To determine whether occipital and cingulate hypometabolism is being under-reported or missed on 18-fluorodeoxyglucose positron emission tomography (FDG-PET) CT scans in patients with Dementia with Lewy Bodies (DLB).Recent studies have reported higher sensitivity and specificity for occipital and cingulate hypometabolism on FDG-PET of DLB patients.This retrospective chart review looked at regions of interest (ROI’s) in FDG-PET CT scan reports in 35 consecutive patients with a clinical diagnosis of probable, possible, or definite DLB as defined by the latest DLB Consortium Report. ROI’s consisting of glucose hypometabolism in frontal, parietal, temporal, occipital, and cingulate areas were tabulated and charted separately by the authors from the reports. A blinded Nuclear medicine physician read the images independently and marked ROI’s separately. A Cohen’s Kappa coefficient statistic was calculated to determine agreement between the reports and the blinded reads.On the radiology reports, 25.71% and 17.14% of patients reported occipital and cingulate hypometabolism respectively. Independent reads demonstrated significant disagreement with the proportion of occipital and cingulate hypometabolism being reported on initial reads: 91.43% and 85.71% respectively. Cohen’s Kappa statistic determinations demonstrated significant agreement only with parietal hypometabolism (p<0.05).in vivo biomarkers.Occipital and cingulate hypometabolism is under-reported and missed frequently on clinical interpretations of FDG-PET scans of patients with DLB, but the frequency of hypometabolism is even higher than previously reported. Further studies with more statistical power and receiver operating characteristic analyses are needed to delineate the sensitivity and specificity of these  Dementia with Lewy Bodies (DLB) is the second-most common cause of dementia in North America behind Alzheimer’s disease, and is characterized by cognitive, motor, and neuropsychiatric disturbances that usually follow a fluctuating, progressive course . While tMinoshima et al. found that antemortem occipital hypometabolism on FDG-PET had 90% sensitivity and 80% specificity for DLB . The larThese findings cast doubt to the overall reliability of occipital hypometabolism on its own as a biomarker for dementia with Lewy bodies. Other regions of interest have been identified in DLB, such as preservation of posterior cingulate island perfusion, which can enhance specificity for DLB on FDG-PET studies up to 100% when taken alongside occipital hypometabolism concurrently  found thThe study was conducted according to the human subject study protocol approved by Barrow Neurological Institute (BNI) Institutional Review Board. Because this was a retrospective chart review with minimal inherent risk to patients, expedited approval was granted. Informed consent was waived as this retrospective cohort study did not involve direct patient participation, obtaining informed consent was time-consuming and unnecessary given minimal risk to patient privacy, and the records were studied under protocols enforced by our organization’s Institutional Review Board.Outpatient electronic medical record database was queried for all patients carrying ICD-9 code diagnosis 331.82 or ICD-10 code diagnosis G31.83, namely Dementia with Lewy Bodies, who have had diagnostic FDG-PET scans within the last three years . Thirty-[18F]-Fluorodeoxyglucose (FDG) PET acquisition and pre-processing: FDG-PET was used to compare regional cerebral glucose metabolism across groups as described in previous literature .The clinical reports were gathered with review of the impression and technical aspects. The data-gathering portion of the study involved reviewing radiological reports and tabulating hypometabolism in regions of interest (ROI’s)-frontal, temporal, parietal, occipital, and cingulate as either present or absent (1 or 0 respectively). The analytical portion of the study involved a single-blinded nuclear medicine physician (FS) read of FDG-PET scans of the patients compiled in the abovementioned manner in the descriptive portion of the study. All patients queried in the above manner with probable or possible DLB had their FDG-PET scans read by a blinded Nuclear Medicine physician who determined regional hypometabolism. The Nuclear medicine physician marked regions of interest (ROI’s) exhibiting hypometabolism based on 0-1 scale of either absent or present respectively. Primary visual and visual association cortical metabolism was also investigated.The proportions of hypometabolism for each region of interest  in both the radiological and independent reads were calculated by dividing the number of positive scans for that ROI by the total number of patients. These proportions were compared side-by-side, and a Cohen’s kappa coefficient was calculated to assess for independent reader agreeability with the prior reported regions of hypometabolism .The demographic characteristics, clinical diagnoses, and functional outcome measures are shown in . The samOn independent reads by the nuclear medicine physician, similar proportions of regional hypometabolism were tabulated for frontal, temporal, and parietal hypometabolism. Discrepancies in proportion existed in occipital and cingulate hypometabolic reads between clinical reports and nuclear medicine reads blinded to the clinical reads, with 32 and 30 (91.43% and 85.71%) patients out of 35 exhibiting occipital and cingulate hypometabolism respectively. 91.43% exhibited hypometabolism in the visual association cortex and 11/32 (34.38%) in the primary visual cortex. Only one patient had unilateral occipital hypometabolism, whereas the majority with occipital hypometabolism had it bilaterally. in vivo biomarker was found to be grossly under-reported on clinical reports. Further, we find that 91.43% of patients exhibit occipital hypometabolism, whether in the primary visual or visual association cortices, compared to 25.71% on prior radiological reports. Significant disagreement existed between radiology reports and our independent reads, with a Cohen’s kappa coefficient 0.063 and a p-value of 0.282>0.05. The novelty is that these data suggest the occipital hypometabolism might be missed clinically but the frequency is actually higher than previously reported [The significance of this study is that occipital hypometabolism as an Literature surrounding occipital hypometabolism in Dementia with Lewy Bodies share certain discrepancies in reporting specifically the nature of occipital hypometabolism. Some authors indicate that the hypometabolism is localized to the primary visual cortex, whereas other studies indicate that the visual association cortex is primarily affected ,15. ConcOne recent study found that hypometabolism in the visual association cortices is probably a more sensitive indicator of Lewy body disease while hypometabolism in the primary visual cortex is probably more specific . Our datFrom these data, it is possible to speculate that when a general radiologist rather than a nuclear medicine specialist is reading PET scans for a local hospital, there will likely be differences. It is common practice for nuclear medicine, Neuroradiologists, and general radiologists to read a wide variety of scans. This could account for the heterogeneity in detection of hypometabolic changes. This study is not without its limitations. The first is that core clinical criteria were used in the inclusion of patients into this study, and as such DLB was considered to the primary diagnosis for these patients at the time of FDG-PET scanning. Therefore, coexisting pathology was not taken into consideration. That being said, the second limitation is that probable DLB carries with it a high proportion of coexisting Alzheimer’s Dementia pathology on previous studies, and this study did not specifically address the distinction between DLB and mixed Lewy Body and Alzheimer pathologies as evidenced on cingulate hypometabolism. However, clinical features strongly suggested a predominantly Lewy Body Dementia picture for most patients. The third is that although 90% of patients had their eyes open during the study as per protocol, around 2 had their eyes closed per the technician and a handful had indeterminate eye opening/closure status. This influences the scan by causing hypometabolism in the occipital lobe, which can confound the diagnostic picture .However, the proportion of patients with eyes closed during the scan was felt to be negligible in this study. Another potential limitation is selection bias, since the primary selection apart from diagnosis is whether they had had FDG-PET which was largely determined by whether the scans were underwritten by insurance companies. The primary objective of this study is to demonstrate the under-reporting of occipital hypometabolism by identifying patients with occipital hypometabolism per radiologist reports, and determining the agreeability of such a read with an independent, blinded Nuclear Medicine physician. Occipital hypometabolism is therefore not reliably reported and often missed. These findings could establish a cohort for longitudinal research of FDG-PET biomarkers in DLB and improve clinical practices in diagnosing and managing DLB from an investigational standpoint. Furthermore, this study stresses the importance of identifying the primary visual and visual association cortices in patients with suspected Dementia with Lewy Bodies let alone any dementia syndrome to begin with .in vivo biomarker was found to be grossly under-reported on clinical reports.Occipital hypometabolism as an Our data suggest the occipital hypometabolism might be missed clinically but the frequency is actually higher than previously reported.Future directions would include reproducing these data using large datasets and comparing the central reads with the local reads. Also, a retrospective analysis of existing imaging datasets to confirm these findings would be of interest.


This classification was originally developed by a 1995 World Health Organization (WHO) expert committee, and the definition is based on a birthweight-for-gestational-age measure compared to a gender-specific reference population Successful pregnancy, including optimal growth of the fetus, relies on a careful balance between immune tolerance and suppression. Several mechanisms work together to protect the fetus from rejection Dysfunction of the maternal innate immune response may predispose to placentally mediated diseases such as pre-eclampsia (PET), fetal growth restriction (FGR), placental abruption, and intrauterine fetal death. The complement system can affect angiogenesis-related endothelial cell function. It can indirectly, through macrophages, upregulate the anti-angiogenic soluble vascular endothelial growth factor receptor-1 (SFlt-1). In addition, SFlt-1 can combine with soluble endoglin (sEnd) to induce PET, FGR, and coagulation defects Traditionally, the causes for “pathological” growth restriction are subdivided into fetal, placental and maternal. Genetic and chromosomal disorders, fetal malformation, infection , and toxic substances  can contribute to FGR. Maternal diseases such as anemia and malnutrition may also affect fetal growth. However, classical utero-placental dysfunction accounts for the vast majority of cases of “placental” FGR, as well as to a variety of conditions such as pre-eclampsia and placental abruption Toxoplasma gondii, rubella, cytomegalovirus, herpes simplex virus (HSV), varicella-zoster virus, Treponema, and HIV contribute to 5–10% of fetal growth restriction Congenital infections by Placental malaria is a major cause of fetal growth restriction. In a case-control study of 492 pregnant Malawian women, a significant increase of placental complement C5a levels was associated with an increased risk of delivering a small-for-gestational-age infant Maternal vaccination during pregnancy has emerged as a recommended public health approach to prevent maternal and childhood infections. All current maternal vaccines were initially designed for and tested in non-pregnant populations, but the diverse immune modulations during pregnancy may cause pregnant women to respond sub-optimally or differently compared with non-pregnant populations Tetanus and influenza vaccines were the first vaccines recommended for use during pregnancy. Trotta and colleagues evaluated the safety of A/H1N1 pandemic vaccination of 6246 pregnant women Placentally mediated severe FGR, indicated by abnormal uterine and umbilical artery Doppler velocimetry, is associated with impaired transplacental gas transfer and fetal hypoxaemia. This triggers compensatory re-distribution of blood towards essential organs  and decreases blood flow to other organs (kidneys and bowel). This “compensatory phase” can be recognised by observing Doppler changes (reduced resistance) in the middle cerebral artery (MCA), decreased amniotic fluid, and/or bright echogenic bowel. The duration of this compensatory phase is variable. This phase is followed by a phase of myocardial dysfunction and haemodynamic decompensation. This “decompensation phase” can be recognised by abnormal venous Doppler waveforms (absent or negative ‘a’ wave) and it is associated with fetal acidaemia. Both hypoxaemia and acidaemia can also be detected clinically by changes in fetal heart rate as well as the biophysical profile. The Brighton Collaboration growth restriction and fetal distress guidelines further explore these issues Despite the presence of many pathophysiological events that may lead to intrauterine growth restriction, SGA is not universally associated with growth restriction. Small for gestational age (SGA), is commonly used as a proxy for intrauterine growth restriction (IUGR), particularly in settings where serial ultrasonography is not readily available A related term is low birth weight (LBW), defined as a birth weight of less than 2500 g, regardless of gestational age at the time of birth. Additional related terms include very low birth weight (VLBW) which refers to less than 1500 g, and extremely low birth weight (ELBW) which is less than 1000 g. Normal weight at term delivery is 2500–4200 g. LBW is discussed further in a separate document for this definition. It is important to be clear that SGA is not a synonym of LBW, VLBW or ELBW. Approximately one third of LBW babies weighing less than 2500 g are also SGA In this case definition and associated guideline, we propose a systemic tool for evaluating the adverse event of SGA after maternal immunisation. It is important to emphasize that these tools have been developed in the absence of any data supporting such an association but rather to facilitate studies of the safety of vaccines used in pregnancy. The outcome of SGA has been examined in several published studies of the safety of influenza and pertussis vaccination during pregnancy. In one randomised clinical trial of influenza immunisation in pregnant women in Bangladesh, SGA was defined as less than 10th percentile weight for gestational age The remaining published studies were observational in design and used different SGA definitions and reference standards  [32], [3Among the national population-based weight references used by the investigators, two older US population based standards were mentioned The WHO definition of SGA, outlined by a 1995 WHO expert committee, remains the most widely utilized definition of SGA Essential to the SGA definition is accurate dating of gestational age A main challenge in defining SGA is selecting the appropriate comparison population Customizing fetal size for maternal height, weight and ethnicity, has been shown to improve the identification of babies who are small because of FGR, rather than constitutional reasons Additionally important for preterm infants, the birth weight for gestational age reference charts differ from ultrasound-based fetal weight charts. Preterm infants are known to be smaller than in utero infants given the underlying pathological determinants, such as preeclampsia and other hypertensive disorders that impair fetal growth and increase the risk of preterm birth Although there is a broadly accepted definition of SGA, the aforementioned complexities involved in its evaluation, including the accurate measurement of birth weight, the determination of gestational age, and the reference chart used to analyze these data, indicate that a standardized definition of SGA is desirable. This need is especially apparent in studies of maternal immunisation where SGA may be a critical endpoint, either as a positive outcome related to vaccination or as related to safety. A positive effect of immunisation in pregnancy might be that the infant is less likely to be SGA. On the other hand, if the study vaccine somehow adversely affects maternal health or other factors that impact birth weight, then the increased incidence of SGA may indicate a safety signal. A standard definition and evaluation of SGA would support the comparability of conclusions related to the benefits and safety concerns attributed to maternal immunisation with a given vaccine across studies. Herein, to facilitate data interpretation and promote scientific understanding of the same, we propose the tools necessary for determination of SGA in the setting of clinical trials as well as post-licensure surveillance systems.1.2http://www.brightoncollaboration.org/internet/en/index/process.html, the Brighton Collaboration Small for Gestational Age Working Group was formed in 2016 and included members of clinical, academic, public health, and industry backgrounds. The composition of the working and reference group as well as results of the web-based survey completed by the reference group with subsequent discussions in the working group can be viewed at: http://www.brightoncollaboration.org/internet/en/index/working_groups.html.Following the process described in the overview paper To guide the decision-making for the case definition and guidelines, a literature search in PubMed was performed and identified over twenty vaccine studies in which SGA was mentioned and defined. (The search strategy used was as follows: (pregnancy OR pregnant) AND (vaccine OR vaccination OR immunisation) AND (pertussis OR Tdap OR tetanus OR influenza); article publication dates between 1 January 2006 and 1 June 2016.) All abstracts were screened for possible reports of small for gestational age following immunisation. This review resulted in a summary of 26 articles, including information on the diagnostic criteria or case definition put forth and the vaccine used (summarized in 1.31.3.1diagnostic certainty (see below).Small for gestational age (SGA) is commonly used as a surrogate marker of low fetal growth trajectories, and is indeed associated with increased perinatal mortality and morbidity. In order to define perinatal outcomes and identify safety issues during maternal immunisation trials, this Brighton Collaboration case definition of small for gestational age focuses on recommendations to simultaneously define both birthweight and gestational age. Within the definition context, however, the three diagnostic levels must not be misunderstood as reflecting different grades of clinical severity. They instead reflect 1.3.2The working group considered several other related outcomes in its discussions. Principle consideration was given to both the assessment of gestational age and assessment of size/weight as both these formed the foundation for our definition. Accordingly, we worked closely with the GAIA workgroups assigned to assessment of prematurity In addition, SGA, which assesses the size of the infant in relation to its maturity after birth, is closely related to inter-uterine growth retardation which assesses the growth of the fetus up until the time of birth and when present predicts for an SGA infant. These two entities, while closely related, use very different assessment tools, so our definition presented here acknowledges the work of the GAIA IUGR group 1.3.3It needs to be re-emphasised that the grading of definition levels is entirely about diagnostic certainty, not clinical severity of an event. Thus, a clinically very severe event may appropriately be classified as Level Two or Three rather than Level One if it could reasonably be of non-small for gestational age aetiology. Detailed information about the severity of the event should additionally always be recorded, as specified by the data collection guidelines.The number of symptoms and/or signs that will be documented for each case may vary considerably. The case definition has been formulated such that the Level 1 definition is highly specific for the condition. As maximum specificity normally implies a loss of sensitivity, two additional diagnostic levels have been included in the definition, offering a stepwise increase of sensitivity from Level One down to Level Three, while retaining an acceptable level of specificity at all levels. In this way it is hoped that all possible cases of SGA can be captured.1.3.4Our approach is to provide adequate diagnostic specificity without being overly restrictive with the objective of making available a definition that is applicable in high, middle, and low-income countries. Laboratory and pathology findings are not included in the case definition as these examinations are not required to meet the case definition of SGA. Assessment through imaging (ultrasound) at different gestational ages in pregnancy has been included to meet case definition for levels of certainty 1A to 3A, as ultrasound represents the most accurate method for assessment of gestational age.1.3.5The Working Group decided against using “treatment” or “treatment response” towards fulfillment of the SGA case definition, as specific SGA treatments are not currently used or accepted.1.3.6The diagnosis of SGA is made at birth after the measurement of birth weight, calculation of gestational age and ascertainment of weight for gestational age percentile when compared to a reference standard. Once the diagnosis has been made, no further change would be anticipated. It is expected that the birth weight and gestational age would have been obtained by a method consistent with the Brighton Collaboration standards.The timing of the vaccine receipt or the interval from maternal immunisation and the neonatal birth are not elements of the SGA definition. In fact, the definition is meant to stand alone independent of whether the mother was vaccinated. A definition designed to be a suitable tool for describing relationships requires ascertainment of the outcome (e.g. SGA) independent from the exposure (e.g. vaccination). Therefore, to avoid selection bias, a restrictive time interval from vaccination to birth should not be an integral part of such a definition. Instead, where feasible, information on the timing of vaccine administration during pregnancy should be collected, assessed and reported as described in the data collection guidelines and the ascertainment of whether or not the infant is SGA and the associated Brighton level should be determined by personnel blinded to the vaccine status of the mother.Further, SGA often occurs outside the controlled setting of a clinical trial or hospital. In some settings it may be impossible to obtain a clear timeline of the event, particularly in less developed or rural settings. In order to avoid selecting against such cases, the Brighton Collaboration case definition avoids setting arbitrary time frames.1.3.7As described above, other similar disorders to SGA include IUGR. While IUGR refers to reduced growth velocity in the fetus as supported by at least two intrauterine growth assessments, SGA does not reflect fetal growth but size of the infant at birth 1.4As mentioned in the overview paper, the case definition is accompanied by guidelines which are structured according to the steps of conducting a clinical trial, i.e. data collection, analysis and presentation. Neither case definition nor guidelines are intended to guide or establish criteria for management of ill infants, children, or adults. Both were developed to improve data comparability.1.5Similar to all Brighton Collaboration case definitions and guidelines, review of the definition with its guidelines is planned on a regular basis (i.e. every three to five years) or more often if needed.2SGA  definition: weight below 10th percentile for gestational age as assessed against a validated global, regional or local standard.2.1•Weight below 10th percentile for gestational ageAND•oNewborn weighed within 24 h of birthoWeight assessed using a calibrated electronic scale with 10 g resolutionThe following used in assessment of weight:AND•oCertain LMP or IUI or embryo transfer date AND confirmatory ultrasound in first trimesterThe following for assessment of gestational age:OR•oFirst trimester ultrasoundThe following for assessment of gestational age:2.2•Weight below 10th percentile for gestational ageAND•oNewborn weighed within 24 h of birth on any scale with a <50 g resolution, tared to zero and calibratedThe following used in assessment of weightAND•oCertain LMP with first or second trimester ultrasoundThe following for assessment of gestational age:oCertain LMP with first trimester physical exam4OR2.3•Weight below 10th percentile for gestational ageAND•oNewborn weighed within 24 h of birth on any scale with a <50 g resolution, tared to zero and calibratedThe following used in assessment of weightAND•oUncertain LMP with second trimester ultrasoundThe following assessment of gestational age2.4•Weight below 10th percentile for gestational ageAND•oInfant weighed within the first 48 h of lifeoNewborn weighed on any scale with a <50 g resolution, tared to zero and calibratedANDThe following used in assessment of weight•oCertain LMP with third trimester ultrasoundORoCertain LMP with confirmatory 2nd trimester fundal heightORoCertain LMP with birthweightORoUncertain LMP with first trimester physical examThe following assessment of gestational age2.5•Weight below 10th percentile for gestational ageAND•oInfant weighed within the first 48 h of lifeoNewborn weight assessed by measuring the difference between an adult holding the infant and the adult being weighed alone on any scaleThe following used in assessment of weightAND•oUncertain LMP with fundal heightThe following assessment of gestational ageoUncertain LMP with newborn physical assessmentORoUncertain LMP with birthweightOR2.6–Baby noted to be small, but no actual weight–Baby with GA assessed only by infant examination–Diagnosis extracted from billing codes or chart, with no documentation of actual birth weight or GA2.7–No evidence of SGA or a confirmed diagnosis other than SGA.3Small for Gestational Age Working Group for small for gestational age (SGA) to recommend the following guidelines to enable meaningful and standardized collection, analysis, and presentation of information about SGA. However, implementation of all guidelines might not be possible in all settings. The availability of information may vary depending upon resources, geographical region, and whether the source of information is a prospective clinical trial, a post-marketing surveillance or epidemiological study, or an individual report of SGA. Also, as explained in more detail in the overview paper in this volume, these guidelines have been developed by this working group for guidance only, and are not to be considered a mandatory requirement for data collection, analysis, or presentation.It was the consensus of the Brighton Collaboration 3.1These guidelines represent a desirable standard for the collection of data on availability following immunisation to allow for comparability of data, and are recommended as an addition to data collected for the specific study question and setting. The guidelines are not intended to guide the primary reporting of SGA to a surveillance system or study monitor. Investigators developing a data collection tool based on these data collection guidelines also need to refer to the criteria in the case definition, which are not repeated in these guidelines.Guideline numbers below have been developed to address data elements for the collection of adverse event information as specified in general drug safety guidelines by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use 3.1.1(1)Date of report.(2)Name and contact information of person reporting(3)Name and contact information of the investigator responsible for the subject, as applicable.(4)Relation to the patient .For all cases and/or all study participants, as appropriate, the following information should be recorded:3.1.23.1.2.1(5)Case/study participant identifiers  or code (or in accordance with country-specific data protection laws). Full name should be used if privacy rules permit to avoid a misclassification.(6)Date of birth, age, and sex.(7)For infants: Gestational age and birth weight.For all cases and/or all study participants, as appropriate, the following information should be recorded:3.1.2.2(8)Past medical history, including hospitalisations, underlying diseases/disorders, pre-immunisation signs and symptoms including identification of indicators for, or the absence of, a history of allergy to vaccines, vaccine components or medications; food allergy; allergic rhinitis; eczema; asthma.(9)Any medication history (other than treatment for the event described) prior to, during, and after immunisation including prescription and non-prescription medication, as well as medication or treatment with long half-life or long term effect. .(10)Immunisation history (i.e. previous immunisations and any adverse event following immunisation (AEFI)), in particular occurrence of SGA after a previous immunisation.For all cases and/or all study participants, as appropriate, the following information should be recorded:3.1.3(11)Date and time of immunisation(s).(12)Description of vaccine(s)  and number of dose if part of a series of immunisations against the same disease).(13)The anatomical sites (including left or right side) of all immunisations .(14)Route and method of administration , other injection devices).(15)Needle length and gauge.For all cases and/or all study participants, as appropriate, the following information should be recorded:3.1.4(16)For all cases at any level of diagnostic certainty and for reported events with insufficient evidence, the criteria fulfilled to meet the case definition should be recorded.(17)Clinical description of signs and symptoms of SGA, and if there was medical confirmation of the event (i.e. patient seen by physician).(18)Date/time of onset,10(19)Concurrent signs, symptoms, and diseases.(20)•Values and units of routinely measured parameters  – in particular those indicating the severity of the event;•Method of measurement ;•Results of laboratory examinations, surgical and/or pathological findings and diagnoses if present.Measurement/testing(21)Treatment given for SGA.(22)Outcome(23)Objective clinical evidence supporting classification of the event as “serious”.11(24)Exposures other than the immunisation 24 h before and after immunisation  considered potentially relevant to the reported event.Specifically document:3.1.5(25)The duration of surveillance for SGA should be predefined based on the relatively narrow window of time for diagnosis at birth.(26)The duration of follow-up reported during the surveillance period should be predefined likewise. It should aim to continue to resolution of the event.(27)Methods of data collection should be consistent within and between study groups, if applicable.(28)Follow-up of cases should attempt to verify and complete the information collected as outlined in data collection guidelines 1 to 24.(29)Investigators of patients with SGA should provide guidance to reporters to optimise the quality and completeness of information provided.(30)Reports of SGA should be collected throughout the study period regardless of the time elapsed between immunisation and the adverse event. If this is not feasible due to the study design, the study periods during which safety data are being collected should be clearly defined.3.2(31)Reported events should be classified in one of the following five categories including the three levels of diagnostic certainty. Events that meet the case definition should be classified according to the levels of diagnostic certainty as specified in the case definition. Events that do not meet the case definition should be classified in the additional categories for analysis.The following guidelines represent a desirable standard for analysis of data on SGA to allow for comparability of data, and are recommended as an addition to data analysed for the specific study question and setting.3.2.13.2.1.1Level 1: Criteria as specified in the SGA case definition.Level 2: Criteria as specified in the SGA case definitionLevel 3: Criteria as specified in the SGA case definition3.2.23.2.2.1(4) Reported SGA with insufficient evidence to meet the case definition13(5) Not a case of SGA14(32)The interval between immunisation and reported SGA could be defined as the date/time of immunisation to the date/time of diagnosis. It should be noted that the diagnosis of SGA is made at birth whereas any damage due to immunisation or another exposure happened during the pregnancy. Thus the interval between immunisation date and the date of diagnosis is less useful than in classical vaccine association studies.3.33.3.1Immunisation >12 weeks prior to SGA diagnosis.Immunisation >8 and <12 weeks prior to SGA diagnosis.Immunisation >4 and <8 weeks prior to SGA diagnosis.Immunisation <4 weeks prior to SGA diagnosis.Weekly increments thereafter.4(33)The duration of a possible SGA could be analysed as the interval between the date/time of diagnosis or birth. Whatever start and ending are used, they should be used consistently within and across study groups.(34)If more than one measurement of a particular criterion is taken and recorded, the value corresponding to the greatest magnitude of the adverse experience could be used as the basis for analysis. Analysis may also include other characteristics like qualitative patterns of criteria defining the event.(35)The distribution of data (as numerator and denominator data) could be analysed in predefined increments , where applicable. Increments specified above should be used. When only a small number of cases is presented, the respective values or time course can be presented individually.(36)Data on SGA obtained from subjects receiving a vaccine should be compared with those obtained from an appropriately selected and documented control group(s) to assess background rates of hypersensitivity in non-exposed populations, and should be analysed by study arm and dose where possible, e.g. in prospective clinical trials.4.1(37)All reported events of SGA should be presented according to the categories listed in guideline 31.(38)Data on possible SGA events should be presented in accordance with data collection guidelines 1–24 and data analysis guidelines 31–36.(39)Terms to describe SGA such as “low-grade”, “mild”, “moderate”, “high”, “severe” or “significant” are highly subjective, prone to wide interpretation, and should be avoided, unless clearly defined.(40)Data should be presented with numerator and denominator (n/N) (and not only in percentages), if available.These guidelines represent a desirable standard for the presentation and publication of data on SGA following immunisation to allow for comparability of data, and are recommended as an addition to data presented for the specific study question and setting. Additionally, it is recommended to refer to existing general guidelines for the presentation and publication of randomised controlled trials, systematic reviews, and meta-analyses of observational studies in epidemiology , of Improving the quality of reports of meta-analyses of randomised controlled trials (QUORUM), and of meta-analysis Of Observational Studies in Epidemiology (MOOSE), respectively) (41)The incidence of cases in the study population should be presented and clearly identified as such in the text.(42)If the distribution of data is skewed, median and range are usually the more appropriate statistical descriptors than a mean. However, the mean and standard deviation should also be provided.(43)•The study design;•The method, frequency and duration of monitoring for SGA;•The trial profile, indicating participant flow during a study including drop-outs and withdrawals to indicate the size and nature of the respective groups under investigation;•The type of surveillance (e.g. passive or active surveillance);•The characteristics of the surveillance system ;•The search strategy in surveillance databases;•Comparison group(s), if used for analysis;•The instrument of data collection ;•Whether the day of immunisation was considered “day one” or “day zero” in the analysis;•Whether the date of onset•Use of this case definition for SGA, in the abstract or methods section of a publication.15Any publication of data on SGA should include a detailed description of the methods used for data collection and analysis as possible. It is essential to specify:Although immunisation safety surveillance systems denominator data are usually not readily available, attempts should be made to identify approximate denominators. The source of the denominator data should be reported and calculations of estimates be described .The findings, opinions and assertions contained in this consensus document are those of the individual scientific professional members of the working group. They do not necessarily represent the official positions of each participant’s Organization . Specifically, the findings and conclusions in this paper are those of the authors and do not necessarily represent the views of their respective institutions.


Four time periods (T) were defined: T1 birth to arrival at resuscitation table, T2 arrival to application of NIRS sensor, T3 application to first displayed cTOI or crSO2 value, and T4 from arrival at resuscitation table to first displayed values. Additionally, we compared first displayed values of cTOI and crSO2. Thirty neonates were included. Twenty-four were term and six late-preterm neonates. Fifteen neonates measured with NIRO were compared to 15 measured with INVOS. T1 was 49 (6–163) s with NIRO versus 59 (15–87) s with INVOS, T2 14 (4–20) s versus 12 (15–18) s, T3 33 (13–138) s versus 17 (6–290) s and T4 46 (20–153) s and 34 (14–300) s. The first displayed value tended to be higher for cTOI [54% (18–80)] compared to crSO2 [35% (15–87)]. There were no significant differences between devices in time periods and first values displayed. Cerebral tissue oxygenation can be measured within 1 min after arriving at the resuscitation table in term and preterm neonates after birth without difference between devices.Feasibility of cerebral tissue oxygenation measurements immediately after birth has been published starting with first values 2 min after birth. Aim of this study was to evaluate, the time periods from birth and from arrival at the resuscitation table to obtain the first cerebral tissue oxygenation values with two different near infrared spectroscopy (NIRS) devices. The present study is an analysis of exploratory parameters of two prospective observational studies. Cerebral tissue oxygen saturation was measured by the NIRO 200NX measuring “cerebral-tissue-oxygenation-index” (cTOI) or the INVOS5100C measuring “cerebral-regional-oxygen-saturation” (crSO Unfortunately, these methods do not provide information about potentially compromised oxygen delivery to the brain. Therefore, there is a growing interest, to monitor the cerebral regional tissue oxygenation by using near-infrared spectroscopy (NIRS) during immediate postnatal transition [2). With both NIRS devices centiles of cerebral tissue oxygenation immediately after birth starting with first values 2 min after birth have been already published [2 values with pulse oximetry immediately after birth [2 values in less than 1 min [2 values after the arrival of a newborn infant at the resuscitation table. Therefore, the aim of this study was to evaluate, the time periods from birth and from arrival at the resuscitation table to obtain the first cerebral tissue oxygenation values with two different devices. We hypothesized that there is no difference between these two devices.During immediate transition after birth beside the clinical assessment of newly born infants, routine monitoring with pulse oximetry/ECG is recommended. These two non-invasive continuous monitoring methods enable measurement of the arterial oxygen saturation . Parental informed consent was obtained from all individual participants included in the study. Videos of term and preterm infants during immediate transition after birth were analysed, which were recorded during these prospective studies. The video started when the whole body was delivered. Immediately after birth, the neonates were brought by the midwife from the operating theatre and placed on the resuscitation table under an overhead heater. The forehead skin area was cleaned and dried.2). Neonates were excluded when the arrival-time or application of sensor was not clearly visible on video recordings or if both NIRS sensors were applied simultaneously in one neonate. For analyses neonates, in whom INVOS 5100C was applied, were matched for gestational age (±1 week) to neonates in whom NIRO 200 NX was applied. Neonates with application of both sensors simultaneously were excluded. The sensor was fixed in both groups on the forehead with a double adhesive plaster and/or gauze bandage by a research team member, who was not involved into resuscitation. Four time periods (T) were defined: T1 from birth to arrival of the neonate on the resuscitation table, T2 from arrival to application of the NIRS sensor, T3 from application to first cTOI or crSO2 values on the monitor, and T4 from arrival to first displayed NIRS values. Additionally, we analysed first displayed values of cTOI and crSO2.In neonates either the NIRS sensor of the NIRO 200 NX  was positioned on the right forehead to evaluate the “cerebral tissue oxygenation index” (cTOI) or the neonatal sensor of INVOS 5100C  on the left forehead for evaluating the “cerebral regional oxygen saturation” (crSOThe data are presented as mean ± standard-deviation (±SD) for normally distributed continuous data and median (range) when the distribution was skewed. Data of NIRO group and INVOS group were compared using paired t-test and Wilcoxon-rank-sum-test for parametric and non-parametric continuous variables, respectively, and chi square or Fisher’s exact test for categorical variables. A p value of 0.05 was considered significant.2, also without reaching significance.Out of the 150 neonates with NIRS measurements during the first 15 min after birth, 15 neonates measured with INVOS 5100C were included, in whom time of arrival and application of the sensors were clearly visible. Main exclusion criterion was hindered visibility caused by attending staff (Fig. 2 using the Nellcor OxiMax it has been demonstrated that it took 22–32 s [2 and NIRS monitoring require careful technical and practical preparations to obtain the initial values within 1 min [The present study demonstrates that after the arrival of the neonate on the resuscitation table non-invasive cerebral NIRS monitoring is feasible within 1 min. The application of the NIRS sensor on the neonate’s forehead can be performed quickly independently of which device was used enabling first values even within 20 s after arrival of the neonate at the resuscitation table. However, most studies present data of cerebral regional tissue oxygenation starting 2 min after birth –5. The m 22–32 s , using t 22–32 s  and usin 22–32 s . However 22–32 s , 9. Bothin 1 min . In the in 1 min  and publin 1 min , 5.Cerebral tissue oxygenation can be measured within 1 min after arriving at the resuscitation table in term and preterm neonates after birth without difference between devices. Therefore, NIRS has the potential to become an additional routinely used tool for cerebral monitoring during immediate transition and resuscitation after birth.


A rare case of type-II jejunoileal atresia with mesenteric cyst in a neonate is being reported here with a brief review of literature. A full term five-day old male neonate born by normal delivery weighing 2.7 kg was referred to our hospital with complaints of bilious vomiting and abdominal distention for three days. Examination of the neonate revealed abdominal distention along with visible bowel loops and bilious nasogastric aspirates. Antenatal ultrasound was normal. Erect radiograph of abdomen revealed distended bowel loops along with few air fluid levels and absent distal gas in pelvis suggestive of jejunoileal atresia. On exploratory laparotomy, type-II jejunoileal atresia at proximal ileum with distal mesenteric cyst measuring 4 x 4 cm causing bowel volvulus around it was noted . The cyst was compressing on the distal ileal segment for about 5 cm and could not be separated from it. Hence, ileal derotation and resection of segment of atretic ileum along with distal mesenteric cyst and end to oblique ileo-ileal anastomosis was done. The histopathology report confirmed it a mesenteric cyst. Postoperative course was uneventful. Follow-up of the child at one year is also satisfactory.Jejunoileal atresia (JIA) is a major cause of intestinal obstruction in neonates, with an incidence of about 1 in 5000 live births. [1] Jejunal atresia has been associated with number of other congenital malformations such as cystic fibrosis, malrotation, congenital heart disease, Down’s syndrome, congenital dislocation of hips, anorectal and vertebral anomalies, neural tube defects and microcephaly. It can also coexist with other anomalies like biliary atresia, duodenal atresia, colonic atresia, gastric atresia and Hirschsprung’s disease. [2-4] The association of mesenteric cyst with JIA is extremely rare with less than 10 cases reported so far in literature. [5]Intrauterine mesenteric vascular disruptions to a segment of developed intestine seemed to result in JIA. [6] Intestinal atresias secondary to late intrauterine mesenteric vascular insults are often seen in patients with volvulus, intussusceptions, internal hernia, and tight anterior abdominal wall defects.  As in our case, mesenteric cyst causing secondary bowel volvulus distally could be the causative factor for the vascular compromise leading to JIA.We report this extremely rare association of mesenteric cyst causing secondary bowel volvulus and proximal type-II JIA which further reinforces the theory of mechanical obstruction as the cause for JIA.Source of Support: NilConflict of Interest: Nil


A detailed ME measurement reveals a nonlinear ME effect instead of a linear ME effect in CNO single crystal. By fitting the magnetization-electric field (M-E) curve, it can be found that the linear , magnetic and electric control of magnetic properties in Co Because weak coupling between magnetic moments and electric polarization is usually observed in single-phase materials3, there is an important research effort towards novel materials with improved magnetoelectric coupling. Indeed, highly efficient control of magnetism by means of an electric field4 may find a plethora of applications in magnetic storage and magnetic random-access memory devices.Multiferroics have attracted a lot of attention as they exhibit coexistence of two or more switchable states such as polarization, magnetization or strain4Nb2O9 (CNO) is very attractive. In polycrystalline form, it has been shown to display a large linear ME coupling as well as an electric field control of the magnetism5, a manipulation which remains quite rarely reported. According to previous report by Kolodiazhnyi et al.6, the structural space group of CNO is N = 27.5 K) under a high external magnetic field (>12 kOe). Interestingly, both the magnetically-induced electric polarization and the control of magnetization with an electric field were observed in polycrystalline CNO by Fang et al.5. Our former work showed that the magnetic moments of CNO are located in ab-plane7 but not along the c-axis. Moreover, Khanh et al. proposed a magnetic structure with space group C2/c’ by using single-crystal neutron diffraction8. If the magnetic structure corresponds to that space group, an antiferromagnetic phase transition along c-axis should be therefore observed. Surprisingly, there is no antiferromagnetic phase transition in our c-axis magnetic measurements7, which was also unseen by Khanh et al.8. In very recent reports, Khanh et al.8 and Solovyev et al.9 finally clarified the origin of ME effect in the centrosymmetric trigonal Co4Nb2O9 and Co4Ta2O9. Furthermore, a structural phase transition with a-axis shrinkage and c-axis expansion at TN was reported by Yin et al.10.In the route towards materials having strong magnetoelectric (ME) responses, Co11. In this work, our detailed ME measurements reveal a nonlinear ME effect instead of a linear one as previously reported in CNO single crystals. More importantly, a pronounced response was observed under a small cooling magnetic field for which it cannot even cause the spin flop transition. Furthermore, we also found that the magnetization of every axis responds to electric field applied along a-axis, but unchanged when the electric field is applied c-axis.In order to better understand the magnetic behavior in this material with large ME coupling, we conducted a new neutron diffraction measurement and suggested a mechanism of the ME coupling in the single crystals of CNO11, we carefully studied the magnetic structure by using neutron powder diffraction and irreducible representation analysis. We found that the magnetic space group is C2/c’ (the magnetic point group is 2/m’) with two independent sites for Co. Spins on the Co atoms are canted in the ab-plane and along c-axis to form ferromagnetic chains. Two ferromagnetic chains within the unit cell are coupled antiferromagnetically leading to the overall magnetic moments equal to zero. The magnetic moments calculated for each Co site are 2.32(6) and 2.52(8) µB, respectively. The magnetic structure drawn by VESTA software12  does not take place suddenly but continuously.Prior to the electrical measurements, the sample was first cooled down from 70 to 10 K with an electric field of 1.2 MV/m and a magnetic field of 0, 20, 40 and 80 kOe was applied along the 2. It is worth noting that the P-H curve presents an abnormal behavior in the vicinity of 7.5 kOe, which is just correspondent to the critical magnetic field of spin flop as shown in our previous work7. Such a consistency sufficiently proves that there indeed exists a nonlinear ME effect in the studied sample, which is originated from the change of spin configuration.In order to further clarify the relationship between polarization P and magnetic field H, P-H curve was calculated by integrating displacement current which was measured as a function of the magnetic field after ME cooling. The polarization could also be reversed by changing the direction of magnetic field as shown in Fig. 4Nb2O9, the effect of electric control of magnetization was reported5 in its ferroelectric state (under a cooling magnetic field of 50 kOe). Interestingly here, the control of magnetization by electric field occurs in the paraelectric state for CNO single crystal along the a-axis. As shown in Fig. a-axis are measured at 0.1 kOe and for selected electric field values . In that case, the sample is in its paraelectric state because for such a low magnetic field, the spin flop transition does not occur . Before these measurements, an ME cooling is performed under 0.1 kOe  and 1.2 MV/m in order to ensure the same initial magnetization-polarization state of the sample. As shown in Fig. N~27.5 K. Indeed, for temperatures below TN, each electric field value gives a different magnetization value. It is clear that the magnetization value increases or decreases of the same magnitude with respect to the magnetization at zero electric field when an electric field, of same amplitude but opposite in sign, is applied. In contrast, the magnetization above TN keeps unchanged with the different applied electric field values, which is ascribed to the disappearance of polarization. It is interesting to stress here that below TN the magnetization can be tuned using a small electric field even under a weak cooling magnetic field. In these low magnetic field conditions, CNO is expected to be in its paraelectric state. However, this state shows non-ergodic behavior as the response of the system depends on the way the state is achieved . At this stage, it is possible to invoke the existence of some clusters which size and/or number might depend on the applied fields.For the polycrystalline Cosee Fig.  in ref.7a-axis at 10 K was measured. As is shown in Fig. 5 and single crystal CNO10, the nonlinear M-E curve of the single crystal CNO which implies that CNO is a linear ME material with high order (nonlinear) component. This result is consistent with the P-H curve at 10 K  dependence of magnetization (M) along See Fig. . To apprsee Fig.  show thaC2/c’ while the magnetic point group is 2/m’ for CNO. Actually, for the magnetic point group 2/m’, which is the zero-field magnetic structure of CNO, it has no quadratic term for ME coupling. However, for the mixed magnetic phase under magnetic field or electric field (due to magnetoelectric effect). For example, under electric field, the two polarizations (up and down) will be effected by the electric field. The response from the up one will increase while the other one will suppress or even change (flip) the direction. This would cause the change of magnetic structure due to the formula m has quadratic term for ME coupling. For this speculation, more work, such as neutron diffraction under magnetic or electric field, is needed to confirm it.The magnetic space group is To further investigate the responses of magnetization to the electric field, as shown in Fig. a and c direction electric field were measured and shown in Fig. a-axis, but fails to do so when the electric field is applied c-axis. The magnetic response under different directional electric field makes it possible for us to study the interaction between the electric field and the spin. As we know, the antiparallel Co2+ spins locate in ab plane, a-axis electric field will yield a net electric field along the spin but c axis electric field could only be perpendicular to the spin.In order to clarify the directional relationship between magnetic response and applied electric field, the magnetic responses along different axes under 11, the magnetic-field-induced electrical polarization is along the [110] direction due to the spin-current effect14. Reversely, if applying electric fields in any direction in the ab plane, the electric fields should induce variations of magnetization in the corresponding directions. However, this effect will not exist along the c axis because the electrical polarization along the c axis is always zero. Therefore, the observed magnetization response under electric fields in this study is understandable on the basis of our ME model11. At the same time, the systematic electrical and magnetic measurement provides new evidence about the spin-current mechanism of the ME in CNO proposed in our recent work11. The ME measurement by Khanh et al.8 indicates the ME effect along the c axis, which is contradictive to the above discussion and could be due to the slight misalignment of the sample in the measurement. Similar problem was observed in the earlier work of Cr2O315.According to our recent explanation to the ME coupling mechanism in CNOapplied along a-axis, but fails to do so when the electric field is applied c-axis. These findings further indicate that the spin-current mechanism is the nature of the ME effect in CNO single crystal.In summary, we have studied the detailed magnetoelectric (ME), magnetic and electric control of magnetic properties in CNO crystal. A detailed ME measurement reveals a nonlinear ME effect, whose linear  with VSM (Vibrating Sample Magnetometer) option. To measure magnetization as a function of electric field, a homemade insert which allows the application of electric field was installed in the magnetometer. The plates with the large [100] and [001] plane of 2 * 2 mm2 were sliced out from the crystal rod, and both the end [100] and [001] surfaces were painted with silver paste as the electrodes. The pyroelectric current was collected using an electrometer (Keithley 6517B) after poling the sample in an electric and magnetic field. The electric polarization as a function of temperature and magnetic field was calculated by integrating displacement current with time. Specifically, the specimen was cooled down to 10 K while applying a poling electric field of 1.2 MV/m along [100] direction. In order to release any charges accumulated on the sample surfaces or inside the sample, the sample was short-circuited for a long-enough time (1 h). During the recording of pyroelectric current, the sample was heated slowly at a warming rate of 2 K/min. Note that the magnetic field was applied throughout the cooling and warming processes.A single-crystal specimen of Co


Low birth weight has been shown to be closely associated with neonatal mortality and morbidity, inhibited growth, poor cognitive development, and chronic diseases later in life. Some studies have also shown that excessive mobile phone use in the postnatal period may lead to behavioral complications in the children during their growing years; however, the relationship between mobile phone use during pregnancy and neonatal birth weight is not clear. The aim of the present study was to determine the associations of excessive mobile phone use with neonatal birth weight and infant health status.A sample of 461 mother and child pairs participated in a survey on maternal characteristics, infant characteristics, and maternal mobile phone usage information during pregnancy.Our results showed that pregnant women tend to excessively use mobile phones in Japan. The mean infant birth weight was lower in the excessive use group than in the ordinary use group, and the frequency of infant emergency transport was significantly higher in the excessive use group than in the ordinary use group.Excessive mobile phone use during pregnancy may be a risk factor for lower birth weight and a high rate of infant emergency transport. Birth weight is the body weight of a baby at birth . There iRecently, mobile phones have rapidly become important and widely available tools that are routinely used for a variety of purposes by a large number of people –12. Mostn = 1415), it was found that female individuals aged 20 years or older were nearly three times more likely than male individuals to agree with the statement, “I cannot imagine life without the mobile” (25 vs. 9%) [Some studies reported that female individuals are prone to the adverse effects of excessive mobile phone use, and several studies have found that the levels of attachment to mobile phones and dependence on mobile phones are higher among female individuals than among male individuals , 17–21.  vs. 9%) ; howeverThe present study aimed to determine the associations of excessive mobile phone use with neonatal birth weight and infant health status and to provide basic data about excessive mobile phone use during pregnancy in a local area of Japan.Data were obtained from the Japan Environment and Children’s Study (JECS) and JECS Adjunct Study in Kumamoto. In the JECS, three self-administered questionnaires and four medical record-transfer questionnaires were administered to the participants. Clinical measurements and biological samples were collected by trained nurses. The JECS included 103,106 expecting mothers, and the consent rate was 78.5%. The recruitment and exposure protocols are available elsewhere , 24. TheIn this study, we extracted basic data during pregnancy obtained with two maternal self-administered questionnaires and fetal data obtained with the first medical record-transfer questionnaire from JECS. Additionally, an original paper questionnaire in the JECS Adjunct Study was used to collect maternal mobile phone usage information during pregnancy  of the mobile phone during sleep). We distributed the questionnaire about daily mobile phone use when the expecting mothers were hospitalized before delivery or after delivery.Igarashi et al. developed the Self-Perception of Text-Message Dependency Scale (STDS) for assessing text message dependency . This seAll expecting mothers from one rural area in Kumamoto, Japan, were considered for recruitment between 2012 and 2014. Recruitment was performed with the following two protocols: (1) recruitment at the time of the first prenatal examination at cooperating hospitals and (2) recruitment at local government offices.We enrolled 521 participants and excluded (1) those who did not complete the first or second trimester questionnaires (MT1 or MT2) or the first medical record-transfer questionnaire (Dr-0M); (2) those who did not complete the mobile phone daily usage questionnaire; (3) those with missing data for the maternal MT1, MT2, Dr-0M, or mobile phone daily usage questionnaire; and (4) those who had multiple pregnancies. Finally, 461 mother and child pairs were included in our analysis.Outcomes of this study were birth weight and infant health status , infant emergency transport, and premature birth.t test, χ2 test, linear regression analysis, and logistic regression analysis. All statistical analyses were performed using SPSS . A P value <0.05 was considered to indicate statistical significance.The results are expressed as mean ± standard deviation (SD) or number (percentage). In our study, we used a cutoff of 15 points for the excessive use score in the STDS to determine excessive mobile phone use. Participants were divided into an ordinary use group (excessive use score ≤15 points) or excessive use group (excessive use score >15 points) . For datP < 0.05).The prevalence of excessive mobile phone use was 9.98% in our study. Table P < 0.05, and 32.45 ± 1.65 cm vs. 31.94 ± 1.77 cm, P < 0.05, respectively). The frequency of emergency transportation was higher in the excessive use group than in the ordinary use group (P < 0.05). However, the proportion of low-birth-weight infants was not significantly different between the two groups.Table P < 0.05).On assessing the correlation between predictor variables and body weight, we found that maternal age, maternal body mass index before pregnancy, birth height, birth head circumference, birth chest circumference, and placental weight were positively correlated with birth weight. With regard to sex differences, the birth weight was lower in female infants than in male infants. However, maternal smoking history and excessive mobile phone use were not significantly correlated with birth weight. Additionally, primiparity and the designated location for the mobile phone were not significantly associated with birth weight. The correlation coefficient in univariate analysis in terms of the association of excessive mobile phone use with birth weight was −0.10  .With regard to maternal characteristics, the maternal age and age at first use of a mobile phone were lower in the excessive use group than in the ordinary use group. These findings are consistent with the results of previous studies , 16. YouWith regard to infant characteristics, birth weight and chest circumference at birth were lower and the emergency transport rate was higher in the excessive use group than in the ordinary use group. In the linear regression analysis, excessive mobile phone use was a significant predictor of low birth weight. In the logistic regression analysis, interestingly, we found that excessive mobile phone use increased the emergency transport rate, even after adjusting for confounding factors. Many factors affect the duration of gestation and fetal growth and, thus, the birth weight. They relate to the infant, mother, or physical environment and play important roles in determining birth weight and the future health of the infant. Our results showed that excessive mobile phone use during pregnancy may decrease infant birth weight, although this does not result in low-birth-weight infants. With regard to the mechanism, it has been shown that the levels of depression and state-trait anxiety are higher, and sleep quality is poorer in users who showed texting and digital audio player dependence than in ordinary users . AnotherThe present study had some limitations. First, the sample size was relatively small, and therefore, it may not provide sufficient power to estimate the association between excessive mobile phone use and infant birth weight. The number of emergency transports was only 10, and there was a possibility of chance with regard to our finding. Second, we did not account for the potential effects of mental health, such as depression and anxiety, which were mainly noted in excessive mobile phone users and users with high dependency and may be predictors of birth weight. Third, all information was reported by the participants themselves; therefore, the reliability of the responses may not be high. Despite these limitations, our study had some merits and values. Finally, the subjects were not representative of all pregnant Japanese women, as they were recruited from a local area of Japan. Therefore, we might need a larger sample from all areas of Japan to verify our results. Although our research is important, there are many shortcomings. To our knowledge, this is the first study to analyze the prevalence of excessive mobile phone use during pregnancy in a local area in Japan.Pregnant women tend to excessively use mobile phones in Japan. Excessive mobile phone use during pregnancy may be a risk factor for lower birth weight and a high rate of infant emergency transport.


Little information is available on the prevalences of birth defects in Korea. The aims of this study were to estimate recent prevalences of selected birth defects and to analyze the prevalence trends of these defects during the period from 2008 to 2014. Prevalences were calculated for 69 major birth defects using health insurance claim data obtained from the Korea National Health Insurance Service (NHIS). Prevalence rate ratios were calculated using Poisson regression to analyze trends over the 7-year study period. The overall prevalence of a major birth defect was 446.3 per 10,000 births (95% CI: 444.0–448.6); 470.9 per 10,000 births (95% CI: 467.6–474.2) for males and 420.2 per 10,000 births (95% CI: 417–423.4) for females. The prevalence rates of the most common birth defects over the study period were; septal defect , congenital hip dislocation , and ventricular septal defect . During the study period, a significant increase in the prevalence of a major birth defect was observed with a prevalence rate ratio (PRR) of 1.091. The strongest trend was observed for renal dysplasia, which had a PRR of 1.275 (95% CI: 1.211–1.343), and upward trends were observed for urogenital anomalies, such as, renal agenesis , undescended testis  and hypospadias . This study shows an overall increase in the prevalences of birth defects, including hypospadias and undescended testis, which are known to be associated with endocrine factors. In the future, standardized birth defect registries should be established to enable these trends to be monitored. Worldwide, about 3–6% of infants are born with a major defect , and 11.Trends of congenital anomalies in Europe during 1999–2008 showed abdominal wall, gastroschisis, hypospadias, trisomy 18 and renal dysplasia significantly increased, and that neural tube defect (NTD), anophthalmos/microphthalmos, severe congenital heart defects (CHDs) and limb reduction significantly decreased, and suggested decreases in neural tube defects were due to improved periconceptional folic acid supplementation . Cleft lThe causes of 65–75% of congenital malformations are unknown, of the remainder 15–25% are caused by genetic factors and 10% are attributed to environmental factors . In partNo recent data is available on the prevalences of birth defects in Korea. The detection of trends can indicate the emergence of new teratogens and are valuable for the epidemiological surveillance of birth defects and for identifying and issuing warnings about environmental risk factors. The aims of this study were to estimate the recent prevalence of selected birth defects and to analyze the prevalence trends of selected birth defects during the period 2008–2014.We used health insurance claim data from the Korea National Health Insurance Service (NHIS). On the NHISS database, the subjects were congenital anomalies are coded according to the International Classification of Diseases, 10th Revision (ICD-10) within the first year after birth. We investigated 69 major birth defects, which were also monitored by NBDPN, ICBDSR, and EUROCAT. The study period was 2008–2014.http://cran.r-project.org) was used for the data analysis.The prevalences of birth defects were calculated by dividing the number of registered birth defects by the total number of births and expressing this as the number of cases per 10,000 live births. The Poisson distribution was used to calculate 95% confidence intervals for prevalences, and prevalence rate ratios were calculated using Poisson regression to analyze trends over the study period. R version 3.40 , microcephaly , and congenital hydrocephalus  . The preThe most common birth defects were microtia , congenital cataract , and congenital glaucoma . The prevalence of anophthalmos was 0.09 per 10,000 births (95% CI: 0.06–0.13). In addition, 150 cases of microphthalmos , 51 cases of absence of iris , and 150 cases of anotia  were reported . While tPrevalences of cleft palate without cleft lip, cleft lip with or without cleft palate, and choanal atresia were 9.3 per 10,000 births (95% CI: 9.0–9.7), 7.2 per 10,000 births (95% CI: 6.9–7.5), and 0.45 per 10,000 births (95% CI: 0.38–0.53), respectively . During The three most common birth circulatory system defects were atrial septal defect , ventricular septal defect , and patent ductus arteriosus  . The preHirschsprung’s disease , anorectal atresia/stenosis , and small intestine atresia/stenosis  were most prevalent anomalies of the digestive system . The preThe most common anomalies of the urogenital system were undescended testis , obstructive genitourinary defect , congenital hydronephrosis , and hypospadias . The prevalences of obstructive genitourinary defect and congenital hydronephrosis were greater among males than females. In addition, 392 cases of indeterminate sex , 945 cases of renal agenesis , and 418 cases of renal dysplasia  were reported. Furthermore, most urogenital anomalies showed a significant increase of the study period ; undesceIn the present study, the three most common anomalies of the musculoskeletal system were congenital hip dislocation , polydactyly  and craniosynostosis  . StatistDown syndrome  was the most prevalent chromosomal anomaly. During the study period, the prevalence of Turner’s syndrome was 0.33 per 10,000 births (95% CI: 0.27–0.40), Klinefelter’s syndrome was 0.34 per 10,000 births (95% CI: 0.28–0.41), Trisomy 18 was 0.21 per 10,000 births (95% CI: 0.16–0.27), and Cri-du-chat syndrome was 0.16 per 10,000 births (95% CI: 0.12–0.21) . In addiIn the current study, a significant increase in the prevalence of 69 major birth defects with a prevalence rate ratio (PRR) of 1.091 was observed during the study period 2008–2014) in Korea, which means that the overall prevalence of birth defects increased by 9.1% per year on average. We identified apparent upward trends in the prevalences of urogenital anomalies, particularly, renal dysplasia, renal agenesis, undescended testis, and hypospadias. In Korea, previous studies have reported increases in the prevalence of some urogenital anomalies ,14. Kim  in KoreaTrends in the prevalences of urogenital anomalies vary among countries. In the EU 1999–2008), renal dysplasia increased (3.8% increase per 2 years), but congenital hydronephrosis decreased (6.8% decrease per 2 years) , renal d, a decreUrinary malformations are caused by complex interactions between genetic and non-genetic factors, some of which have been identified . Some stThe present study shows that the most common birth defects of the circulatory system were atrial septal defect , congenital hip dislocation , and ventricular septal defect . This finding is consistent with those of previous studies that showed atrial septal defect and ventricular septal defect are the most common defects in Korea ,38. Cong2.5 and increased CHD prevalence in Florida in a retrospective cohort study [3 change in PM2.5 during the 7th to 10th weeks of pregnancy [Furthermore, the current study shows the prevalence of some CHD subtypes increased at 3.4–14.3% per year during the study period (2008–2014). A meta-analysis indicated that the increase in total CHD worldwide showed a steep increase from the late 1970s until 1995, and stabilized from 1995 . The autrt study , and Zharegnancy . Others regnancy ,47, and regnancy .In the present study, the overall prevalence of omphalocele was 4.2 per 10,000 births per annum, which is higher than that reported in the US (1995–2005) , and wasThe strength of the present study is that it had substantial statistical power because it was conducted using nationally representative data from the NHIS. The national health insurance system in Korea covers almost all of the population, and thus, the use of NHIS data minimizes selection-associated risks and related potential bias. In addition, the dataset analyzed provided sufficient power to analyze trends. However, there were several limitations to this study. First, the prevalences were likely to be underestimated due to using the data that did not include stillbirth, miscarriage, and abortion. Second, the present study is subject to limitations associated with the use of insurance claims data, particularly with respect to coding, diagnostic criteria and the timings for follow-up of patients, which differ between hospitals. Furthermore, it was difficult to validate accuracies of diagnoses using claim data due to a lack of detailed records. Finally, it was difficult to adjust for maternal characteristics  affecting the trends in the prevalence because the NHIS data could not be merged with the birth and maternal data due to the privacy protection.The current study shows the prevalence of major birth defects increased significantly in Korea from 2008 to 2014. In particular, apparent upward trends in the prevalences of hormone-mediated urogenital anomalies, such as, undescended testis and hypospadias, may suggest the involvement of environmental factors. Furthermore, congenital heart defects also showed increasing trends over the study period, possibly due to the development of diagnostic techniques and more frequent prenatal diagnosis. However, increasing trends were not consistent across all categories of birth defects, as significant decreases were observed in the prevalences of holoprosencephaly, Hirschsprung’s disease and club foot-talipes equinovarus. In future, it is needed to establish a nationwide surveillance system for birth defects to evaluate the risk factors for congenital anomalies and prevention efforts.


Higher genetically predicted birth weight was associated with lower risk of IHD (odds ratio (OR) 0.96 per 100 grams, 95% confidence interval (CI) 0.93 to 0.99), but the association was not robust to sensitivity analyses excluding SNPs related to height or use of weighted median methods. Genetically predicted birth weight was not associated with low density lipoprotein cholesterol or triglycerides, but was associated with lower high density lipoprotein cholesterol  and the association was more robust to the sensitivity analyses. Our study does not show strong evidence for an effect of birth weight on IHD and lipids.Low birth weight is a risk factor for cardiovascular disease. However, the association could be confounded by many factors. We used Mendelian randomization to clarify the role of birth weight in ischemic heart disease (IHD) and lipids. We used all 7 single nucleotide polymorphisms (SNPs) independently contributing to birth weight at genome wide significance (p < 5 × 10 Following seminal observations from the 1980 s onwards showing lower birth weight associated with higher blood pressure6Instrumental variable analyses, using an external variable as an instrument instead of assuming no unmeasured confounding, provides an alternative means of assessing the role of birth weight in health. To date, studies using instruments, such as birth rank131415LCORL), rs900400 (CCNL1), rs1042725 (HMGA2), rs1801253 (ADRB1), rs4432842 (5q11.2), rs6931514 (CDKAL1), rs9883204 (ADCY5) reaching genome wide significance for birth weight were identifiedCDKAL1) and rs9883204 (ADCY5) are associated with type 2 diabetes. Whether any association of these 5 SNPs with IHD operates solely via birth weight or instead directly via height, blood pressure or diabetes is not known, so estimates are provided with and without these SNPs.Based on the largest GWAS of birth weight to date, 7 uncorrelated SNPs  and MI  using CARDIoGRAMplusC4D 1000 Genomes based GWAS, as shown in This novel study using Mendelian randomization, a potentially less confounded study design, is consistent with previous meta-analysis of observational studies suggesting that lower birth weight may be associated with a slightly higher risk of IHD18We used separate sample instrumental variable analysis with genetic instruments which is less susceptible to residual confounding than observational studies. However, limitations exist. First, Mendelian randomization has stringent assumptions concerning the validity of the genetic instruments, i.e., the genetic variants predicting birth weight. These assumptions include that the genetic variants reliably predict birth weight, no confounders of the genetic variants and the outcomes exist and all the effects of the genetic variants on each outcome are only via the exposure, i.e., birth weight. The genetic predictors of birth weight strongly predicted birth weight at genome wide significance, which reduces the risk of false positives. Confounding of the relation between genetic variants and the outcomes is unlikely because we used separate samples for birth weight and the outcomes which reduces the risk of chance associations generated by any common underlying data structure. Overlaps between the samples used to obtain genetic predictors of birth weight and their effects were not substantial. The samples used were largely of people of European descent and included genomic control to avoid any hidden genetic associations or confounding by population stratification. However, the estimates for IHD were not robust to the use of different cases-control studies. Use of CARDIoGRAMplusC4D 1000 Genomes based GWAS with a larger number of cases and controls but with more non-Europeans gave an inverse association of genetically predicted birth weight with IHD while CARDIoGRAMplusC4D metabochip/CARDIoGRAM GWAS with fewer cases for some SNPs, such as rs900400, and fewer non-Europeans gave a null association. Similarly, the estimates were not robust to different methodological approaches, such as use of a weighted median estimation, which may be more robust to inclusion of invalid instruments. We also assumed homogeneity and linearity between birth weight and the outcomes with no effect modificationLCORL and HMGA2)CDKAL1 and ADCY5)ADRB1)CCNL1)The genetic predictors of birth weight are in genes associated with height  using the largest published GWAS of birth weighthttp://www.broad.mit.edu/mpg/snap/ldsearchpw.php). To rule out the possibility of violation of the instrumental variable exclusion restriction assumption by pleiotropic SNPs directly affecting the CAD/MI or lipids other than via birth weight, we also checked for pleiotropic effects of each of the selected SNPs on these outcomes from a comprehensive genotype to phenotype cross-reference, Ensembl (http://www.ensembl.org/index.html), which contains information on any traits strongly associated with any given SNP.Genetically predicted birth weight (z-score) was obtained from all single nucleotide polymorphisms (SNPs) strongly associated /myocardial infarction (MI) have been contributed by CARDIoGRAMPLUSC4D investigators and have been downloaded from Estimates of the effect of genetically predicted birth weight on CAD/MI, MI and lipids were obtained from separate sample instrumental variable analysis by combining the SNP-specific Wald estimates using inverse variance weighting (IVW) with fixed effects−5) to rule out bias due to inclusion of insufficient instruments. Third, we examined the intercept in the analysis with all 7 SNPs using MR-Egger regression, which provides a test for directional horizontal pleiotropyWe conducted three sensitivity analyses to assess whether the estimates were robust to methodological choices. First, we repeated the analyses excluding SNPs that might be associated with the specific outcome other than via birth weight . Second, we repeated the analysis including SNPs that did not meet GWAS significance for birth weight, but were strongly associated with birth weight  and R version 3.2.3 . This study only used publicly available data and hence no ethical approval from Institutional Review Board was required.How to cite this article: Au Yeung S. L. et al. Birth weight and risk of ischemic heart disease: A Mendelian randomization study. Sci. Rep.6, 38420; doi: 10.1038/srep38420 (2016).Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


The rise and spread of the Internet has led to the emergence of a new form of word of mouth (WOM): electronic word of mouth (eWOM), considered one of the most influential informal media among consumers, businesses, and the population at large. Drawing on these ideas, this paper reviews the relevant literature, analyzing the impact of traditional WOM and eWOM in the field of consumer behavior and highlighting the main differences between the two types of recommendations, with a view to contributing to a better understanding of the potential of both. Consumers increasingly use online tools  to share their opinions about the products and services they consume  and to rThe rapid growth of online communication through social media, websites, blogs, etc., has increased academic interest in word of mouth (WOM) and electronic word of mouth (eWOM) e.g., . SpecifiWord of mouth is one of the oldest ways of conveying information , and it Similarly, previous research indicates that consumers regard WOM as a much more reliable medium than traditional media  . It is tToday’s new form of online WOM communication is known as electronic word-of-mouth or eWOM . This foOne of the most comprehensive conceptions of eWOM was proposed by As a result of ICT, today consumers from all over the world can leave comments that other users can use to easily obtain information about goods and services. Both active and passive consumers use this information medium (eWOM). Individuals who share their opinions with others online are active consumers; those who simply search for information in the comments or opinions posted by other customers are passive consumers .Electronic word of mouth also provides companies with an advantage over traditional WOM insofar as it allows them both to try to understand what factors motivate consumers to post their opinions online and to gauge the impact of those comments on other people . HoweverUnderstandably, companies view both types of recommendations – WOM and eWOM – as a new opportunity to listen to customers’ needs and adjust how they promote their products or services to better meet them, thereby increasing their return. A negative or positive attitude toward the product or service will influence customers’ future purchase intentions by allowing them to compare the product or service’s actual performance with their expectations .In the field of consumer behavior, some previous studies e.g.,  have shoAdditionally, eWOM offers businesses a way to identify customers’ needs and perceptions and even a cost-effective way to communicate with them . Today, Table 1). The first such difference is credibility as an information source  for two reasons. First, they can get the information more quickly, as there is no need to wait for someone else – a friend or family member – to offer an opinion about what they wish to consume. Second, if they have already received WOM reviews, they can use eWOM to corroborate the information received. Therefore, credibility and speed are the two main features not only distinguishing the two media, but also influencing consumer behavior.Finally, the analysis of the review showed that these two concepts – WOM and eWOM – while seemingly the same, are at the same time very different. The Internet has transformed traditional WOM into eWOM. The communication of opinions is no longer done interpersonally , but rather is mediated by ICT. However, the many studies conducted e.g.,  agree thThis paper tries to offer a clearer understanding of the two concepts through a literature review and an exploration of how, as a result of advances in ICT, traditional WOM has given rise to eWOM. The author has made an important, direct, intellectual contribution to this paper and has approved it for publication.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.