There was no relevant decrease in rating during the surgery in 2D and 3D iUS (p > 0.46). The benefit was rated 2.2 in 2D iUS and 2.6 in 3D iUS (p = 0.08). The benefit remained stable in 2D, while there was a slight decrease in the benefit in 3D after complete tumor resection (p = 0.09). The accuracy was similar in both (mean 2.2 p = 0.88). Seven patients had a small tumor remnant in intraoperative MRT (mean 0.98 cm3) that was not appreciated with iUS. Crucially, 3D iUS allows for an accurate intraoperative update of imaging with slightly lower image quality than 2D iUS. Our preliminary data suggest that the benefit and accuracy of 2D and 3D iUS navigation do not undergo significant variations during tumor resection.The aim of the study was to assess the quality, accuracy and benefit of navigated 2D and 3D ultrasound for intra-axial tumor surgery in a prospective study. Patients intended for gross total resection were consecutively enrolled. Intraoperatively, a 2D and 3D iUS-based resection was performed. During surgery, the image quality, clinical benefit and navigation accuracy were recorded based on a standardized protocol using Likert’s scales. A total of 16 consecutive patients were included. Mean ratings of image quality in 2D iUS were significantly higher than in 3D iUS ( The most recent scientific evidence demonstrates how maximal safe resection positively influences the prognosis of patients with high-grade gliomas. The extent of resection (EOR) is an independent prognostic factor associated with an improved clinical outcome ,2. More ®, which we evaluated in the current study. The objective of this prospective study was to assess the image quality, surgical benefit in terms of tumor orientation, control and navigational accuracy of navigated 2D and 3D iUS in intra-axial tumor surgery.Moreover, the lack of familiarity among neurosurgeons with this technology due to the loss of three standard orthogonal planes and generally to a lack of specific training must be recognized ,14. FurtA prospective study protocol was conducted in which adult patients with preoperative radiological suspicion of a potentially malignant intra-axial brain tumor, in particular brain metastasis, low- and high-grade brain glioma , were prospectively enrolled.. Inclusion criteria were a potential resection of the lesion of at least 95%  and patient’s informed consent. Patients who underwent first surgery or surgery for tumor recurrence were included .3 by means of MR images using the Elements® software . The operating times and interruption times of the intervention during the iMRI, the patient’s personal data as well as the histological and molecular indicators of the diagnosis were also collected. The pre- and postoperative clinical data, both at the time of admission and at least three days after surgery, were obtained through the use of the Neurological Assessment in Neuro-Oncology (NANO) and the Karnofsky Performance Status (KPS). The statistical analysis of the descriptive qualitative evaluations, was carried out through non-parametric tests. We used Wilcoxon test to compare the results of 2D and 3D iUS in the various fields of investigation and through the Sign test, to compare the coresponding ratings at different times throughout the surgery. A p-value of <0.05 was considered statistically significant. All statistical procedures were performed using IBM® SPSS® Statistics software, version 28.0 .A surgical resection guided by intraoperative 2D and 3D ultrasound (BK 5000) integrated with the neuro-navigation system  was performed for each case. Data was collected on the image quality, surgical benefit and navigational accuracy of both types of techniques according to a questionnaire provided intraoperatively to the operating surgeon. Ratings were collected at fixed times during the operation, in particular at the opening of the dura mater, at the time of 50% presumed tumor mass resection and finally at the presumed achievement of complete white light resection. For this purpose, the surgeon’s assessment was requested by using a Likert scale . Furthermore, a 5–13 MHz micro-convex transducer was used during all surgical steps. The 2D scan did not follow a specific orientation but varied according to tumor location. The 3D dataset was acquired by a single wide sweep following the orientation that ensured greater tumor coverage through craniotomy. After the alleged GTR, intraoperative high-field magnetic resonance imaging  was performed to assess the achieved extent of the resection. A follow-up postoperative MRI was performed in all patients within 48 h after the surgery. The preoperative volumes of the lesions and intra- and postoperative volumes of any residual tumors were then measured in cmFrom October 2021 to March 2022, 16 patients who met the inclusion criteria were consecutively enrolled in the study. The average age was 56 years. Six patients had glioblastoma WHO IV, and one of these was a recurrent glioblastoma. One patient was diagnosed with WHO IV astrocytoma IDH-mutant. Two patients were diagnosed with WHO III IDH-mutant astrocytoma, with one of these being a recurrence, and two others with WHO II IDH-mutant astrocytoma. Two patients had an oligodendroglioma (WHO II and III). Three patients with single brain metastases were included. The primary tumors were gastric adenocarcinoma, renal cell carcinoma and cutaneous melanoma .3. The hemisphere where the most frequent lesions were located was the right . Nine cases involved the frontal lobe, five the temporal, one the parietal and one the occipital lobe. In 10 cases, the tumor occurred in a non-eloquent area, while in 6 cases the areas of speech (3), sight (2) and motor (1) were involved. The average operating time was 308 min, while the time needed to perform the iMRI until the resumption of surgery was on average 64 min (3) that was not appreciated with iUS. p < 0.001). Otherwise, there are no statistically significant differences between the averages in terms of benefit and accuracy regarding the two ultrasound modalities .The calculated mean preoperative tumor volume was 32 cme 64 min . After ip = 0.046), at the halfway point of surgical resection (p = 0.016) and at the end of resection (p = 0.010)  . The Sigp = 0.092). The subjective benefit for the surgeon when using iUS does not appear to vary significantly during the course of the resection with regard to 2D; however, there was a slight worsening of 3D ratings at the completion of the resection , althougIn a subgroup analysis, an attempt was made to highlight any differences in terms of iUS benefit by differentiating the ratings obtained for the three main categories of tumors: high grade gliomas, low grade gliomas and metastases . Among tThe accuracy of 2D and 3D navigation was judged on average as “good” in the three surgical phases, but negative ratings were recorded for 3D in a small number of cases due to the imprecision of the neuro-navigation software .White circles = White circles = low potential outlier However, the statistical analysis performed did not show significant differences between the accuracy values for 2D and 3D in the various phases of the resection , as it dp = 0.099 for NANO scale; 83.13 vs. 75.63, p = 0.061 for KPS).The clinical values found in the postoperative period, collected from the third day onwards, were marginally worse than those recorded at the time of admission. The difference in the average scores of the NANO scale and KPS in the two periods, however, did not reach statistical significance . Preoperative MRI with DTI sequences showed a left frontal expansive lesion of 78 cmentricle .Surgical removal, performed with the aid of intraoperative neurophysiological monitoring, was completed and the patient experienced a temporary postoperative worsening of speech, which improved at discharge (postoperative NANO score = 6). The histological report documented a WHO II Oligodendroglioma. A 67-year-old man underwent surgical resection of a right frontal glioblastoma (preoperative NANO score = 3). An initial neuronavigation showed inaccurate image matching between iUS and MRI . In this3 out of an initial volume of 88.1 cm3; A 68-year-old man presenting hemianopia and left hemiparesis associated with Gerstmann syndrome (preoperative NANO score = 4) underwent the surgical resection of a right parietal glioblastoma , iMRI doThe prognostic importance of maximal safe tumor resection requires surgeons to take extra effort to achieve this goal. Intraoperative imaging is often an essential tool along this path. There is good evidence for use of iMRI to increase the extent of resection, both for high and low grade gliomas ,31,32,33However, a quick imaging update may often be necessary in particular situations, such as brain swelling caused by intracranial hypertension or awake surgery, to increase safety and accuracy. Iintraoperative ultrasound (iUS) allows for such an update as well as iMRI. iUS is available for neurosurgical use even longer than iMRI and 5-ALA. It has seen a resurgence of interest in recent years due to technological advancements, which overcame some relevant intrinsic issues. Among them, the suboptimal image quality of old ultrasound devices and presence of artifacts are now minimized by the possibility of using different types of probes at various frequencies ,34. In sCombining conventional iUS with neuro-navigation was an important step to overcome the orientation issue caused by oblique images with little overview provided by 2D iUS. The next step is calculating 3D volume models based on 2D iUS images. In this way, even the familiar three standard orthogonal planes can be provided in addition to an increased overview spanning the entire lesion .The main features of interest in the use of navigated iUS, both in 2D and 3D, are the quality of the ultrasound images, the surgical benefit in terms of orientation and the control of the tumor and the accuracy of navigation. They were investigated in the present study in order to verify the differences between the two methods and to validate their use in the surgical routine. The ratings of each of these investigated fields settled around the value of “2” of the Likert scale used in the study, corresponding to “good” . In partIt is also known that during the course of the resection the number of artifacts progressively increases at the bottom of the surgical cavity ,23. For Solheim et al. investigated the quality of 2D iUS images through a questionnaire provided to the surgeon after high-grade glial tumor surgery . A good The perceived benefit of 3D ultrasound was rated as good before dural opening and in the middle of the resection, while it was rated ‘fair’ after complete tumor removal. Compared to an earlier series of our group comparing linear and sector array probes in a work flow assessment, high-resolution linear array probes reached a similar benefit rating of 2.3 as 3D reconstructed US in our series (2.0), while conventional sector array probes only reached a level of 3.8, showing a remarkable rating for an interpolated 3D reconstruction . During Recently, Bastos et al. conducted a retrospective evaluation of patients undergoing image-guided tumor resection, in which both 3D iUS and iMRI were employed . The autIn recent years, research and technological development has led to growing evidence supporting the application of ioUS in order to obtain GTR in low- and high-grade gliomas. In particular, clinical studies are emerging to evaluate the impact of ioUS on EOR ,40,41,42The evaluations recorded concerning the benefit of 3D iUS in patients with brain metastasis presented a wide dispersion, reducing the reliability of the test and lowering the median score for this section compared to the others . FurtherThe experience of the surgeon in the use of iUS can affect both the usefulness of 2D and 3D images as well as 3D reconstructions results. Further limitations of this study include the small sample of patients from the prospective series and the subjectivity of the assessments provided by the surgeons. Since there was not the same rater for all surgeries, the expressed ratings could be influenced by the personal experience of each surgeon with iUS. No distinction was made between assessments based on the initial volume and eloquent or non-eloquent site of the tumor, and thus the limit deriving from the anatomical characteristics of resectability of the approached lesions was not considered. Furthermore, the limited number of patients did not allow for the performance of subgroup analysis for recurrent cases.3D reconstructed iUS allows for an accurate intraoperative update of imaging with slightly lower image quality than 2D iUS. Yet, when used by experienced surgeons, it was still rated as “good” as was the perceived benefit of 3D iUS for the resection. The benefit for of tumor control and navigation accuracy were equally rated among 2D and 3D iUS navigation and did not undergo significant variations during tumor resection. The surgeons’ subjective sense of the benefit in terms of tumor orientation and control was independent of the type of lesion and its grade.In a future phase of this ongoing prospective study, the comparison of EOR and neurological outcome with a matched paired series of patients on whom the use of any imaging aids prior to iMRI was not performed could better help to evaluate the impact of navigated 3D iUS on a patient’s outcome.


Despite this, we showed that both methods produced patterns of white matter injury that are consistent with findings reported in the literature and with DTI profiles generated from these methodologies. Scatter plots comparing DTI metrics obtained from each methodology showed that the pseudo-atlas method produced metrics that implied a more preserved neural structure compared to its counterpart. When comparing DTI metrics against a measure of ventriculomegaly , we showed that the standard atlas-based method was able to detect decreasing white matter integrity with increasing ventriculomegaly, while in contrast, metrics obtained using the pseudo-atlas method were sensitive for stretch or compression in the posterior limb of the internal capsule. Additionally, both methods were able to show an increase in white matter disruption with increasing ventriculomegaly, with the pseudo-atlas method showing less variability and more specificity to changes in white matter tracts near to the ventricles. In this study, we found that there was no true gold-standard for DTI methodologies or atlases. Whilst there was no congruence between absolute values from DTI metrics, differing DTI methodologies were still valid but must be appreciated to be variably sensitive to different changes within white matter injury occurring concurrently. By combining both atlas and pseudo-atlas based methodologies with DTI profiles, it was possible to navigate past such challenges to describe white matter injury changes in the context of confounders, such as neurodegenerative disease and ventricular enlargement, with transparency and consistency.Diffusion tensor imaging (DTI) is a relatively novel magnetic resonance-based imaging methodology that can provide valuable insight into the microstructure of white matter tracts of the brain. In this paper, we evaluated the reliability and reproducibility of deriving a semi-automated pseudo-atlas DTI tractography method vs. standard atlas-based analysis alternatives, for use in clinical cohorts with neurodegeneration and ventriculomegaly. We showed that the semi-automated pseudo-atlas DTI tractography method was reliable and reproducible across different cohorts, generating 97.7% of all tracts. However, DTI metrics obtained from both methods were significantly different across the majority of cohorts and white matter tracts ( Diffusion tensor imaging (DTI) is a relatively novel magnetic resonance-based imaging methodology that maps the water diffusion properties within the brain . Since wDTI has been used to investigate patterns of white matter changes at a microstructural level in various cohorts, such as normal pressure hydrocephalus (NPH), optic nerve decompression and in the developing human brain . DiffusiHowever, DTI acquisition, processing, and analysis is a complex multi-step process that is subject to many variables which may affect the results and interpretation thereof . The posIn this paper, we evaluated the reliability and reproducibility of differing automated DTI tractography methods to produce diffusion metrics of various white matter tracts in the presence of known confounders such as atrophy in aging, neurodegeneration and significant ventriculomegaly. We firstly aimed to develop a cohort-specific pseudo atlas-based semi-automated tractography method that was comparable to an atlas-based DTI analysis currently utilized by the ADNI group; as we interrogated ADNI datasets for this study, we have therefore defined the latter method as the “gold-standard” approach for reference. We found that the diffusion metrics generated from the former were significantly different from those generated by the latter.We hypothesized that the results from differing DTI methodologies could be subject to the impact of different algorithmic modifications. To test our hypotheses, we designed the following experiments to optimize the application of DTI methodologies to describe white matter injury patterns in the presence of confounders such as neurodegenerative disease and degree of ventriculomegaly:1.We developed a cohort-specific pseudo atlas-based semi-automated tractography to generate white matter tracts of interest and compared it to that of the “gold standard” atlas-based DTI analysis currently utilized by ADNI, in order to assess the reproducibility and reliability of the novel methodology.2.We performed initial comparisons on this pilot to examine the agreement of DTI metrics obtained from white matter tracts generated by both methodologies.a. Due to the poor agreement of the metrics, we proceeded to test the differing DTI methodologies under different processing algorithms to assess how these impacted the agreement of the metrics generated.3.We performed testing using a known model of white matter at-risk of injury. This ROI model allowed us to test for white matter distortion patterns in three cohorts of patients with different levels of confounders, namely varying degrees of neurodegeneration and atrophy along the spectrum from cognitively normal to Alzheimer’s disease.4.In addition, we performed testing to examine the effect of increasing ventriculomegaly on this ROI model of white matter at-risk. We performed independent quantification of ventricular size by measuring the Evans’ index (EI) and concurrently examined changes in DTI metrics in the context of increasing ventriculomegaly for the ROI model of white matter tracts at risk.5.Finally, we performed a further layer of analysis to confirm the diffusivity changes in this study by generating morphological patterns of DTI metrics for independent interpretation. We utilized DTI profiles, radar graphs of all DTI metrics , in order to illustrate differences between DTI methodologies and across cohorts. The concept and utility of DTI profiles has been previously described by our group in describing patterns of white matter injury across clinical cohorts .1 ADNI DTI metrics used for comparison were the UCLA DTI ROI summary measures for ADNIGO and ADNI2.Data used in the preparation of this article were obtained from the ADNI database.The ADNI study recruited patients between the ages of 55 and 90 from 57 sites in the United States and Canada. For this study, we retrospectively selected subjects who had screening/baseline MRI scans with diffusion-weighted images (DWI) from the ADNI image data archive. The selected scans included 51 cognitively normal (CN) subjects , 48 patients with Alzheimer’s disease (AD)  and 70 patients with early mild cognitive impairment (EMCI) . These cohorts were selected because we wanted to interrogate the methodologies in patients with varying degrees of cognitive impairment and atrophy.3D slicer is an open source quantitative imaging network tool we used to derive ventricular morphological indices and to conduct 3D volumetric segmentation (MRIcroGL is an open source software developed by Neuroimaging Tools and Resources Collaboratory (NITRC) used in this study to convert DICOM images to NIfTI format [ExploreDTI is a graphical toolbox written in MATLAB that was used in this project for DTI and white matter tractography  and 5 b0 images. More information on the MRI protocol is available at http://adni.loni.usc.edu/methods/documents/mri-protocols/.MRI scans were performed on 3T GE Medical Systems scanners across participating ADNI sites. Diffusion scans were acquired with 256 × 256 matrix; voxel size 2.7 mm × 2.7 mm × 2.7 mm; 41 DWI , Genu of the corpus callosum (gCC), Inferior fronto-occipital Fasciculus (IFO), Inferior Longitudinal Fasciculus (ILF), Anterior Thalamic Radiation (ATR), Posterior Thalamic Radiation (PTR), Posterior Limb of the Internal Capsule (PLIC), and Uncinate Fasciculus (UF) . The bCCMethod 1) where a randomly selected image in each cohort is used as a template for white matter tract generation in the remaining images. The second method was an automated atlas-based ROI analysis (termed Method 2) where a standardized lab-based atlas was used as the template. These two methods were tested on the AD and CN cohorts. We followed this up by implementing additional algorithmic modifications to assess if they affected the results of the methodologies.In this paper, two methods of automated tractography were compared. The first method was a cohort-specific pseudo atlas-based semi-automated tractography method (termed Method 3). The second was to optimize the alignment to the ACPC plane prior to performing the DTI analysis by following protocol adapted from the Human Connectome Project (HCP) pre-processing pipelines . The type of ROI placed enforced different conditions within the area enclosed by the ROI. Placing an AND ROI generated tracts that passed through this area. Placing a NOT ROI excluded fibers that passed through this area. With the pseudo-atlas and ROIs as input, the software applied similar ROIs to the remaining images in the cohort using a deterministic streamline method . White mA widely used standardized DTI template with its associated white matter tracts was used as an atlas. The white matter tracts in the atlas were generated from ROIs determined by the template creator. The atlas template was warped, and the associated ROIs transformed and applied to each image in the dataset. The diffusion metrics were then automatically generated from the resulting white matter tracts defined by the ROIs. The problem of missing data as in Method 1 was also found to occur using this method but was not as significant as in Method 1.Method 2 utilized the ICBM-DTI-81 atlas from the ICBM DTI workgroup . This atMethod 3 utilized the JHU white matter tractography atlas from the Laboratory of Brain Anatomical MRI, Johns Hopkins University . This atThe atlas used in Method 2 contained all 8 unique white matter tracts we wanted to investigate whereas the atlas used in Method 3 only identified 5 of the 8 tracts we required: gCC, ATR, IFO, ILF, and UF.The Evans’ index (EI) is commonly used to characterize the degree of ventriculomegaly from a patient’s MRI or CT scan . It is dt-tests were used to test for differences between the different methodologies. Linear correlation was used to investigate the association between diffusion metrics and ventriculomegaly measured by the Evans’ index. Scatter plots of FA and MD obtained from both methodologies for all tracts across the AD, EMCI, and CN cohorts were plotted to show the agreement of metrics and the variance within each methodology. All statistical analyses were performed using R statistical software (version 4.0.4)  . A p-valalong each white matter tract , in order to provide a simplistic illustration of differences between the various methods, as well as differences across the spectrum of disease for AD. We have previously demonstrated the utility of DTI profiles to describe and compare disease processes in white matter tracts across different cohorts . White mer tract .Method 1 generated 96.3% (647/672) of all white matter tracts in the AD cohort and 96.9% (678/700) in the CN cohort. Method 1 was unable to generate 25 tracts in the AD cohort and 22 tracts in the CN cohort. This is in contrast to Method 2 which was able to generate 99.6% (669/672) and 100% (700/700) tracts in the AD and CN cohorts, respectively. This amounts to 3 missing tracts in the AD cohort. After the implementation of the ACPC alignment, the reliability and reproducibility of Method 1 improved with 98.7% (663/672) and 98.9% (692/700) success rate in the AD and CN cohort, respectively. There were 9 missing tracts in the former and 8 in the latter. Method 2 generated 100% of tracts in both AD and CN cohorts. Implementation of Methods 1 and 2 on the ACPC aligned-EMCI cohort likewise showed high success rates of 96.2% (916/952) and 99.9% (951/952), respectively.t-tests conducted on the DTI metrics obtained from the two methodologies across all 8 white matter tracts. p < 0.001) from Methods 2 and 3 for all tracts in AD and CN cohorts, except for PTR MD in CN. After ACPC alignment and co-registration, Method 1 was significantly different (p < 0.001) from Methods 2 and 3 for all tracts in AD, CN, and EMCI cohorts, except for PTR MD in AD and CN  was reliable and reproducible. This was evidenced by the high success rate of generating white matter tracts across both AD and CN sub cohorts. Upon implementing the ACPC alignment , the number of missing tracts decreased from 25 to 9 tracts in the AD cohort and 22–8 tracts in the CN cohorts. This showed that the intracohort variability in image orientation could be a main contributor to the missing tracts and that this refinement improved the reliability and reproducibility of the methodology.Surprisingly, we could not show that the actual DTI metrics generated from the pseudo atlas-based semi-automated tractography DTI analysis method (Method 1) were exactly comparable to the standardized atlas-based DTI analysis (Methods 2). This was despite implementing the both modifications to the algorithm including an alternative published and verified atlas Method 3) and applying the ACPC alignment. From observing the scatter plots in  and applFrom The DTI profiles in Despite the variability of DTI values along the tracts  as well As we have previously discussed, the success rate in generating white matter tracts is marginally higher  for Method 2 compared to Method 1. This is likely because our use of a single subject pseudo atlas restricted the automated tractography, rendering it more selective in its ability to generate the white matter tracts. This can be seen as an advantage to Method 1 as its selectiveness may reduce the likelihood of generating spurious tracts and thus erroneous data. The use of Method 2 incorporated the use of validated atlases which have been derived from group-averaging from a sample cohort. This may also be perceived as providing this option with a technical advantage over Method 1, which used a single subject selected from the dataset to generate the pseudo-atlas. However, as we have discovered, the use of a pseudo-atlas may equally be argued to be advantageous as it promotes a template that is more representative of the cohorts compared to the standardized atlases used in Methods 2 and 3. Our study has shown that this resulted in Method 1 (the pseudo-atlas) being more sensitive than standardized atlas-based DTI analyses, in characterizing changes in the model of white matter at-risk due to pathophysiological processes of distortion and disease. In terms of processing, Method 1 required a much longer time to produce the DTI data compared to Methods 2 or 3. This was for two main reasons. The first was that the white matter tracts had to be manually generated in the pseudo-atlas template prior to performing the tractography. This process could be lengthy and required individuals with a working knowledge of neuroanatomy to perform. Additionally, there could be inherent subjectivity when it came to generating the tracts because it was difficult to determine if there were missing “strands” of white matter or conversely, if spurious “strands” were being generated. Secondly, the tractography itself of Method 1 also required a long time, which required approximately 3 h to generate a single tract from a single DWI. In contrast, Methods 2 and 3 did not require manual generation of the white matter tracts as it utilized readily available atlases compiled and verified by other groups. In terms of processing speed, Method 2 was about 50 times faster than Method 1, requiring 3 h to generate a single tract from a cohort of 50 DWIs.DTI has a low specificity and is generally due to its low signal to noise ratio . As a reIn this study, we only considered two disease cohorts (AD and EMCI) and healthy controls (CN). The full ADNI dataset included other cohorts along the disease spectrum, such as the late mild cognitive impairment (LMCI) and significant memory concern (SMC) cohorts. With further analysis it may have been possible that one of the three methods chosen would have emerged as the predominantly reliable and reproducible method of DTI analysis, with findings entirely consistent with literature. In addition, despite widespread use of ROI methodologies in literature, manual specifications and semi-automated tractography may be considered less reliable than fully automated white matter analytical approaches. Nevertheless, due to their ubiquity, results from this study would be easily translated to other settings involving DTI analysis at the clinical-research interface.In Method 1, a randomly selected image from each study cohort was used as an atlas. This may have potentially introduced bias as we could not be certain that the selected images were adequately representative of the entire cohort. However, the selected images were inspected for abnormal or outrightly distinctive features that could render them significantly different from other images within the cohort. Future work might include creating a more representative atlas by generating a grouped average of multiple images from the cohort.We also recognize that previous studies that have utilized a representative cohort-specific subject-based approach to DTI analysis have explored and demonstrated its limitations. For example, It is also important to note that the use of Evans’ Index as a marker for ventriculomegaly is imperfect because it is dependent on the inter-rater reliability at measuring the maximal width of the frontal horns and the internal diameter of the skull. These measurements are also highly dependent on the chosen slice and location at which the markers are placed. In addition, the orientation of each image has a large influence on the slices and thus the measurements. Although this effect is mitigated by alignment of the commissures, such technical considerations should be addressed and optimized by each rater, prior to its application as a biomarker for ventricular enlargement across a range of datasets.We plan to expand our analyses using both DTI methodologies, to include other cohorts of interest along the spectrum of AD and other neurodegenerative diseases. We also aim to use other anatomical segmentation methods to examine macro-structural features of white matter, such as its volume and thickness, as well as to create topological maps of adjacent surfaces, in order to augment the interpretation of the morphology of white matter changes, as described by DTI profiles. In the context of ventriculomegaly, we plan to utilize complementary biomarkers for both 2-dimensional and 3-directional measures in specific groups that possess significant ventriculomegaly such as cohorts with NPH. Finally, we aim to further expand the concept of DTI profiles as an invaluable tool toward boosting our capacity to compare the interpretation of DTI findings across methodologies which are not directly comparable using conventional statistical methods.In this study, we found that there was no true gold-standard for DTI methodologies or atlases. It was possible to create a pseudo-atlas that was cohort-specific for immediate study use. Whilst there was no congruence between absolute values from DTI metrics, differing DTI methodologies were still valid but must be appreciated to be variably sensitive to different changes within white matter injury occurring concurrently. When such changes were found to exist in the same dataset, the use of differing methods were complementary in elucidating the characterization of such DTI changes. We found that, despite such algorithmic modifications, the use of DTI profiles, a methodology of distilling the complexity of DTI changes to their most simplistic, graphical forms, confirmed the morphology of white matter injury as described by DTI metrics, remained consistent. By combining both atlas and pseudo-atlas based methodologies with DTI profiles, it was possible to navigate past such challenges to describe white matter injury changes in the context of confounders, such as neurodegenerative disease and ventricular enlargement, with transparency and consistency.The data will be made available but is subject to approval from the ADNI (Alzheimer’s Disease Neuroimaging Initiative) as they own the scans that the data were derived from.adni.loni.usc.edu). Written informed consent was obtained from all ADNI subjects, and participating sites in the ADNI study received approval from their respective governing Institutional Review Boards.Data used in preparation of this article were obtained from the ADNI database (CK, NK, and CL conceptualized and designed the study methodology, wrote the manuscript, and contributed to the analysis and interpretation of study data. CK, NK, CL, and TA contributed to data collection and validation. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Low birth weight (LBW) and preterm birth are associated with an increased risk of neonatal death and chronic conditions across the life course. Reducing LBW is a global public health priority and requires strategies to improve healthcare during pregnancy. We aimed to assess the effect of a health policy providing full coverage of illness-related costs from 13 weeks of gestation through 8 weeks postpartum on birth outcomes and neonatal mortality in Switzerland.We applied a regression discontinuity design to administrative data gathered as part of a Swiss research program (NCCR on the Move). We included all children  born between March 1, 2013 and February 28, 2015. The outcomes were birth weight (BW), gestational age (GA), LBW  and very low birth weight , preterm (<37 weeks of gestation), and extremely preterm (<28 weeks), and neonatal (≤ 28 days) death. Children were exposed to the policy if they were born from March 1, 2014 onwards. We estimated the intention-to-treat effect of the policy using parametric regression models.Children had a mean BW of 3,291 g and mean GA of 275 days. The prevalence of LBW was 6.4%, VLBW 1%, preterm 7.2%, and extremely preterm 0.4%, respectively. Some 0.3% newborn died within one month. The policy increased BW : 1, 25]) and decreased the risk of LBW  and VLBW . Additionally, the policy slightly decreased the risk of preterm birth , while it did not affect GA. Effect estimates for extremely preterm and neonatal mortality were imprecise and inconclusive.This quasi-experimental and population based-study of 166,709 live births between 2013 and 2015 in Switzerland provides evidence of a reduction in the risk of LBW, VLBW and preterm birth thanks to a health policy that fully covered healthcare services during maternity.• Free access to healthcare during pregnancy may mitigate adverse newborn health outcomes.• A Swiss health policy that fully covered healthcare services during pregnancy reduced the risk of low birth weight and preterm births.


One of the major factors contributing to newborn morbidity and mortality across the globe is respiratory distress. In resource-constrained developing nations like Ethiopia, it is a significant issue. Depending on the quality of the care provided, the incidence and time to recovery may differ amongst medical facilities. However, Ethiopia still lacks appropriate data on the incidence and time to recovery from respiratory distress.The aim of the study was to assess the incidence, time to recovery, and predictors among neonates admitted with respiratory distress in the neonatal intensive care unit at the University of Gondar Comprehensive Specialized Hospital.An institution-based retrospective follow-up study design was conducted among 452 neonates with respiratory distress. Data were collected using a data extraction checklist from the medical registry. The extracted data were entered into EPI INFO version 7.2.1.0 and then exported to STATA version 14 for analysis. The median time to recovery, the Kaplan Meier curve, and the log-rank test was computed. Both bi-variable and multivariable Cox regression models were applied to analyze the data. p-value ≤ 0.05 was considered statistically significant.Of all respiratory distressed neonate,311 were recovered. The overall incidence rate of neonates admitted with from respiratory distress was 11.5 per 100-neonate day (95% CI: 10.30–12. 87) with 2,703-person day observation and the median time to recovery from respiratory distress was 7 days with (IQR = 3–13 days). Predictors of time to recovery from respiratory distress were very low birth weight , low birth weight , very preterm , sepsis (AHR = 0.50 95% CI: 0.38–0.65), hypothermia , and Apgar scores less than seven at first  and fifth minute .The incidence and time to recovery in this study were discreetly acceptable as compared to previous study. The aforementioned predictors could be used to identify neonates with respiratory distress who are at risk of developing a long-term illness and guide prompt referral to hospitals. This will also provide clinicians with prognostic information, as longer recovery times have economic and social implications in resource limited countries like Ethiopia. Respiratory distress (RD) in neonates is a significant cause of morbidity and mortality and a common condition requiring admission to the neonatal intensive care unit (NICU) , 2.After birth or throughout the change from foetal to neonatal life, RD is a significant issue for neonates , 4. For Around 10% of newborns require some assistance to start breathing after they are born, and up to 1% may need significant resuscitation, according to the American Academy of Pediatrics . NeonateRespiratory distress affects 2.2% to 7.6% of all term deliveries worldwide, and 50%, 75%, and 90% of newborns born at 30 weeks, 28 weeks, and 26 weeks, respectively . FurtherThere are recognized causes of RD in both developed and developing nations, such as preterm, low first and fifth-minute Apgar scores, meconium aspiration syndrome, caesarean birth, gestational diabetes, maternal chorioamnionitis, sepsis and premature rupture of membranes (PROM) –15.RD, regardless of the cause, can lead to respiratory failure, cardiopulmonary arrest, and even death if not recognized and treated promptly. As a result, any health care worker caring for newborn neonates must be able to recognize the signs and symptoms of RD, differentiate the various causes, and initiate management strategies to avoid significant complications or death. As a result, neonates who require critical medical attention are typically admitted to the NICU. These infants are typically preterm, have a low birth weight, or have serious medical conditions such as RD .The Sustainable Development Goals, as well as other policies, strategies, and programs, work to prevent and care for preterm neonates and their birth outcomes, including RD , 18. DesThe study was conducted in UOGCSH Northern Ethiopia, which is located approximately 728 km away from the capital city, Addis Ababa, 175 km from the Regional Capital, Bahir Dar. The hospital serves a population of over 7 million people in northwest Ethiopia. The NICU is a unit within the department of pediatrics and child health that provides an intensive care unit for neonates and has a capacity of approximately 40 beds at any given time. The space also accommodates invasive and non-invasive ventilations. On average, 845 births occur in the hospital each month from gestational ages of twenty-eight weeks and above, which are considered viable. The study was conducted from 01/01/2021 to 30/06/2021.An institution-based retrospective study was conducted among neonates admitted with respiratory distress in the NICU.All neonates admitted with respiratory distress to the NICU at UOGCSH were the source populations, and all neonates admitted with respiratory distress during the study period were the study populations.All neonates admitted with the diagnosis of RD in UOGCSH during the study period were included in the study. Neonates who recorded the date of admission/date of discharge and had missing charts were excluded from the studyTime to recovery from RD in (days).Sociodemographic factors; residence, sex, birth weight of the neonate and gestational age.Obstetric and related factors: parity, mode of delivery, place of delivery, multiple pregnancies, PROM, preeclampsia, and placental abruption.Medical disorders in mother: gestational hypertension, maternal diabetes mellitus and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS).Neonatal outcome condition: birth asphyxia, Apgar score, sepsis, jaundice, hypothermia, hypoglycemia, meconium aspiration and congenital anomalies.If a neonate was recovered from RD after completing treatment based on physician diagnosis.A period of time between the neonate’s admission by RD and his or her discharge while the neonate is recovered. It was calculated by subtracting the date of admission from the date of discharge (time in days until recovery/discharge).It refers to a neonates referred, died, transferred or defaulted from treatment.>60 breaths/min, bradypnea <30 breaths/minute, respiratory pauses, or apnea) or signs of labored breathing , with or without cyanosis  neIn this study,the median recovery time from RD was 7 days (IQR = 3–13). This study is in line with the overall median survival recovery time of all neonates of admission in neonatal intensive care units of Dire Dawa l Hospital, which is 7 days.This study shares similarities with it in that it was conducted among neonates admitted to hospitals, the age range,and the sample size was nearly the same, and both confirmed and clinically diagnosed cases were taken into account .Several factors, including very low birth weight, low birth weight, very preterm birth, sepsis, hypothermia, and an Apgar score of less than seven at the first and fifth minutes, were found to be significant predictors of the length of time it took neonates to recover from RD after being admitted to the hospital.The current study showed that neonates who had very low birth weight had 83% delayed to recovery from RD and that of low birth weight had 50% risk of delayed compared to normal birth weights. These findings are supported by a study performed in South Africa  and UganIn this study, very preterm neonates admitted with RD showed 58% delayed recovery compared with term neonates. This was supported by the clinical evidence thatas gestational age increases, fetal lung maturity and the production of surfactants will be advanced, and the risk of developing different comorbidities associated with prematurity may increase, which leads to lengthen the admission and elongated the recovery time.In this study, neonates with sepsis at admission were delayed by 45% to recover from respiratory distress compared to those who had no sepsis. This study is comparable with a study performed in Ethiopia . This isThis result showed that hypothermic neonates admitted with RD had 39% delayed recovery compared with those not hypothermic with RD. Studies in China  and IranOn the other hand, respiratory distress in neonates is most often associated with hypothermia, especially in very preterm infants, and very low birth weights cause morbidity and prolonged hospitalization because of the double burden .This study reveals that the survival time of neonates was increased for a neonate who had an Apgar score of less than seven at the first and fifth minute compared with those having an Apgar score greater than or equal to seven. The findings are supported by studies performed in the USA  and ChinAs an implication, there is a scarcity of data on RD incidence, time to recovery, and predictors. As a result, the discovery could be used to forecast the length of recovery time in neonates with RD. It could also be used to predict the severity of problems in RD identified with predictors of time to recovery and aid in clinical decision making at hospitals. Furthermore, it is prognostic information for clinicians caring for neonates and their families that RD with the identified features may have a longer recovery time as these have economic and social implications on the family, especially in resource-constrained areas.Since the data were collected from secondary sources, some important predictors, such as socioeconomic factors such as nutritional status of mother, educational level, and birth interval, might be missed, which may have a significant effect on recovery time from RD. The study area covers only UOGCSH; its generalizability to all hospitals of the region and Ethiopia may not be possible, and this might also decrease our precision.The incidence and time to recovery in this study were discreetly acceptable as compared to previous study. The predictors that were independently associated with incidence and time to recovery of respiratory distress were very low birth weight, low birth weight, very preterm, sepsis, hypothermia, and Apgar scores less than seven at first and fifth minute. The aforementioned predictors could be used to identify neonates with respiratory distress who are at risk of developing a long-term illness and guide prompt referral to hospitals. This will also provide clinicians with prognostic information, as longer recovery times have economic and social implications in resource limited countries like Ethiopia.S1 File(DOCX)Click here for additional data file.S2 File(DTA)Click here for additional data file.


A cyst is a blind pouch of tissue, which may be containing air, fluid, pus or any other substance. Vaginal wall cysts are located on or under the vaginal wall lining, are usually asymptomatic and may present as a small lump felt in the vagina or protruding from the vagina. These cysts can be of varying sizes, ranging from the size of a pea to that of an orange. These may get infected and present with inflammatory signs and symptoms.We report here a case of a 38-year-old female who presented with complaints of something coming out of her vagina, initially mistaken to be uterovaginal prolapse, which, on detailed clinical examination, was diagnosed to be a posterior vaginal wall cyst. The cyst was managed surgically by excision, and on histopathological examination, it was later confirmed to be a Gartner's duct cyst over the posterior vaginal wall, rare in its location. Cysts of vaginal origin are rare. Several categories of cysts have been identified and are classified based on histology, that is, according to the lining epithelium of the cyst wall: epidermal inclusion cyst, Mullerian cyst, endometroid cyst, and Bartholin cyst or abscess; Gartner’s duct cyst; and unclassified types . GartnerA 38-year-old female , with a history of previous two full-term vaginal deliveries, presented with a complaint of a mass protruding from the vagina for the last one year. Initially, the mass was very small, the size of a peanut, which progressed gradually to the size of a lemon, resulting in discomfort to the patient in doing day-to-day activities. The mass was not reducible on lying down and did not increase in size on straining or coughing.She had a history of on-and-off vague abdominal discomfort for the last six months. The history of past menstrual cycles was normal, with 3 to 4 days of menstrual bleeding every 28 to 30 days, regular with the average flow and no complaints of the passage of clots or dysmenorrhoea.The patient was vitally stable with normal general and systemic examination findings. On per speculum examination, a posterior vaginal wall cyst of approximately 3 cm × 3 cm in size and pale pink with a smooth intact surface was protruding out of the vaginal introitus. The cyst was non-tender, mobile and fluctuant Figure . The ant-3, platelet count 3.40 lacs/mm3, Na+ 137 mmol/L, K+ 4.3 mmol/L, serum creatinine 0.53 mg/dL and cancer antigen 125 (CA 125) 12 units/mL .Her investigations show haemoglobin 10.6 g/dL, total leukocyte count 7,600 mmExcision of the cyst was planned under all aseptic precautions using intravenous sedation with lignocaine 2% + adrenaline injected around the base of the cyst. The posterior vaginal wall was dissected from the fourchette upwards. The base of the cyst was identified. The incision is taken over the most dependent part of the cyst. Cystic fluid was drained. Planes were separated, and the cyst wall was excised from the posterior vaginal wall and sent for a histopathological examination. Per-rectal examination was done to ensure the integrity of the posterior vaginal wall and anterior wall of the rectum. The posterior vaginal wall was sutured with Vicryl 2-0 , and hemostasis was ensured. Vaginal packing was carried out. The patient withstood the procedure well. The post-operative period was uneventful (Figure The histopathology report showed tall cuboidal to columnar epithelial lining of the cyst wall Figure .Gartner's ducts are found in approximately 25% of women, of which nearly 1% transform into the formation of Gartner's duct cysts . These cVarious differential diagnoses, as enumerated in Table Large posterior vaginal wall Gartner's duct cysts are symptomatic and cause discomfort to patients, compelling them to visit gynaecologists, which can be easily mistaken to be a case of uterovaginal prolapse. Clinical examination solves the confusion. Treatment includes conservative management or surgical excision. The histopathological examination helps confirm the diagnosis. Thus, not all patients who present with mass coming out of the vagina have to be a case of uterovaginal prolapse.


Empagliflozin (Jardiance®) is an insulin independent antihyperglycemic agent used in treatment of T2D.The drug is a sodium glucose cotransporter-2 (SGLT2) inhibitor approved in USA and Europe and other countries of the world. As empagliflozin demonstrates cardioprotective and Reno protective properties its prime target are patients having CVD and CKD complicated by T2D.This review sheds light on mechanism of action of the drug and with the help of clinical outcomes establishes the use of empagliflozin in T2D patients.Although empagliflozin is a well-tolerated and easy to administer drug, it has some side effects and contraindications which are discussed in the article to help the reader weigh its beneficial effects against its adverse effect and understand its use in clinical medicine. AddressAntidiabetic agents (ADA) that inhibit Sodium glucose cotransporter-2 (SGLT2) such as Gliflozins are used as pharmacological intervention in diabetic patients . Glifloz1c and improving cardiovascular symptoms ,1813,18]1.2In the proximal convoluted tubules (PCT) of the kidney, SGLT2 are present where maximal glucose reabsorption occurs in the blood. Empagliflozin inhibits these transporters int the PCT of the kidneys and lead to glucosuria hence lowering the blood glucose levels in patients with T2DM .The molecular as well as cellular mechanisms for CVD and chronic kidney disease (CKD) in patients of type 2 diabetes mellitus (T2DM) have been found to be similar . Hence t1c, body weight or SBP. Furthermore, the small decreases in eGFR due to SGLT2 inhibition in the starting three to four weeks of treatment with the drug suggests that the reduced intraglomerular pressure also contributes to a decrease in ACR [There were five different trails performed in patients of T2DM and albuminuria . accordie in ACR .Empagliflozin also produces a favorable effect on the systemic and neurohormonal pathways like RAAS, and markers of arterial stiffness and vascular resistance including pulse pressure, ambulatory arterial stiffness, mean arterial pressure and double product, and lastly on the serum uric acid levels and hence majorly reduces the risk for renal dysfunctions in patients with T2DM ,24. Furt22.1A randomized, multicenter, double-blind, placebo-controlled trial of empagliflozin in people with T2D and established CVD was called the EMPA-REG OUTCOME study. 7028 participants from 42 different nations were randomly assigned to receive one of two dosages of the medication empagliflozin (10 or 25 mg) or a placebo in addition to receiving the best care possible for their T2D and CV risk factors. Based on the combined results of the empagliflozin 10 mg or 25 mg groups vs placebo, the primary statistical analysis was performed. The mean follow-up time was 3.1 years .2.1.1Empagliflozin  improved the primary outcomes  compared to placebo ; HR, 0.86. . The primary outcome was improved by a 38% drop in CV mortality, but there was no detectable decline in MI or stroke. Empagliflozin reduced CV mortality incredibly quickly (with just under 3 months of therapy), and the expanding gap between the treatment and control survival curves suggests a persistent treatment advantage. Additionally, empagliflozin decreased mortality from all causes by 32%. The decrease in CV deaths was seen in a variety of subgroups, including those with preexisting CVD, age, gender, rising or falling HbA1c levels, and changes in HbA1C and kidney function .2.1.2The evaluated result of HF hospitalization was lowered by empagliflozin by 35%. Empagliflozin significantly decreased deaths from HF and other non-adjudicated markers of HF outcomes, such as investigator-reported HF and the use of loop diuretics . With su2.22.2.1In individuals with T2DM, treatment with empagliflozin reduces HbA1c by 0.79% with monotherapy and 0.61% with add-on treatments to other glucose-lowering medications, according to a meta-analysis of 45 randomized trials . Empagli2.2.2Empagliflozin medication decreases body weight by 1.7 kg (2.4%) in T2DM patients, as well as diastolic and systolic blood pressure by 2 and 4 mmHg, respectively, without raising the heart rate . Treatme2.2.3Empagliflozin has a lower risk of hypoglycemia, and when administered as monotherapy, this risk is equivalent to that of a placebo ,38. Howe2.2.4Rather than increasing insulin production, empagliflozin improves beta-cell function ,41 by re2.2.5The sodium-glucose cotransporter 2 (SGLT2) inhibitor, empagliflozin, was the subject of the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME) , the verThe cumulative kidney outcome in the EMPA-REG OUTCOME study was the prevalence of occurrence or deteriorating nephropathy, which was characterized as the development of macroalbuminuria, a twofold increase of creatinine concentration, with eGFR of 45 ml/min/1.73 m2, starting of dialysis, or mortality from kidney impairment . CompareIn accordance with the baseline UACR score , pre-determined and post-hoc studies were carried out to evaluate alterations in UACR scores. 59% of patients were having normoalbuminuric at baseline, followed by microalbuminuria (29%) and macroalbuminuria (11%) ,52. As c3Empagliflozin provides many benefits but consideration should be given to the potential dangers and drawbacks of taking SGLT-2 inhibitors in addition to potential advantages when determining the clinical usefulness of empagliflozin . If the Ketoacidosis, acute kidney injury, dyslipidemia, hypoglycemia in patients taking insulin, hypotension , genital mycotic infections, hypotension , and, very rarely, peripheral amputations and Fournier gangrene  are someEuglycemic ketoacidosis has been recorded more frequently while taking SGLT-2 inhibitors, which necessitates ketoacidosis avoidance by switching from oral medication to IV insulin. Hospitalization for any emergency health condition or surgery predisposes individuals to this disease . EmpagliA recent FDA caution was just released highlighting the heightened risk of bone fractures driven by reduced bone mineral density and osteoporosis with the use of SGLT2 inhibitors . It is s4The most recent studies on the benefits and drawbacks of empagliflozin, a drug used to treat both heart failure and diabetes mellitus, have been emphasized in this review. Empagliflozin is the first drug to demonstrate advantages in cardiovascular events in the setting of devoted CV outcomes studies and is a paradigm-shifting treatment for T2DM therapy. Across a number of patient populations, including those with or without HF at baseline, there is a persistent, significant efficacy in lowering HF hospitalizations and cardiovascular deaths. These advantages could be achieved through empagliflozin's influence on uric acid, body weight, oxidative stress, arterial stiffness, blood pressure, and fat distribution. In contrast to other T2DM therapy, empagliflozin has a distinct effect on natriuresis and diuresis. People with HF frequently have complicated medical histories with several illnesses, most frequently diabetes and kidney failure. A medication like empagliflozin with such broad pleiotropic effects that has the capability to delay the point of crossover between these conditions appears particularly useful because several of these comorbidities can both be a source and a consequence of heart failure.However, the risks associated with empagliflozin use should be addressed when deciding whether to include it in treatment. Significant renal dysfunction, the second and third trimesters of gestation, and type 1 diabetes are the major contraindications. In HF patients receiving diuretics and ACE inhibitors, the potential for experiencing hypotension should also be considered, particularly in those with low blood pressure at the start of their treatment. The patients must be made aware of the potential genitourinary infection and adverse effects of empagliflozin and given guidance on how to avert them to avoid non-compliance of the medication. Additionally, it is uncertain whether the advantages of empagliflozin are specific to the medication or if there is a class effect. As a result, more extensive clinical trials are needed to verify the efficacy of other SGLT2 inhibitors in the management of HF and T2DM as well as the benefits and drawbacks of their use concerning the contraindications and negative effects they encourage. Furthermore, to investigate the impact of empagliflozin on hemodynamics, left ventricular function and structure, New York Heart Association class is to decide whether there are differences between HF with reduced or preserved ejection fraction, additional research in specialized HF populations with pre-specified HF analyses is required.Future trials of empagliflozin could be able to better understand how it affects markers of the severity of HF and how well it responds to treatment by using measurements of cardiac function and biomarkers like natriuretic peptides. The sustainability of the HF and cardiovascular and renal advantages as well as the possibility of late-onset unfavorable effects require long-term studies.N/A.None.All authors equally contributed.1.Name of the registry: N/A2.Unique Identifying number or registration ID: N/A3.Hyperlink to your specific registration (must be publicly accessible and will be checked): N/AN/A.N/A.Not commissioned, externally peer reviewed.None declared.


Birth weight is considered not only to undermine future growth, but also to induce lifelong diseases; the aim of this study is to explore the relationship between birth weight and adult bone mass.We performed multivariable regression analyses to assess the association of birth weight with bone parameters measured by dual-energy X-ray absorptiometry (DXA) and by quantitative ultrasound (QUS), independently. We also implemented a systemic Mendelian randomization (MR) analysis to explore the causal association between them with both fetal-specific and maternal-specific instrumental variables.β-coefficient= 0.17, P < 2.00 × 10−16; lateral spine, β-coefficient = 0.02, P = 0.04), decrease bone mineral content-adjusted bone area (BMCadjArea) , and decrease adult bone mineral density (BMD) , and we observed that the effect of birth weight on bone size was larger than that on BMC. In MR analyses, the higher fetal-specific genetically determined birth weight was identified to be associated with higher bone area  but lower BMD . In addition, we found that the higher maternal-specific genetically determined offspring birth weight was associated with lower offspring adult heel BMD .In the observational analyses, we found that higher birth weight could increase the adult bone area (lumbar spine, The observational analyses suggested that higher birth weight was associated with the increased adult bone area but decreased BMD. By leveraging the genetic instrumental variables with maternal- and fetal-specific effects on birth weight, the observed relationship could be reflected by both the direct fetal and indirect maternal genetic effects.The online version contains supplementary material available at 10.1186/s12916-022-02531-w. Osteoporosis is a common skeletal disease characterized by the loss of bone mass and the risk of brittle fracture. It has become a major global public health problem, affecting about 200 million people around the world . OsteopoThe Developmental Origins of Health and Disease (DOHaD) hypothesis was initially proposed in the 1990s , which pTherefore, the aim of this study is to investigate the effect of birth weight on adult BMD by integrating the observational data and both fetal and maternal genetic evidence. We first performed multivariable regression analyses to assess the association of birth weight with BMD-related parameters measured by dual-energy X-ray absorptiometry (DXA) and by quantitative ultrasound (QUS) in the UK Biobank. We also applied the MR approach to test whether the observational relationship between birth weight and adult BMD could be reflected by either indirect maternal or direct fetal genetic effects or both.N = 84), (2) birth weight < 2.5 kg, (3) birth weight > 4.5 kg , and (4) non-Europeans . We calculated the mean value of the birth weight if there were more than one visit. The outcomes were the spine DXA BMD and ultrasound-derived heel BMD. The spine DXA data in the UK Biobank were provided as lumbar spine (LS) and lateral spine (LaS), the scanning of the lumbar spine (from L1 to L4) requested the lower legs of the participant be placed on a polystyrene block, bringing the hips and knees to 80° flexion. The scanning of the lateral spine (from L4 to T4) requested the participant to lie on their side and acquire the spine in the lateral plane. Here, we extracted the corresponding bone parameters including the LS BMD (Field ID 23204), LS bone mineral content (BMC) (Field ID 23203), LS bone area (BA) (Field ID 23200), LaS BMD (Field ID 23234), LaS BMC (Field ID 23312), and LaS BA (Field ID 23311). Finally, we got 20,367 participants with both LS data and birth weight measurements, and 21,364 participants with both LaS data and birth weight measurements. Furthermore, we calculated the area-adjusted bone mineral content (BMCadjArea) as an additional outcome; to generate the measurement of BMCadjArea, we first performed a linear regression for BMC with the independent variable bone area, and the residual of BMC for each individual was predicted, then, the BMCadjArea of each individual was calculated as the sum of the mean of BMC and the residual. The heel BMD  was estimated from the quantitative ultrasound (QUS) measurement with the following formula: heel estimated BMD = 0.0025926 × (bone ultrasound attenuation + speed of sound) − 3.687. We excluded the unusually large or small heel BMD value , and we also excluded the individuals which were measured by DXA scan, leaving 177,675 individuals with both QUS heel BMD and birth weight measurements.An overview of the study design is illustrated in Fig. We extracted the potential confounding factors from the questionnaires such as sex (Field ID 31), age (Field ID 21003), weight (Field ID 21002), smoking status (Field ID 20116), alcohol intake frequency (Field ID 1558), physical activity , and assessment center (Field ID 54). The physical activity was assessed whether the individual accorded with at least one of the 4 criteria: (1) at least moderate physical activity 5 days a week, (2) vigorous activity once a week, (3) more than 150 min of moderate activity per week, and (4) more than 75 min of vigorous activity per week.r2 < 0.1) associated with birth weight at genome-wide significance P < 6.6 × 10−9. Of which, 63 autosomal SNPs that have a fetal-only effect on own birth weight represent the effect of own genotype on own birth weight after adjusting the maternal effect on birth weight using the weighted linear regression , and 31 autosomal SNPs that had a maternal-only effect on offspring birth weight represent the effect of maternal genotype on offspring birth weight after adjusting the fetal effect on birth weight; 41 autosomal SNPs have both fetal and maternal effects   × R2/(1 − R2), where the N was the sample size, K was the number of included SNPs, and the R2 was the proportion of variance explained by the genetic variants [F-statistic > 10 were considered as the strong and validated instrumental variables [n = 49,988) [http://www.gefos.org/). We also obtained the GWAS summary-level data for bone areas including the femoral neck area, intertrochanteric area, trochanter area, and total hip area [https://www.decode.com/summarydata). The abovementioned datasets were shown in Additional file The fetal single nucleotide polymorphisms (SNPs) associated with own birth weight  and the maternal SNPs associated with offspring birth weight  were extracted from the large-scale GWAS meta-analyses from the Early Growth Genetics (EGG) Consortium and the UK Biobank dataset . Specifihip area  from thez-scores) for the outcomes to give a mean = 0 and standard deviation = 1 and then conducted the above analyses. All observational analyses were performed using the R software (https://www.r-project.org/), and P < 0.05 was set as the significant threshold.Firstly, we attempted to test the potential non-linear relationship between the birth weight and each of the bone parameters  using the multivariable restricted cubic spline (RCS) model with four knots (using the “ols” function from the “rms” library in R) adjusting for age, gender, weight, alcohol status, smoking status, and physical status. Then, we performed a multivariable linear regression to explore the association of birth weight with the spine DXA scan results including the lumbar spine and the lateral spine sites in 20,367 and 21,364 participants, respectively; here, the outcomes were LS/LaS BMC, LS/LaS BA, LS/LaS BMCadjArea, and LS/LaS BMD. The confounding factors were sex, age, weight, smoking, alcohol, and physical activity. The baseline characteristics of the DXA measured datasets were shown in Additional file http://zzz.bwh.harvard.edu/plink/) in the UK Biobank individuals; briefly, the wGRS was calculated by the summation of the individual’s effect alleles, weighted by corresponding effect sizes [--score sum to obtain the sum of valid per-allele scores [P < 0.05 was considered as the significant level. Additionally, we also calculated the statistical power for MR analyses using the “online sample size and power calculator for Mendelian randomization” (https://sb452.shinyapps.io/power/), with the parameters of the sample size, the proportion of variance explained (R2), the causal effect, and the significance level (0.05).We performed a weighted genetic risk score (wGRS) analysis in the UK Biobank using the individual-level data to test the relationship between genetically determined birth weight and BMC, bone area, BMCadjArea, and BMD. Here, we constructed the wGRS with the selected instrumental variables   using thct sizes , and we e scores –28. All e scores , 29. In P < 5 × 10−8). Previous studies have suggested some risk factors for bone mineral density, including anorexia nervosa [https://www.ebi.ac.uk/gwas/) to exclude any of the pleiotropic instrumental variables , vitamin D (Field ID 30890), oestradiol (Field ID 30800), calcium (Field ID 30680), and inflammatory markers including C-reactive protein (Field ID 30710), rheumatoid factor (Field ID 30820), and urea (Field ID 30670) as the confounding risk factors. We performed a linear regression to test the associations between the genetically determined birth weight (wGRS) and the potential risk factors of bone parameters in a one-sample MR analysis. Additionally, we also evaluated the pleiotropic association of instrumental variables (SNPs associated with birth weight) with potential confounders . The kinship information file contained kinship coefficients and estimates of the proportion of SNPs with zero identical-by-state (IBS0). The parent-offspring pairs were defined using the formula With the UK Biobank individual-level dataset, we also examined whether the intrauterine environment  was associated with the offspring adult BMD. Firstly, we confirmed the parent-offspring pairs in the UK Biobank with the released kinship information file “ukbA_rel_sP.txt”  and higher LS area    (Table P = 0.83); however, when the area was adjusted, we found a strong negative association between birth weight and LaS BMCadjArea   , and the direction of the effect was consistent with the findings from DXA-measured spine BMD  (R2) of the own birth weight, and the corresponding F-statistic was 88. We calculated the weighted genetic risk score (wGRS) for each individual with these 63 fetal-only effect SNPs within the UK Biobank dataset, and the weighted effect size  of each SNP on birth weight was extracted from Warrington et al. [β-coefficient = 0.15, P = 1.26 × 10−6) but associated with lower LS BMCadjArea  and lower LS BMD   and lower LaS BMD   (Table R2) of the own birth weight, respectively, and the corresponding F-statistics were 58 and 75. Furthermore, we conducted a sensitivity analysis to address the horizontal pleiotropy assumption of the MR analysis. Within the selected confounding risk factors such as the bone metabolic markers  and inflammatory markers , we only found a significant relationship between the fetal-only effect SNP-determined birth weight (wGRS) and serum calcium , the intertrochanteric area , and the trochanter area  in two-sample MR-PRESSO analysis . Furthermore, we also performed a two-sample MR analysis with 104 and 205 SNPs (see the “Methods” section) as the instrumental variables and obtained similar trends of association , and the statistical power was 94–100% as evaluated by the online tool  and after conditioning on offspring GRS  in 4284 mother-offspring pairs  and after  adjusting for offspring GRS in 4284 mother-offspring pairs (Table R2) of the offspring birth weight, respectively, and the corresponding F-statistics were 74, 58, and 34. We did not detect any significant relationship in 1935 father-offspring pairs with these types of maternal SNPs   with 31 maternal-only effect SNPs in 4284 mother-offspring pairs and 1935 father-offspring pairs. We first checked whether the maternal GRS was associated with offspring birth weight and found that the maternal GRS was indeed strongly associated with increased offspring birth weight before  hypothesis proposes that exposure to a hostile uterine environment would change the fetus’ structure, function, and metabolism in ways that lead to significantly adverse consequences on an individual’s short- and long-term health, followed by the reduced fetal growth rate, low body weight at birth, and the high risk of future related diseases , 52. TheA previous study has tried to investigate the relationship between birth weight and osteoporosis risk, but as they listed as a limitation, they failed to analyze the DXA data, which is the gold standard for the diagnosis of osteoporosis . In our Mendelian randomization (MR) is an approach to test the causality of an observed relationship between an exposure and an outcome . Recentl2). Therefore, the results should be interpreted with caution when facing the extreme value of birth weight.Acknowledged as a limitation of this study, we excluded the individuals with extreme birth weight  in our study to exclude likely pre-term births and fetal macrosomia. Hovi et al. found that adults born with very low birth weight (< 1.5 kg) had lower LS BMD compared with the participants born at normal birth weight at ages 18.5 to 27.1 . When weIn summary, we observed that higher birth weight would lead to lower bone mass in later adulthood; this might be because of the larger effect of birth weight on bone size than on BMC. By leveraging the genetic instrumental variables with maternal- and fetal-specific SNP information, we detected the fetal genetic contributions to birth weight had a casually positive effect on the bone area but a negative effect on BMD. Furthermore, the maternal intrauterine environment, as proxied by maternal genetic variants that influence offspring birth weight, was also a determinant of adult BMD.Additional file 1: Fig. S1. Restricted cubic spline analysis to show the relationship between birth weight and Lumbar spine bone parameters. Fig. S2. Restricted cubic spline analysis to show the relationship between birth weight and Lateral spine bone parameters. Fig. S3. Restricted cubic spline analysis to show the relationship between birth weight and heel BMD. Table S1. Characteristics of the single nucleotide polymorphisms associated with the birth weight. Table S2. Detailed information on the GWAS summary-statistic data for birth weight and bone parameters. Table S3. Characteristics of participants from the UK Biobank dataset in the observational analysis for the Spine DXA data. Table S4. Characteristics of participants from the UK Biobank dataset in the model 3 observational analysis for heel BMD measured by QUS. Table S5. Summary statistics for the 63 SNPs used in instrumental variable analysis to assess the effect of fetal birth weight on the hip bone parameters. Table S6. Summary statistics for the 104 SNPs used in instrumental variable analysis to assess the effect of fetal birth weight on the hip bone parameters. Table S7. Summary statistics for the 205 SNPs used in instrumental variable analysis to assess the effect of fetal birth weight on the hip bone parameters. Table S8. P values for the associations of 205 birth weight variants with potential risk factors. Table S9. The association between fetal SNPs determined birth weight and potential risk factors in UK biobank dataset. Table S10. The association between fetal SNPs determined birth weight and adult BMC, Bone area, BMCadjArea and BMD in UK biobank dataset . Table S11. Causal associations of the fetal genotype effects on birth weight  with hip bone parameters in two-sample MR analyses. Table S12. Causal associations of the fetal genotype effects on birth weight  with hip bone parameters in two-sample MR analyses.


In the era of health disruption 4.0, there are still many hospitals and health care facilities that face various challenges. The main challenges are felt in terms of unclear laws and regulations and the lack of harmonization of regulations between related ministries. In addition, from internal factors, the lack of openness, motivation, and good knowledge management on the part of hospital management, medical service doctors, and IT teams in the organization also need to be addressed. Hospitals need to be motivated to immediately implement SIMRS in their management in order to realize optimal data integration on a national scale. The problem of using big data, data security and protection, data privacy, and the use of cloud computing systems is also one of the issues that is quite challenging to understand and apply in business.According Kristijono et al.  the actiThe healthcare industry is entering an era of digital innovation where patients are looking for services that can directly answer their needs because they are limited by their daily activities. According to DMN3 data, consumers looking for medical information on the internet, 47% seek information about doctors, 38% for hospitals and health facilities, and 77% to book a health check-up schedule. Based on these facts, it is necessary for the hospital management team to find out the needs of target consumers or patients and incorporate them into a digital system . This market need is being exploited by several health technology companies, which are currently growing in the community.According to Banuara  and WijaAccording to Wijayaa et al.  and ThenAccording to Sitorus et al.  viral maInterest is the driving force that causes a person to pay attention to other people or other objects. Interest is one source of motivation for a person to do activities that are liked According to Ngelyaratan et al.  which wiAccording to Renwarin  and SitoE-WOM has a positive and significant effect on visiting interest. An increase in the E-WOM variable will encourage a significant increase in the visiting interest variable and a decrease in the E-WOM variable will encourage a significant increase in the visiting interest variable. The results of this study are supported by research conducted by Wijaya et al. , Then anViral marketing has a positive and significant effect on Visiting Interest. An increase in the Viral marketing variable will encourage a significant increase in the Visiting Interest variable and a decrease in the Viral marketing variable will encourage a significant increase in the Visiting Interest variable. This study has similar results with research conducted by Banuara , David eE-WOM has a positive and significant effect on visiting decisions. An increase in the E-WOM variable will encourage a significant increase in the visiting decision variable and a decrease in the E-WOM variable will encourage a significant increase in the visiting decision variable. The results of this study are supported by the research of Wijaya et al.  and ThenViral marketing has a positive and significant effect on visiting decisions. An increase in the Viral marketing variable will encourage a significant increase in the visiting decision variable and a decrease in the Viral marketing variable will encourage a significant increase in the visiting decision variable. The results of this study are supported by research conducted by Wijaya et al. , Then anVisit interestt has a positive and significant effect on visiting decisions. An increase in the variable interest in visiting will encourage a significant increase in the visiting decision variable and a decrease in the variable interest in visiting will encourage a significant increase in the variable in the decision to visit. The results of this study are supported by research conducted by Wijaya et al. , Then anTechnology and information today have experienced very rapid development. Technology has opened as much access as possible for consumers to access a variety of information. The development of increasingly sophisticated technology accompanied by the use of the internet in the marketing process makes it easier for users to interact with each other. This has a positive impact on business people where the delivery of information can be done quickly, with a wide reach, and does not require expensive costs. Consumers are facilitated in finding information about the desired product without having to meet face to face. Word-of-mouth (WOM) is a phenomenon in the field of marketing, because nowadays consumers are always looking for references and trusting opinions in the community about a product. It is undeniable that the power of word-of-mouth has a big influence in developing the image of the goals to be conveyed by the company. Many studies have found how WOM exerts a stronger influence than other traditional communication media such as advertising or editorial recommendations. WOM is considered superior because information is more reliable. eWOM is a communication medium for sharing information about a product or service that has been consumed between consumers who initially did not know each other and met previously that were delivered electronically. eWOM has been shown to play a major role in consumer purchasing decisions by influencing consumer choices. Existing studies outline the statement that eWOM has become a permanent element of the online marketing mix by making a major contribution to consumers' online purchasing decisions. By using eWOM companies can benefit at low costs. With the internet and online media, consumers are now able to influence other consumers with their opinions and experiences. The possibility that people have received the information also helps spread the message on social media.The various trends and benefits that exist in the health 4.0 era should make the health industry more initiative and competitive to participate in developing a similar system in their respective service facilities. However, this certainly cannot be separated from various obstacles and challenges in the implementation process. In the next part of this white paper.E-WOM has a positive and significant effect on Visiting Interest. An increase in the E-WOM variable will encourage a significant increase in the visiting interest variable and a decrease in the E-WOM variable will encourage a significant increase in the visiting interest variable. Viral marketing has a positive and significant effect on visiting interest. An increase in the Viral marketing variable will encourage a significant increase in the Visiting Interest variable and a decrease in the Viral marketing variable will encourage a significant increase in the Visiting Interest variable. E-WOM has a positive and significant effect on visiting decisions. An increase in the E-WOM variable will encourage a significant increase in the visiting decision variable and a decrease in the E-WOM variable will encourage a significant increase in the visiting decision variable. Viral marketing has a positive and significant impact on visiting decisions. An increase in the Viral marketing variable will encourage a significant increase in the visiting decision variable and a decrease in the Viral marketing variable will encourage a significant increase in the visiting decision variable. Interest in visiting has a positive and significant effect on visiting decisions. An increase in the visiting interest variable will encourage a significant increase in the visiting decision variable and a decrease in the visiting interest variable will encourage a significant increase in the visiting decision variable.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Exposure to air pollutants has several effects on human health, including during pregnancy. To identify whether exposure to benzene and toluene among pregnant women contributes to preterm delivery. Longitudinal study using data on newborns from mothers living in São José dos Campos (SP) in 2016, who had been exposed to benzene and toluene. A logistic regression model with three hierarchical levels was constructed using maternal variables relating to newborns, and using benzene and toluene concentrations in quartiles. Occurrences of cesarean births, twins or malformations were excluded. Maternal exposure windows of 5, 10, 15, 30, 60 and 90 days prior to delivery were considered. Out of the 9,562 live births, 3,671 newborns were included and 343 newborns were born at less than 37 weeks of gestation (9.3%). The average birth weight was 3,167.2 g. Exposure to benzene and toluene was significantly associated (P = 0.04) with preterm delivery in the five-day window. There was no association in any of the other exposure windows. It was possible to identify that maternal exposure to benzene and toluene has an acute effect on preterm delivery. Preterm birth is defined as birth before 37 full weeks of gestation and is associated with higher neonatal morbidity and mortality,In a multicenter study conducted in Brazil, the prematurity rate was estimated to be 11.7%. However, the rate reported through the national information system for live births (SINASC) was 7.1%.,Many factors have been associated with preterm delivery, including pregnancies at ages of below 19 and above 34 years, low maternal schooling level, low number of prenatal visits, twin pregnancy, shortened cervix, premature rupture of the amniotic membrane, inflammation and recent exposure to environmental pollutants.3), nitrogen dioxide (NO2) and sulfur dioxide (SO2) are the gaseous pollutants that have been most studied.10) has also been investigated. This is composed of a mixture of solid and liquid particles that adsorb polycyclic aromatic hydrocarbons and ions such as sulphates, nitrates and metals.Carbon monoxide (CO), ozone , Brazil, in 2016. This municipality has a population of approximately 700,000 inhabitants. It is a regional center with several industries, including automobile, aerospace and petrochemical industries, among which the Petrobras oil refinery stands out. Via Dutra, the busiest highway in Brazil, connecting the metropolitan areas of São Paulo and Rio de Janeiro, crosses this municipality.Data were obtained from birth certificates, i.e. declarations of live birth  that are recorded in the live birth information system .Data on the pollutants benzene and toluene were obtained from the database of the Environmental Company of the State of São Paulo , which is in the public domain.Statistical analysis was performed using a hierarchical logistic regression model. The pollutants were divided into quartiles and considered in relation to the first quartile (reference category).The dependent variable was the presence of preterm birth. The independent variables were classified into three levels: distal, intermediate and proximal. The classification of the variables as such is described below.The distal level included maternal age, marital status and schooling level. Maternal age was categorized as favorable when it was within the range from 20 to 34 years; or as unfavorable when it was 19 years or younger or 35 years or older, i.e. with greater risk of preterm birth. Marital status was categorized as single, separated or widowed (unfavorable); or as married or in a stable union (favorable). Schooling level was classified as elementary and high school only (unfavorable); or as tertiary-level, i.e. university or technical college (favorable).The intermediate level included the number of prenatal visits, which was categorized as unfavorable when this number was between zero and six or as favorable when it was seven or more; and the time at which prenatal care began, which was categorized as favorable when this was no later than the third month or as unfavorable when this was from the fourth month onwards.The proximal level included the sum of concentrations of the pollutants recorded in the 5, 10, 15, 30, 60 and 90-day windows prior to childbirth.3. For analysis purposes, the sums of the concentrations in the 5, 10, 15, 30, 60 and 90-day windows before childbirth were considered. The aim of this procedure was to assess whether the cumulative effects of these pollutants on the onset of preterm delivery occurred in an acute or a chronic manner. Bivariate analysis was performed on the variables within the three levels, separately. At the distal level, variables with a P-value ≤ 0.20 were included in the multivariate analysis and variables that presented P-value < 0.05 at this level were maintained at the next phase of the analysis.The pollutants benzene and toluene were analyzed in terms of daily averages, in µg/mThe same procedure was performed for intermediate-level variables, and then those with P-value < 0.05 were adjusted according to the variables of the previous level. At that moment, the hierarchical model contained two levels of variables: distal and intermediate. Lastly, for each of the pollutant exposure windows with P-value ≤ 0.20, the variables at this level were maintained for each window with P-value < 0.05, thus completing the three levels of this analysis.2 trend test to identify any possible dose-response effect.For the exposure windows that continued to present P-values < 0.05 in the final model and thus were retained in the model, we also performed a χFor the statistical analysis, we used the Epi Info software, version 7.2. The significance level used in the analyses was alpha = 5%.Because this study used data that are available online with public access, and it was impossible to identify the subjects analyzed, the study was not submitted to a research ethics committee.Out of the total number of 9,562 live births in 2016 in São José dos Campos, Brazil, 3,671 (38.0%) that met the inclusion criteria were analyzed. There were 1,826 male newborns (50.9%) and 1,845 female newborns (49.1%). Their mean birth weight was 3,167.2 g . Among the live births that met the inclusion criteria, 343 (9.3%) were found to have taken place at a gestational age of less than 37 weeks.3 (SD = 4.83); and toluene 21.38 µg/m3 (SD = 16.66).The mean daily levels and respective standard deviations (SD) for the pollutants were as follows: benzene 6.56 µg/mThe results from the bivariate analysis on the distal and intermediate levels showed that only the number of prenatal care consultations was significant . These results are shown in In the final analysis, both of the pollutants were considered at the proximal level, adjusted for the number of prenatal care consultations. The odds ratios (ORs) and their respective 95% confidence interval (95% CI) for the accumulated 5, 10 and 15 days relating to benzene and toluene exposure, with emphasis on the accumulated five-day concentration regarding benzene  and toluene  are shown in 2 trend for the accumulated five-day periods is shown in The χThis study identified an association between preterm birth and maternal exposure to benzene and toluene five days before delivery, after adjusting for the number of consultations attended by the pregnant woman during prenatal care. Thus, a possible acute effect was found.It is known that exposure to air pollutants is associated with several respiratory and cardiovascular diseases, as well as with preterm birth.The analysis on distal and intermediate factors  showed tHowever, the factor of maternal age was not found to be associated with preterm birth, contrary to the findings from a Chinese study. In that study, two age groups were formed and the group older than 30 years presented higher risk of prematurity.There was also no association with maternal marital status, since women living without partners were not found to be at higher risk of preterm birth. This was discordant with the findings from an American study, which showed that those living without a partner presented significantly higher risk , in relation to those with a partner .Regarding schooling level as a risk factor for low birth weight, our findings were concordant with those from a Brazilian study carried out in the city of Rio de Janeiro, where no association between low schooling level and low birth weight (OR = 0.93) was found.10 was found on the day of delivery (lag 0), the day before delivery (lag 1) and three days prior to delivery. However, a different approach was used in their study.Other comparisons with the Brazilian literature are very difficult, given the scarcity of studies on the effect of maternal exposure to air pollutants and occurrence of premature delivery. In a single study conducted by Lima et al.,3 .Analysis on acute exposure  showed tIn a study conducted in Canada, Poirier et al. showed that there was an association between exposure of pregnant women to toluene in the second quartile of toluene concentrations  and preterm delivery. In this Canadian study, exposure was considered throughout the gestational period and the findings are partially concordant with our results, in which we found an association with maternal exposure for five days.On the other hand, there was no significant association between maternal exposure to benzene and toluene over other exposure windows such as 30, 60 and 90 days.2 trend analysis on the five-day windows, with adjustment for the number of consultations, showed that the higher the concentrations of benzene and toluene were, the greater the chance of birth of a preterm fetus was. This highlights the possible cumulative effect of exposure.The χOne possible mechanism for the onset of preterm birth caused by exposure to air pollutants is thought to relate to release of cytokines and reactive oxygen species, thereby causing oxidative stress.This study had certain limitations. The mothers’ socioeconomic conditions, home address, living conditions, preexisting diseases and smoking status were not available through SINASC. The concentrations of the air pollutants were considered homogeneous throughout the city, which might not reflect the reality. Moreover, the pregnant women had been free to circulate during their pregnancies. Another possible limitation of the present study may have been its non-inclusion of other air pollutants. However, a previous analysis had not shown any correlation between these air pollutants and the outcome.Despite the limitations of the present study, it was possible to identify the deleterious effect of maternal exposure to benzene and toluene on the preterm delivery in a medium-sized city in Brazil, and to ascertain that this was an acute effect. The results presented here may be useful for public policy implementation, with the aim of reducing these concentrations.