Description of simple bone cyst (SBC) content has been controversial. This study aimed to assess and give a clearer picture of the SBC cavity contents. Between 2014 and 2016, 19 patients with SBC verified by histopathological examination were included in this study. SBC cavity content was investigated using clinical, radiographic, surgical, and laboratory findings. The difference in components among cavity fluid, blood, and serum was evaluated using a paired sample t-test for statistical analysis. All 19 SBC cases radiographically and surgically revealed a fluid-filled cavity. The patients’ average age was 21.3 ± 13.2 years, with no sex predominance found. SBCs were found mostly in the anterior mandible . All lesions were filled with clear straw-colored or blood-colored floods with low concentration. Although the fluid components were similar to those in the blood and serum in the laboratory analysis, the statistical analysis revealed that the fluid components were not significantly different only for eosinophil (p = 0.43) and basophil (p = 0.06) counts as blood components and sodium (p = 0.76), potassium (p = 0.08), and chloride (p = 0.13) concentration as serum components. The results show that SBC is a fluid-filled cavity, with the cavity fluid being more likely similar to serum rather than blood regarding internal components. Traumatic bone cyst, solitary bone cyst, hemorrhagic bone cyst, extravasation cyst, unicameral bone cyst, and idiopathic bone cavity have all been used in the literature to describe the lesion5. According to studies, SBC is more common in the second decade of life7. The sex and site distribution of SBC is quite controversial, in which female predominance and involvement in the posterior region of the mandible have been documented8. However, Chranovich and Gomez6 observed in a recent study that SBC is equally distributed between the two sexes. SBC has been reported in the anterior region of the mandible by several authors7. In the majority of cases, this cyst is discovered accidentally due to the absence of any clinical symptoms. SBC in the jaw is usually detected by panoramic radiography during routine dental examinations. SBCs are characterized as areas of well-defined unilocular radiolucency with typical interdental scalloping on radiographs5.As defined, a simple bone cyst (SBC) is a benign bone lesion that lacks epithelial lining, so called 9. The fluid’s nature was also described as serous or bloody10. The question of whether SBC cavities contain blood or serum may arise at this time. Therefore, we collected and analyzed data of 19 patients diagnosed with SBC in our clinic between 2014 and 2016. We sought to examine the SBC cavity content compared with the components of blood and serum of the same patient and to give more comprehensive insights into SBC of the jawbone.Furthermore, a lot of conflicting information about the content of the SBC cavity exist. Some authors believed that cavities are always filled with fluid, whereas others argued that an empty cyst cavity containing air might existFrom June 2014 to May 2016, 21 of the 27 patients diagnosed with SBCs volunteered to participate in this study. However, two patients were excluded due to a lack of fluids necessary for analysis. Hence, 19 patients were included in this study. This study was reviewed and approved by the institutional review board of Kyungpook National University Hospital (KNUH 2014-01-023) and was in compliance with the Helsinki Declaration.Before evaluation, all participants were informed of the study’s goals and procedures, as well as signed written consent. Relevant data were retrieved from the electronic database. Age, sex, history of trauma, presence of any symptoms, and cyst location were among the clinical data. For the radiographic examination, the results of cone-beam computed tomography (CBCT) were used Fig. . A radioSurgery was performed by a skilled surgeon with more than 10 years of professional expertise to accurately collect the SBC cavity content. To prevent contamination from surrounding blood or saliva, thorough hemostasis and suction were performed after mucosal incision. Under CBCT guidance, the needle of a 10 mL syringe was introduced through the thinnest cortical bone site, and fluid was aspirated Fig. . If the For complete blood count (CBC) and white blood cell differential count analyses, preoperative blood samples and collected cyst liquid samples were anticoagulated with dipotassium ethylenediaminetetraacetic acid (EDTA) and evaluated on a Siemens ADVIA® 2120i hematology analyzer . Preoperative serum samples were collected using a serum-separating tube (SST) and properly centrifuged, and liquid samples obtained in SST were measured on Cobas® 8000 Modular chemistry analyzer  to determine total protein, total cholesterol, sodium, potassium, and chloride levels. Every CBC and chemistry test was determined within 4 h of blood and liquid collection.Standard software  was used to conduct the statistical analysis. Mean with SD values and range were used for descriptive statistics. The paired sample t-test was used to assess statistical differences between SBC fluid content and blood and serum components. The 5% cut point was set for statistical significance.Informed consent was obtained for all patients involved in the study including for minors from their parents and/or legal guardians.This study evaluated 19 cases. Table All lesions were located in the mandible, with seven (36.8%) cases being found in the mandibular posterior region, while the rest were in the anterior region .On CBCT imaging, the SBC had a mean anteroposterior length of 19.3 ± 5.1 mm, a mean buccolingual width of 10.1 ± 3.6 mm, and a mean height of 15.6 ± 3.7 mm. All SBCs were unilocular on radiography. SBC manifested as radiolucency with radiopaque mass in all three middle-aged patients. And there was no tooth displacement or resorption.Radiographically and by needle aspiration, all lesions were filled with fluid. The aspirated fluid was either a straw-colored clear liquid or reddish liquid similar to blood, but with a low concentration.The internal fluid from the lesion had components similar to those found in the blood and serum, according to the laboratory analysis.Components such as red and white blood cells, hemoglobin, hematocrit, segmented neutrophils, lymphocytes, and monocytes showed notable differences between blood and liquid cavity in the statistical analysis. Lymphocyte and monocyte counts were higher in the cavity liquid, while red and white blood cell counts including hemoglobin, hematocrit, and segmented neutrophils were higher in blood than in the cavity liquid.Chemical analysis revealed that the number of serum components such as total protein and cholesterol differed significantly from those in the SBC fluid. Total protein was higher in the serum than in the fluid, while total cholesterol was higher in the cavity fluid.However, only eosinophils p = 0.43) and basophils (p = 0.06) as blood components, as well as sodium (p = 0.76), potassium (p = 0.08), and chloride (p = 0.13) concentration as serum components, were shown to be substantially different in the cavity fluids. The internal components of SBC cavity fluid, blood, and serum are compared in Tables  and baso4; therefore, most studies are case reports. Only a few studies have looked at the relationship between SBC of the jaws and its internal fluid components. This study aimed to report clinical, radiographic, surgical, and laboratory findings of 19 patients with SBC, with a particular focus on the components of the cyst liquid contents.SBC of the jaw is considered rare16. In a recent systematic analysis of SBC of the jaw, more than half of all reported cases have empty cavities6. However, the cavity being vacant might be mistaken evaluation10. All 19 SBC cavities in this study were consistently filled with fluid, as confirmed both radiographically and surgically.SBC cavity in the jaw is often reported to be empty18. To our knowledge, no studies evaluating internal components of cyst content have found any similarities SBC cavity content and blood. Contamination of the fluid during the creation of a window in the cyst wall is thought to be a possible explanation for the blood-contained SBC cavity fluid. The internal fluid was clear at the onset of needle aspiration, according to our findings. To avoid misdiagnosis owing to a surgical error, thorough suction and chilling were planned. Although some fluid samples included blood, it is believed that blood was drawn off the cavity wall at the end of the aspiration. This study reveals that fluid contents have substantially different concentrations of blood components, except for eosinophils and basophils. Eosinophils and basophils were found in the cytological findings of aspirates from idiopathic bone cysts, according to Rivero et al.2. However, there is no clear explanation for this phenomenon. In 47 cases of odontogenic cysts, Madhusudan et al.19 explored the role of eosinophils in bone resorption. They believe that a factor secreted by mast cells attracts eosinophils. The exact presence and function of these inflammatory cells in SBCs are still unknown. Despite this, the authors claim that SBC is a fluid-filled cavity that shows no signs of inflammation21. Although fluid has contained inflammatory cell, this complied with the cases in our research.Moreover, researchers suggest that blood or serous fluid is present in the cyst cavity23. The formation of cyst content has been investigated using fluid aspirates. It is believed that fluid aspirates have similar contents to that in serum with respect to proteins and electrolytes24. Although this was in consistent with our findings, the statistical analysis of total protein concentrations in the fluid and serum revealed significant differences . Consequently, studies have suggested that the SBC fluid content represents transudate 25. Accordingly, plasma diffusion may have a role in the formation of SBC fluid contents, according to Skaug24. Suzuki26 investigated the fluid components of jaw cysts, other than bone cysts, and proposed an electrolyte diffusion mechanism from serum through the cyst wall.The mechanism of cyst formation has been the subject of numerous studies. In the literature, the trauma and hemorrhagic and vascular blockage concepts are most commonly encountered6. In this study, 18 cases were detected after routine radiographic examination. This supports prior observations that most SBCs are asymptomatic6.The majority of SBCs (14 of 19 cases) were found in patients in their second decade of life, with similar prevalence in both sexes6, which correlates with our findings. Although the posterior mandible is the most common location4, the anterior mandible was most frequently implicated (12 of 19 cases) in the current study.Lesions are commonly found in the mandible28.A combination of cemento-osseous dysplasia with SBC was notably present in three middle-aged female patients. This was backed up by prior reportsThe study’s drawback can be attributed to the small number of participants. Therefore, future research should focus on SBC fluid contents in a larger number of cases.During radiographic examination and surgery, all SBC cavities were filled with fluid. The results reveal that SBC cavities are filled with serum-like fluid rather than blood. The nature of SBC fluid contents may have been described incorrectly in the literature, at least in cases where an accurate aspiration procedure was not performed. The use of a meticulous aspiration technique to obtain true and non-contaminated fluid is proposed to explain the nature of the fluid contents.


A tumour-positive proximal margin (PPM) after extended gastrectomy for oesophagogastric junction (OGJ) adenocarcinoma is observed in approximately 2–20% of patients. Although a PPM is an unfavourable prognostic factor, the clinical relevance remains unclear as it may reflect poor tumour biology. This narrative review analyses the most relevant literature on PPM after gastrectomy for OGJ cancers. Awareness of the risk factors and possible measures that can be taken to reduce the risk of PPM are important. In patients with a PPM, surgical and non-surgical treatments are available but the effectiveness remains unclear. The incidence of oesophagogastric junction (OGJ) adenocarcinoma has been gradually increasing both in Western and Asian countries , 2. OGJ Most surgeons would agree that the preferred surgical treatment for type I  is oesophagectomy with mediastinal lymph node dissection. For type III cancers , total gastrectomy with partial oesophagectomy is performed . For typThe main goal of any surgical treatment with curative intention is to achieve a complete resection of the tumour. However, the prevalence of a (microscopic) positive resection margin––proximal, distal or circumferential––after extended total gastrectomy for OGJ and gastric cancer ranges from 2.8 to 20% . Here, iZ-line, gastric folds and the diaphragmatic pinch. Submucosal extension of the tumour makes it particularly difficult to judge the degree of oesophageal involvement. In this instance, EUS can be helpful. Furthermore, a minimum length of macroscopic oesophageal safety margin should be respected during surgical resection [A PPM is often only diagnosed on definitive histopathological examination of the resection specimen. This is generally due to an underestimation of the proximal extension of the tumour intraoperatively by the surgeon, often within the submucosal layer. It is therefore important to have a rigorous preoperative assessment by endoscopy and endoscopic ultrasonography (EUS). Three endoscopically visible landmarks should be assessed: the esection , althougIn some patients, the possibility of a PPM is accepted by the surgeon during the operation. For example, if the patient is considered too frail to undergo a more extensive resection. However, one should always consider the need to change the surgical approach and take this into account when selecting patients for total gastrectomy for OGJ cancer.Distal gastrectomy may treat cancer-related symptoms  that are difficult to palliate with other modalities. In selected patients, this approach improves quality of life even when an incomplete tumour resection has been performed . Total gKnowledge of the risk factors associated with a PPM could help increase the awareness of the surgical team leading to adaptation of surgical strategy or intraoperative assessment of the resection margin. The most frequently reported risk factors for a positive resection margin are shown in Table . Large dA systematic review and meta-analysis including 19,992 patients found an association of R1 status  with poorer overall survival (OS). A positive resection margin was also an independent prognostic factor irrespective of tumour stage . MuneokaT status and the extent of infiltration into the oesophagus. Tumour-positive regional lymph nodes in the mediastinum may also guide the surgeon in defining the surgical approach and as a result the oesophageal resection margin [Accurate preoperative assessment of the tumour is crucial to limit the chance of an incomplete resection. Endoscopy and computed tomography (CT), often combined with EUS, are mandatory for assessment of n margin . The valn margin . One of n margin .Data about the biological nature of the tumour in addition to tumour location may be helpful, although there are no clear guidelines yet. Poorly differentiated tumours and the presence of signet ring cells should raise the suspicion of submucosal extension. Neoadjuvant therapy is indicated for locally advanced tumours. Both chemotherapy (FLOT)  and chemThere is no consensus about the length of macroscopic appearing normal oesophagus that should be resected . Some stIntraoperatively, manual palpation is helpful in open surgery but is not possible during minimally invasive procedures. Hence, the threshold for conversion  should be low if the complete resection cannot be assured by laparoscopy. Intraoperative endoscopy may help assess the proximal margin of the tumour. This could be used in minimally invasive and open approaches. Kawakatsu et al. described the systematic combination of preoperative placement of marking clips and intraoperative endoscopy to determine the surgical margin in patients who undergo laparoscopic extended gastrectomy. They achieved a success rate of 98.9% negative margins during the initial transection .Intraoperative evaluation of the proximal resection margin by performing a frozen section analysis may be the best technique to assess margin status. The accuracy lies between 93 and 99% , 43, 44.When a positive proximal margin is diagnosed intraoperatively , re-resection should follow. This may entail the need for changing the surgical approach as discussed earlier. When the proximal margin is positive at histopathological examination of the resection specimen after the operation, further treatments should be considered and tailored to tumour and patient characteristics. There is controversy regarding the benefit of performing a re-resection by a second operation. Some studies have described a lower incidence of local relapse after re-resection, but similar poor survival compared to patients that did not undergo a re-resection , 31. AccMultimodal treatment with adjuvant chemoradiotherapy (CRT) has also been proposed as alternative to surgery. Stiekema et al. showed in a Dutch retrospective cohort study including 409 patients with a R1 resection  that adjuvant CRT was associated with improved survival when compared to patients without adjuvant CRT treatment . In anotTotal gastrectomy for cancer aims to completely remove the primary tumour including locoregional lymph nodes. This is defined as achieving negative resection margins and a D2 nodal dissection. The best surgical strategy can only be planned after a comprehensive preoperative assessment of the patient  and location, stage and biological behaviour of the tumour. The surgeon should be involved in every step of this process. Awareness of risk factors for a positive resection margin could help in clinical decision making but unexpected intraoperative findings may lead to adaptation of the surgical management. When a positive resection margin is involved, further treatments options, such as re-resection and/or (chemo) radiation, should be carefully considered in selected cases.


The intra-uterine components of labor, namely, myometrial contractility, cervical ripening, and decidua/membrane activation, have been extensively characterized and involve a local pro-inflammatory milieu of cellular and soluble immune mediators. Targeted profiling has demonstrated that such processes extend to the intra-amniotic space, yet unbiased analyses of the proteome of human amniotic fluid during labor are lacking. Herein, we utilized an aptamer-based platform to characterize 1,310 amniotic fluid proteins and found that the proteome undergoes substantial changes with term labor . Proteins with increased abundance in labor are enriched for immune and inflammatory processes, consistent with prior reports of labor-associated changes in the intra-uterine space. By integrating the amniotic fluid proteome with previously generated placental-derived single-cell RNA-seq data, we demonstrated the labor-driven upregulation of signatures corresponding to stromal-3 and decidual cells. We also determined that changes in amniotic fluid protein abundance are reflected in the maternal plasma proteome. Collectively, these findings provide novel insights into the amniotic fluid proteome in term labor and support its potential use as a source of biomarkers to distinguish between true and false labor by using maternal blood samples. A strong body of evidence indicates that the intra-uterine components include a local pro-inflammatory milieu characterized by increased concentration of soluble and number of cellular immune mediators in the myometrium16, cervix25, decidua35, and chorioamniotic membranes40. Such an intra-uterine inflammatory response is also reflected in the intra-amniotic space. Indeed, prior targeted studies have shown that the concentrations of several cytokines, including Interleukin-1β (IL-1β)41 and Interleukin-6 (IL-6)42, are elevated in the amniotic fluid of women with term labor compared to those without labor. Furthermore, cytomic approaches have shown that innate immune cells, such as neutrophils and monocytes/macrophages, are abundant in the amniotic fluid of women at term gestation43. In line with this concept, we recently profiled the amniotic fluid proteome from early to late pregnancy and found that immune-specific signatures were enriched in term gestation44. Notably, placental- and uterine-derived signatures were modulated in the amniotic fluid proteome44, showing that the fetal and maternal components are present in the intra-amniotic space. Taken together, these findings led us to hypothesize that amniotic fluid harbors cellular and soluble mediators at the end of gestation in preparation for the physiologic intra-amniotic inflammatory process of term parturition. Hence, the primary aim of the current study was to explore the human proteome of amniotic fluid during term parturition.Labor is a well-orchestrated process that includes physiological, biochemical, endocrinological, and immunological pathways in the mother and the fetus, culminating in a successful delivery. This complex process involves intra-uterine and extra-uterine components, with the former consisting of increased myometrial contractility, cervical ripening, and decidual/membrane activation4. Indeed, the detection of cell-free RNA and DNA derived from the fetus has been an invaluable clinical tool in evaluating fetal development as well as in screening for fetal abnormalities and obstetrical disease59. Moreover, the use of high-dimensional techniques such as transcriptomics, proteomics, and metabolomics has allowed for the exploration of the complex and dynamic processes that are modulated in the maternal circulation prior to and during labor70. Recently, we leveraged the maternal blood transcriptome to monitor single-cell signatures derived from placental tissue and demonstrated the increasing abundance of such transcripts with advancing gestation71 as well as in women with term71 or spontaneous preterm labor and birth66. Similarly, labor-specific transcriptomic changes in the maternal circulation can be correlated with those derived from the chorioamniotic membranes, cervix, or myometrium, suggesting that tissue signatures of labor are partly mirrored in this compartment70. By intersecting single-cell RNA-seq data of the laboring myometrium with maternal transcriptomic datasets, we also demonstrated that specific cell signatures were modulated throughout gestation and enriched with the process of labor72. Together, these prior observations demonstrate that labor-specific changes taking place in the gestational and reproductive tissues can be tracked in the maternal circulation. Yet, whether the processes occurring in the amniotic fluid during term labor are also reflected in the maternal circulation has not been investigated.In addition to intra-uterine components, labor also includes extra-uterine components such as processes taking place in the maternal circulation73 to characterize changes in the concentrations of 1,310 amniotic fluid proteins during the normal process of labor at term. In addition to identifying amniotic fluid proteins dysregulated with labor, we tested in independent patient sets whether the amniotic fluid-derived signature can discriminate between women in labor and those not in labor based on blood protein profiles.Herein, we utilized the aptamer-based SOMAscan proteomics platformThis study included amniotic fluid samples collected from women at term in labor  or not in labor TNL, n = 11)  and TNL n = 21) patients -based concentrations of C–X–C motif chemokine ligand 10 (CXCL10), neutrophil elastase (ELANE), interleukin (IL)-6, and secretory leukocyte protease inhibitor (SLPI) that were available for a subset of samples included in this study  analysis was utilized. Despite some overlap, most amniotic fluid samples showed clear separation according to labor status ]. This finding is most likely due to the narrow range of gestational ages wherein amniocentesis was performed in the current study. Thus, we have not adjusted for gestational age at amniocentesis in our subsequent analyses.Although there was no significant difference in gestational age at amniocentesis between the two study groups Table , we and 2 fold changes) against the statistical significance  of these differences  proteins in a color scale, indicating consistent patterns of protein abundance within each study group. These results illustrate the distinct amniotic fluid proteomic profile that characterizes labor at term.A comparison of amniotic fluid protein abundance between the TIL and TNL groups resulted in 251 (19.2%) proteins with significant differences (q < 0.1 and fold change ≥ 1.25)  of the MSigDB C5 gene set collection and identified Gene Ontology (GO) terms  associated with labor status. We identified 184 biological processes, 24 molecular functions, and 9 cellular components that were enriched in proteins with higher abundance in the TNL compared to TIL samples (q < 0.25)  in amniotic fluid samples from TIL patients compared to TNL patients  was significantly higher in maternal plasma samples collected at term labor compared to gestational age-matched samples collected from women not in labor 99, colony stimulating factor-3 (CSF3)99, matrix metallopeptidase-8 (MMP8)110, matrix metallopeptidase-9 (MMP9)126, and heat shock protein family A (Hsp70) member 1A (HSPA1A)120. We also reproduced the previously reported decrease in amniotic fluid concentrations of tumor necrosis factor ligand superfamily member 6, soluble form (FASLG)127, intercellular adhesion molecule-1 (ICAM1)122, and lymphotoxin alpha (LTA)104 with labor. Yet, the application of an aptamer-based multiplex proteomics platform has enabled deeper exploration beyond markers of inflammation to describe labor-associated changes in proteins involved in other processes such as intracellular signaling, cell metabolism, intracellular transport, and cell–cell communications.Prior research into amniotic fluid proteins in term labor has primarily utilized targeted approaches to evaluate individual proteins or specific protein sets43. Moreover, our previous study comparing the amniotic fluid proteome between samples collected at term (without labor) and those collected during mid-trimester also identified neutrophil-mediated immunity as the most enriched functional term among proteins that increased in concentration at term44. Neutrophils produce matrix metalloproteinases that degrade the extracellular matrix, a process crucial for two key events of parturition: rupture of the fetal membranes and cervical ripening130. Indeed, GO and pathway analyses identified terms such as proteolysis, genes encoding enzymes and their regulators involved in the remodeling of the extracellular matrix, and extracellular matrix organization as enriched among proteins with increased abundance during labor.Herein, pathway analysis of the amniotic fluid protein changes in term labor identified innate immune responses and neutrophil degranulation as being enriched among upregulated proteins. This observation is in line with a previous report of amniotic fluid immunophenotyping, showing that neutrophils are the most abundant cell types in the amniotic fluid at term132. Other studies of term and preterm pregnancies have also found an increase in the concentrations of proteins involved in carbohydrate metabolism with the spontaneous onset of labor in amniotic fluid and cervicovaginal fluid136. For example, analysis of paired cervicovaginal fluid samples collected a week before and a week after the onset of spontaneous term labor showed a significant increase in ENO1 with labor133. In addition, mass spectral proteomics analysis of amniotic fluid samples collected from women with spontaneous preterm labor has identified glycolysis/gluconeogenesis-associated proteins as differentially abundant in women who delivered preterm with134 and without135 intra-uterine infection or intra-uterine inflammation.Another set of functional terms that emerged from the functional profiling of proteins with increased abundance in term labor was related to carbohydrate metabolism. The top three upregulated proteins in labor were glycolytic enzymes: alpha-enolase (ENO1), fructose-bisphosphate aldolase A (ALDOA), and gamma-enolase (ENO2). Parturition requires diverse effector functions of multiple cell types across the maternal and fetal intrauterine tissues, making energy generation and consumption essential for accomplishing parturition without complications. Glucose metabolism meets a major portion of this increased energy demand139. However, it was observed that SP-A concentrations were lower in human amniotic fluid samples collected at term in labor compared to those at term without labor118. While SP-A was not measured in the current study, a functionally related protein, pulmonary surfactant-associated protein D (SFTPD), was among the most abundant in amniotic fluid samples collected after labor onset. Of note, while a moderate increase in the amniotic fluid concentration of SFTPD in amniotic fluid has been reported throughout the third trimester140, we did not previously observe a similar change in the amniotic fluid samples collected at term without labor compared to those collected during mid-pregnancy44. Thus, the observed changes in amniotic fluid concentrations of SFTPD could be specific to labor rather than to advanced gestational age. In addition, a genetic study has previously shown a significant association between SFTPD gene polymorphism and spontaneous preterm birth among women with recurrent preterm birth141.Studies in murine pregnancy have indicated that the fetal lung secretes surfactant components, particularly surfactant protein A (SP-A), into the amniotic fluid, where it can activate macrophages and induce inflammation and parturition79, suggesting that a labor-specific activation of the decidual cells occurs. Indeed, decidual activation is a crucial component of the common pathway of parturition143. Consistently, in addition to the increased meta-protein signature of decidual cells, we also observed that the biological pathway of myometrial contraction and relaxation was enriched among proteins that were more abundant in samples collected after labor. Given that myometrial contractility represents another component of the common pathway of parturition142, these findings further support the reflection of labor-specific changes in the intra-uterine tissues by the amniotic fluid proteome.Moreover, we showed that the meta-protein signature corresponding to decidual cells was increased in amniotic fluid samples collected during labor. Notably, we previously determined that the meta-RNA expression of decidual cells decreases with gestational age in amniotic fluid samples collected before the onset of labor144; thus, the development of diagnostic biomarkers that can be evaluated by using minimally invasive samples, such as maternal blood, is essential. To determine the potential of non-invasive biomarker discovery based on information derived from amniotic fluid, we followed a previously described analytic approach to define and track disease-specific69, single cell-specific79, and tissue-specific signatures145 in the maternal circulation and amniotic fluid. First, we defined a labor-specific signature as consisting of amniotic fluid proteins that increased the most in abundance with labor in a Hispanic population. Next, we showed that this meta-protein signature is significantly increased with term labor in the maternal plasma proteome of an independent set of predominantly African-American mothers74. The simple average of standardized plasma protein abundance distinguished between the groups, which is encouraging when considering that the proteins were identified in the amniotic fluid analysis. Moreover, when the list of candidate proteins was expanded from the top 15 to all amniotic fluid proteins significantly increased with labor, a plasma proteomic random forest model led to substantially improved accuracy. The set of proteins that most contributed to prediction accuracy included many previously known to be associated with labor in gestational tissues. For example, the expression of the gene coding for SERPINE1 was previously shown to be elevated during labor in the myometrium and placenta149. Moreover, mass spectrometry-based proteomic analysis of placental membranes collected after spontaneous labor (term or preterm) showed that ERP29 was detected only in term placentas150. The concentration of decidual IGFBP1 was shown to increase in vaginal secretions after fetal membrane rupture151, and an increased concentration of IGFBP1 in the cervicovaginal fluid has been proposed as a biomarker of PPROM154. These findings indicate that the amniotic fluid proteomic changes associated with term labor have biological plausibility and are translatable to the maternal circulation and across diverse cohorts of patients.Amniocentesis is an invasive procedure that is no longer a part of routine maternal care44. Finally, while amniotic fluid proteomic analysis was performed in a Hispanic population, the observed labor-specific changes were translatable to the maternal plasma proteome of a predominantly African-American population. The primary limitation of this study is the moderate sample size of the TNL group, which is to be expected since amniocenteses are not commonly performed in term deliveries. Yet, to overcome such a limitation, we utilized robust differential analysis and functional profiling methods with particular emphasis on controlling the false discovery rate. In addition, our study design  was not ideally suited to discriminate between events that cause labor and those that accompany labor since amniocentesis was performed either in the absence of labor or during labor. Nevertheless, by using robust functional profiling strategies, we provide corroborating evidence for several biological processes previously implicated in the onset of labor, including fetal lung maturity and decidual activation.The strengths of this study include the unbiased analysis of the proteome , although we recognize that this protein set represents a fraction of the human proteome. Another strength is the use of gestational age-matched samples to control for this variable, given that we have demonstrated its influence on the amniotic fluid proteomeWhether the observed association between molecular changes in the amniotic fluid and maternal blood extends to other ethnicities and obstetrical syndromes, such as spontaneous preterm labor and birth, remains to be determined in future studies.Collectively, the findings herein provide the first characterization of the amniotic fluid proteome during term parturition, thus demonstrating that such a process is reflected by the altered proteomic composition in this fetal compartment. Moreover, we validated our findings by corroborating the enrichment of specific immune and inflammatory processes associated with labor onset in other intrauterine compartments. Importantly, labor-driven perturbations of the amniotic fluid proteome can be observed in the maternal plasma proteome, thereby supporting its potential use as a biomarker to inform optimal patient management.Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Detroit, MI, USA . All patients provided written informed consent prior to sample collection. All experiments were performed in accordance with relevant guidelines and regulations.The study protocol, collection of samples, and use of clinical data were approved by the Human Investigation Committee of Sotero del Rio Hospital, Santiago, Chile (amniotic fluid), and the Institutional Review Boards of Wayne State University and the Pregnancy Research Branch (formerly known as the Perinatology Research Branch), an intramural program of the Amniotic samples were collected from pregnant women seeking care at the Sotero del Rio Hospital, Santiago, Chile. A cross-sectional study was designed to include 35 women: 11 who underwent amniocentesis at term before the onset of labor and 24 who had an amniocentesis at term after the spontaneous onset of labor  and the gestational age-matched samples from women who were not in labor (n = 21) were used  and 1125 proteins in maternal plasma samples was determined with the SOMAmer (Slow Off-rate Modified Aptamers) platforms v3 and v2, respectively , as previously describedClinical characteristics and demographics of the study participants were summarized as the median and interquartile range for continuous variables and as proportions for categorical variables. To compare data between groups, Welch's t-test and Fisher's exact test were used for continuous and categorical variables, respectively. A p-value < 0.05 was considered statistically significant.limma R package156. A fold change ≥ 1.25 and a false discovery rate adjusted p-value  < 0.1 were used to determine statistical significance. The results of differential expression analysis were summarized and visualized with volcano plots and heatmaps, using the R packages EnhancedVolcano157 and pheatmap158, respectively.The abundance of 1,310 proteins in the amniotic fluid was compared between samples collected from patients at term in labor and from those at term without labor by using moderated t-tests implemented in the 113. These data were used to assess cross-platform reproducibility via Spearman's correlation analysis. The correlations were visualized with scatter plots created with the R package ggplot2159.Amniotic fluid concentrations of four proteins—CXCL10, ELANE, IL-6, and SLPI—were determined previously by specific immunoassays, ELISA, or radioimmunoassay, according to the manufacturer's instructions160 to analyze the molecular signatures database (MSigDB)161 C5 sub-collection of gene sets corresponding to GO biological processes, molecular functions, and cellular components. We also performed the same analysis for the MSigDB C2 collection of canonical biological pathways curated from popular online databases, e.g., KEGG and Reactome. The analysis was restricted to gene sets with at least five genes having corresponding proteins measured on the SOMAScan platform. A q-value < 0.25 was considered statistically significant, as recommended by the authors of GSEA160. The enrichment of selected biological pathways was visualized as a gene-concept network created using the R/Bioconductor package, clusterProfiler162.All proteins were mapped to Entrez gene identifiers per the manufacturer's provided annotation. We used GSEA66. The log2 transformed relative fluorescence units reflecting the abundance of proteins encoded by these genes and measured herein with the SOMAmer assay were standardized by subtracting the mean and dividing by the standard deviation calculated from the reference (TNL) study group145. The standardized values referred to as Z-scores were then averaged and compared between groups with the Wilcoxon rank sum test. A q-value of less than 0.1 was considered significant. To obtain robust summaries of signatures, we considered only those cell types having at least five signature genes with corresponding proteins measured by the SOMAscan platform.We previously defined sets of genes as specific to a given population of cells identified by single-cell RNA-seq analyses of the placenta69 to define an amniotic fluid labor signature consisting of the top 20 proteins most increased in abundance after the onset of labor. Of these 20 amniotic fluid proteins, 15  were also measured in maternal plasma by using the SOMAScan platform (v2) . The receiver operating curve was plotted using the R package, Supplementary Information 1.Supplementary Information 2.Supplementary Information 3.Supplementary Information 4.Supplementary Information 5.Supplementary Information 6.Supplementary Information 7.Supplementary Information 8.Supplementary Information 9.Supplementary Information 10.


VGCV is approved for prophylaxis in adult KTRs at high risk for CMV disease (donor CMV-seropositive/recipient CMV-seronegative [D+/R-]); however, its use is limited by myelosuppression. LET is non-myelotoxic, does not require dose modification in renal impairment, and is approved for prophylaxis of CMV infection and disease in adult CMV-seropositive allogeneic hematopoietic stem cell transplant recipients. This randomized, double-blind, Phase 3 non-inferiority study  evaluated CMV prophylaxis with LET vs. VGCV in adult CMV D+/R- KTRs.Adult CMV D+/R- KTRs were randomized 1:1 within 7 days post-kidney transplant (KT) to receive either LET 480 mg QD (PO/IV) with acyclovir , or VGCV , through Week 28 post-KT and followed up through Week 52 post-KT. Randomization was stratified by use of lymphocyte-depleting induction immunosuppression. The primary endpoint was the proportion of participants (pts) with CMV disease adjudicated by blinded committee through Week 52 post-KT .Table 1). Drug-related adverse events (AEs) were reported in 19.9% of pts with LET and 35.0% of pts with VGCV through Week 28 post-KT. The rate of discontinuations due to an AE was 4.1% in the LET arm and 13.5% in the VGCV arm (Table 2). The incidence of neutropenia (absolute neutrophil count < 1000/µL) during the treatment phase was lower with LET than with VGCV .A total of 601 pts were randomized; 589 received ≥ 1 dose of study medication , of whom two had detectable CMV viral DNA on Day 1 and one was CMV R+ . The proportion of pts with CMV disease through Week 52 post-KT was 10.4% with LET vs. 11.8% with VGCV  KTRs through Week 52 post-KT, and led to a lower rate of myelotoxicity than VGCV.Ajit P. Limaye, MD, AiCuris: Advisor/Consultant|MedPace: Data Safety Monitoring Boards|Merck: Advisor/Consultant|Merck: Grant/Research Support|Moderna: Advisor/Consultant|Novartis: Data Safety Monitoring Boards|Sana: Advisor/Consultant Klemens Budde, MD, Abbvie: Grant/Research Support|Abbvie: Honoraria|Alexion: Grant/Research Support|Alexion: Honoraria|Astellas: Grant/Research Support|Astellas: Honoraria|Bristol Myers Squibb: Grant/Research Support|Bristol Myers Squibb: Honoraria|Chiesi: Grant/Research Support|Chiesi: Honoraria|CSL Behring: Grant/Research Support|CSL Behring: Honoraria|Fresenius: Grant/Research Support|Fresenius: Honoraria|Hansa: Grant/Research Support|Hansa: Honoraria|Hexal: Grant/Research Support|Hexal: Honoraria|Hookipa Biotech: Grant/Research Support|Hookipa Biotech: Honoraria|Merck Sharp & Dohme: Grant/Research Support|Merck Sharp & Dohme: Honoraria|Novartis: Grant/Research Support|Novartis: Honoraria|Otsuka: Grant/Research Support|Otsuka: Honoraria|Pfizer: Grant/Research Support|Pfizer: Honoraria|Roche: Grant/Research Support|Roche: Honoraria|Sandoz: Grant/Research Support|Sandoz: Honoraria|Shire: Grant/Research Support|Shire: Honoraria|Siemens: Grant/Research Support|Siemens: Honoraria|Takeda: Grant/Research Support|Takeda: Honoraria|Veloxis: Grant/Research Support|Veloxis: Honoraria|Vitaeris: Grant/Research Support|Vitaeris: Honoraria Atul Humar, MD, MSc, FRCPC, Merck: Advisor/Consultant|Merck: Grant/Research Support|Roche: Grant/Research Support|Takeda: Advisor/Consultant Julia Garcia-Diaz, MD, Astellas Pharma US, Inc.: Advisor/Consultant|Astellas Pharma US, Inc.: Speaker's Bureau Robert P. Carroll, BM BCh (Oxon), FRACP, DM (Oxon), Bristol Myers Squibb: Grant/Research Support|HANSA Biopharma: Advisor/Consultant Yoshihiko Murata, MD, PhD, Former employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.,: Stocks/Bonds Valerie L. Teal, MS, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.,: Current Employee|Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.,: Stocks/Bonds Christopher L. Gilbert, n/a, Current employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.,: Stocks/Bonds Barbara A. Haber, MD, Current employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co.,: Stocks/Bonds.


Little data exist on the time spent by emergency department (ED) personnel providing intravenous (IV) fluid to ‘responsive’ versus ‘unresponsive’ patients.∆) during the PC. The duration, in minutes, of each bag of IV fluid administered was recorded.A prospective, convenience sample of adult ED patients was studied; patients were enrolled if preload expansion was indicated for any reason. Using a novel, wireless, wearable ultrasound, carotid artery Doppler was obtained before and throughout a preload challenge (PC) prior to each bag of ordered IV fluid. The treating clinician was blinded to the results of the ultrasound. IV fluid was deemed ‘effective’ or ‘ineffective’ based on the greatest change in carotid artery corrected flow time  were ‘effective’, comprising 51.7 L of IV fluid, whereas, 32 (37%) were ‘ineffective’ comprising 30 L of IV fluid. 29.75 total hours across all 51 patients were spent in the ED providing IV fluids categorized as ‘ineffective.’53 patients were recruited and 2 excluded for Doppler artifact. There were 86 total PCs included in the investigation comprising 81.7 L of administered IV fluid. 19,667 carotid Doppler cardiac cycles were analyzed. Using ccFTWe report the largest-known carotid artery Doppler analysis  in ED patients requiring IV fluid expansion. A clinically significant amount of time was spent providing physiologically ineffective IV fluid. This may represent an avenue to improve ED care efficiency. As a concept, fluid responsiveness has grown and evolved over the last 20 years –3. At itmore IV fluids without any patient-centered improvement [Despite the aforementioned physiological rationale for individualizing IV fluid therapy, there is little and conflicting data supporting better outcome with this paradigm, especially in the emergency department (ED) . For exarovement , 17. Improvement .unresponsive rates . Simila.e., 21%  and in A.e., 21%  trials. .e., 21% . Therefo∆) and stroke volume (SV∆) using this device [∆ could accurately detect SV∆ in undifferentiated shock [∆ during a preload challenge prior to each bag of IV fluid and with the treating clinician blind to the results of the Doppler ultrasound.With the above, the STudying the Over-Prescription of IV FLuids via an ObservatiOnal Doppler INvestiGation (STOP-FLOODING) was designed and completed as a pilot study in a community ED. Our primary goal was to quantify the burden of fluid unresponsiveness early in ED care; our secondary goal was to calculate the time spent providing physiologically ineffective IV fluid. These objectives were accomplished using a novel, wireless, wearable Doppler ultrasound system . We haves device , 21. Fured shock . TherefoA prospective, convenience sample of adult patients presenting to a single community ED in Peoria, Illinois, U.S.A. was studied. The patients were enrolled between February and April 2022. The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments. Patients or their legal representative provided written, informed consent and the study was approved by the Peoria Institutional Review Board (# 1697834-5).Adult patients were enrolled if the treating clinician determined that IV fluid expansion would be beneficial for any indication. Patients were excluded if they were not at least 18 years old, if they did not provide informed consent, if they were unable to cooperate with a Doppler ultrasound assessment of the carotid artery  or if there were anatomical contraindications precluding assessment of at least one carotid artery .Prior to each IV fluid bag of at least 500 mL, 30–60 s of resting carotid Doppler was recorded using a wireless, wearable Doppler ultrasound . The wearable Doppler system automatically traces the maximum velocity envelope of the carotid artery Doppler pulse and calculates the corrected flow time (ccFT) by the equation of Wodey –23 Fig.. ImmediaThe RFC consisted of the first 250 mL of the fluid bag delivered at a rate of at least 100 mL/min –26. This∆. The number of cardiac cycles averaged before and during preload augmentation was dictated by the coefficient of variation of the ccFT to ensure change could be detected with statistical confidence [The Doppler spectra were analyzed for the absolute and % ccFTnfidence . The assAfter completing the PC by either RFC or PLR, IV fluid was infused at the discretion of the treating clinician. For example, if a patient was ordered for 1.5 Liters (L) of IV fluid, 2 PCs were performed, 1 prior to the 1-L bag and 1 prior to the 500-mL bag. If the PCs were accomplished by RFC, the first 250 mL of each bag were infused into the patient at 100 mL/min with carotid Doppler recording  and the remainder of each bag continued at any rate with no Doppler recording . If instead, PLR was chosen as the PC, then the patient would have also received 2 PLRs (1 prior to the 1-L bag and 1 prior to the 500-mL bag) with carotid Doppler recording only during the PLR  but not during fluid administration .Prior to and immediately after each PC, vital signs were documented, as well, the total time required for each bag of IV fluid was recorded. The total time for each bag began with the onset of the RFC (or the beginning of the infusion after the PLR) and ended when the entire bag of fluid was administered. Only IV fluid administered for resuscitation was considered in this analysis , maintenance fluids were not included.ineff) administered to these patients. The secondary outcome measure was the time spent in the ED delivering IVFineff, per patient. IVFineff was defined as any volume of fluid administered for which the antecedent PC disclosed an absolute ccFT∆ of less than + 7 ms. This was the optimal threshold for detecting a 10% SV∆ as identified by Barjaktarevic and colleagues [The primary outcome measure was the fraction of fluid unresponsive patients early in ED care and, therefore, total volume of ‘ineffective’ IV fluid , in beats per minute (bpm), and mean arterial pressure (MAP∆), in millimeters of mercury (mmHg) as calculated from immediately before to immediately after the preload challenge were compared via a 2-tailed Student’s t-test between ‘effective’ and ‘ineffective’ preload challenges as determined for the different ccFT∆ thresholds listed above, but only if determined to be normally distributed by Kolmogorov–Smirnov testing. We tested the null hypothesis that there is no difference between the HR∆ (or MAP∆) between ineffective and effective preload challenges. Lastly, using Chi-squared we tested the relationship between ‘effective’ and ‘ineffective’ preload challenges and the clinician’s use of an RFC or PLR.As exploratory analyses, the change in heart rate  were via RFC and, of these, 65 (84%) were achieved via the LifeFlow device. In total, 81.7 L of IV fluid were delivered to the 51 patients ; the average infusion duration was 67 min/L, or 97.8 min per patient, on average. The distribution of these 81.7 L into ‘effective’ or ‘ineffective’ based upon different ccFT thresholds is shown in Fig. ∆, in bpm) and change in MAP  before and after a PC for ‘effective’ and ‘ineffective’ assessments is shown in Table The relationship between change in HR , a higher, ‘fluid conservative’, ccFT∆ threshold might be employed to dichotomize fluid non-responders from responders. Future, prospective evaluations wherein these thresholds are used to guide management could resolve which is clinically superior.Lastly, and from more of a clinical-physiological perspective, we appreciate that the + 7 ms threshold has a lower sensitivity  than specificity , meaning that those marked as fluid unresponsive are more likely to be a false negative than those above this threshold are to be a false positive . This is∆ as a reference standard for determining the physiological effect of IV fluid. It might be considered that the lack of change in heart rate and blood pressure between ‘effective’ and ‘ineffective’ preload challenges , admini


LRM) could predict FR during perioperative period.Excessive or inadequate fluid administration during perioperative period affects outcomes. Adjustment of volume expansion (VE) by performing fluid responsiveness (FR) test plays an important role in optimizing fluid infusion. Since changes in stroke volume (SV) during lung recruitment maneuver (LRM) can predict FR, and peripheral perfusion index (PI) is related to SV; therefore, we hypothesized that the changes in PI during LRM /PI before LRM]*100) were obtained before and after LRM. After SV  and PI had returned to the baseline values, VE was infused, and the values of these variables were recorded again, before and after VE. Fluid responders (Fluid-Res) were defined by an increase in SV ≥10% after VE. Receiver operating characteristic curves of the baseline values and ΔPILRM were constructed and reported as areas under the curve (AUC) with 95% confidence intervals, to predict FR.Patients who were scheduled for elective non-laparoscopic surgery under general anesthesia with a mechanical ventilator and who required VE  were included. Before VE, LRM was performed by a continuous positive airway pressure of 30 cm HLRM was greater in the Fluid-Res group than in Fluid-NonRes group . After VE, only SV and cardiac index increased in the Fluid-Res group. ΔPILRM had the highest AUC [0.81 (0.66–0.97)] to predict FR with a cut-off value of 40% .Of 32 mechanically ventilated adult patients included, 13 (41%) were in the Fluid-Res group. Before VE and LRM, there were no differences in the mean arterial pressure (MAP), heart rate, SV, and PI between patients in the Fluid-Res and fluid non-responders (Fluid-NonRes) groups. After LRM, SV, MAP, and, PI decreased in both groups, ΔPILRM can be applied to predict FR in mechanical ventilated patients during the perioperative period.ΔPI Perioperative fluid administration has a crucial role during perioperative management. Both excessive –3 and inDynamic parameters such as pulse pressure variation (PPV) or stroke volume variation (SVV) predict fluid responsiveness better than static parameters such as mean arterial pressure (MAP) or central venous pressure (CVP) –13. NevePeripheral perfusion index (PI), which shows the ratio between pulsatile and non-pulsatile portions, is obtained using pulse oximetry, similar to PVI, which is a measure of the dynamic changes in PI that occur during one or more complete respiratory cycles. PI depends on SV, CO, and peripheral vascular tone , 27. The2), and pregnancy.This prospective diagnostic study was conducted in operating rooms at the Faculty of Medicine, Ramathibodi Hospital, Bangkok, Thailand, from November 2020 to April 2021. The study protocol was approved by the local ethical committee . The informed consent was obtained from each patient on the day before surgery. Patients were included if they were aged ≥18 years, were scheduled for elective non-laparoscopic surgery under general anesthesia with a controlled mechanical ventilation, and required their first VE during perioperative period. We excluded patients who had uncontrolled hemodynamic status , 30, int2O, respiratory rate that was adjusted to obtain an appropriate end-tidal carbon dioxide (EtCO2) amount between 30 and 35 mmHg, and an inspiratory oxygen fraction (FiO2) was set to achieve an SpO2 of at least 95%.After anesthesia induction, an endotracheal tube and arterial catheter were placed in all included patients. The dose or type of anesthesia agents and an anesthesia mechanical ventilator were managed by the attending anesthesiologists. An anesthesia machine ventilator was set to achieve a low tidal volume , positive end-expiratory pressure (PEEP) of 3–5 cm H2, and SpO2 (measured by pulse oximetry), were monitored during the perioperative period. VE, defined as 250 mL of crystalloid solution infusion over 10 min, was decided by the attending physicians. Esophageal Doppler probe  and PI (on the third or fourth finger) were placed before the initiation of LRM until the end of VE. The esophageal Doppler probe was positioned to attain the best aortic blood velocity signal. LRM had been performed before surgery began and thus with closed abdomen by applying a continuous positive airway pressure (CPAP) of 30 cm H2O for 30 s before VE was infused. Systolic blood pressure (SBP), diastolic blood pressure (DBP), MAP, CO, SV, PVV, SVV, PVI, and PI were obtained before LRM as the first baseline values (T1) and after LRM (T2). After SV and PI returned to their baseline values (variations <10%), hemodynamic variables and PI were obtained as the second baseline values (T3); then, VE was infused and these hemodynamic variables and PI were recorded immediately after VE (T4) /SVT1)*100Relative change of SV (ΔSVLRM) = ([COT1- COT2]/COT1)*100Relative change of CO (ΔCOLRM) = ([MAPT1- MAPT2]/MAPT1)*100Relative change of MAP (ΔMAPLRM) = ([PPVT2- PPVT1]/PPVT1)*100Relative change of PPV (ΔPPVLRM) = ([PVIT2- PVIT1]/PVIT1)*100Relative change of PVI (ΔPVIBefore (T3) vs. after VE (T4)VE) = ([SVT4-SVT3]/SVT3)*100Relative change of SV (ΔSVVE) = ([COT4- COT3]/COT3)*100Relative change of CO (ΔCOVE) = ([MAPT4- MAPT3]/MAPT3)*100Relative change of MAP  ≥10% after VE. All the patients were included once.SV, SVV, and CO were derived from the esophageal Doppler. PPV was derived from the PhilipsTM R2–25 . The PI was calculated as the ratio of the pulsatile over non-pulsatile amplitudes detected by the sensor. The short-time method was used to display the PI values during LRM. A percent decrease in PI according to the LRM (ΔPILRM) was calculated using this formula:PI, a unit expressed as a percentage, was measured using a pulse oximeter, the Radical-7 Pulse CO-Oximeter device  with an adult disposable spectrophotometric sensor, ReSposableLRM) = ([PIT1- PIT2]/PIT1)*100Relative change of PI  of 1.222. The risk of alpha error at 5% and beta error at 10% were accounted for. In total, 27 patients were needed. The sample size was calculated using Obuchowski's method . Sensitivity (Sn), specificity (Sp), positive predictive value, negative predictive value, positive likelihood ratio (LR+), and negative likelihood ratio (LR-) were reported accordingly. The best cut-off value was determined by the Youden Index (Sn + Sp−1).Continuous data are expressed as the mean ± standard deviation (SD). Categorical data are expressed as counts (n) and percentages (%). The comparison of hemodynamic parameters before (T1) and after LRMs (T2) and before (T3) and after VE (T4) were performed using the paired LRM that could not determine whether the patients were fluid responders or non-responders, was constructed using two approaches. First, the bootstrap resampling of 1,000 replications was performed to identify the best cut-off point and its 95% confidence interval (CI) (representative of the gray zone). Second, the three class responses for ΔPILRM, including inclusion, inconclusion, and exclusion, were determined. Thresholds related to the Sn <90% and Sp <90% were set. Then, the remaining area was deemed inconclusive or designated a gray zone. The larger size from the two approaches was used to indicate the gray zone .The gray zone approach to identifying inconclusive ranges of ΔPIray zone , 35. CorThe baseline characteristics of the 32 patients included in this study are shown in LRM were greater in fluid responders than in non-responders . ΔSVLRM , ΔMAPLRM , ΔPVILRM , and ΔPPVLRM  did not differ between fluid responders and non-responders. Individual changes in PI and SV in fluid responders and non-responders are presented in Before LRM, there were no differences in MAP, CO, PVI, PI between fluid responders and non-responders . PVV andBefore VE, MAP, CO, SV, and HR did not differ between fluid responders and non-responders . After VLRM [0.81 (0.66–0.97)] and PPVT1 [0.82 (0.66–0.99)] showed higher AUCs than ΔCOLRM, ΔSBPLRM, ΔMAPLRM, PVIT1, and PIT1 to predict fluid responsiveness  and ΔSVLRM   , but not with ΔSVLRM.ΔPIctively) . The rel4%) SDC, . There wLRM. A decrease in ΔPILRM of <35% could guide the decision-making for fluid non-responders with a Sn ≥90%. In contrast, a decrease in ΔPILRM of more than 60% could detect fluid responsiveness with a Sp ≥90%. Over 21.9 and 50.0% of our population, respectively, could undergo guided decision-making by the ΔPILRM regarding whether to receive VE or not. However, in 28.1% of the population, this was inconclusive.In this study, we demonstrated that a reduction in PI during LRM and the baseline PPV had better ability to predict fluid responsiveness in surgical patients who underwent elective open abdominal surgery than the baseline MAP, CO, and PVI.Predicting fluid responsiveness plays an important role in optimizing perioperative fluid infusion. Inappropriate fluid administration including inadequate fluid infusion during perioperative period are related to the development of acute kidney injury or an increase in postoperative complications such as infection, which is associated with mortality –5. DynamBiais et al.  and WataLRM was related with changes in SV during LRM and after VE and ΔPILRM was a good indicator to predict fluid responsiveness in patients undergoing open abdominal surgery; similar to the baseline PPV. Therefore, these findings confirmed the use of PI to detect a change in SV during LRM or VE. Moreover, ΔPILRM can be applied in patients with mechanical ventilator who are not requiring arterial catheter to detect fluid responsiveness. Furthermore, in this study, ΔPILRM had better ability to indicate fluid responders than PVI at baseline. This finding is similar to that of a previous meta-analysis  and peripheral vasomotor tone. Thus, low PI could indicate either vasoconstriction and/or low SV , 27. Whianalysis , which rIn this study, PI did not change after VE in both fluid responders and non-responders. Ryu et al.  reportedIn fluid non-responders, PI and SV also decreased; this may be explained by the negative effect of the increase in the intrathoracic pressure during LRM on hemodynamic variables , 30 and LRM in a low tidal volume setting (6–8 mL/predicted kg). Moreover, a higher tidal volume, rather than a lower tidal volume, could emphasize the effects of LRM and thus produce a greater ΔPILRM, even in patients with good lung compliance and good transmission of pleural pressure. Therefore, confirming this hypothesis requires further investigations. Third, the sample size calculation did not take into account the accuracy of the esophageal Doppler to detect the changes in SV. Therefore, the number of participants in this study might be smaller than the actual required sample size. Fourth, an inconclusive zone of ΔPILRM between 35 and 60% needs further attention. Another test to predict fluid responsiveness is needed for these populations. Fifth, LRM in this study was performed shortly after an induction of the anesthetic agents; therefore, the effect of LRM on hemodynamic status might have been impacted by the degree of vasodilatation due to the anesthetic agents. Nevertheless, fluid administration in patients with various vasoplegia during anesthetic period should be based on clinical decision.Our study also had some limitations. The first related to the esophageal Doppler technique. The cross-sectional area of the descending aorta was not applied in our technique. Therefore, this could lead to an underestimation of SV . AlthougDespite these limitations, a reduction in PI after LRM obtained non-invasively by pulse oximetry can be applied as an indicator to predict fluid responsiveness in patients undergoing abdominal surgery, similar to the baseline PPV.The original contributions presented in the study are included in the article/http://www.thaiclinicaltrials.org/show/TCTR 20201202001), on 2 December 2020. The patients/participants provided their written informed consent to participate in this study.The study protocol was approved by the Institutional Review Board of Human Research Ethics Committee of the Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand (COA. MURA2020/1844). The study was registered with the Thai Clinical Trials Registry, code TCTR20201202001 (SM and NP created the conception and designation of the study. PPer wrote and submitted the proposal. PPer and SM obtained the data. NP, SM, PPin, and KT analyzed and interpreted the results. PPer and PPin drafted the work. NP, SM, WM, and KT substantively revised the manuscript. SM provided the greatest contribution to the study. All authors read and approved the final version of the manuscript.Grant support for the study was provided by the Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. The funder had no role in the study design, data collection, analysis, interpretation of the data, and preparation of the manuscript. In addition, all equipments in this study were provided by the Department of Anesthesiology, Faculty of Medicine Ramathibodi Hospital.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.


In addition, there was an increasing trend in the proportion of female and young adults (18–35 years old) mentioning quitting vaping on Twitter after the announcement and implementation of the policy compared to that before the policy. Our results showed that the FDA flavor enforcement policy did have a positive impact on quitting vaping on Twitter. Our study provides an initial evaluation of the potential influence of the FDA flavor enforcement policy on user vaping behavior.In January 2020, the FDA announced an electronic cigarette (e-cigarette) flavor enforcement policy to restrict the sale of all unauthorized cartridge-based flavored e-cigarettes except tobacco and menthol flavors, which was implemented on 6 February 2020. This study aimed to understand the potential influence of this policy on one vaping behavior change—quitting vaping—using Twitter data. Twitter posts (tweets) related to e-cigarettes were collected between June 2019 and October 2020 through a Twitter streaming API. Based on the geolocation and keywords related to quitting vaping, tweets mentioning quitting vaping from the US were filtered. The demographics (age and gender) of Twitter users who mentioned quitting vaping were further inferred using a deep learning algorithm (deepFace). The proportion of tweets and Twitter users mentioning quitting vaping were compared between before and after the announcement and implementation of the flavor policy. Compared to before the FDA flavor policy, the proportion of tweets (from 0.11% to 0.20% and 0.24%) and Twitter users (from 0.15% to 0.70% and 0.86%) mentioning quitting vaping were significantly higher after the announcement and implementation of the policy ( Electronic cigarettes (e-cigarettes) are one of the tobacco products that release aerosols by heating a liquid including propylene glycol or glycerol, nicotine, and flavoring chemicals . E-cigarWhile long-term health effects of e-cigarette use await further investigation, recent studies showed several health effects associated with e-cigarette use, including respiratory symptoms or diseases, cardiovascular diseases, and cognitive defects ,12,13,14The appeals of various flavors have been identified as one of the major reasons for attracting youth to e-cigarette use ,19. In rTwitter, a popular social media platform in the United States, has been used to examine public perceptions of flavored e-cigarettes and identify topics discussed about e-cigarettes ,22,23,24In this study, using Twitter data, we aimed to investigate the potential impact of the FDA flavor enforcement policy on one e-cigarette use behavior change—quitting vaping—by applying natural language processing techniques. Using a deep learning algorithm, we inferred demographic characteristics such as the age and gender of Twitter users who mentioned quitting vaping and examined their changes with the announcement and implementation of the FDA flavor enforcement policy.Twitter data on e-cigarettes were collected between June 2019 and October 2020 using a Twitter streaming application programming interface (API) with e-cigarette related keywords, including “e-cig”, “e-cigs”, “ecig”, “ecigs”, “electroniccigarette”, “vape”, “vapers”, “vaping”, “vapes”, “e-liquid”, “ejuice”, “eliquid”, “e-juice”, “vapercon”, “vapeon”, “vapefam”, “vapenation”, and “juul” . FurtherTo filter the tweets that mentioned quitting vaping, we employed frequent itemset mining to identify the list of relevant keywords. We utilized the FP-growth (frequent pattern growth) algorithm to perform the task of frequent itemset mining. First, we substituted all punctuation with spaces, then tokenized each transaction by space. Furthermore, we removed stop words, including but not limited to “I”, “is”, “are”, “do”, “we”, “it”, “in”, “on”, “at”, “to”, and “the”. Then, we updated the list with more irrelevant words and characters by lowering the support threshold and association rule probability threshold. In the end, the support threshold was set to 1000, and the association rule probability threshold was set to 0.30. The terms “stop” and “vaping” have a support of 2037 and an association rule probability of 0.53, The terms “quit” and “vaping” have a support of 2459 and an association rule probability of 0.30. Thus, we decided to use “stop” and “quit” and their variants as keywords to identify tweets mentioning quitting vaping because they have the highest support within the dataset and the highest association with “vaping”. To compare the proportion of tweets and Twitter users mentioning quitting vaping between different periods, the two-proportion Z test was conducted with a significance level set at 5%.We employed deepFace, a deep learning facial recognition algorithm, to obtain an inference of the age and gender of Twitter users . The deep-value < 0.001. Furthermore, we compared the number of unique Twitter users who mentioned quitting vaping between different periods . In addition, as shown in While we observed that the proportion of Twitter users who mentioned quitting vaping significantly increased with the announcement and implementation of the FDA flavor enforcement policy, it is very important to understand the demographic characteristics of Twitter users who mentioned quitting vaping with the announcement and implementation of the FDA flavor enforcement policy. Among 2149 unique Twitter users who mentioned quitting vaping in our study, 220 of them (10.24%) could be inferred in terms of their age and gender. As shown in In this study, using Twitter data, we showed that the proportion of US Twitter users mentioning quitting vaping significantly increased after the announcement and implementation of the FDA flavor enforcement policy. Furthermore, we showed that females and young adults were slightly more likely to mention quitting vaping on Twitter after the announcement and implementation of the FDA flavor enforcement policy.The objective of any tobacco product policy or ban is to reduce or prevent the use of targeted tobacco products. One previous study showed that with the FDA menthol cigarette ban in 2009, among US tobacco users about 25–64% would attempt to quit smoking and 11–46% would consider switching to other tobacco products . AnotherIn this study, we showed there was a significant increase in mentioning quitting vaping on Twitter after the announcement and implementation of the FDA flavor enforcement policy, suggesting that the FDA flavor enforcement policy had some positive effects on one user behavior change: quitting vaping. While more studies with a large sample size are needed to further validate our findings, our study showed some preliminary but valuable evidence about the potential impacts of the FDA flavor enforcement policy on one user vaping behavior change, which provides useful guidance for future tobacco regulatory policymaking.There were several limitations in this study. First, only Twitter data were used to investigate the influence of the FDA flavor enforcement policy, whereas Twitter users cannot represent the general population. In addition, Twitter is not the most popular social media platform among young people. Therefore, our findings might not apply to adolescents. Based on a previous study on Twitter users’ geographical locations , people Our results provided valuable information about the potential influence of the FDA flavor enforcement policy on quitting e-cigarette use on Twitter, which provides valuable feedback on the FDA flavor enforcement policy.


Appropriate diagnostic testing can be used to inform infection control measures and reduce SARS-CoV-2 transmission, yet the test kinetics, infectivity, and immunological responses during acute, non-severe SARS-CoV-2 infection need clarity.We conducted a prospective cohort study between Nov 2020-July 2021 in Seattle, Washington of 95 unvaccinated, immunocompetent adults with no prior SARS-CoV-2 infection. Nasal swabs  and blood serum samples were serially collected at six visits over two months. Viral RNA, N and S antigen concentrations, and viral growth/infectivity were measured from nasal samples. Anti-S total antibody and IgG assays were performed on serum. We fit loess curves to quantitative data corresponding to each testing modality by days since symptom onset (DSSO) and compared qualitative test results across time points to demonstrate time-dependent agreement of PCR, N antigen, and culture results. Generalized estimating equations were used to approximate relative risk of culture positivity (a proxy for infectiousness) for positive vs. negative test results (antigen and PCR), stratified by presence/absence of symptoms and DSSO.Sampling SchemaNasal swabs and venous blood were collected at visits 1-4; venous blood only at visits 5-6. All participants were enrolled within 14 days of symptom onset (median: 6) and 7 days of a positive test (median: 4).Infections in this cohort (median age: 29y) were mild . Median (IQR) time to negative result was 11 (4), 13 (6), and 20 (7) DSSO for culture growth, N antigen, and PCR tests, respectively. Viral RNA quantities declined more slowly than antigen and culturable virus; antibody titers rose rapidly 5-15 DSSO and plateaued 20-30 DSSO. All culture-positive samples collected 0-5 DSSO were positive by PCR, but relative risk of culture positivity (infectiousness) for positive vs. negative PCR results declined 6-10 DSSO. Relative risk of culture positivity for positive vs. negative antigen results was consistently high 0-10 DSSO, with similar results when stratified by presence of symptoms.Diagnostic test kinetics and immunological responsesDiagnostic test kinetics and immunological responses measured in adults with non-severe, symptomatic SARS-CoV-2 infection: loess trendlines and 95% confidence intervals are given for SARS-CoV-2 viral load , TCID50 from viral culture, mean concentrations of nucleocapsid and spike antigen proteins, and anti-S total and IgG antibody concentrations.The results reinforce the importance of molecular PCR testing as a highly sensitive diagnostic tool but with limited utility as an indicator of viral culturability and likely infectiousness. N antigen testing may be a preferable diagnostic test within two weeks of symptom onset, especially 6-10 DSSO, because it more closely correlates with culture growth over the course of infection.Daphne Hamilton, BA, Roche (spouse is employed by Roche): Employee Alexander L. Greninger, MD, PhD, Abbott: Contract Testing|Cepheid: Contract Testing|Gilead: Grant/Research Support|Gilead: Contract Testing|Hologic: Contract Testing|Merck: Grant/Research Support|Novavax: Contract Testing|Pfizer: Contract Testing Geoffrey S. Gottlieb, MD, PhD, Abbott Molecular Diagnostics: Grant/Research Support|Alere Technologies: Grant/Research Support|BMGF: Grant/Research Support|BMS: Grant/Research Support|Cerus Corp.: Grant/Research Support|Gilead Sciences: Grant/Research Support|Janssen Pharmaceutica: Grant/Research Support|Merck & Co: Grant/Research Support|Roche Molecular Systems: Grant/Research Support|THERA Technologies/TaiMed Biologics: Grant/Research Support|ViiV Healthcare: Grant/Research Support.


Abundant oil and gas reserves have been proved in carbonates, but formation damage affects their production. In this study, the characteristics and formation-damage mechanism of the carbonate reservoir formation of the MS Oilfield in the Middle East were analyzed—utilizing X-ray diffraction, a scanning electron microscope, slice identification, and mercury intrusion—and technical measures for preventing formation damage were proposed. An ‘improved ideal filling for temporary plugging’ theory was introduced, to design the particle size distribution of acid-soluble temporary plugging agents; a water-based drill-in fluid, which did not require gel-breaker treatment, was formed, and the properties of the drill-in fluid were tested. The results showed that the overall porosity and permeability of the carbonate reservoir formation were low, and that there was a potential for water-blocking damage. There were micro-fractures with a width of 80–120 μm in the formation, which provided channels for drill-in fluid invasion. The average content of dolomite is 90.25%, and precipitation may occur under alkaline conditions. The polymeric drill-in fluid had good rheological and filtration properties, and the removal rate of the filter cake reached 78.1% in the chelating acid completion fluid without using gel breakers. In the permeability plugging test, the drill-in fluid formed a tight plugging zone on the surface of the ceramic disc with a pore size up to 120 μm, and mitigated the fluid loss. In core flow tests, the drill-in fluid also effectively plugged the formation core samples by forming a thin plugging layer, which could be removed by the chelating acid completion fluid, indicated by return permeability higher than 80%. The results indicated that the drill-in fluid could mitigate formation damage without the treatment of gel breakers, thus improving the operating efficiency and safety. A large number of oil and gas reserves are in carbonate formations. It is reported that the oil and gas production of carbonate reservoirs accounts for about 60% of the total oil and gas production in the world . At presOil and gas resources in the Middle East are extremely rich, and the main target reservoir formation of some oil fields is subsalt carbonate formations. The MS Oilfield is a large oilfield identified in this area, and the main reservoir is the carbonate formation. In preliminary explorations, the test production was far lower than expected, indicating serious reservoir formation damage during drilling and completion operations. The damage of such reservoir formations can be generated by multiple sources . The mecIn order to effectively clean the borehole during drilling in the reservoir formation, high-molecular-weight polymers are required in drill-in fluids, including xanthan gum, polyanionic cellulose, and polyacrylamide ,22,23,24This study aimed to systematically analyze reservoir characteristics and formation-damage mechanisms, and to optimize a low-damage drill-in fluid to mitigate formation damage in drilling and completion operations, thus helping to fully release the productivity in the subsequent production operations. Firstly, the mineral composition was analyzed. The results for the mineral composition of reservoir core samples at different depths are shown in Secondly, the microstructure of the reservoir rocks was observed. SEM photographs of reservoir rock samples are shown in Thirdly, the porosity and permeability characteristics were measured. The results of mercury injection analysis and gas permeability analysis of reservoir rock samples at different depths are shown in Based on the above experimental results, the mechanism and control strategy of the formation damage was analyzed as follows.(1)The micro-fractures in the formation provided a natural channel for solids and filtrates of drilling fluids to invade the formation, and even lost circulation of drilling fluids could occur, causing serious formation damage. In accordance with the size of the micro-fractures in the reservoir formation, it was necessary to select a temporary plugging agent that could be subsequently removed, and to reasonably design the particle size gradation, in order to achieve effective temporary plugging of the micro-fractures in the process of drilling in the reservoir formation, thus preventing formation damage caused by drilling-fluid invasion;(2)Because of the low porosity and permeability of the reservoir formation, the main seepage channels were micro-fractures and micro-throats, which caused high irreducible water saturation of the reservoir rock ,14. As a(3)2, as shown in Equation (1) [From the point of view of mineral composition, the reservoir rock was mainly composed of dolomite, which could react with alkali liquor to produce a new mineral phase Mg(OH)tion (1) . The minFirstly, the optimization design of the temporary plugging agent was performed.Dmax was the maximum particle diameter, fD was the maximum fracture opening, m; and q was the empirical coefficient, generally 1/3–1/2, and 5/12 in this study.In accordance with the ‘ideal filling’ theory and D90 criterion , the calP(nD) was the cumulative mass fraction of particles smaller than nD, %; and V(nD) was the mass fraction of particles in a range of particle diameters nD−1 to nD, %.Based on the Horsefield theory, the optimal particle size of multi-stage close packing could be obtained . This thAccording to the maximum fracture opening (120 μm) of the reservoir formation, the suitable particle size gradation of the temporary plugging agent could be calculated based on the above equations, as shown in Based on the control strategy for the formation damage, and considering the comprehensive properties of the drill-in fluid—rheological and filtration properties, lubricity, etc.—the formula of the water-based drill-in fluid was formed: water + 1.6 wt.% FLO (filtrate reducer) + 0.5 wt.% modified xanthan gum (viscosifier) + 0.5 wt.% PAC (filtrate reducer) + 3 wt.% KCl  + 6.5 wt.% acid-soluble temporary plugging agent + 1 wt.% JLX (lubricant) + 0.3 HAR (anti-water-blocking agent). The density of the drill-in fluid was adjusted by sodium formate, and the pH value was adjusted by NaOH to 9.5.The basic properties of the drill-in fluid before and after 16 h hot rolling at 120 °C were tested, and the results are shown in 2+ and shale cuttings; thus, 1 wt.% CaCl2 and 8 wt.% bentonite were added to the drill-in fluid, and the rheological property and filtrate loss of the drill-in fluid were tested after hot rolling at 120 °C for 16 h. 2; after being contaminated by 8 wt.% bentonite, the viscosity and yield point increased, but no serious thickening occurred, and the filtration loss remained stable. Therefore, the drill-in fluid had good Ca2+ and shale cuttings tolerance performance, and could meet the actual drilling requirements.Because there were shale interlayers and anhydrite in the reservoir formation, the drill-in fluid was required to have good tolerance to CaIn plugging performance tests, a ceramic disc with a pore throat diameter of 120 μm was used to simulate the formation fractures, and the plugging performance of the optimized drill-in fluid was evaluated. The results show that, under conditions of 120 °C and 7 MPa, the fluid loss volume was only 4. 8 mL in 30 min. By comparison, the fluid loss of the drill-in fluid designed according to the traditional particle size gradation design criterion was 18.2 mL, and the drill-in fluid without temporary plugging agents was completely lost. After the experiment, the ceramic disk was dried, and observed by SEM ; it can The removal effects of the filter cake of the drill-in fluid in the HTA completion fluid, and in the non-acid gel breaker #1, the non-acid gel breaker #2, and the GPC gel-breaker solutions, are shown in The experimental results of the static and dynamic damage experiments with the reservoir formation core samples are shown in In order to efficiently develop the targeted carbonate reservoirs, the formation damage-mechanism was investigated, and a suitable drilling fluid was developed. The conclusions of this study are as follows.A comprehensive analysis of the reservoir cores showed that the overall porosity and permeability of the carbonate reservoirs in the MS Oilfield in the Middle East were low, and that micro-fractures had developed. The reservoir rocks were mainly composed of dolomite, with a very low content of clay minerals. The main formation damage mechanisms were as follows: the micro-fractures provided channels for the invasion of drilling fluid solids and filtrate; in the formation, there existed potential water-blocking damage; the dolomite reacted with alkaline working fluid, to form precipitation.2 and 8 wt.% bentonite contaminations. The filter cake could be effectively removed from the HTA completion fluid without gel breakers, which was beneficial to improving operating efficiency and safety. The drill-in fluid could form a tight temporary plugging layer on the surface of the ceramic disc, with pore throat size up to 120 μm, thus reducing the invasion of drill-in fluid into the reservoir formation. Static and dynamic damage experiments showed that the drill-in fluid effectively formed a thin temporary plugging layer on the surface of the core samples, which could be removed by acid completion fluid or subsequent acidification, to release the oil productivity.Based on the size of the reservoir formation fractures, and the ‘improved ideal filling for temporary plugging’ theory, the particle size distribution of the acid-soluble temporary plugging agent was determined, and a drill-in fluid suitable for carbonate reservoir formation was optimized. The drill-in fluid had good rheological and filtration properties, and could tolerate 1 wt.% CaClThe reservoir formation rock samples were obtained from the MS Oilfield, and the depth was 2976–3030 m. The additives of the drill-in fluid and completion fluid—which included modified xanthan gum, modified starch (FLO), polyanionic cellulose (PAC-LV), polymeric alcohol (JLX), fluorocarbon surfactant (HAR), acid-soluble temporary plugging agent, sodium formate, chelating acid (HTA), and corrosion inhibitor (CA101)—were supplied by China Oilfield Services . The non-acid gel breakers were supplied by Land Co. Ltd .API) of the drilling fluid was measured by a ZNS-2A filtration apparatus  at 25 °C and 0.7 MPa for 30 min. The permeability plugging apparatus was used to evaluate the plugging performance of the drill-in fluid during drilling [The reservoir formation core samples were analyzed using the following methods. Mineral compositions of reservoir rocks were analyzed with an X’Pert Pro MPD X-ray diffractometer  . The micdrilling . Then, 3The removal efficiency of the filter cakes after gel breaking was tested as follows. The filter cake was obtained by an API filtration test with the drill-in fluid. The filter cake was dried to a constant weight, and the mass of the filter cake was accurately measured. After that, the filter cake was placed in a gel-breaker solution, or a completion fluid at 90 °C, for standing for different times, and the residual filter cake, after soaking, was taken out, dried, and weighed. The ratio of the mass difference of the filter cake before and after soaking, to the mass of the original filter cake, was the removal rate of the filter cake.According to SY-T/6540-2002, ‘Lab testing method of drilling and completion fluids damaging oil formation’ , the dam


Analysis of broad-spectrum antibiotic use in pneumonia revealed that 60% of patients were overtreated, highlighting the need for effective antibiotic stewardship practices.Systems such as the Drug Resistance in Pneumonia (DRIP) score select patients who are more likely to need broad spectrum antibiotics but still leads to overtreatment as it does not target specific pathogens. Rapid diagnostics such as the Unyvero Lower Respiratory Tract Panel (LRTP) can identify specific pathogens to narrow antibiotic use even further when combined with the DRIP score.max and DRIPmin were calculated assuming all missing elements were positive or negative respectively. The sensitivity and specificity of the DRIP score vs culture and LRTP were determined. An algorithm for antibiotic selection based on the results of the DRIP score combined with the LRTP was applied to each patient  .Using an existing patient pool from a clinical trial of the LRTP (NCT01922024) a DRIP score was determined for each patient. When data elements of the DRIP score were unavailable a DRIPStenotrophomonas maltophilia Applying the algorithm to each patient based on the DRIP score and the LRTP improved antibiotic choices by reducing broad spectrum antibiotic and by more selectively targeting the identified pathogens earlier and eliminating use of multiple empiric antibiotics.The sensitivity of the DRIP score vs culture in this population was 91.2% and the specificity was 65.1%. DRIP score vs culture + LRTP combined had a sensitivity of 86.6% and a specificity of 66.3%., the lower sensitivity was mainly due to Using an antibiotic stewardship algorithm combining DRIP score with LRTP rapid diagnostic data, which results in 5 hours, can lead to improved prediction of the presence of drug resistant pathogens and aid in narrowing antibiotics. The LRTP compensates for the DRIP score only predicting presence of antibiotic resistant pathogens, not specific pathogens. The DRIP score can compensate for the LRTP only having limited antibiotic resistance markers on panel and not supplying phenotypic antibiotic resistance testing. Further study using a prospectively collected cohort with antibiotic adjustment in real time is needed for validation of our results.Matthew Sims, MD PhD, Astra Zeneca: Grant/Research Support|ContraFect: Grant/Research Support|Crestone: Grant/Research Support|Diasorin Molecular LLC: Grant/Research Support|Epigenomics Inc: Grant/Research Support|EUROIMMUN US: Grant/Research Support|Finch Theraputics: Grant/Research Support|Genentech USA Inc: Grant/Research Support|Janssen Research and Development LLC: Grant/Research Support|Kinevant Sciences GmBH: Grant/Research Support|Leonard-Meron Biosciences: Grant/Research Support|Lysovant: Grant/Research Support|Merck: Grant/Research Support|OpGen: Grant/Research Support|Prenosis: Advisor/Consultant|Prenosis: Grant/Research Support|Qiagen: Grant/Research Support|Regeneron Pharmaceuticals: Grant/Research Support|Seres Therapeutics Inc: Grant/Research Support|Shire: Grant/Research Support|Summit Therapeutics: Grant/Research Support.


Respiratory syncytial virus (RSV) is a major cause of infant morbidity and mortality worldwide and could be preventable by vaccination in pregnancy.We conducted a randomized, placebo-controlled phase 2b trial evaluating safety, immunogenicity, and potential efficacy of a bivalent RSV prefusion F vaccine (RSVpreF) in pregnant women and their infants. Participants were randomized between 24- and 36-weeks’ gestation to receive 120 or 240 µg RSVpreF, with or without aluminum hydroxide, or placebo.This final analysis includes 579 women and 572 infants in 4 countries ; 462 (79.8%) women received RSVpreF. Postvaccination reactions, most commonly injection site pain, fatigue, and myalgia, were generally mild-to-moderate. Adverse events (AEs) in the month following vaccination  or birth (infant) were mostly anticipated events in pregnancy and the neonatal period, respectively, and were similar between vaccine and placebo groups. No AEs were considered related to vaccination.For all RSVpreF groups, 50% neutralizing titers for both RSV-A and RSV-B rose sharply by 2 weeks after vaccination. At delivery occurring a mean of ∼8 weeks later, geometric mean titer (GMT) ratios for combined RSV-A/B between vaccine and placebo recipients’ infants were 10.9 to 13.6. Transplacental transfer ratios  were 1.39 to 1.83. Infant GMTs were higher in infants whose mothers had received RSVpreF versus placebo through 6 months of life; the estimated half-life of infant combined 50% RSV-A/B neutralizing titers was 41 days. Infants of women immunized across the range of assessed gestational ages had similar cord blood titers and transplacental transfer ratios. Observed efficacy (95% CI) against medically attended and severe medically attended infant RSV lower respiratory tract illness (LRTI) through 180 days in an exploratory analysis was 84.7%  and 91.5% , respectively.RSVpreF was well-tolerated in pregnant women, elicited robust neutralizing responses with efficient transplacental transfer, and has the potential to prevent infant RSV LRTI.Eric A. F. Simões, MD, M.B., B.S., DCH, Abbvie: DSMB|Astra Zeneca: Grant/Research Support|Bill and Melinda Gates Foundation: Grant/Research Support|Bill and Melinda Gates Foundation: DSMB|GSK Inc.: DSMB|Johnson and Johnson: Grant/Research Support|Merck Inc: Advisor/Consultant|Merck Inc: Grant/Research Support|Nivavax: Grant/Research Support|Pfizer Inc: Advisor/Consultant|Pfizer Inc: Grant/Research Support|Regeneron: Grant/Research Support|Sanofi Pasteur: Advisor/Consultant Shabir A. Madhi, MBBCh, FCPaeds, MMed, PhD, AstraZeneca: Funding to institution for conduct of study Kimberly J. Center, M.D., Pfizer: Employee|Pfizer: Stocks/Bonds Jose M. Novoa Pizarro, MD, AstraZeneca: Grant/Research Support|Medimmune: Grant/Research Support|MSD: Grant/Research Support|Pfizer: Grant/Research Support|Regeneron: Grant/Research Support Kena A. Swanson, Ph.D., Pfizer: employee of Pfizer David Radley, MS, Pfizer: Employee|Pfizer: Stocks/Bonds Stephanie B. McGrory, B.S.N., Pfizer: Employee|Pfizer: Stocks/Bonds Emily A. Gomme, Ph.D., Pfizer: Stocks/Bonds Daniel A. Scott, MD, Pfizer: Employee|Pfizer: Stocks/Bonds Kathrin U. Jansen, PhD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds William C. Gruber, MD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Alejandra C. Gurtman, M.D., Pfizer: employee of Pfizer.


Some years ago, I went to an art exhibition in Barcelona that posed an interesting question to other artists as well as the viewing public. Are contemporary artists sufficiently ambitious? The conclusion of those organizing the exhibition was negative. The kind of ambition they were concerned with was not about becoming famous or rich, but rather about achieving something of real and enduring value that was aimed at revealing something fundamental about ourselves and our relationships with others as well as nature. The towering achievements of, for example, Michelangelo, Raphael, Rembrandt, and Titian, revealing humanity’s deepest emotions and relationships, are certainly difficult to compare with, for example, Claes Oldenburg’s displays of gigantic toilet seats and kitchen sinks, or Damien Hirst’s preserved carcasses.Caenorhabditis elegans as a model organism, is even more relevant to biology today.” Data are of course essential, but so are ideas, theories, and context. Data that do not lead to a theory or model, and therefore cannot be used to make predictions that can be tested, do not represent useful knowledge.In preparation for the celebration early next month of the centenary of the award of the Nobel Prize in Physics to Niels Bohr, arranged by the Royal Danish Academy of Sciences and Letters of which I am a member, I have been wondering whether the worries about lack of real ambition by contemporary artists might also be relevant to science. The Nobel Laureate Paul Nurse recently recollected a warning from Sydney Brenner, expressed when he received his Nobel Prize, about biologists “drowning in a sea of data and starving for knowledge.”J Physiol in 1952, were collected in just 1 mo in the summer of 1949. The next 2 yr were spent on analysis, model building, and formulation of equations that finally allowed the reconstruction of the nerve action potential, demonstrating that the theory could predict correctly its precise shape and time course.Alan Hodgkin understood this point better than most. In his Annual Review Prize Lecture, delivered at the Physiological Society’s centenary meeting in Cambridge in 1976, which I was privileged to attend, he recalled that virtually all the electrophysiological data from squid axons that went into the famous five Hodgkin and Huxley papers published in In today’s science world, in which the only title respected by increasingly powerful University Administrators, is “Mr or Ms Grant Holder,” the value of a scientist seems essentially to be assessed according to the size of his/her grant income. In contrast, one has the impression that there is generally little concern amongst university leaders about gaining real new knowledge. Inevitably, the primary ambition of the majority of scientists is therefore to obtain as much grant money as possible, as this is seen to be the most secure route to advancement. There is certainly little incentive to perform experiments with the cheapest possible equipment, as this would limit grant income and, most worryingly, there is little time to develop theories and new models because increasing proportions of time have to be spent on writing, and rewriting, grant applications. The absurdity of the current system is highlighted by remarks heard with increasing frequency, such as “I don’t have time to write  papers because I am too busy preparing yet another grant application.”To re-establish a focus on what really matters, namely to gain useable knowledge from data, it would seem a good idea to rethink our working and assessment culture and start by placing much more emphasis on theory and model building as well as context.