Association of Opioid Disposal Practices with Parental Education and a Home Opioid Disposal Kit Following Pediatric Ambulatory Surgery.

BACKGROUND: The majority of opioid analgesics prescribed for pain after ambulatory pediatric surgery remain unused. Most parents do not dispose of these leftover opioids or dispose of them in an unsafe manner. We aimed to evaluate the association of optimal opioid disposal with a multidisciplinary quality improvement (QI) initiative that proactively educated parents about the importance of optimal opioid disposal practices and provided a home opioid disposal kit before discharge after pediatric ambulatory surgery. METHODS: Opioid disposal behaviors were assessed during a brief telephone interview pre- (Phase I) and post-implementation (Phase II) after surgery. For each phase, we aimed to contact the parents of 300 pediatric patients ages 0 to 17 years who were prescribed an opioid after an ambulatory surgery. The QI initiative included enhanced education and a home opioid disposal kit including DisposeRX®, a medication disposal packet that renders medications inert within a polymeric gel when mixed with water. Weighted segmented regression models evaluated the association between the QI initiative and outcomes. We considered the association between the QI initiative and outcome significant if the beta coefficient for the change in intercept between the end of Phase I and the beginning of Phase II was significant. Safe opioid disposal and any opioid disposal were evaluated as secondary outcomes. RESULTS: The analyzed sample contained 161 pediatric patients in Phase I and 190 pediatric patients in Phase II. Phase II (post-QI initiative) cohort compared to Phase I cohort reported higher rates of optimal (58%, n = 111/190 vs 11%, n = 18/161) and safe (66%, n = 125/190 vs 34%, n = 55/161) opioid disposal. Weighted segmented regression analyses demonstrated significant increases in the odds of optimal (odds ratio [OR], 26.5, 95% confidence interval [CI], 4.0-177.0) and safe (OR, 4.4, 95% CI, 1.1-18.4) opioid disposal at the beginning of Phase II compared to the end of Phase I. The trends over time (slopes) within phases were nonsignificant and close to 0. The numbers needed to be exposed to achieve one new disposal event were 2.2 (95% CI, 1.4-3.7]), 3.1 (95% CI, 1.6-7.4), and 4.3 (95% CI, 1.7-13.6) for optimal, safe, and any disposal, respectively. CONCLUSIONS: A multidisciplinary approach to educating parents on the importance of safe disposal of leftover opioids paired with dispensing a convenient opioid disposal kit was associated with increased odds of optimal opioid disposal.

Early Complications of Planned Resection Versus Unplanned Excision of Sarcomas in the Distal Upper Extremity.

Purpose: Unplanned excisions are defined as excisions of malignant tumors performed without preoperative cross-sectional imaging or diagnostic biopsy, frequently resulting in residual disease and re-excision secondary to positive surgical margins. The purpose of this study was to compare the relative morbidity of planned versus unplanned upper-extremity sarcoma excisions. Methods: A single tertiary referral hospital pathology database was queried from January 2015 through 2022 for primary upper-extremity sarcomas (forearm, wrist, hand, and finger). Demographics, tumor features, survival characteristics, and outcomes were retrospectively reviewed. Results: Forty-two upper-extremity sarcoma patients were identified, two-thirds of whom had unplanned excisions. Those with unplanned excisions were more likely to be female (relative risk [RR]: 1.9; P = .002), undergo initial excision at a nonsarcoma center (RR: 14.0; P < .001), have masses distal to the forearm (RR: 1.6; P = .02), and have smaller masses (4.8 vs 7.4 cm, P = .03). 71.4% of tumors were high grade, and 60.7% less than 5 cm in size.Unplanned excisions had positive margins in 96.4% of cases and were more likely to undergo re-excision (odds ratio [OR]: 20.0; P = .001), more total resections (2.7 vs 1.4, P = .009), sacrifice of neurovascular structures (OR: 6.1; P = .04), adjuvant radiation therapy (OR: 4.5; P = .05), adjuvant systemic therapy (OR: 10.9; P = .03), or experience a complication (OR: 17.6; P = .002) at an average of 38.0 months of follow-up.Nearly half of all unplanned excision patients developed a local recurrence or metastatic disease. Six patients required an amputation versus one in the planned cohort (P = .17), and 26.5% of patients died at an average of 32.5 months from presentation. Conclusions: Distal upper-extremity sarcoma excisions are frequently unplanned, with high rates of morbidity compared with planned excisions. Surgeons should have a low threshold for cross-sectional imaging and core needle biopsy of atypical lesions, irrespective of size, with referral to a sarcoma center. Type of study/level of evidence: Prognostic IV.

Treatment of a Carpal Giant Cell Tumor of Bone With Curettage and Cemented Capitohamate Fusion.

Carpal giant cell tumor of bone spanning multiple bones is a rare condition. We present a case of a man in his fifth decade with wrist pain who was found to have giant cell tumor of bone involving his capitate and hamate bones. This condition was successfully treated with intralesional curettage, argon beam coagulation, chemical cauterization and a cemented limited carpal fusion with satisfactory outcomes and no recurrence at 1-year postoperative follow-up.

Antimüllerian hormone levels are associated with time to pregnancy in a prospective cohort study of 3,150 women.

OBJECTIVE: To study the association between antimüllerian hormone (AMH) levels and time of pregnancy. Although it has been hypothesized that serum AMH levels may indicate the chance of conception, findings have been mixed. Given that any association is expected to be modest, and it is possible that previous studies have been underpowered, we investigated this relationship in the largest prospective cohort to date. DESIGN: Prospective time-to-pregnancy cohort study. SETTING: Community. PATIENT(S): A total of 3,150 US women who had been trying to conceive for <3 months and had purchased a Modern Fertility hormone test. INTERVENTION(S): We developed a discrete time-to-event model using a binomial complementary log-log error structure within a generalized additive modeling framework, adjusting for confounding factors such as age, body mass index, parity, smoking status, polycystic ovary syndrome, and others. Sensitivity analyses were performed in women with regular menstrual cycles (21-35 days), who did not report using fertility treatments, using alternate AMH level categories (<0.7, 0.7-8.5, >8.5 ng/mL), and AMH levels as a continuous measure. MAIN OUTCOME MEASURE(S): Primary outcomes included cumulative conception probability within 12 cycles and relative fecundability per menstrual cycle. Conception was defined by a self-reported positive pregnancy test. RESULT(S): Participants contributed 7.21 ± 5.32 cycles, with 1,325 (42.1%) achieving a pregnancy. Women with low AMH levels (<1 ng/mL, n = 427) had a lower chance of natural conception (adjusted hazard ratio [adjHR], 0.77; 95% confidence interval [CI], 0.64-0.94) compared with women with normal AMH levels (1-5.5 ng/mL). There was no difference between high (5.5+ ng/mL) and normal AMH level categories (adjHR, 1.11; 95% CI, 0.94-1.31). The inclusion of AMH improved the model (net reclassification index 0.10 [0.06-0.14]). The instantaneous probability of conception was highest in cycle four across all AMH categories: the probability of natural conception was 11.2% (95% CI, 9.0-14.0) for low AMH levels, 14.3% (95% CI, 12.3-16.5) for normal AMH levels, and 15.7% (95% CI, 12.9-19.0) for high AMH levels. In the regular cycles sensitivity analysis (n = 1,791), the low AMH group had a lower chance of conception (adjHR, 0.77; 95% CI, 0.61-0.97) in the low AMH group compared with normal AMH, and similarly in the continuous model (adjHR, 0.90; 95% CI, 0.85-0.95). CONCLUSION(S): Low AMH levels (<1 ng/mL) are independently associated with a modest but significant reduction in the chance of conception.

Latent Epstein-Barr virus infection collaborates with Myc over-expression in normal human B cells to induce Burkitt-like Lymphomas in mice.

Epstein-Barr virus (EBV) is an important cause of human lymphomas, including Burkitt lymphoma (BL). EBV+ BLs are driven by Myc translocation and have stringent forms of viral latency that do not express either of the two major EBV oncoproteins, EBNA2 (which mimics Notch signaling) and LMP1 (which activates NF-κB signaling). Suppression of Myc-induced apoptosis, often through mutation of the TP53 (p53) gene or inhibition of pro-apoptotic BCL2L11 (BIM) gene expression, is required for development of Myc-driven BLs. EBV+ BLs contain fewer cellular mutations in apoptotic pathways compared to EBV-negative BLs, suggesting that latent EBV infection inhibits Myc-induced apoptosis. Here we use an EBNA2-deleted EBV virus (ΔEBNA2 EBV) to create the first in vivo model for EBV+ BL-like lymphomas derived from primary human B cells. We show that cord blood B cells infected with both ΔEBNA2 EBV and a Myc-expressing vector proliferate indefinitely on a CD40L/IL21 expressing feeder layer in vitro and cause rapid onset EBV+ BL-like tumors in NSG mice. These LMP1/EBNA2-negative Myc-driven lymphomas have wild type p53 and very low BIM, and express numerous germinal center B cell proteins (including TCF3, BACH2, Myb, CD10, CCDN3, and GCSAM) in the absence of BCL6 expression. Myc-induced activation of Myb mediates expression of many of these BL-associated proteins. We demonstrate that Myc blocks LMP1 expression both by inhibiting expression of cellular factors (STAT3 and Src) that activate LMP1 transcription and by increasing expression of proteins (DNMT3B and UHRF1) known to enhance DNA methylation of the LMP1 promoters in human BLs. These results show that latent EBV infection collaborates with Myc over-expression to induce BL-like human B-cell lymphomas in mice. As NF-κB signaling retards the growth of EBV-negative BLs, Myc-mediated repression of LMP1 may be essential for latent EBV infection and Myc translocation to collaboratively induce human BLs.

A Randomized Trial of Two Remote Health Care Delivery Models on the Uptake of Genetic Testing and Impact on Patient-Reported Psychological Outcomes in Families With Pancreatic Cancer: The Genetic Education, Risk Assessment, and Testing (GENERATE) Study.

BACKGROUND & AIMS: Genetic testing uptake for cancer susceptibility in family members of patients with cancer is suboptimal. Among relatives of patients with pancreatic ductal adenocarcinoma (PDAC), The GENetic Education, Risk Assessment, and TEsting (GENERATE) study evaluated 2 online genetic education/testing delivery models and their impact on patient-reported psychological outcomes. METHODS: Eligible participants had ≥1 first-degree relative with PDAC, or ≥1 first-/second-degree relative with PDAC with a known pathogenic germline variant in 1 of 13 PDAC predisposition genes. Participants were randomized by family, between May 8, 2019, and June 1, 2021. Arm 1 participants underwent a remote interactive telemedicine session and online genetic education. Arm 2 participants were offered online genetic education only. All participants were offered germline testing. The primary outcome was genetic testing uptake, compared by permutation tests and mixed-effects logistic regression models. We hypothesized that Arm 1 participants would have a higher genetic testing uptake than Arm 2. Validated surveys were administered to assess patient-reported anxiety, depression, and cancer worry at baseline and 3 months postintervention. RESULTS: A total of 424 families were randomized, including 601 participants (n = 296 Arm 1; n = 305 Arm 2), 90% of whom completed genetic testing (Arm 1 [87%]; Arm 2 [93%], P = .014). Arm 1 participants were significantly less likely to complete genetic testing compared with Arm 2 participants (adjusted ratio [Arm1/Arm2] 0.90, 95% confidence interval 0.78-0.98). Among participants who completed patient-reported psychological outcomes questionnaires (Arm 1 [n = 194]; Arm 2 [n = 206]), the intervention did not affect mean anxiety, depression, or cancer worry scores. CONCLUSIONS: Remote genetic education and testing can be a successful and complementary option for delivering genetics care. (Clinicaltrials.gov, number NCT03762590).

Clinical compatibility of magnetic resonance imaging with magnetic intramedullary nails: a feasibility study.

INTRODUCTION: The use of magnetic resonance imaging (MRI) with a magnetic intramedullary lengthening nail in place is contraindicated per the manufacturer due to the concern of implant activation and migration. A prior in vitro study did not confirm these complications only noting that a 3.0 T MRI weakened the internal magnet. Therefore, a retrospective analysis of patients who underwent an MRI with a magnetic nail in place was performed to determine if any adverse effects occurred in the clinical setting. MATERIALS AND METHODS: A retrospective review of all patients who underwent an MRI with a magnetic lengthening nail in place was performed. The time spent being imaged in the MRI, number of times the patient entered the MRI suite, and the images obtained were recorded. Radiographs were performed before and after the MRI to determine if any hardware complications occurred. The patients were monitored for any adverse symptoms while they were in the suite. RESULTS: A total of 12 patients with 13 nails were identified. Two patients underwent imaging with a 3.0 T MRI while the remaining 10 underwent imaging with a 1.5 T MRI. Each patient entered the MRI suite 2.1 times and spent an average of 84.7 min being imaged in the MRI (range 21-494). No patients noted any adverse symptoms related to the nail while in the suite and no hardware complications were identified. CONCLUSION: MRI appears to be safe with a magnetic nail in place and did not result in any complications. Given the manufacturer's recommendations, informed consent should be obtained prior to an MRI being performed and a 3.0 T MRI should be avoided when possible if further activation of the nail is required.

Luteal phase support in assisted reproductive technology.

Infertility affects one in six couples, with in vitro fertilization (IVF) offering many the chance of conception. Compared to the solitary oocyte produced during the natural menstrual cycle, the supraphysiological ovarian stimulation needed to produce multiple oocytes during IVF results in a dysfunctional luteal phase that can be insufficient to support implantation and maintain pregnancy. Consequently, hormonal supplementation with luteal phase support, principally exogenous progesterone, is used to optimize pregnancy rates; however, luteal phase support remains largely 'black-box' with insufficient clarity regarding the optimal timing, dosing, route and duration of treatment. Herein, we review the evidence on luteal phase support and highlight remaining uncertainties and future research directions. Specifically, we outline the physiological luteal phase, which is regulated by progesterone from the corpus luteum, and evaluate how it is altered by the supraphysiological ovarian stimulation used during IVF. Additionally, we describe the effects of the hormonal triggers used to mature oocytes on the degree of luteal phase support required. We explain the histological transformation of the endometrium during the luteal phase and evaluate markers of endometrial receptivity that attempt to identify the 'window of implantation'. We also cover progesterone receptor signalling, circulating progesterone levels associated with implantation, and the pharmacokinetics of available progesterone formulations to inform the design of luteal phase support regimens.

Beyond the Umbrella: A Systematic Review of the Interventions for the Prevention of and Reduction in the Incidence and Severity of Ovarian Hyperstimulation Syndrome in Patients Who Undergo In Vitro Fertilization Treatments.

Ovarian hyperstimulation syndrome (OHSS) is the main severe complication of ovarian stimulation for in vitro fertilization (IVF) cycles. The aim of the current study was to identify the interventions for the prevention of and reduction in the incidence and severity of OHSS in patients who undergo IVF not included in systematic reviews with meta-analyses of randomized controlled trials (RCTs) and assess and grade their efficacy and evidence base. The best available evidence for each specific intervention was identified, analyzed in terms of safety/efficacy ratio and risk of bias, and graded using the Oxford Centre for Evidence-Based Medicine (CEBM) hierarchy of evidence. A total of 15 interventions to prevent OHSS were included in the final analysis. In the IVF population not at a high risk for OHSS, follitropin delta for ovarian stimulation may reduce the incidence of early OHSS and/or preventive interventions for early OHSS. In high-risk patients, inositol pretreatment, ovulation triggering with low doses of urinary hCG, and the luteal phase administration of a GnRH antagonist may reduce OHSS risk. In conclusion, even if not supported by systematic reviews with homogeneity of the RCTs, several treatments/strategies to reduce the incidence and severity of OHSS have been shown to be promising.

Interventions to prevent or reduce the incidence and severity of ovarian hyperstimulation syndrome: a systematic umbrella review of the best clinical evidence.

Ovarian hyperstimulation syndrome (OHSS) is a potentially life-threating iatrogenic complication of the early luteal phase and/or early pregnancy after in vitro fertilization (IVF) treatment. The aim of the current study was to identify the most effective methods for preventing of and reducing the incidence and severity of OHSS in IVF patients. A systematic review of systematic reviews of randomized controlled trials (RCTs) with meta-analysis was used to assess each potential intervention (PROSPERO website, CRD 268626) and only studies with the highest quality were included in the qualitative analysis. Primary outcomes included prevention and reduction of OHSS incidence and severity. Secondary outcomes were maternal death, incidence of hospital admission, days of hospitalization, and reproductive outcomes, such as incidence of live-births, clinical pregnancies, pregnancy rate, ongoing pregnancy, miscarriages, and oocytes retrieved. A total of specific interventions related to OHSS were analyzed in 28 systematic reviews of RCTs with meta-analyses. The quality assessment of the included studies was high, moderate, and low for 23, 2, and 3 studies, respectively. The certainty of evidence (CoE) for interventions was reported for 37 specific situations/populations and resulted high, moderate, and low-to-very low for one, 5, and 26 cases, respectively, while it was not reported in 5 cases. Considering the effective interventions without deleterious reproductive effects, GnRH-ant co-treatment (36 RCTs; OR 0.61, 95% C 0.51 to 0.72, n = 7,944; I2 = 31%) and GnRH agonist triggering (8 RCTs; OR 0.15, 95% CI 0.05 to 0.47, n = 989; I2 = 42%) emerged as the most effective interventions for preventing OHSS with a moderate CoE, even though elective embryo cryopreservation exhibited a low CoE. Furthermore, the use of mild ovarian stimulation (9 RCTs; RR 0.26, CI 0.14 to 0.49, n = 1,925; I2 = 0%), and dopaminergic agonists (10 RCTs; OR 0.32, 95% CI 0.23 to 0.44, n = 1,202; I2 = 13%) coadministration proved effective and safe with a moderate CoE. In conclusion, the current study demonstrates that only a few interventions currently can be considered effective to reduce the incidence of OHSS and its severity with high/moderate CoE despite the numerous published studies on the topic. Further well-designed RCTs are needed, particularly for GnRH-a down-regulated IVF cycles.

Fibroblast Activation Protein Expression in Sarcomas.

Objectives: Fibroblast activation protein alpha (FAP) is highly expressed by cancer-associated fibroblasts in multiple epithelial cancers. The aim of this study was to characterize FAP expression in sarcomas to explore its potential utility as a diagnostic and therapeutic target and prognostic biomarker in sarcomas. Methods: Available tissue samples from patients with bone or soft tissue tumors were identified at the University of California, Los Angeles. FAP expression was evaluated via immunohistochemistry (IHC) in tumor samples (n = 63), adjacent normal tissues (n = 30), and positive controls (n = 2) using semiquantitative systems for intensity (0 = negative; 1 = weak; 2 = moderate; and 3 = strong) and density (none, <25%, 25-75%; >75%) in stromal and tumor/nonstromal cells and using a qualitative overall score (not detected, low, medium, and high). Additionally, RNA sequencing data in publicly available databases were utilized to compare FAP expression in samples (n = 10,626) from various cancer types and evaluate the association between FAP expression and overall survival (OS) in sarcoma (n = 168). Results: The majority of tumor samples had FAP IHC intensity scores ≥2 and density scores ≥25% for stromal cells (77.7%) and tumor cells (50.7%). All desmoid fibromatosis, myxofibrosarcoma, solitary fibrous tumor, and undifferentiated pleomorphic sarcoma samples had medium or high FAP overall scores. Sarcomas were among cancer types with the highest mean FAP expression by RNA sequencing. There was no significant difference in OS in patients with sarcoma with low versus high FAP expression. Conclusion: The majority of the sarcoma samples showed FAP expression by both stromal and tumor/nonstromal cells. Further investigation of FAP as a potential diagnostic and therapeutic target in sarcomas is warranted.

The landscape of drug sensitivity and resistance in sarcoma.

Sarcomas are a family of rare malignancies composed of over 100 distinct histological subtypes. The rarity of sarcoma poses significant challenges in conducting clinical trials to identify effective therapies, to the point that many rarer subtypes of sarcoma do not have standard-of-care treatment. Even for established regimens, there can be substantial heterogeneity in responses. Overall, novel, personalized approaches for identifying effective treatments are needed to improve patient out-comes. Patient-derived tumor organoids (PDTOs) are clinically relevant models representative of the physiological behavior of tumors across an array of malignancies. Here, we use PDTOs as a tool to better understand the biology of individual tumors and characterize the landscape of drug resistance and sensitivity in sarcoma. We collected n=194 specimens from n=126 sarcoma patients, spanning 24 distinct subtypes. We characterized PDTOs established from over 120 biopsy, resection, and metastasectomy samples. We leveraged our organoid high-throughput drug screening pipeline to test the efficacy of chemotherapeutics, targeted agents, and combination therapies, with results available within a week from tissue collection. Sarcoma PDTOs showed patient-specific growth characteristics and subtype-specific histopathology. Organoid sensitivity correlated with diagnostic subtype, patient age at diagnosis, lesion type, prior treatment history, and disease trajectory for a subset of the compounds screened. We found 90 biological pathways that were implicated in response to treatment of bone and soft tissue sarcoma organoids. By comparing functional responses of organoids and genetic features of the tumors, we show how PDTO drug screening can provide an orthogonal set of information to facilitate optimal drug selection, avoid ineffective therapies, and mirror patient outcomes in sarcoma. In aggregate, we were able to identify at least one effective FDA-approved or NCCN-recommended regimen for 59% of the specimens tested, providing an estimate of the proportion of immediately actionable information identified through our pipeline. Highlights: Standardized organoid culture preserve unique sarcoma histopathological featuresDrug screening on patient-derived sarcoma organoids provides sensitivity information that correlates with clinical features and yields actionable information for treatment guidanceHigh-throughput screenings provide orthogonal information to genetic sequencingSarcoma organoid response to treatment correlates with patient response to therapyLarge scale, functional precision medicine programs for rare cancers are feasible within a single institution.

Epstein-Barr virus LMP1 protein promotes proliferation and inhibits differentiation of epithelial cells via activation of YAP and TAZ.

Latent Epstein-Barr virus (EBV) infection promotes undifferentiated nasopharyngeal carcinomas (NPCs) in humans, but the mechanism(s) for this effect has been difficult to study because EBV cannot transform normal epithelial cells in vitro and the EBV genome is often lost when NPC cells are grown in culture. Here we show that the latent EBV protein, LMP1 (Latent membrane protein 1), induces cellular proliferation and inhibits spontaneous differentiation of telomerase-immortalized normal oral keratinocytes (NOKs) in growth factor-deficient conditions by increasing the activity of the Hippo pathway effectors, YAP (Yes-associated protein) and TAZ (Transcriptional coactivator with PDZ-binding motif). We demonstrate that LMP1 enhances YAP and TAZ activity in NOKs both by decreasing Hippo pathway-mediated serine phosphorylation of YAP and TAZ and increasing Src kinase-mediated Y357 phosphorylation of YAP. Furthermore, knockdown of YAP and TAZ is sufficient to reduce proliferation and promote differentiation in EBV-infected NOKs. We find that YAP and TAZ are also required for LMP1-induced epithelial-to-mesenchymal transition. Importantly, we demonstrate that ibrutinib (an FDA-approved BTK inhibitor that blocks YAP and TAZ activity through an off-target effect) restores spontaneous differentiation and inhibits proliferation of EBV-infected NOKs at clinically relevant doses. These results suggest that LMP1-induced YAP and TAZ activity contributes to the development of NPC.

FAPI PET Signal in Hibernoma Reflects FAP Expression in Tumor Vasculature Cells.

ABSTRACT: A 43-year-old man with a growing mass in the right groin, concerned for liposarcoma, underwent MRI and 68 Ga-fibroblast activation protein inhibitor (FAPI)-46 PET/CT before surgery. Fibroblast activation protein inhibitor PET/CT demonstrated increased uptake (SUV max , 3.2) predominantly in the solid portion, where MRI showed gadolinium enhancement. The patient subsequently underwent surgery and was diagnosed with hibernoma. The immunohistochemistry of the tumor revealed the fibroblast activation protein expression in the fibrovascular network and myofibroblastic cells of the tumor. This case suggests that the FAPI uptake can be affected by the vascular cells, and thus, a careful interpretation of the FAPI PET signal may be needed.

Study protocol: examining the impacts of COVID-19 mitigation measures on pregnancy and birth outcomes in Scotland-a linked administrative data study.

INTRODUCTION: This protocol outlines aims to test the wider impacts of the COVID-19 pandemic on pregnancy and birth outcomes and inequalities in Scotland. METHOD AND ANALYSIS: We will analyse Scottish linked administrative data for pregnancies and births before (March 2010 to March 2020) and during (April 2020 to October 2020) the pandemic. The Community Health Index database will be used to link the National Records of Scotland Births and the Scottish Morbidity Record 02. The data will include about 500 000 mother-child pairs. We will investigate population-level changes in maternal behaviour (smoking at antenatal care booking, infant feeding on discharge), pregnancy and birth outcomes (birth weight, preterm birth, Apgar score, stillbirth, neonatal death, pre-eclampsia) and service use (mode of delivery, mode of anaesthesia, neonatal unit admission) during the COVID-19 pandemic using two analytical approaches. First, we will estimate interrupted times series regression models to describe changes in outcomes comparing prepandemic with pandemic periods. Second, we will analyse the effect of COVID-19 mitigation measures on our outcomes in more detail by creating cumulative exposure variables for each mother-child pair using the Oxford COVID-19 Government Response Tracker. Thus, estimating a potential dose-response relationship between exposure to mitigation measures and our outcomes of interest as well as assessing if timing of exposure during pregnancy matters. Finally, we will assess inequalities in the effect of cumulative exposure to lockdown measures on outcomes using several axes of inequality: ethnicity/mother's country of birth, area deprivation (Scottish Index of Multiple Deprivation), urban-rural classification of residence, number of previous children, maternal social position (National Statistics Socioeconomic Classification) and parental relationship status. ETHICS AND DISSEMINATION: NHS Scotland Public Benefit and Privacy Panel for Health and Social Care scrutinised and approved the use of these data (1920-0097). Results of this study will be disseminated to the research community, practitioners, policy makers and the wider public.

Lifelong Imaging Surveillance is Indicated for Patients with Primary Retroperitoneal Liposarcoma.

BACKGROUND: Surveillance imaging of patients with retroperitoneal liposarcoma (RP-LPS) after surgical resection is based on a projected risk of locoregional and distant recurrence. The duration of surveillance is not well defined because the natural history of RP-LPS after treatment is poorly understood. This study evaluated the long-term risk of recurrence and disease-specific survival (DSS) for a cohort of patients with at least 10 years of progression-free survival (10yr-PFS) from their primary resection. METHODS: The prospective University of California, Los Angeles (UCLA) Sarcoma Database identified RP-LPS patients with 10yr-PFS after initial resection. The patients in the 10yr-PFS cohort were subsequently evaluated for recurrence and DSS. The time intervals start at date of initial surgical resection. Cox proportional hazards models were used to determine factors associated with recurrence and DSS. RESULTS: From 1972 to 2010, 76 patients with RP-LPS had at least 10 years of follow-up evaluation. Of these 76 patients, 39 (51%) demonstrated 10yr-PFS. The median follow-up period was 15 years (range 10-33 years). Among the 10yr-PFS patients, 49% (19/39) experienced a recurrence at least 10 years after surgery. Of those who experienced recurrence, 42% (8/19) died of disease. Neither long-term recurrence nor DSS were significantly associated with age, sex, tumor size, LPS subtype, surgical margin, or perioperative treatment with radiation or chemotherapy. CONCLUSION: Patients who have primary RP-LPS treated with surgical resection ± multimodality therapy face a long-term risk of recurrence and disease-specific death unacknowledged by current surveillance imaging guidelines. Among the patients with 10yr-PFS, 49% experienced a recurrence, and 42% of those died of disease. These findings suggest a need for lifelong surveillance imaging for patients with RP-LPS.

Prediction of ovarian response using the automated Elecsys anti-Müllerian hormone assay in gonadotrophin-releasing hormone antagonist cycles.

RESEARCH QUESTION: What is the capability of serum anti-Müllerian hormone (AMH) measured using the automated Elecsys® AMH immunoassay to (Roche Diagnostics International Ltd) determine ovarian response after fertility treatment? DESIGN: Single-centre, retrospective, observational, cohort study including women undergoing ovarian stimulation. Serum AMH concentrations were determined using the Elecsys AMH immunoassay based on one blood sample drawn 6 months or less before treatment. Stimulation was conducted in accordance with a gonadotrophin-releasing hormone (GnRH) antagonist protocol. Patients were divided into four ovarian response categories based on their oocyte yield: low (0-3), suboptimal (4-9), optimal (10-15) and high (>15). Areas under the curve were calculated for each ovarian response group. RESULTS: Overall, 1248 patients were enrolled. The AMH concentration had a strong positive correlation with oocyte yield (Spearman's rho = 0.74, P < 0.001). Areas under the curve (95% CI) for AMH predicting ovarian response were 0.85 (0.83 to 0.88) for low and 0.89 (0.87 to 0.91) for high response. Optimal serum AMH cut-offs for predicting a low and high response using the Elecsys AMH immunoassay were 6.4 pmol/l (0.89 ng/ml) and 14.2 pmol/l (1.99 ng/ml), respectively. Multivariable regression analysis showed that 47% (R2 = 0.470) of variation in ovarian response could be attributed to AMH alone, increasing to 50.9% (R2 = 0.509) with the addition of age, body weight, and total dose of gonadotrophin. CONCLUSION: Ovarian response and oocyte yield after stimulation in a GnRH antagonist cycle can be predicted with high accuracy using a single determination of serum AMH before ovarian stimulation.

General health in a cohort of children conceived after assisted reproductive technology in the United Kingdom: a population-based record-linkage study.

BACKGROUND: Assisted reproductive technology use is increasing annually; however, data on long-term child health outcomes including hospital admissions are limited. OBJECTIVE: This study aimed to examine the potential effects of assisted reproductive technology on any and cause-specific hospital admissions unrelated to perinatal diagnoses. STUDY DESIGN: This was a population-based record-linkage study that included a previously established cohort of children born after assisted reproductive technology in the United Kingdom between 1997 and 2009 (n=63,877), their naturally conceived siblings (n=11,343), and matched naturally conceived population controls (n=127,544) linked to their postnatal health outcomes up to March 31, 2016 to provide robust risk estimates of the potential effects of assisted reproductive technology on any and cause-specific hospital admissions unrelated to perinatal diagnoses. In addition, comparison of hospital admissions by type of treatment was made. Cox regression was used to estimate the risk of hospital admission, and negative binomial regression was used to compare the number of hospital admissions per year. RESULTS: This study had 1.6 million person-years of follow-up (mean, 12.9 years; range, 0-19 years), and the mean age at the time of first hospital admission was 6.5 years (range, 0-19 years). Singletons born after assisted reproductive technology had increased risk of any hospital admission compared with naturally conceived population controls (hazard ratio, 1.08; 95% confidence interval, 1.05-1.10) but not naturally conceived siblings (hazard ratio, 1.01; 95% confidence interval, 0.94-1.09). We observed increased risk of diagnoses related to neoplasms and diseases of the respiratory, musculoskeletal, digestive, and genitourinary systems, and lower risk of injury, poisoning, and consequences of external causes compared with naturally conceived population controls. Children born after intracytoplasmic sperm injection had a lower risk of hospital admission compared with those born after in vitro fertilization, although no such differences were observed between children born after fresh embryo transfers and those born after frozen embryo transfers. CONCLUSION: Children born after assisted reproductive technology had greater numbers of hospital admissions compared with naturally conceived population controls. Attenuation of these differences in relation to their naturally conceived siblings suggested that this could be partially attributed to the influence of parental subfertility on child health, increased parental concerns, and an actual increase in morbidity in children born after assisted conception.

Label-free intraoperative histology of bone tissue via deep-learning-assisted ultraviolet photoacoustic microscopy.

Obtaining frozen sections of bone tissue for intraoperative examination is challenging. To identify the bony edge of resection, orthopaedic oncologists therefore rely on pre-operative X-ray computed tomography or magnetic resonance imaging. However, these techniques do not allow for accurate diagnosis or for intraoperative confirmation of the tumour margins, and in bony sarcomas, they can lead to bone margins up to 10-fold wider (1,000-fold volumetrically) than necessary. Here, we show that real-time three-dimensional contour-scanning of tissue via ultraviolet photoacoustic microscopy in reflection mode can be used to intraoperatively evaluate undecalcified and decalcified thick bone specimens, without the need for tissue sectioning. We validate the technique with gold-standard haematoxylin-and-eosin histology images acquired via a traditional optical microscope, and also show that an unsupervised generative adversarial network can virtually stain the ultraviolet-photoacoustic-microscopy images, allowing pathologists to readily identify cancerous features. Label-free and slide-free histology via ultraviolet photoacoustic microscopy may allow for rapid diagnoses of bone-tissue pathologies and aid the intraoperative determination of tumour margins.