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Methadone maintenance treatment for opioid dependent mothers is standard of care. Infants of methadone maintained opioid dependent (MMOD) mothers have better outcomes compared to infants of opioid dependent mothers without treatment. However, when compared to non-exposed infants, infants of MMOD mothers are associated with worse outcomes. We conducted a pilot study to examine genome wide differential DNA methylation using cord blood samples from sixteen term and near-term infants of MMOD and opioid naïve mothers, excluding Infants with chorioamnionitis. A total of 152 differentially methylated loci were identified at a difference >  + 2, < − 2 and p-value < 0.05. There were 90 hypermethylated loci (59 annotated genes) and 62 hypomethylated loci (38 annotated genes) observed. The hypermethylated and hypomethylated DNA changes involved multiple genes, pathways and networks that may explain some of the changes seen in infants of MMOD mothers. Top hypermethylated and hypomethylated genes involved areas of cell growth, neurodevelopment, vision and xenobiotic metabolism functions. Our data may explain the role of key pathways and genes relevant to neonatal outcomes seen from methadone exposure in pregnancy. Functional studies on the identified pathways and genes could lead to improved understanding of the mechanisms and identify areas for intervention.

Histological chorioamnionitis (HCA) is an infection of fetal membranes and complicates 5.2% to 28.5% of all live births. HCA is associated with increased mortality and morbidity in both premature and term neonates. Exposure to HCA may have long-term consequences, including an increased risk for allergic disorders and asthma later in childhood, the mechanism(s) of which are still not yet well understood. The objective of this study was to determine the mRNA transcriptome of cord blood mononuclear leukocytes from term neonates to identify key genes and pathways involved in HCA. We found 366 differentially expressed probe IDs with exposure to HCA (198 upregulated, 168 downregulated). These transcriptomes included novel genes and pathways associated with exposure to HCA. The differential gene expression included key genes regulating inflammatory, immune, respiratory and neurological pathways, which may contribute to disorders in those pathways in neonates exposed to HCA. Our data may lead to understanding of the role of key genes and pathways identified on the long-term sequelae related to exposure to HCA, as well as to identifying potential markers and therapies to prevent HCA-associated complications.

BackgroundThe COVID-19 disease outbreak that first surfaced in Wuhan, China, in December 2019, has taken the world by storm and ravaged almost every country in the world. Emergency departments (ED) in hospitals are on the frontlines, serving an essential function in identifying these patients, isolating them early whilst providing urgent medical care. This outbreak has reinforced the role of Emergency Medicine in public health. This paper documents the challenges faced and measures taken by a tertiary hospital’s ED in Singapore, in response to the outbreak.Main bodyThe ED detected the first case of COVID-19 in Singapore on 22 January 2020 in a Chinese tourist and also the first case of locally transmitted COVID-19 on 3 February 2020. The patient journeys through the patient reception area in the ED and undergoes fever screening before being shunted to isolation areas within the ED. Management and disposition of suspect COVID-19 patients are guided by a close-knit collaboration between ED and department of infectious diseases. With increasing number of patients, back-up plans for expansion of space and staff augmentation have been enacted. Staff safety is also of utmost importance, with provision and guidelines for personal protective equipment and team segregation to ensure no cross-contamination across staff. These have been made possible with an early setup of an operational command and control structure within the ED, managing manpower, logistics, operations, communication and information management and liaison with other clinical departments.ConclusionWith the large numbers of undifferentiated patients managed by the ED to date, more than 820 patients with COVID-19 have been identified in the hospital. Not a single member of the staff of the SGH Emergency Department has come down with the illness. The various measures undertaken by the department have helped to ensure good staff morale and strict adherence to safety procedures. We share the lessons learnt so that others who manage EDs around the world can benefit from our experience.

Undergraduate medical education traditionally consists of 2 years of lecture-based courses followed by 2 years of clinical clerkships. However, over the past couple decades, undergraduate medical education has been evolving toward non-lecture-based integrated curriculums, requiring a collaborative curriculum. Additionally, e-learning platforms have become efficacious and essential to delivering education asynchronously to students. At Thomas Jefferson University, the Pathology and Obstetrics and Gynecology departments collaborated to create a pilot series of case-based asynchronous interactive modules to teach gynecologic pathology in a clinical context, while interweaving other educational components, such as evidence-based medicine, clinical skills, and basic sciences. The case-based asynchronous interactive modules were given to third-year medical students during their obstetrics and gynecology clerkship. Students interpreted histologic and clinical images while being evaluated on clinical management skills, gynecologic diagnoses, general principles of population health and pathology. Sixty-eight students from 3 blocks completed a pre and posttest. All participants showed improvement in interpreting gynecologic pathology in routine clinical scenarios as well as improved case-based decision-making, with an average score increase by 5.7%. Learner feedback was positive, with suggestions to apply this method to other medical specialties, particularly radiology. Asynchronous interactive modules are an efficacious and popular method of pathology education.

Umbilical cord complications (UCC), such as true knots (TK), velamentous (VEL) insertion, marginal umbilical cord (MUC) insertion, umbilical cord entanglement (UCE) (both nuchal and non-nuchal), excessively long umbilical cord (ELUC), and excessively twisted umbilical cord (ETUC), can lead to decreased UC blood flow and have been associated with adverse fetal outcome and intrauterine fetal demise (IUFD). Few large series exist that correlate UCC with specific pathologic findings of the placenta. We present the largest series of UCC at this time. Eight hundred forty-one 3rd-trimester placentas with UCC were identified, as well as 858 randomly selected gestational age–matched placentas with grossly unremarkable UC. Lesions associated with circulatory stasis and thrombosis, including villous capillary congestion (VC), umbilical vessel distension (UVD), chorionic plate vessel distension (CPD), umbilical vessel thrombosis (UVT), fetal vascular thrombosis (FVT), intimal fibrin cushions (IFC), and avascular villi (AV), were noted, as well as other pathologic lesions. Data were analyzed by analysis of variance and Fisher exact tests, with P < 0.05 statistically significant. Umbilical cord complications as a group was associated with a significant increase in placental circulatory stasis lesions. Lesions associated with hypoxia, namely nucleated red blood cells and chorangiosis, were also increased. Finally, the presence of any UCC was significantly associated with IUFD. We also found that multiple UCC are associated with nonreassuring fetal heart rate and chorangiosis but that the presence of a single UCC was not. This indicates that UCC may lead to intrauterine hypoxia and subsequent adverse fetal outcome and that multiple UCC may be cumulative in effect.

Castration-resistant prostate cancer is a heterogeneous disease with variable phenotypes commonly observed in later stages of the disease. These include cases that retain expression of luminal markers and those that lose hormone dependence and acquire neuroendocrine features. While there are distinct transcriptomic and epigenomic differences between castration-resistant adenocarcinoma and neuroendocrine prostate cancer, the extent of overlap and degree of diversity across tumor metastases in individual patients has not been fully characterized. Here we perform combined DNA methylation, RNA-sequencing, H3K27ac, and H3K27me3 profiling across metastatic lesions from patients with CRPC/NEPC. Integrative analyses identify DNA methylation-driven gene links based on location (H3K27ac, H3K27me3, promoters, gene bodies) pointing to mechanisms underlying dysregulation of genes involved in tumor lineage (ASCL1, AR ) and therapeutic targets (PSMA, DLL3, STEAP1, B7-H3). Overall, these data highlight how integration of DNA methylation with RNA-sequencing and histone marks can inform intraindividual epigenetic heterogeneity and identify putative mechanisms driving transcriptional reprogramming in castration-resistant prostate cancer. The epigenetic mechanisms underlying phenotypic diversity across different metastatic sites in castration-resistant prostate cancer (CRPC) remain to be characterised. Here, multi-omic profiling across metastatic lesions identifies regulatory networks driving tumour lineage programs and potential therapeutic targets.

Lutetium-177 [177Lu]Lu-PSMA-I&T (177Lu-PSMA-I&T) and the bone-seeking α-emitter radium-223 (223Ra) are established life-extending therapies for patients with metastatic castration-resistant prostate cancer; however, resistance and progression are inevitable. We aimed to evaluate the safety and preliminary antitumour activity of 177Lu-PSMA-I&T combined with 223Ra in this patient group. We conducted an investigator-initiated, single-centre, single-arm, phase 1/2 trial (AlphaBet) at the Peter MacCallum Cancer Centre in Melbourne, Australia. Adults (aged ≥18 years) with a diagnosis of progressive, metastatic castration-resistant prostate cancer, an Eastern Cooperative Oncology Group performance status score of 0–2, at least two visible bone metastases not treated with radiotherapy, previous exposure to an androgen receptor pathway inhibitor, prostate-specific membrane antigen (PSMA)-positive disease (defined by maximum standardised uptake value ≥20 at a site of disease), and no discordant sites (ie, avid on 2-[18F]fluoro-2-deoxy-D-glucose-PET–CT with minimal PSMA expression and no uptake on bone scintigraphy) were eligible for inclusion. Phase 1 dose-escalation assessed two dose levels of 223Ra (27·5 kBq/kg and 55·0 kBq/kg) combined with 7·4 GBq 177Lu-PSMA-I&T, administered intravenously every 6 weeks for up to six cycles. Phase 2 dose expansion continued with the recommended phase 2 dose. Co-primary endpoints were the maximum tolerated or administered dose and the recommended phase 2 dose (phase 1), and the PSA response rate (phase 2), analysed in all patients treated at the maximum tolerated or administered dose in either phase. Safety was assessed in all patients who received at least one dose of either protocol treatment in phase 1 or 2. Herein, we report the results of an interim analysis, which was added to the protocol following an amendment on May 30, 2024. This trial is registered at ClinicalTrials.gov (NCT05383079) and follow-up is ongoing. Between Nov 3, 2022, and Nov 5, 2024, 37 patients were enrolled, of whom 36 (97%; median age 72·5 years [IQR 67·0–78·0]) were included in the safety analysis and 33 (89%) were included in the preliminary activity analysis. No dose-limiting toxicities were observed. The recommended phase 2 dose of 223Ra was 55·0 KBq/kg combined with 7·4 GBq 177Lu-PSMA-I&T, administered every 6 weeks. With a median follow-up of 13·3 months (IQR 8·7–17·1), 11 (31%) patients completed all six cycles of both treatments. 18 (50%) patients discontinued treatment early, primarily due to unequivocal disease progression (11 [61%]) or adverse events (three [17%]). A reduction in PSA of at least 50% was observed in 18 (55%; 95% CI 36–72) patients. Grade 3 or higher treatment-related adverse events occurred in five (14%) of 36 patients, including anaemia (four [11%]) and neutropenia (three [8%]), with no treatment-related deaths. Non-clinically significant grade 3 lymphopenia occurred in ten (28%) patients. The combination of 177Lu-PSMA-I&T and 223Ra is safe and feasible in patients with metastatic castration-resistant prostate cancer and bone metastases. These findings warrant further evaluation of combined α-emitting and β-emitting approaches. Prostate Cancer Foundation, Bayer, and National Health and Medical Research Council.

Background: The global pandemic of coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). About 18.4% of total Covid-19 cases were reported in children. Even though vertical transmission from mother to infant is likely to occur at a low rate, exposure to COVID-19 during fetal life may alter DNA methylation patterns with potential long-term effects. Objective: To determine if COVID-19 infection during pregnancy alters the DNA methylation patterns in umbilical cord blood cells from term infants and to identify potential pathways and genes affected by exposure to COVID-19 infection. Methods: Umbilical cord blood was collected from 8 infants exposed to COVID-19 during pregnancy and 8 control infants with no COVID-19 exposure. Genomic DNA was isolated from umbilical cord blood cells and genome-wide DNA methylation was performed using Illumina Methylation EPIC Array. Results: 119 differentially methylated loci were identified at the FDR level of 0.20 (64 hypermethylated loci and 55 hypomethylated loci) in umbilical cord blood cells of COVID-19 exposed neonates compared to the control group. Important canonical pathways identified by Ingenuity Pathway Analysis (IPA) were related to stress response (corticotropin releasing hormone signaling, glucocorticoid receptor signaling, and oxytocin in brain signaling pathway), and cardiovascular disease and development (nitric oxide signaling in the cardiovascular system, apelin cardiomyocyte signaling pathways, factors promoting cardiogenesis, and renin-angiotensin signaling). The genes affected by the differential methylations were associated with cardiac, renal, hepatic, neurological diseases, developmental and immunological disorders. Conclusions: COVID-19 induces differential DNA methylation in umbilical cord blood cells. The differentially methylated genes may contribute to hepatic, renal, cardiac, developmental and immunological disorders in offspring born to mothers with COVID-19 infection during pregnancy, and their developmental regulation.

Background: The emergency department at the Singapore General Hospital is an emergency department with an annual census of 140,000 and oncology-related attendances of about 4000 (2.8%). These patients are often admitted for further care. Palliative care in the emergency department for these patients is often minimal. The aim of this study was to determine the state of current management of oncology-related emergencies at the Singapore General Hospital's emergency department, hence identifying specific areas for intervention. Methods: We carried out a retrospective data review of all Singapore General Hospital's emergency department patients who had either cancer-related diagnoses or were admitted to the Medical Oncology Department in October 2018. Simple statistical analysis was then performed using IBM SPSS version 21. Results: Of 308 identified patients, there was approximately equal distribution by sex. The women were generally younger than the men (61.33 +- 13.63 years vs 67.36 +- 12.02 years, p = 0.063, confidence interval −8.94 to −3.13). Seventy- two (23.4%) of the patients arrived at emergency department by ambulance. The mean emergency department length of stay was 4.25 h. About half of the patients had either lung, colorectal, or breast as their primary site of cancer. There was no correlation between clinical severity according to the National Early Warning Scores and triage complaint-type or emergency clinical diagnosis. More than 90% were admitted, with about 32.6% dying during their inpatient stay. High National Early Warning Scores were significantly associated with mortality. Conclusion: There is large potential for interventions to improve patient well-being in the pre-hospital setting and emergency department. Given the sizable number of patients with poor outcomes, palliative care is also of paramount importance.

Background Pseudomyxoma peritonei (PMP) syndrome is a disease process that typically occurs from ruptured appendiceal mucocele neoplasms. PMP syndrome arising from malignant transformation of an ovarian primary mature cystic teratoma (MCT) is a pathogenesis rarely encountered. Case Presentation Herein, we report a 28-year-old patient evaluated and treated for a right ovarian mass and large volume symptomatic abdominopelvic mucinous ascites. Molecular profiling and genetic analysis revealed mutations in ATM, GNAS, and KRAS proteins while IHC demonstrated gastrointestinal-specific staining for CK20, CDX2, CK7, and SATB2. Peritoneal cytology showed paucicellular mucin. Diffuse peritoneal adenomucinosis (DPAM) variant of PMP arising from a ruptured ovarian primary MCT after malignant transformation to a low-grade appendiceal-like mucinous neoplasm was ultimately confirmed. Treatment included staged therapeutic tumor debulking and right salpingo-oophorectomy followed by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). Conclusions Our report builds upon the existing literature supporting this aggressive treatment option reserved for advanced abdominal malignancies utilized in this patient with a rare clinical entity.