Spatial Single-cell Analysis Decodes Cortical Layer and Area Specification.

The human cerebral cortex, pivotal for advanced cognitive functions, is composed of six distinct layers and dozens of functionally specialized areas1,2. The layers and areas are distinguished both molecularly, by diverse neuronal and glial cell subtypes, and structurally, through intricate spatial organization3,4. While single-cell transcriptomics studies have advanced molecular characterization of human cortical development, a critical gap exists due to the loss of spatial context during cell dissociation5,6,7,8. Here, we utilized multiplexed error-robust fluorescence in situ hybridization (MERFISH)9, augmented with deep-learning-based cell segmentation, to examine the molecular, cellular, and cytoarchitectural development of human fetal cortex with spatially resolved single-cell resolution. Our extensive spatial atlas, encompassing 16 million single cells, spans eight cortical areas across four time points in the second and third trimesters. We uncovered an early establishment of the six-layer structure, identifiable in the laminar distribution of excitatory neuronal subtypes by mid-gestation, long before the emergence of cytoarchitectural layers. Notably, while anterior-posterior gradients of neuronal subtypes were generally observed in most cortical areas, a striking exception was the sharp molecular border between primary (V1) and secondary visual cortices (V2) at gestational week 20. Here we discovered an abrupt binary shift in neuronal subtype specification at the earliest stages, challenging the notion that continuous morphogen gradients dictate mid-gestation cortical arealization6,10. Moreover, integrating single-nuclei RNA-sequencing and in situ whole transcriptomics revealed an early upregulation of synaptogenesis in V1-specific Layer 4 neurons, suggesting a role of synaptogenesis in this discrete border formation. Collectively, our findings underscore the crucial role of spatial relationships in determining the molecular specification of cortical layers and areas. This work not only provides a valuable resource for the field, but also establishes a spatially resolved single-cell analysis paradigm that paves the way for a comprehensive developmental atlas of the human brain.

Caudal regression in fetus with de novo SMARCA2 pathogenic variant.

Nicolaides-Baraitser syndrome (NCBRS) is a rare autosomal dominant genetic condition that is characterized by severe intellectual disability, dysmorphic facial features, short stature, sparse hair, and early onset seizures. This diagnosis is established by suggestive clinical findings and the identification of a heterozygous SMARCA2 pathogenic variant by molecular genetic testing. There are not, however, consensus clinical diagnostic criteria for this condition as there are so few documented cases. Here, we present a case of prenatally diagnosed caudal regression with sacral agenesis and congenital vertical talus (rocker bottom feet) that was ultimately found to have a de novo SMARCA2 pathogenic variant. The patient had an amniocentesis with normal karyotype and microarray followed by failed direct rapid whole exome sequencing (WES) due to maternal cell contamination. She elected for termination of the pregnancy based on the clinical prognosis of the ultrasound findings; WES revealed a pathogenic variant after her termination. We believe this is the first case of these findings associated with NCBRS. If any future cases of either finding are found in association with a SMARCA2 genetic variant, caudal regression and rocker bottom feet should be included in the spectrum of physical traits associated with this pathogenic variant.

Triaging and Evaluation of Products of Conception in Abortions and Post-Partum Hemorrhage.

The proper evaluation of abortion specimens and placentas from stillbirth and post-partum cases is important for adequate clinical care of post-abortion and post-partum patients. The following topics will be reviewed: (1) the importance of evaluation of both fetal and placental tissue in first trimester abortions to confirm an intrauterine pregnancy versus an ectopic pregnancy; (2) the clinical history associated with an abortion specimen or retained products of conception (POC) influences how the pathologist should triage the specimen; (3) the criteria for diagnosis of a molar pregnancy, which is critical for clinicians to know which patients need follow-up; (4) the utility of genetic studies for both diagnosis and appropriate follow-up of the patient; and (5) the pathologic evaluation of specimens from patients with post-partum hemorrhage for placenta accreta spectrum and subinvolution of maternal vessels.

Diagnosis and Management of an Enlarging Placental Immature Teratoma: A Case Report.

The clinical imaging and pathology of a rare case of immature teratoma of the placenta is presented with a discussion of controversies related to classification and clinical suggestions for therapy and follow-up.

An Unexpected Discovery: Postmenopausal Pyloric Endometriosis.

Endometriosis is a benign, estrogen-dependent condition, usually occurring in menstruating and, rarely, in postmenopausal women, in which endometrial glands and stroma grow ectopically outside the uterus. Most often, ectopic endometrial tissue is found within the pelvis and nearby structures. However, endometrial tissue within the upper gastrointestinal tract is very rare and can be a source of bleeding and abdominal pain. Here, we report a case of a 71-year-old postmenopausal woman with hematochezia and diffuse abdominal pain, who was found to have pyloric endometriosis, the pathogenesis of which we will briefly explore.

Lifetime Exposure to Cigarette Smoke, B-Cell Tumor Immune Infiltration, and Immunoglobulin Abundance in Ovarian Tumors.

BACKGROUND: Cigarette smoke exposure has been linked to systemic immune dysfunction, including for B-cell and immunoglobulin (Ig) production, and poor outcomes in patients with ovarian cancer. No study has evaluated the impact of smoke exposure across the life-course on B-cell infiltration and Ig abundance in ovarian tumors. METHODS: We measured markers of B and plasma cells and Ig isotypes using multiplex immunofluorescence on 395 ovarian cancer tumors in the Nurses' Health Study (NHS)/NHSII. We conducted beta-binomial analyses evaluating odds ratios (OR) and 95% confidence intervals (CI) for positivity of immune markers by cigarette exposure among cases and Cox proportional hazards models to evaluate hazard ratios (HR) and 95% CI for developing tumors with low (

Society of Critical Care Medicine Guidelines on Recognizing and Responding to Clinical Deterioration Outside the ICU: 2023.

RATIONALE: Clinical deterioration of patients hospitalized outside the ICU is a source of potentially reversible morbidity and mortality. To address this, some acute care hospitals have implemented systems aimed at detecting and responding to such patients. OBJECTIVES: To provide evidence-based recommendations for hospital clinicians and administrators to optimize recognition and response to clinical deterioration in non-ICU patients. PANEL DESIGN: The 25-member panel included representatives from medicine, nursing, respiratory therapy, pharmacy, patient/family partners, and clinician-methodologists with expertise in developing evidence-based Clinical Practice Guidelines. METHODS: We generated actionable questions using the Population, Intervention, Control, and Outcomes (PICO) format and performed a systematic review of the literature to identify and synthesize the best available evidence. We used the Grading of Recommendations Assessment, Development, and Evaluation Approach to determine certainty in the evidence and to formulate recommendations and good practice statements (GPSs). RESULTS: The panel issued 10 statements on recognizing and responding to non-ICU patients with critical illness. Healthcare personnel and institutions should ensure that all vital sign acquisition is timely and accurate (GPS). We make no recommendation on the use of continuous vital sign monitoring among unselected patients. We suggest focused education for bedside clinicians in signs of clinical deterioration, and we also suggest that patient/family/care partners' concerns be included in decisions to obtain additional opinions and help (both conditional recommendations). We recommend hospital-wide deployment of a rapid response team or medical emergency team (RRT/MET) with explicit activation criteria (strong recommendation). We make no recommendation about RRT/MET professional composition or inclusion of palliative care members on the responding team but suggest that the skill set of responders should include eliciting patients' goals of care (conditional recommendation). Finally, quality improvement processes should be part of a rapid response system. CONCLUSIONS: The panel provided guidance to inform clinicians and administrators on effective processes to improve the care of patients at-risk for developing critical illness outside the ICU.

Executive Summary: Society of Critical Care Medicine Guidelines on Recognizing and Responding to Clinical Deterioration Outside the ICU.

RATIONALE: Clinical deterioration of patients hospitalized outside the ICU is a source of potentially reversible morbidity and mortality. To address this, some acute care facilities have implemented systems aimed at detecting and responding to such patients. OBJECTIVES: To provide evidence-based recommendations for hospital clinicians and administrators to optimize recognition and response to clinical deterioration in non-ICU patients. PANEL DESIGN: The 25-member panel included representatives from medicine, nursing, respiratory therapy, pharmacy, patient/family partners, and clinician-methodologists with expertise in developing evidence-based clinical practice guidelines. METHODS: We generated actionable questions using the Population, Intervention, Control, and Outcomes format and performed a systematic review of the literature to identify and synthesize the best available evidence. We used the Grading of Recommendations Assessment, Development, and Evaluation approach to determine certainty in the evidence and to formulate recommendations and good practice statements (GPSs). RESULTS: The panel issued 10 statements on recognizing and responding to non-ICU patients with critical illness. Healthcare personnel and institutions should ensure that all vital sign acquisition is timely and accurate (GPS). We make no recommendation on the use of continuous vital sign monitoring among "unselected" patients due to the absence of data regarding the benefit and the potential harms of false positive alarms, the risk of alarm fatigue, and cost. We suggest focused education for bedside clinicians in signs of clinical deterioration, and we also suggest that patient/family/care partners' concerns be included in decisions to obtain additional opinions and help (both conditional recommendations). We recommend hospital-wide deployment of a rapid response team or medical emergency team (RRT/MET) with explicit activation criteria (strong recommendation). We make no recommendation about RRT/MET professional composition or inclusion of palliative care members on the responding team but suggest that the skill set of responders should include eliciting patients' goals of care (conditional recommendation). Finally, quality improvement processes should be part of a rapid response system (GPS). CONCLUSIONS: The panel provided guidance to inform clinicians and administrators on effective processes to improve the care of patients at-risk for developing critical illness outside the ICU.

Defining the Nature and Clinicopathologic Significance of Mallory-Denk-like Inclusions in Ovarian Fibromas: A Potential Degenerative Phenomenon Associated With Torsion.

Mallory-Denk bodies (MBD), described in alcoholic hepatitis, are composed of intermediate filaments admixed with other proteins. These cytoplasmic inclusions are irregularly shaped and eosinophilic as seen under the light microscope. MBD-like inclusions have rarely been described outside the hepatobiliary tree. Though rare, intracytoplasmic inclusions have been reported in ovarian fibromas. This study evaluates a series of torsed ovarian fibromas with intracytoplasmic inclusions resembling MDBs. Forty-three ovarian fibromas were retrieved from the pathology archives. The H&E slides were evaluated for the presence of MBD-like inclusions and histologic evidence of torsion. The cases with histologic features of torsion were included in the study group while the nontorsed fibromas formed the control group. Among the 15 cases of fibromas with torsion, MBD-like intracytoplasmic inclusions were seen in 5 cases, predominantly in the interface between necrotic areas and viable stroma. None of the cases from the control group showed any inclusions. There was no significant difference in the size of the fibroma or patient demographics between cases with and without inclusions. The inclusions were positive for cytokeratin and ubiquitin while being negative for per acidic Schiff and periodic acid-Schiff with diastase reaction, in the 3 cases selected for immunohistochemistry and special stains. Electron microscopy of the index case revealed a predominance of type 3 Mallory hyaline. This is the first report describing MDB-like inclusions in ovarian fibromas. These MDB-like inclusions appear to be limited to a fraction of ovarian fibromas that underwent torsion, suggesting that these inclusions likely result from subacute hypoxic damage to the cells.

Placenta accreta spectrum care infrastructure: an evidence-based review of needed resources supporting placenta accreta spectrum care.

The incidence of placenta accreta spectrum, the deeply adherent placenta with associated increased risk of maternal morbidity and mortality, has seen a significant rise in recent years. Therefore, there has been a rise in clinical and research focus on this complex diagnosis. There is international consensus that a multidisciplinary coordinated approach optimizes outcomes. The composition of the team will vary from center to center; however, central themes of complex surgical experts, specialists in prenatal diagnosis, critical care specialists, neonatology specialists, obstetrics anesthesiology specialists, blood bank specialists, and dedicated mental health experts are universal throughout. Regionalization of care is a growing trend for complex medical needs, but the location of care alone is just a starting point. The goal of this article is to provide an evidence-based framework for the crucial infrastructure needed to address the unique antepartum, delivery, and postpartum needs of the patient with placenta accreta spectrum. Rather than a clinical checklist, we describe the personnel, clinical unit characteristics, and breadth of contributing clinical roles that make up a team. Screening protocols, diagnostic imaging, surgical and potential need for critical care, and trauma-informed interaction are the basis for comprehensive care. The vision from the author group is that this publication provides a semblance of infrastructure standardization as a means to ensure proper preparation and readiness.

A systematic review of the facilitators and barriers to rapid response team activation.

BACKGROUND: Outcomes associated with rapid response teams (RRTs) are inconsistent. This may be due to underlying facilitators and barriers to RRT activation that are affected by team leaders and health systems. AIMS: The aim of this study was to synthesize the published research about facilitators and barriers to nurse-led RRT activation in the United States (U.S.). METHODS: A systematic review was conducted. Four databases were searched from January 2000 to June 2023 for peer-reviewed quantitative, qualitative, and mixed methods studies reporting facilitators and barriers to RRT activation. Studies conducted outside the U.S. or with physician-led teams were excluded. RESULTS: Twenty-five studies met criteria representing 240,140 participants that included clinicians and hospitalized adults. Three domains of facilitators and barriers to RRT activation were identified: (1) hospital infrastructure, (2) clinician culture, and (3) nurses' beliefs, attributes, and knowledge. Categories were identified within each domain. The categories of perceived benefits and positive beliefs about RRTs, knowing when to activate the RRT, and hospital-wide policies and practices most facilitated activation, whereas the categories of negative perceptions and concerns about RRTs and uncertainties surrounding RRT activation were the dominant barriers. LINKING EVIDENCE TO ACTION: Facilitators and barriers to RRT activation were interrelated. Some facilitators like hospital leader and physician support of RRTs became barriers when absent. Intradisciplinary communication and collaboration between nurses can positively and negatively impact RRT activation. The expertise of RRT nurses should be further studied.

Associations between prediagnostic aspirin use and ovarian tumor gene expression.

BACKGROUND: Aspirin use has been associated with reduced ovarian cancer risk, yet the underlying biological mechanisms are not fully understood. To gain mechanistic insights, we assessed the association between prediagnosis low and regular-dose aspirin use and gene expression profiles in ovarian tumors. METHODS: RNA sequencing was performed on high-grade serous, poorly differentiated, and high-grade endometrioid ovarian cancer tumors from the Nurses' Health Study (NHS), NHSII, and New England Case-Control Study (n = 92 cases for low, 153 cases for regular-dose aspirin). Linear regression identified differentially expressed genes associated with aspirin use, adjusted for birth decade and cohort. False discovery rates (FDR) were used to account for multiple testing and gene set enrichment analysis was used to identify biological pathways. RESULTS: No individual genes were significantly differentially expressed in ovarian tumors in low or regular-dose aspirin users accounting for multiple comparisons. However, current versus never use of low-dose aspirin was associated with upregulation of immune pathways (e.g., allograft rejection, FDR = 5.8 × 10-10 ; interferon-gamma response, FDR = 2.0 × 10-4 ) and downregulation of estrogen response pathways (e.g., estrogen response late, FDR = 4.9 × 10-8 ). Ovarian tumors from current regular aspirin users versus never users were also associated with upregulation in interferon pathways (FDR <1.5 × 10-4 ) and downregulation of multiple extracellular matrix (ECM) architecture pathways (e.g., ECM organization, 4.7 × 10-8 ). CONCLUSION: Our results suggest low and regular-dose aspirin may impair ovarian tumorigenesis in part via enhancing adaptive immune response and decreasing metastatic potential supporting the likely differential effects on ovarian carcinogenesis and progression by dose of aspirin.

"The System Tends to Scoop You Up and Spit You Out and They're Done With You": The Intersection of Intellectual/Developmental Disability and Homelessness From the Perspectives of Service Providers.

People with intellectual and developmental disabilities (IDD) experience elevated risk for poor health and social outcomes in adulthood and are at risk for experiencing homelessness and housing instability. Although the exact prevalence of IDD among homeless populations is unknown, a small body of literature related to the intersection of IDD and homelessness suggests differential health needs and service use patterns, with a need for targeted health and social services. In this study, we explore the perceptions and experiences of 18 homeless or disability service providers about (a) their clients at the intersection of IDD and homelessness and (b) their role and the services provided at the intersection of IDD and homelessness. Participants struggled to provide appropriate, accessible services for this population, owing to lack of training and awareness of specific needs, fragmented systems, and inadequately funded healthcare and housing support. Our findings also reveal that clients at this intersection have high contact with public systems, which places them at risk for losing their right to self-determination. Recommendations center on systems transformation to facilitate the ability of providers to collaborate and to make data-driven decisions to deliver person-centered care.

A genetic basis for cancer sex differences revealed in Xp11 translocation renal cell carcinoma.

Xp11 translocation renal cell carcinoma (tRCC) is a female-predominant kidney cancer driven by translocations between the TFE3 gene on chromosome Xp11.2 and partner genes located on either chrX or on autosomes. The rearrangement processes that underlie TFE3 fusions, and whether they are linked to the female sex bias of this cancer, are largely unexplored. Moreover, whether oncogenic TFE3 fusions arise from both the active and inactive X chromosomes in females remains unknown. Here we address these questions by haplotype-specific analyses of whole-genome sequences of 29 tRCC samples from 15 patients and by re-analysis of 145 published tRCC whole-exome sequences. We show that TFE3 fusions universally arise as reciprocal translocations with minimal DNA loss or insertion at paired break ends. Strikingly, we observe a near exact 2:1 female:male ratio in TFE3 fusions arising via X:autosomal translocation (but not via X inversion), which accounts for the female predominance of tRCC. This 2:1 ratio is at least partially attributable to oncogenic fusions involving the inactive X chromosome and is accompanied by partial re-activation of silenced chrX genes on the rearranged chromosome. Our results highlight how somatic alterations involving the X chromosome place unique constraints on tumor initiation and exemplify how genetic rearrangements of the sex chromosomes can underlie cancer sex differences.

Knowledge Gaps in Placenta Accreta Spectrum.

Since its first description early in the 20th Century, placenta accreta and its variants have changed substantially in incidence, risk factor profile, clinical presentation, diagnosis and management. While systematic use of diagnostic tools and a multidisciplinary team care approach has begun to improve patient outcomes, the condition's pathophysiology, epidemiology, and best practices for diagnosis and management remain poorly understood. The use of large databases with broadly accepted terminology and diagnostic criteria should accelerate research in this area. Future work should focus on non-traditional phenotypes, such as those without placenta previa-preventive strategies, and long term medical and emotional support for patients facing this diagnosis. KEY POINTS: · Placenta accreta spectrum research may be improved with standardized terminology and use of large databases.. · Placenta accreta prediction should move beyond ultrasound with the addition of biomarkers, and needs to extend to those without traditional risk factors.. · Future research should identify practices that can prevent future accreta development..

Basal Plate Myofibers and the Risk of Placenta Accreta Spectrum in the Subsequent Pregnancy: A Large Single-Center Cohort.

OBJECTIVE: We aimed to evaluate whether there is a significant association between a placental pathology diagnosis basal plate myofibers (BPMF) in an index pregnancy with placenta accreta spectrum (PAS) in the subsequent pregnancy. STUDY DESIGN: We conducted a retrospective nested cohort study of all cases with a histopathological finding of BPMF between August 2012 and March 2020 at a single tertiary referral center. Data were collected for all subjects (cases and controls) with at least two consecutive pregnancies (the initial index pregnancy and at least one subsequent pregnancy) accompanied by a concomitant record of histopathological study of the placenta at our center. The primary outcome was pathologically confirmed PAS in the subsequent pregnancy. Data are presented as percentage or median, interquartile range accordingly. RESULTS: A total of n = 1,344 participants were included, of which n = 119 (index cases) carried a contemporaneous histopathological diagnosis of BPMF during the index pregnancy and n = 1,225 did not (index controls). Among the index cases, patients with BPMF were older (31.0 [20, 42] vs. 29.0 [15, 43], p < 0.001), more likely to have undergone in vitro fertilization (IVF) for conception (10.9 vs. 3.8%, p = 0.001) and were of a more advanced gestational age at delivery (39.0 [25, 41] vs. 38.0 [20, 42], p = 0.006). In the subsequent pregnancy, the rate of PAS was significantly higher among the BPMF index cases (6.7 vs. 1.1%, p < 0.001). After adjusting for maternal age and IVF, a histopathological diagnosis of BPMF in an index pregnancy was shown to be a significant risk factor for PAS in the subsequent gestation (hazard ratio: 5.67 [95% confidence interval: 2.28, 14.06], p < 0.001). CONCLUSION: Our findings support that a histopathological diagnosis of BPMF is an independent risk factor for PAS in the subsequent pregnancy. KEY POINTS: · BPMF may indicate morbid adherence of placenta.. · Patients with BPMF were older and more likely to have undergone IVF for conception.. · The BPMF in the current pregnancy is an independent risk factor for PAS in the subsequent pregnancy..

Perinatal assessment of complex cesarean delivery: beyond placenta accreta spectrum.

Multiple cesarean deliveries are known to be associated with long-term postoperative consequences because of a permanent defect of the lower uterine segment wall and the development of thick pelvic adhesions. Patients with a history of multiple cesarean deliveries often present with large cesarean scar defects and are at heightened risk in subsequent pregnancies of cesarean scar ectopic pregnancy, uterine rupture, low-lying placenta or placenta previa, and placenta previa accreta. Moreover, large cesarean scar defects will lead to progressive dehiscence of the lower uterine segment with the inability to effectively reapproximate hysterotomy edge and repair at birth. Major remodeling of the lower uterine segment associated with true placenta accreta spectrum at birth, whereby the placenta becomes inseparable from the uterine wall, increases the rates of perinatal morbidity and mortality, especially when undiagnosed before delivery. Ultrasound imaging is currently not routinely used to evaluate the surgical risks of patients with a history of multiple cesarean deliveries, beyond the risk assessment of placenta accreta spectrum. Independent of accreta placentation, a placenta previa under a scarred, thinned partially disrupted lower uterine segment, covered by thick adhesions with the posterior wall of the bladder, poses a surgical risk and requires fine dissection and surgical expertise; however, data on the use of ultrasound to evaluate uterine remodeling and adhesions between the uterus and other pelvic organs are scarce. In particular, transvaginal sonography has been underused, including in patients with a high probability of placenta accreta spectrum at birth. Based on the best available knowledge, we discuss the role of ultrasound imaging in identifying the signs suggestive of major remodeling of the lower uterine segment and in mapping the changes in the uterine wall and pelvis, to enable the surgical team to prepare for all different types of complex cesarean deliveries. The need for postnatal confirmation of the prenatal ultrasound findings for all patients with a history of multiple cesarean deliveries, regardless of the diagnosis of placenta previa and placenta accreta spectrum, is discussed. We propose an ultrasound imaging protocol and a classification of the level of surgical difficulty at elective cesarean delivery to stimulate further research toward the validation of ultrasound signs by which these signs may be applied to improve surgical outcomes.

Measurement of Ovarian Tumor Immune Profiles by Multiplex Immunohistochemistry: Implications for Epidemiologic Studies.

BACKGROUND: Despite the immunogenic nature of many ovarian tumors, treatment with immune checkpoint therapies has not led to substantial improvements in ovarian cancer survival. To advance population-level research on the ovarian tumor immune microenvironment, it is critical to understand methodologic issues related to measurement of immune cells on tissue microarrays (TMA) using multiplex immunofluorescence (mIF) assays. METHODS: In two prospective cohorts, we collected formalin-fixed, paraffin-embedded ovarian tumors from 486 cases and created seven TMAs. We measured T cells, including several sub-populations, and immune checkpoint markers on the TMAs using two mIF panels. We used Spearman correlations, Fisher exact tests, and multivariable-adjusted beta-binomial models to evaluate factors related to immune cell measurements in TMA tumor cores. RESULTS: Between-core correlations of intratumoral immune markers ranged from 0.52 to 0.72, with more common markers (e.g., CD3+, CD3+CD8+) having higher correlations. Correlations of immune cell markers between the whole core, tumor area, and stromal area were high (range 0.69-0.97). In multivariable-adjusted models, odds of T-cell positivity were lower in clear cell and mucinous versus type II tumors (ORs, 0.13-0.48) and, for several sub-populations, were lower in older tissue (sample age > 30 versus ≤ 10 years; OR, 0.11-0.32). CONCLUSIONS: Overall, high correlations between cores for immune markers measured via mIF support the use of TMAs in studying ovarian tumor immune infiltration, although very old samples may have reduced antigenicity. IMPACT: Future epidemiologic studies should evaluate differences in the tumor immune response by histotype and identify modifiable factors that may alter the tumor immune microenvironment.

Predictors of residual disease after debulking surgery in advanced stage ovarian cancer.

Objective: Optimal debulking with no macroscopic residual disease strongly predicts ovarian cancer survival. The ability to predict likelihood of optimal debulking, which may be partially dependent on tumor biology, could inform clinical decision-making regarding use of neoadjuvant chemotherapy. Thus, we developed a prediction model including epidemiological factors and tumor markers of residual disease after primary debulking surgery. Methods: Univariate analyses examined associations of 11 pre-diagnosis epidemiologic factors (n=593) and 24 tumor markers (n=204) with debulking status among incident, high-stage, epithelial ovarian cancer cases from the Nurses' Health Studies and New England Case Control study. We used Bayesian model averaging (BMA) to develop prediction models of optimal debulking with 5x5-fold cross-validation and calculated the area under the curve (AUC). Results: Current aspirin use was associated with lower odds of optimal debulking compared to never use (OR=0.52, 95%CI=0.31-0.86) and two tissue markers, ADRB2 (OR=2.21, 95%CI=1.23-4.41) and FAP (OR=1.91, 95%CI=1.24-3.05) were associated with increased odds of optimal debulking. The BMA selected aspirin, parity, and menopausal status as the epidemiologic/clinical predictors with the posterior effect probability ≥20%. While the prediction model with epidemiologic/clinical predictors had low performance (average AUC=0.49), the model adding tissue biomarkers showed improved, but weak, performance (average AUC=0.62). Conclusions: Addition of ovarian tumor tissue markers to our multivariable prediction models based on epidemiologic/clinical data slightly improved the model performance, suggesting debulking status may be in part driven by tumor characteristics. Larger studies are warranted to identify those at high risk of poor surgical outcomes informing personalized treatment.

Cervical microRNA expression and spontaneous preterm birth.

BACKGROUND: Preterm birth remains a major public health issue affecting 10% of all pregnancies and increases risks of neonatal morbidity and mortality. Approximately 50% to 60% of preterm births are spontaneous, resulting from preterm premature rupture of membranes or preterm labor. The pathogenesis of spontaneous preterm birth is incompletely understood, and prediction of preterm birth remains elusive. Accurate prediction of preterm birth would reduce infant morbidity and mortality through targeted patient referral to hospitals equipped to care for preterm infants. Two previous studies have analyzed cervical microRNAs in association with spontaneous preterm birth and the length of gestation, but the extent to which microRNAs serve as predictive biomarkers remains unknown. OBJECTIVE: This study aimed to examine associations between cervical microRNA expression and spontaneous preterm birth, with the specific goal of identifying a subset of microRNAs that predict spontaneous preterm birth. STUDY DESIGN: We performed a prospective, nested, case-control study of 25 cases with spontaneous preterm birth and 49 term controls. Controls were matched to cases in a 2:1 ratio on the basis of age, parity, and self-identified race. Cervical swabs were collected at a mean gestational age of 17.1 (4.8) weeks of gestation, and microRNAs were analyzed using a quantitative polymerase chain reaction array. Normalized microRNA expression was compared between cases and controls, and a false discovery rate of 0.2 was applied to account for multiple comparisons. Histopathologic analysis of slides of cervical swab samples was performed to quantify leukocyte burden for adjustment in conditional regression models. We explored the use of Relief-based unsupervised identification of top microRNAs and support vector machines to predict spontaneous preterm birth. We performed microRNA enrichment analysis to explore potential biologic targets and pathways in which up-regulated microRNAs might be involved. RESULTS: Of the 754 microRNAs on the polymerase chain reaction array, 346 were detected in ≥75% of participants' cervical swabs. Average cervical microRNA expression was significantly higher in cases of spontaneous preterm birth than in controls (P=.01). There were 95 significantly up-regulated individual microRNAs (>2-fold change) in cases of subsequent spontaneous preterm birth compared with term controls (P<.05; q<0.2). Notably, miR-143, miR-30e-3p, and miR-199b were all significantly up-regulated, which is consistent with the 1 previous study of cervical microRNA and spontaneous preterm birth. A Relief-based, novel variable (feature) selection machine learning approach had low-to-moderate prediction accuracy, with an area under the receiver operating curve of 0.71. Enrichment analysis revealed that identified microRNAs may modulate inflammatory cell signaling. CONCLUSION: In this prospective nested case-control study of cervical microRNA expression and spontaneous preterm birth, we identified a global increase in microRNA expression and up-regulation of 95 distinct microRNAs in association with subsequent spontaneous preterm birth. Larger and more diverse studies are required to determine the ability of microRNAs to accurately predict spontaneous preterm birth, and mechanistic work to facilitate development of novel therapeutic interventions to prevent spontaneous preterm birth is warranted.