Diagnostic Performance of Ultrasonography-Based Risk Models in Differentiating Between Benign and Malignant Ovarian Tumors in a US Cohort

Importance: Ultrasonography-based risk models can help nonexpert clinicians evaluate adnexal lesions and reduce surgical interventions for benign tumors. Yet, these models have limited uptake in the US, and studies comparing their diagnostic accuracy are lacking. Objective: To evaluate, in a US cohort, the diagnostic performance of 3 ultrasonography-based risk models for differentiating between benign and malignant adnexal lesions: International Ovarian Tumor Analysis (IOTA) Simple Rules with inconclusive cases reclassified as malignant or reevaluated by an expert, IOTA Assessment of Different Neoplasias in the Adnexa (ADNEX), and Ovarian-Adnexal Reporting and Data System (O-RADS). Design, setting, and participants: This retrospective diagnostic study was conducted at a single US academic medical center and included consecutive patients aged 18 to 89 years with adnexal masses that were managed surgically or conservatively between January 2017 and October 2022. Exposure: Evaluation of adnexal lesions using the Simple Rules, ADNEX, and O-RADS. Main outcomes and measures: The main outcome was diagnostic performance, including area under the receiver operating characteristic (ROC) curve (AUC), sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios. Surgery or follow-up were reference standards. Secondary analyses evaluated the models' performances stratified by menopause status and race. Results: The cohort included 511 female patients with a 15.9% malignant tumor prevalence (81 patients). Mean (SD) ages of patients with benign and malignant adnexal lesions were 44.1 (14.4) and 52.5 (15.2) years, respectively, and 200 (39.1%) were postmenopausal. In the ROC analysis, the AUCs for discriminative performance of the ADNEX and O-RADS models were 0.96 (95% CI, 0.93-0.98) and 0.92 (95% CI, 0.90-0.95), respectively. After converting the ADNEX continuous individualized risk into the discrete ordinal categories of O-RADS, the ADNEX performance was reduced to an AUC of 0.93 (95% CI, 0.90-0.96), which was similar to that for O-RADS. The Simple Rules combined with expert reevaluation had 93.8% sensitivity (95% CI, 86.2%-98.0%) and 91.9% specificity (95% CI, 88.9%-94.3%), and the Simple Rules combined with malignant classification had 93.8% sensitivity (95% CI, 86.2%-98.0%) and 88.1% specificity (95% CI, 84.7%-91.0%). At a 10% risk threshold, ADNEX had 91.4% sensitivity (95% CI, 83.0%-96.5%) and 86.3% specificity (95% CI, 82.7%-89.4%) and O-RADS had 98.8% sensitivity (95% CI, 93.3%-100%) and 74.4% specificity (95% CI, 70.0%-78.5%). The specificities of all models were significantly lower in the postmenopausal group. Subgroup analysis revealed high performances independent of race. Conclusions and relevance: In this diagnostic study of a US cohort, the Simple Rules, ADNEX, and O-RADS models performed well in differentiating between benign and malignant adnexal lesions; this outcome has been previously reported primarily in European populations. Risk stratification models can lead to more accurate and consistent evaluations of adnexal masses, especially when used by nonexpert clinicians, and may reduce unnecessary surgeries.</p

Expression and regulation of type 2A protein phosphatases and alpha4 signalling in cardiac health and hypertrophy

Abstract Cardiac physiology and hypertrophy are regulated by the phosphorylation status of many proteins, which is partly controlled by a poorly defined type 2A protein phosphatase-alpha4 intracellular signalling axis. Quantitative PCR analysis revealed that mRNA levels of the type 2A catalytic subunits were differentially expressed in H9c2 cardiomyocytes (PP2ACb[PP2ACa[PP4C[PP6C), NRVM (PP2ACb[PP2ACa = PP4C = PP6C), and adult rat ventricular myocytes (PP2ACa[ PP2ACb[PP6C[PP4C). Western analysis confirmed that all type 2A catalytic subunits were expressed in H9c2 cardiomyocytes; however, PP4C protein was absent in adult myocytes and only detectable following 26S proteasome inhibition. Short-term knockdown of alpha4 protein expression attenuated expression of all type 2A catalytic subunits. Pressure overload-induced left ventricular (LV) hypertrophy was associated with an increase in both PP2AC and alpha4 protein expression. Although PP6C expression was unchanged, expression of PP6C regulatory subunits (1) Sit4-associated protein 1 (SAP1) and (2) ankyrin repeat domain (ANKRD) 28 and 44 proteins was elevated, whereas SAP2 expression was reduced in hypertrophied LV tissue. Co-immunoprecipitation studies demonstrated that the interaction between alpha4 and PP2AC or PP6C subunits was either unchanged or reduced in hypertrophied LV tissue, respectively. Phosphorylation status of phospholemman (Ser63 and Ser68) was significantly increased by knockdown of PP2ACa, PP2ACb, or PP4C protein expression. DNA damage assessed by histone H2A.X phosphorylation (cH2A.X) in hypertrophied tissue remained unchanged. However, exposure of cardiomyocytes to H2O2 increased levels of cH2A.X which was unaffected by knockdown of PP6C expression, but was abolished by the short-term knockdown of alpha4 expression. This study illustrates the significance and altered activity of the type 2A protein phosphatase-alpha4 complex in healthy and hypertrophied myocardium

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Immunological Role of the Maternal Uterine Microbiome in Pregnancy: Pregnancies Pathologies and Alterated Microbiota

Understanding what happens at the time of embryo implantation has been the subject of significant research. Investigators from many differing fields including maternal fetal medicine, microbiology, genetics, reproductive endocrinology and immunology have all been studying the moment the embryo interacts with the maternal endometrium. A perfect relationship between the uterus and the embryo, mediated by a tightly controlled interaction between the embryo and the endometrium, is required for successful implantation. Any factors affecting this communication, such as altered microbiome may lead to poor reproductive outcomes. Current theories suggest that altered microbiota may trigger an inflammatory response in the endometrium that affects the success of embryo implantation, as inflammatory mediators are tightly regulated during the adhesion of the blastocyst to the epithelial endometrial wall. In this review, we will highlight the various microbiome found during the periconceptual period, the microbiomes interaction with immunological responses surrounding the time of implantation, its effect on implantation, placentation and ultimately maternal and neonatal outcomes

Anesthetic Considerations for the Parturient After Solid Organ Transplantation

Over the past 40 years, the success of organ transplantation has increased such that female solid organ transplant recipients are able to conceive and carry pregnancies successfully to term. Anesthesiologists are faced with the challenge of providing anesthesia care to these high-risk obstetric patients in the peripartum period. Anesthetic considerations include the effects of the physiologic changes of pregnancy on the transplanted organ, graft function in the peripartum period, and the maternal side effects and drug interactions of immunosuppressive agents. These women are at an increased risk of comorbidities and obstetric complications. Anesthetic management should consider the important task of protecting graft function. Optimal care of a woman with a transplanted solid organ involves management by a multidisciplinary team. In this focused review article, we review the anesthetic management of pregnant patients with solid organ transplants of the kidney, liver, heart, or lung

Risk of preterm delivery and growth restriction in twins discordant for structural anomalies

OBJECTIVE: To determine whether twin gestations with an anomalous fetus are at increased risk of preterm delivery (PTD) or intrauterine growth restriction (IUGR) compared to twins with two normal fetuses. STUDY DESIGN: Retrospective cohort of twins undergoing ultrasound 15–22 weeks gestation. Groups were defined by the presence of one twin with a major anomaly (discordant) or by twins with no major anomalies (normal). The primary outcomes were PTD (<37 weeks) and IUGR (<10(th) percentile). RESULTS: Of 1,977 twin pregnancies, 66 had a twin with a major anomaly. Preterm delivery occurred in 42 (63.6%) discordant twins, compared to 1271 (66.5%) normal twins (risk ratio (RR) 1.0, 95% confidence interval (CI) 0.8–1.2). IUGR was diagnosed in 15 (22.7%) normal co-twins, compared to 406 (21.3%) presenting twins in normal twins (RR 1.1, 95% CI 0.7–1.7). CONCLUSION: Twins discordant for major anomalies are not at increased risk of PTD or IUGR compared to twins with no major anomalies

Ovarian complete hydatidiform mole: case study with molecular analysis and review of the literature

Ectopic complete molar pregnancy in the ovary is an exceptionally rare event. Here we present a case of ovarian complete hydatidiform mole in a 20-year-old gravida 2 para 1 woman. At presentation, the patient underwent excision of a hemorrhagic left ovarian cyst, with routine sections demonstrating a hemorrhagic corpus luteum with a single microscopic focus of detached atypical trophoblast, without chorionic villi. Subsequent left salpingo-oophorectomy for persistently elevated human chorionic gonadotropin led to a final diagnosis of complete hydatidiform mole arising in the ovary. The fallopian tube was unremarkable. Zygosity was determined using short tandem repeat analysis, confirming the diagnosis of monospermic complete mole. In the clinical setting of a markedly elevated human chorionic gonadotropin level and an ovarian mass, histopathologic examination is critical in distinguishing ectopic pregnancy from choriocarcinoma. Short tandem repeat analysis can be a useful adjunct to histologic diagnosis in challenging cases

Neural tube defects and associated low birth weight

To estimate the association between neural tube defects (NTDs) and low birth weight. This was a retrospective cohort study of women undergoing ultrasound from 17 to 22 weeks from 1990 to 2008. Presence or absence of fetal NTD defined the two study groups. The primary outcomes were intrauterine growth restriction (IUGR), birth weight <10th percentile, and severe IUGR <5th percentile. Subgroup analysis was performed to observe if the association with IUGR persisted. Of 66,956 women, 170 were found to have fetal NTD. Only the rate of advanced maternal age differed between the study groups. Fetuses with an NTD were at significantly increased risk for IUGR <10th percentile (adjusted odds ratio [aOR] 2.6, 95% confidence interval [CI] 1.8 to 3.9) and <5th percentile (aOR 2.8, 95% CI 1.9 to 4.3). The association persisted in subgroup analyses. Fetuses with NTD are at increased risk for IUGR, suggesting that a policy of serial growth scans in cases with isolated NTD is justified

Utility of magnetic resonance imaging for suspected appendicitis in pregnant women

The purpose of this study was to estimate the rate and risk of appendix nonvisualization and alternative diagnoses made with magnetic resonance imaging (MRI) for suspected appendicitis in pregnant women. We performed a retrospective cohort study of consecutive pregnant women who underwent MRI for suspected appendicitis at a single center from 2007-2012. Data on clinical presentation, imaging, and surgical pathologic evidence were extracted from electronic medical records. Odds ratios estimated risk factors for nondiagnosis. Radiologic diagnoses were identified, and rates of diagnoses were calculated. Subgroup analysis was performed among women who underwent initial imaging with ultrasound scanning. Over the 5-year period, 171 pregnant women underwent MRI for suspected appendicitis. The rate of nonvisualization was 30.9% (n = 53). Of the remaining 118 women with a visualized appendix, 18 women had imaging findings that were consistent with appendicitis and underwent appendectomy. Twelve cases of appendicitis were confirmed on pathologic evaluation (66.7%). Women with nonvisualization of the appendix on MRI were more likely to be beyond the first trimester (odds ratio, 2.1; 95% confidence interval, 1.0–4.5). Seventy-four women had disease diagnosed on MRI (43.3%). In the group of 43 women who had a nondiagnostic ultrasound scanning before the MRI, the rate of subsequent diagnostic MRI was 65% (n = 28). MRI yields a high diagnostic rate and accuracy in pregnant women with suspected appendicitis and provides alternative diagnoses to guide further management. Given the high rate of appendix nonvisualization on ultrasound scanning that has been reported in the literature, we recommend MRI as the imaging modality of choice for this population in settings in which MRI is readily available