PCHI by age 9 months increases during the teenage years. This strengthens the case for UNHS programmes that lead to early confirmation of permanent hearing loss.ISRCTN03307358. Universal newborn hearing screening (UNHS) is an effective way of increasing rates of early identification of congenital permanent childhood hearing impairment (PCHI).UNHS and early identification of PCHI are associated with benefits to language and reading outcomes in middle childhood.This study is the first to describe the effects of UNHS and early confirmation of PCHI on longer-term literacy outcomes.Early confirmation of PCHI was associated with significant benefits to reading comprehension in the teenage years.The benefit of early confirmation of PCHI to reading comprehension had increased from moderate to large between the ages of 8 and 17 years.Bilateral permanent childhood hearing impairment (PCHI) of moderate, severe or profound severity is the commonest sensory disability affecting 1 in 750 children and is present at birth in more than 80% of affected children.7>40 dB.11–13Identification of PCHI in early childhood enables affected children to receive early intervention to optimise their language access during a ‘sensitive period’ for language development.Systematic reviews have been increasingly supportive of UNHS20Both the US Preventative Services Task Force>40 decibels hearing level (dB HL)  and a comparison group of 63 normally hearing children, were drawn from a birth cohort of 157 000 children born in eight districts of southern England (see online supplementary appendix 1), of whom about half were born in periods with UNHS. We previously reported a number of details relating to this population in infancy and first decade, including the UNHS programmes for PCHI to which they were exposed; the service provision by district and regional audiology and by other services for confirmation and management of their PCHI; and the language and reading abilities of the children at 6–10 years.The children in this prospective follow-up study, 120 children with bilateral PCHI Each participant was assessed by a trained researcher, unaware of their audiological history, using the York Assessment of Reading for Comprehension Secondary Edition,Severity of hearing impairment was categorised from the most recent audiological evaluation at audiology and cochlear implant clinics as moderate (40–69 dB HL), severe (70–94 dB HL) or profound (≥95 dB HL) according to four-frequency averaging of the pure-tone thresholds at 0.5, 1, 2 and 4 kHz. Maternal education was classified according to the 2001 census in the UK.This study was approved by the Southampton and SW Hampshire Research Ethics Committee. Written informed consent for participation in the study was obtained from principal caregivers and from the teenage participants themselves.The primary outcome (reading comprehension) and the analysis strategy were prespecified and the statistical analysis plan was written before examination of the data. The target sample size of 96 with half of the sample born in periods with (or without) UNHS, or, in a parallel set of analyses, exposed to early (or late) confirmation of PCHI, was sufficient to have 90% power to detect a standardised difference in the primary outcome of at least 0.67 SDs at a 5% significance level (two sided) using a uni-factorial test. We prespecified the definition of ‘early’ confirmation of PCHI as confirmation by nine completed months of age, consistent with the definition used in our previous trial of UNHS16The group mean and SD reading scores in the normally hearing comparison group were used to derive z-scores for the teenagers with PCHI where the mean and SD in the normally hearing group was 0 and 1, respectively. The z-scores in the participants with PCHI were thus expressed in terms of the number of SDs from the mean in the normally hearing comparison group. Analyses were run both with and without British Sign Language users. This did not alter the pattern of results which are therefore presented for the combined group of oral and signing communicators. Where statistically significant inter-group differences were found, subgroup analysis was then undertaken in those who had and had not received cochlear implants. The method of adjusting reading z-scores appropriately to look at change in reading ability over time comparing current scores with those previously obtained at aged 6–10 years is described in online supplementary appendix 1.We assessed in a linear regression model the relationships between birth during periods of UNHS or confirmation of PCHI by age 9 months and age-adjusted reading z-scores (using Stata/SE V.12.1) in oral and signing communicators (see online supplementary appendix 1). The extent to which the effect of early confirmation made a significant additional contribution to model fit after screening was included in the model was tested with a likelihood ratio test. Normality and homogeneity of the residual variance were examined for all measures to ensure that the regression models were appropriate.The 114 participating teenagers were similar to the 183 who had previously participated in the study of reading and language at 7.9 years with regard to sex, non-verbal ability and maternal educational level at the time of the previous study . The 76 The early and late confirmed groups showed mean reading comprehension z-scores that were 0.63 and 1.74 SDs, respectively, below the mean reading z-score in the normally hearing comparison group . The tee2=7.61, p=0.006) indicating that early confirmation of PCHI accounted for significant unique variance in reading outcomes beyond that accounted for by exposure to UNHS.Change in the estimates of effect sizes and p values of early confirmation and of screening was minimal when they were modelled together rather than separately, suggesting that these effects were working independently (see online supplementary table e1). Adding the effect of early confirmation into the regression model after screening was included made a significant additional contribution to model fit  with those at age 13–19 years from the present study showed that unadjusted reading comprehension z-scores remained nearly unchanged in the early confirmed group but decreased  in the late confirmed group . CompareThis study of teenagers with PCHI who were involved in trials of UNHS is the first to describe the effects of UNHS and early confirmation of PCHI on outcomes beyond the primary school years. Confirmation of PCHI by nine completed months of age was associated with significantly better performance on reading comprehension, the prespecified primary outcome variable. Comparing the scores from the current study with reading scores obtained 9 years earlier from the same individuals, the teenagers whose PCHI had been confirmed early had maintained their level of performance relative to the hearing controls whereas the late confirmed teenagers had not: the gap between the early and late confirmed groups had doubled between the two assessments. The early superiority in the reading skills of the early confirmed participants may have enabled them to read more demanding reading material more frequently than their peers with later confirmed PCHI, thus increasing the skill gap between the two groups. The superiority resulting from this rich-get-richer ‘Matthew effect’24Non-verbal ability was very similar in the early and late confirmed groups and adjustment for it was included in the regression model. This suggests that the deficit in reading scores in the late confirmed participants did not result from a general cognitive deficit but rather from the specific impact of delayed access to optimal language input early in life on language-related abilities. The early and late confirmed groups did not show different proportions of genetic and non-genetic aetiologies of deafness nor of disabilities additional to deafness that might account for the observed differences in reading z-scores.Factors other than age at confirmation of PCHI appeared to determine reading outcomes for that minority of participants who had received cochlear implantsThe effects of early confirmation were seen in those born in periods with and without UNHS and the effect of UNHS appears to be dependent on the increase in rates of early confirmation of PCHI to which it leads. The same NHS district and regional audiology teams delivered, in almost all cases, the care of both screened and unscreened and of both early and late confirmed populations in this studyThe annual attrition rate  among children with PCHI eligible for the present study is low for a teenage population with a chronic medical condition but limited the power of the study to examine change in reading comprehension between the primary school and teenage assessments. In spite of this limitation in power, the inter-group differences on the prespecified primary outcome of reading comprehension were large enough to be both statistically significant and clinically important.As the Millenium Development Goals project approaches its 2015 target, UNESCO, UNICEF, the World Bank and WHO are increasingly considering early child development, in which infant hearing is a critical component, as a key determinant of subsequent health38–40


Background: Birth weight is an early correlate of disease later in life, and animal studies suggest that low birth weight is associated with reduced activity and increased sedentary time. Whether birth weight predicts later sedentary time in humans is uncertain.Objectives: We examined the relation between birth weight and sedentary time in youth and examined whether this association was mediated by central adiposity.Design: We used pooled cross-sectional data from 8 observational studies conducted between 1997 and 2007 that consisted of 10,793 youth (boys: 47%) aged 6–18 y from the International Children’s Accelerometry Database. Birth weight was measured in hospitals or maternally reported, sedentary time was assessed by using accelerometry (<100 counts/min), and abdominal adiposity (waist circumference) was measured according to WHO procedures. A mediation analysis with bootstrapping was used to analyze data.Results: The mean (±SD) time spent sedentary was 370 ± 91 min/d. Birth weight was positively associated with sedentary time  and waist circumference , whereas waist circumference was positively associated with sedentary time . Results of the mediation analysis showed a significant indirect effect of birth weight on sedentary time through waist circumference , and when waist circumference was controlled for, the effect of birth weight on sedentary time was attenuated by 32% .Conclusion: The association between birth weight and sedentary time appears partially mediated by central adiposity, suggesting that both birth weight and abdominal adiposity may be correlates of sedentary time in youth. The Developmental Origins of Health and Disease hypothesis suggests that nonoptimal growth and environmental conditions during fetal life may result in permanent changes in the body’s structure, function, and metabolism . These iAnimal studies showed that the offspring of undernourished mothers are less active and more sedentary than offspring born within normal birth weights , 12. In A higher birth weight is associated with increased risk of obesity , greaterBecause of the high amount of time spent sedentary in youth , 27 and n = 10,793) were included (P < 0.001) and waist circumference .The International Children’s Accelerometry Database (ICAD)included –40. ThisA detailed description of the assessment of sedentary time and physical activity is available elsewhere . AccelerThe Pelotas study used a 24-h wear protocol , 35, wheHeight and weight were measured by using a standardized procedure across studies. BMI (weight divided by height squared) was calculated for each participant, and age- and sex specific BMI cutoffs were used to categorize participants as normal weight, overweight, or obese . Waist ct test was used to compare descriptive data between sexes.Means (±SDs) are shown for descriptive variables. An independent c path) and direct effect (c′ path) of birth weight on sedentary time and estimate the mediating role of waist circumference . In the current study, a 95% bias-corrected CI (bCI) for each a × b product was obtained with 5000 bootstrap resamples and used to assess whether waist circumference mediated the association between birth weight and sedentary time. A significant indirect effect via the mediator between birth weight and sedentary time was determined if the 95% bCI did not overlap zero.We used resampling strategies and the macro presented by Preacher and Hayes  to assesWe did not have data on gestational age, and therefore, we could not differentiate between participants with low birth weight because of premature birth or growth restriction. The sample consisted of 553 participants who could be considered premature (birth weight <2.5 kg), and therefore, we performed sensitivity analyses by excluding participants with birth weight <2.5 kg.P > 0.10). The association between different categories of birth weights and sedentary time is displayed graphically for illustrative purposes and presented as means and 95% CIs of the sedentary time for each birth weight group (see Results section). Birth weight was divided into 6 categories as follows: <2.75 kg (n = 1164), 2.75–3.25 kg (n = 2822), 3.26–3.75 kg (n = 4160), 3.76–4.25 kg (n = 2117), 4.26–4.75 kg (n = 449), and >4.75 kg (n = 81), and the birth-weight category 3.26–3.75 kg was chosen as the reference category because it contained the largest proportion of participants and in agreement with previous studies  and less time sedentary than did girls .Descriptive statistics by study and sex are summarized in c path; B = 4.04, P = 0.006). When this association was modeled graphically, the association seemed to be mainly driven by individuals in the extreme categories of birth weight (<2.75 and >4.75 kg) , and waist circumference was positively associated with sedentary time . Results of the mediation analysis confirmed the mediating role of waist circumference in the association between birth weight and sedentary time . Furthermore, our results showed that the direct effect of birth weight on sedentary time was attenuated by 32%  when controlling for waist circumference, which suggested partial mediation.c path; B = 4.66, P = 0.01) and waist circumference , and waist circumference was positively associated with sedentary time . In addition, results of the mediation analysis confirmed the mediating role of waist circumference in the association between birth weight and sedentary time  and supported partial mediation .In sensitivity analyses, with the exclusion of individuals with birth weight <2.5 kg, results were mainly unchanged. Birth weight was associated with sedentary time (This study examined whether birth weight acts as a correlate of sedentary time in youth and whether this association is mediated by waist circumference. The results suggested that the association between birth weight and sedentary time was partially mediated by waist circumference in young people aged 6–18 y.We proposed that central adiposity could be an underlying mechanism of the association between birth weight and sedentary time for several reasons. Birth weight appears to be associated with several measures of adiposity , 17, 19,A limitation regarding the mediating role of abdominal adiposity in the current study was that waist circumference was measured at the same point in time as sedentary time. Thus, the temporal sequence between waist circumference and sedentary time was not possible to establish. However, it was previously shown that higher waist circumference predicted higher amounts of sedentary time in youth , 23, whePrevious studies showed that lower birth weight is associated with central adipose tissue in childhood , 18, 19.There were several strengths of this study, including objectively measured sedentary time, a wide range of birth weights, and a large and diverse sample representing different geographical and cultural locations. Even though accelerometer data were re-analyzed in a standardized manner, and all analyses were adjusted for wear time, it was possible that differences in accelerometer wear protocol influenced the results. One of the included studies used a 24-h monitor wear protocol , 35, andThere were some limitations that warrant consideration in interpreting the results of the current study. The accelerometer is regarded as a valid tool for measuring physical activity and sedentary time , 63; howIn conclusion, the prevalence of sedentary time in youth is of public health concern, and therefore, it is important to understand potential biological and behavioral correlates of this behavior. The results suggest that birth weight is positively associated with sedentary time; however, the association appears partially mediated by central adiposity. Therefore, the targeting of both birth weight and obesity may be an important public health strategy to prevent excessive sedentary time in youth.


Preterm birth (PTB) is the major cause of death in newborn and the second major cause of death in children less than 5 years old worldwide. Genetic polymorphism has been implicated as a factor for the occurrence of preterm birth. The aim of this study is to evaluate whether polymorphism in the progesterone receptor (PGR) is associated with susceptibility to preterm birth.A total of 135 women with preterm and 532 women with term deliveries were genotyped for PGR gene polymorphisms  using Sequenom MassARRAY platform.The G allele of PGR rs660149 polymorphism was significantly associated with susceptibility to PTB in the Malay women. The odds of G allele occurring among Malay women with preterm delivery was twice that of Malay women with term delivery . Alternatively, no significant association was observed between PGR rs660149 polymorphisms and susceptibility to PTB in Chinese and Indian women.This study shows that variability in the occurrence of PTB across ethnicities in Malaysia is partly due to differences in genetic background. We therefore suggest that in addition to life style and environmental factors, genetic factor should be greatly considered in this population. Prior information on the genetic composition of women may help in the identification and management of women at risk of preterm birth complication. Preterm birth is the major cause of death in the newborn and the second major cause of death in children less than 5 years old worldwide . ApproxiProgesterone (PG) is a major female ovarian hormone needed for successful pregnancies in women –15. DuriThe study involved a total of 667 women (135 preterm and 532 term) with spontaneous singleton delivery admitted at the University of Malaya Medical Centre (UMMC) from 2011 to 2013 respectively. Subjects were classified into two groups; the preterm group consisted of mothers who delivered their baby between 24 and 36 weeks while the control group consisted of mothers with uncomplicated pregnancy who delivered their babies between 38 and 41 weeks. Prior to sample collection, each participant was allocated a written informed consent form, patient information sheet and a data collection sheet. The data collection sheet consisted of all information about the patient’s demographic, obstetric history, life style, and family history. Ethnicity of the participants was obtained from the data collection sheet in which participants self reported their ethnicities as Malays, Chinese or Indians and declared that there has been no mixed marriage for at least three generations. The study was approved by the University of Malaya Medical Centre (UMMC) Ethics Committee and written informed consent was obtained from all participants.Trained gynecologists assessed the physical well-being of the participants and pregnancy age was calculated from the first day of the last menstrual cycle or obtained from ultrasound results of the patients. The following inclusion criteria was used to select the participants; healthy mothers between the ages of 18–35 years old, mothers with normal competent cervix and uterus, mothers without metabolic or autoimmune disease and mothers who conceived preterm but with normal and healthy fetus. Exclusion criteria included abnormal fetus and still birth, mothers pregnant with twins, birth delivery by induction due to fetal distress or placenta abruption or preeclampsia or hypertension or any known medical problem were excluded, maternal age of less than 18 years or more than 35 years, mothers with history of drug abuse, and mothers who were not able to sign informed consents were also excluded from the studies. Medical records of the participants were reviewed to obtain more patient details.@ ExgeneTM DNA purification kit. Three SNPs in the PGR gene  were genotyped using Sequenom MassARRAY platform. SNPs with call rate of greater than 90 % were considered for statistical analysis. For the three PGR SNPs that were genotyped, two (PGR rs660149 and rs471767) with call rates of 99 % were considered for statistical analysis while the PGR rs10895068 SNP with a call rate of 87 % was excluded from statistical analysis.A volume of 3mls of maternal venous blood was collected in to EDTA tubes and centrifuged at 2000 × g for 10 minutes. The buffy coat and plasma were kept in separate 1.5 ml tubes and stored in the freezer until utilized. Maternal genomic DNA was extracted from buffy coat using the GeneAll2 test. The association and allele-based test for PGR rs660149 and rs471767 with preterm birth was performed using Fisher’s exact test with 2 and 1 degrees of freedom respectively. Pearson’s χ2 test or independent t-test was used to compare categorical and continuous variables between groups and data were presented as percentage or mean ± standard deviation. Multivariate analysis was performed with adjustment for a past history of PTB, gestational diabetes and miscarriage respectively. It should be noted that confounding factors such as smoking, substance abuse, mothers who were themselves born preterm and alcohol consumption were not included for statistical analysis because all subjects were tested and found to be free from these factors. The Quanto version 1.2.4 soft ware was used to calculate power of the study.Statistical analysis of subjects was performed using SPSS version 18.0 . Prior to genetic analysis, Hardy-Weinberg equilibrium (HWE) calculator was used to check for deviation from HWE using a goodness of fit χThe demographic and clinical parameters of subjects are presented in Tables p = 0.042). Following stratification by ethnicity, the G allele of PGR rs660149 was significantly associated with susceptibility to preterm birth in the Malay ethnic subgroup. The odds of the G allele occurring among women with preterm birth was twice that of women with term birth . We observed no significant association between the G allele of PGR rs660149 and susceptibility to preterm birth in Chinese and Indian ethnic groups (Table P = 0.014). The heterozygous CG and homozygous GG genotypes of rs660149 were high among Malay women with preterm delivery compared to term (Table The allelic association test between PGR rs660149 SNP and preterm birth in the overall subjects and in various ethnic subgroups are shown in Table Progesterone plays an important role in the maintenance of pregnancy up to when the baby is fully mature and ready for parturition . The rolIn this study we showed a significant association of PGR rs660149 G variant with susceptibility to preterm birth in the Malay ethnic group. Subjects with the G allele were two times more likely to experience preterm birth than control subjects. It should be noted that the Malays form the largest community in Malaysia and represent more than half of the population. This result is similar to the result of Ehn et al. in which they found associations between PGR SNPs and susceptibility to preterm birth .The significant results obtained after adjustment for confounding factors is an indication that genetic polymorphism is a major risk factor of preterm birth complication in this population. Prior information on the genetic composition of women with spontaneous preterm birth may help in the identification and management of high risk women. Malaysia has a multiethnic population which is composed of three different ethnic subgroups namely Malay, Chinese and Indians with varying genetic background. The present study shows that variability in the occurrence of preterm birth among women in Malaysia is due to differences in their genetic components. In addition to the life style and environment factors in this population, genetic factors play a major role in the disparity of preterm birth amongst ethnic groups. Infants born preterm suffer from major health problems therefore there is a high demand for ethnicity specific genetic and environmental strategies to be put in place to prevent or better manage high risk women in every geographical area. This will enhance survival of neonates who might suffer or die due to preterm birth associated complications.In summary, we showed a significant association between PGR rs660149 polymorphism and susceptibility to PTB in the Malay ethnic group. This finding may have implication for screening and treatment of women at risk of preterm birth complication.