Symptom-triggered testing detects early stage and low volume resectable advanced stage ovarian cancer.

OBJECTIVE: Symptom-triggered testing for ovarian cancer was introduced to the UK whereby symptomatic women undergo an ultrasound scan and serum CA125, and are referred to hospital within 2 weeks if these are abnormal. The potential value of symptom-triggered testing in the detection of early-stage disease or low tumor burden remains unclear in women with high grade serous ovarian cancer. In this descriptive study, we report on the International Federation of Gynecology and Obstetrics (FIGO) stage, disease distribution, and complete cytoreduction rates in women presenting via the fast-track pathway and who were diagnosed with high grade serous ovarian cancer. METHODS: We analyzed the dataset from Refining Ovarian Cancer Test accuracy Scores (ROCkeTS), a single-arm prospective diagnostic test accuracy study recruiting from 24 hospitals in the UK. The aim of ROCkeTS is to validate risk prediction models in symptomatic women. We undertook an opportunistic analysis for women recruited between June 2015 to July 2022 and who were diagnosed with high grade serous ovarian cancer via the fast-track pathway. Women presenting with symptoms suspicious for ovarian cancer receive a CA125 blood test and an ultrasound scan if the CA125 level is abnormal. If either of these is abnormal, women are referred to secondary care within 2 weeks. Histology details were available on all women who underwent surgery or biopsy within 3 months of recruitment. Women who did not undergo surgery or biopsy at 3 months were followed up for 12 months as per the national guidelines in the UK. In this descriptive study, we report on patient demographics (age and menopausal status), WHO performance status, FIGO stage at diagnosis, disease distribution (low/pelvic confined, moderate/extending to mid-abdomen, high/extending to upper abdomen) and complete cytoreduction rates in women who underwent surgery. RESULTS: Of 1741 participants recruited via the fast-track pathway, 119 (6.8%) were diagnosed with high grade serous ovarian cancer. The median age was 63 years (range 32-89). Of these, 112 (94.1%) patients had a performance status of 0 and 1, 30 (25.2%) were diagnosed with stages I/II, and the disease distribution was low-to-moderate in 77 (64.7%). Complete and optimal cytoreduction were achieved in 73 (61.3%) and 18 (15.1%). The extent of disease was low in 43 of 119 (36.1%), moderate in 34 of 119 (28.6%), high in 32 of 119 (26.9%), and not available in 10 of 119 (8.4%). Nearly two thirds, that is 78 of 119 (65.5%) women with high grade serous ovarian cancer, underwent primary debulking surgery, 36 of 119 (30.3%) received neoadjuvant chemotherapy followed by interval debulking surgery, and 5 of 119 (4.2%) women did not undergo surgery. CONCLUSION: Our results demonstrate that one in four women identified with high grade serous ovarian cancer through the fast-track pathway following symptom-triggered testing was diagnosed with early-stage disease. Symptom-triggered testing may help identify women with a low disease burden, potentially contributing to high complete cytoreduction rates.

Dyskeratosis congenita with squamous cell carcinoma of the tongue: A rare case report.

ABSTRACT: Dyskeratosis congenita is a rare inherited bone marrow failure disorder characterized by a classic triad: nail dystrophy, reticulate skin pigmentation, and oral leukoplakia. Patients with dyskeratosis congenita have also been described as having gastrointestinal, genitourinary, neurological, ophthalmic, pulmonary, and skeletal abnormalities. Also, 80% of patients are affected with oral leukoplakia and these areas are more prone to develop into oral squamous cell carcinoma. We hereby report a rare case of oral squamous cell carcinoma of the tongue in a young male patient with dyskeratosis congenita.

Investigating age and ethnicity as novel high-risk phenotypes in mucinous ovarian cancer: retrospective study in a multi-ethnic population.

OBJECTIVES: Primary mucinous ovarian carcinoma represents 3% of ovarian cancers and is typically diagnosed early, yielding favorable outcomes. This study aims to identify risk factors, focussing on the impact of age and ethnicity on survival from primary mucinous ovarian cancer. METHODS: A retrospective observational study of patients treated at Sandwell and West Birmingham Hospitals NHS Trust and University Hospital Coventry and Warwickshire. Patients included were women aged ≥16 years, with primary mucinous ovarian cancer confirmed by specialist gynecological histopathologist and tumor immunohistochemistry, including cytokeratin-7, cytokeratin-20, and CDX2. Statistical analyses were performed using R integrated development environment, with survival assessed by Cox proportional hazards models and Kaplan-Meier plots. RESULTS: A total of 163 patients were analyzed; median age at diagnosis was 58 years (range 16-92), 145 (89%) were International Federation of Gynecology and Obstetrics stage I and 43 (26%) patients had infiltrative invasion. Women aged ≤45 years were more likely to have infiltrative invasion (RR=1.38, 95% CI 0.78 to 2.46), with increased risk of death associated with infiltrative invasion (HR=2.29, 95% CI 1.37 to 5.83). Compared with White counterparts, South Asian women were more likely to undergo fertility-sparing surgery (RR=3.52, 95% CI 1.48 to 8.32), and have infiltrative invasion (RR=1.25, 95% CI 0.60 to 2.58). South Asian women undergoing fertility-sparing surgery had worse prognosis than those undergoing traditional staging surgery (HR=2.20, 95% CI 0.39 to 13.14). In FIGO stage I disease, 59% South Asian and 37% White women received adjuvant chemotherapy (p=0.06). South Asian women exhibited a worse overall prognosis than White women (HR=2.07, 95% CI 0.86 to 4.36), particularly pronounced in those aged ≤45 years (HR=8.75, 95% CI 1.22 to 76.38). CONCLUSION: This study identified young age as a risk factor for diagnosis of infiltrative invasion. Fertility-sparing surgery in South Asian women is a risk factor for poorer prognosis. South Asian women exhibit poorer overall survival than their White counterparts.

Glucosyltriazole amphiphile treatment attenuates breast cancer by modulating the AMPK signaling.

Breast cancer is the second most frequent cancer among women. Out of various subtypes, triple-negative breast cancers (TNBCs) account for 15% of breast cancers and exhibit more aggressive characteristics as well as a worse prognosis due to their proclivity for metastatic progression and limited therapeutic strategies. It has been demonstrated that AMP-activated protein kinase (AMPK) has context-specific protumorigenic implications in breast cancer cells. A set of glucosyltriazole amphiphiles, consisting of acetylated (9a-h) and unmodified sugar hydroxyl groups (10a-h), were synthesized and subjected to in vitro biological evaluation. Among them, 9h exhibited significant anticancer activity against MDA-MB-231, MCF-7, and 4T1 cell lines with IC50 values of 12.5, 15, and 12.55 µM, respectively. Further, compound 9h was evaluated for apoptosis and cell cycle analysis in in vitro models (using breast cancer cells) and antitumour activity in an in vivo model (orthotopic mouse model using 4T1 cells). Annexin-V assay results revealed that treatment with 9h caused 34% and 28% cell death at a concentration of 15 or 7.5 µM, respectively, while cell cycle analysis demonstrated that 9h arrested the cells at the G2/M or G1 phase in MCF-7, MDA-MB-231 and 4T1 cells, respectively. Further, in vivo, investigation showed that compound 9h exhibited equipotent as doxorubicin at 7.5 mg/kg, and superior efficacy than doxorubicin at 15 mg/kg. The mechanistic approach revealed that 9h showed potent anticancer activity in an in vivo orthotopic model (4T1 cells) partly by suppressing the AMPK activation. Therefore, modulating the AMPK activation could be a probable approach for targeting breast cancer and mitigating cancer progression.

Safety and Efficacy of Novel Incretin Co-agonist Cotadutide in Biopsy-proven Noncirrhotic MASH With Fibrosis.

BACKGROUND & AIMS: Cotadutide, a peptide co-agonist at the glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptors, has demonstrated robust improvements in body weight, glycemia, and hepatic fat fraction (HFF) in patients living with obesity and type 2 diabetes mellitus. METHODS: In PROXYMO, a 19-week randomized double-blind placebo-controlled trial, the safety and efficacy of cotadutide (600 µg, 300 µg) or placebo were evaluated in 74 participants with biopsy-proven noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis. Analyses were performed using intent-to-treat and modified intent-to-treat population data. RESULTS: Dose- and time-dependent improvements in HFF, alanine aminotransferase (ALT), and aspartate aminotransferase (AST), markers of liver health, and metabolic parameters were observed with significant improvements after 19 weeks with 600 µg ([least squares] mean difference vs placebo, [95% confidence interval] for absolute HFF: -5.0% [-8.5 to -1.5]; ALT: -23.5 U/L [-47.1 to -1.8]; AST: -16.8 U/L [-33.0 to -0.8]). Incidences of any grade treatment-emergent adverse events (TEAEs) were 91.7%, 76.9%, and 37.5% with cotadutide 600 µg, 300 µg, and placebo, respectively. The majority were gastrointestinal, mild to moderate in severity, and generally consistent with other incretins at this stage of development. TEAEs leading to treatment discontinuation were 16.7%, 7.7%, and 4.2% with cotadutide 600 µg, 300 µg, and placebo, respectively. CONCLUSIONS: PROXYMO provides preliminary evidence for the safety and efficacy of GLP-1/GCG receptor co-agonism in biopsy-proven noncirrhotic MASH with fibrosis, supporting further evaluation of this mechanism in MASH. CLINICAL TRIAL REGISTRATION NUMBER: NCT04019561.

Exploring global barriers to optimal ovarian cancer care: thematic analysis.

OBJECTIVE: To explore the barriers to ovarian cancer care, as reported in the open ended responses of a global expert opinion survey, highlighting areas for improvement in global ovarian cancer care. Potential solutions to overcome these barriers are proposed. METHODS: Data from the expert opinion survey, designed to assess the organization of ovarian cancer care worldwide, were analyzed. The survey was distributed across a global network of physicians. We examined free text, open ended responses concerning the barriers to ovarian cancer care. A qualitative thematic analysis was conducted to identify, analyze, and report meaningful patterns within the data. RESULTS: A total of 1059 physicians from 115 countries completed the survey, with 438 physicians from 93 countries commenting on the barriers to ovarian cancer care. Thematic analysis gave five major themes, regardless of income category or location: societal factors, inadequate resources in hospital, economic barriers, organization of the specialty, and need for early detection. Suggested solutions include accessible resource stratified guidelines, multidisciplinary teamwork, public education, and development of gynecological oncology training pathways internationally. CONCLUSIONS: This analysis provides an international perspective on the main barriers to optimal ovarian cancer care. The themes derived from our analysis highlight key target areas to focus efforts to reduce inequalities in global care. Future regional analysis involving local representatives will enable country specific recommendations to improve the quality of care and ultimately to work towards closing the care gap.

Training the gynecologic oncologists of the future - challenges and opportunities.

Several recent advances in gynecologic cancer care have improved patient outcomes. These include national screening and vaccination programs for cervical cancer as well as neoadjuvant chemotherapy for ovarian cancer. Conversely, these advances have cumulatively reduced surgical opportunities for training creating a need to supplement existing training strategies with evidence-based adjuncts. Technologies such as virtual reality and augmented reality, if properly evaluated and validated, have transformative potential to support training. Given the changing landscape of surgical training in gynecologic oncology, we were keen to summarize the evidence underpinning current training in gynecologic oncology.In this review, we undertook a literature search of Medline, Google, Google Scholar, Embase and Scopus to gather evidence on the current state of training in gynecologic oncology and to highlight existing evidence on the best methods to teach surgical skills. Drawing from the experiences of other surgical specialties we examined the use of training adjuncts such as cadaveric dissection, animation and 3D models as well as simulation training in surgical skills acquisition. Specifically, we looked at the use of training adjuncts in gynecologic oncology training as well as the evidence behind simulation training modalities such as low fidelity box trainers, virtual and augmented reality simulation in laparoscopic training. Finally, we provided context by looking at how training curriculums varied internationally.Whereas some evidence to the reliability and validity of simulation training exists in other surgical specialties, our literature review did not find such evidence in gynecologic oncology. It is important that well conducted trials are used to ascertain the utility of simulation training modalities before integrating them into training curricula.

Efficacious Extraction and Purification Technique of a Potential Antimycobacterial Bacteriocin Produced by Bacillus subtilis (MK733983) of Ethnomedicinal Origin.

The rapid proliferation of antibiotic-resistant microbes has imposed an urgent need for development of novel antimicrobial agents with diverse mechanisms. This study reports a novel extraction method with salting-in and salting-out method for obtaining potential bacteriocin from Bacillus subtilis (MK733983) of ethnomedicinal origin. This technique extracted bacteriocin with desired antimicrobial peptide moieties that showed creditable minimum inhibitory concentrations, thermostability and efficacy compared to all other extraction protocols attempted. Further study used a unique scheme of steps in RP-HPLC purification process using methanol-water as solvents for the bacteriocin that achieved an outstanding antimicrobial activity against Staphylococcus aureus (MTCC 737). The bacteriocin is sensitive to proteases, confirming its proteinaceous nature and showed promising heat stability up to 70 °C for 10 min. Bacteriocin extracted from a series of ammonium sulphate precipitation showed MIC values 350 µg and 300 µg for Mycobacterium smegmatis and Staphylococcus aureus respectively. On the other hand, bacteriocin extracted by using chloroform showed MIC values 400 µg and 300 µg for M. smegmatis and Staphylococcus aureus. All the results implicate the efficacy of bacteriocin and future prospect as an effective antimicrobial agent.

Repeatability of MRI Biomarkers in Nonalcoholic Fatty Liver Disease: The NIMBLE Consortium.

Background There is a need for reliable noninvasive methods for diagnosing and monitoring nonalcoholic fatty liver disease (NAFLD). Thus, the multidisciplinary Non-invasive Biomarkers of Metabolic Liver disease (NIMBLE) consortium was formed to identify and advance the regulatory qualification of NAFLD imaging biomarkers. Purpose To determine the different-day same-scanner repeatability coefficient of liver MRI biomarkers in patients with NAFLD at risk for steatohepatitis. Materials and Methods NIMBLE 1.2 is a prospective, observational, single-center short-term cross-sectional study (October 2021 to June 2022) in adults with NAFLD across a spectrum of low, intermediate, and high likelihood of advanced fibrosis as determined according to the fibrosis based on four factors (FIB-4) index. Participants underwent up to seven MRI examinations across two visits less than or equal to 7 days apart. Standardized imaging protocols were implemented with six MRI scanners from three vendors at both 1.5 T and 3 T, with central analysis of the data performed by an independent reading center (University of California, San Diego). Trained analysts, who were blinded to clinical data, measured the MRI proton density fat fraction (PDFF), liver stiffness at MR elastography (MRE), and visceral adipose tissue (VAT) for each participant. Point estimates and CIs were calculated using χ2 distribution and statistical modeling for pooled repeatability measures. Results A total of 17 participants (mean age, 58 years ± 8.5 [SD]; 10 female) were included, of which seven (41.2%), six (35.3%), and four (23.5%) participants had a low, intermediate, or high likelihood of advanced fibrosis, respectively. The different-day same-scanner mean measurements were 13%-14% for PDFF, 6.6 L for VAT, and 3.15 kPa for two-dimensional MRE stiffness. The different-day same-scanner repeatability coefficients were 0.22 L (95% CI: 0.17, 0.29) for VAT, 0.75 kPa (95% CI: 0.6, 0.99) for MRE stiffness, 1.19% (95% CI: 0.96, 1.61) for MRI PDFF using magnitude reconstruction, 1.56% (95% CI: 1.26, 2.07) for MRI PDFF using complex reconstruction, and 19.7% (95% CI: 15.8, 26.2) for three-dimensional MRE shear modulus. Conclusion This preliminary study suggests that thresholds of 1.2%-1.6%, 0.22 L, and 0.75 kPa for MRI PDFF, VAT, and MRE, respectively, should be used to discern measurement error from real change in patients with NAFLD. ClinicalTrials.gov registration no. NCT05081427 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Kozaka and Matsui in this issue.

Diagnostic performance of circulating biomarkers for non-alcoholic steatohepatitis.

There are no approved diagnostic biomarkers for at-risk non-alcoholic steatohepatitis (NASH), defined by the presence of NASH, high histological activity and fibrosis stage ≥2, which is associated with higher incidence of liver-related events and mortality. FNIH-NIMBLE is a multi-stakeholder project to support regulatory approval of NASH-related biomarkers. The diagnostic performance of five blood-based panels was evaluated in an observational (NASH CRN DB2) cohort (n = 1,073) with full spectrum of non-alcoholic fatty liver disease (NAFLD). The panels were intended to diagnose at-risk NASH (NIS4), presence of NASH (OWLiver) or fibrosis stages >2, >3 or 4 (enhanced liver fibrosis (ELF) test, PROC3 and FibroMeter VCTE). The prespecified performance metric was an area under the receiver operating characteristic curve (AUROC) ≥0.7 and superiority over alanine aminotransferase for disease activity and the FIB-4 test for fibrosis severity. Multiple biomarkers met these metrics. NIS4 had an AUROC of 0.81 (95% confidence interval: 0.78-0.84) for at-risk NASH. The AUROCs of the ELF test, PROC3 and FibroMeterVCTE for clinically significant fibrosis (≥stage 2), advanced fibrosis (≥stage 3) or cirrhosis (stage 4), respectively, were all ≥0.8. ELF and FibroMeter VCTE outperformed FIB-4 for all fibrosis endpoints. These data represent a milestone toward qualification of several biomarker panels for at-risk NASH and also fibrosis severity in individuals with NAFLD.

Exploring international differences in ovarian cancer care: a survey report on global patterns of care, current practices, and barriers.

OBJECTIVE: Although global disparities in survival rates for patients with ovarian cancer have been described, variation in care has not been assessed globally. This study aimed to evaluate global ovarian cancer care and barriers to care. METHODS: A survey was developed by international ovarian cancer specialists and was distributed through networks and organizational partners of the International Gynecologic Cancer Society, the Society of Gynecologic Oncology, and the European Society of Gynecological Oncology. Respondents received questions about care organization. Outcomes were stratified by World Bank Income category and analyzed using descriptive statistics and logistic regressions. RESULTS: A total of 1059 responses were received from 115 countries. Respondents were gynecological cancer surgeons (83%, n=887), obstetricians/gynecologists (8%, n=80), and other specialists (9%, n=92). Income category breakdown was as follows: high-income countries (46%), upper-middle-income countries (29%), and lower-middle/low-income countries (25%). Variation in care organization was observed across income categories. Respondents from lower-middle/low-income countries reported significantly less frequently that extensive resections were routinely performed during cytoreductive surgery. Furthermore, these countries had significantly fewer regional networks, cancer registries, quality registries, and patient advocacy groups. However, there is also scope for improvement in these components in upper-middle/high-income countries. The main barriers to optimal care for the entire group were patient co-morbidities, advanced presentation, and social factors (travel distance, support systems). High-income respondents stated that the main barriers were lack of surgical time/staff and patient preferences. Middle/low-income respondents additionally experienced treatment costs and lack of access to radiology/pathology/genetic services as main barriers. Lack of access to systemic agents was reported by one-third of lower-middle/low-income respondents. CONCLUSIONS: The current survey report highlights global disparities in the organization of ovarian cancer care. The main barriers to optimal care are experienced across all income categories, while additional barriers are specific to income levels. Taking action is crucial to improve global care and strive towards diminishing survival disparities and closing the care gap.

Studies on phytochemical, mineral content, in vitro anti-urolithiatic and anti-diabetic activities of horse gram flour extracts and its biosynthesized Ag nanoparticles.

The current study aims to examine the use of horse gram flour and its extracts as a low-cost source of mineral content with anti-urolithiatic, anti-diabetic properties and to compare the biological activities with its biosynthesized AgNPs. The secondary metabolites and the macro and micronutrients present in the selected herbal product, reinforces the utility of the horse gram as a promising herbal. Present investigation reveals that the biomass chosen for the study as a cheap natural source with valuable mineral content of calcium (43.06 mg/L), followed by potassium (13.78 mg/L) and sodium (6.94 mg/L). The grain's water extracts found to contain carbohydrate as dominating component with the value of (65.10 ± 0.95 mg g-1 equivalent). Whereas both water and ethanol extract contain TPC (phenol) viz; 60.13 ± 2.45 mg g-1, 68.24 ± 1.33 mg g-1, TTC (terpenoids)53.21 ± 1.4 mg g-1,51.27 ± 2.65 mg g-1, followed by TSC (sterol)as 45.58 ± 1.7 mg g-1, 57.27 ± 1.65 mg g-1 in moderate amounts respectively. The aqueous extract of Horse gram was used for the synthesis the AgNPs through a straightforward green approach and characterized by FESEM, TEM, zeta potential, X-ray diffraction, UV spectroscopy and particle size measurement. These studies demonstrate the production of AgNPs with an average particle size of 30 nm-60 nm. Investigation on anti-urolithiatic property with aqueous extract, (HGW), ethanol extract (HGE) and its biosynthesized Ag nanoparticles (HG-Ag) reveal that, among the three samples chosen, the biosynthesized Ag nanoparticles possess the best inhibiting activity. The disintegration of crystals in gel medium further validated the extracts and Ag nanoparticles crystal growth inhibitory activity, at concentrations of 2% for extracts and 200 µg/ml for AgNPs. Further, it is also found that the HG-Ag nanoparticle exhibit good anti-diabetic activity (75.36%) than the other two extracts (HGW Extract-67.18% & HGE Extract-44.29%). Thus, the seed flour extracts and its AgNps demonstrated to be a promising natural herbal product with potential mineral content, antidiabetic and anti-urolithiatic activities which could be a used as a value-added product in the dietary formulations.

Utility of GATA-3 and associated immunohistochemical markers in the differential diagnosis of poorly differentiated urothelial carcinoma.

Aims: The aims are to study the utility of GATA-3 along with panel of immunohistochemical (IHC) markers in the differential diagnosis of primary and metastatic poorly differentiated urothelial carcinoma (UC). Settings and Design: This is a prospective and retrospective observational study. Subjects and Methods: Poorly differentiated carcinomas of urinary tract and metastatic sites from January 2016 to December 2017 were subjected to a panel of four IHC markers including GATA-3, p63, Cytokeratin (CK) 7, and CK20. Additional markers such as p16, an enzyme called alpha-methylacyl-CoA racemase, CDX2, and thyroid transcription factor 1 were also done depending on the morphology and site. Statistical Analysis Used: The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of GATA-3 in making the diagnosis of UC were calculated. Results: Forty-five cases were included in the study and after appropriate IHC, the diagnosis was resolved as UC in 24 cases. GATA-3 was positive in 83.33% of UC; all the four markers positive in 33.33% and all negative in 4.17% of UC. However, at least one of the four markers was present in 95.83% of UC, except in sarcomatoid UC. GATA-3 had 100% specificity in differentiating from prostate adenocarcinoma. Conclusion: GATA-3 is a useful marker in the diagnosis of UC in the primary and metastatic sites with a sensitivity of 83.33%. GATA-3 along with other IHC markers in correlation with clinical and imageological features is necessary for making specific diagnosis of poorly differentiated carcinoma.

A genome-wide CRISPR screen maps endogenous regulators of PPARG gene expression in bladder cancer.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor central in the regulation of key cellular processes including cell metabolism, tissue differentiation, and regulation of the immune system. PPARγ is required for normal differentiation of the urothelium and is thought to be an essential driver of the luminal subtype of bladder cancer. However, the molecular components that regulate PPARG gene expression in bladder cancer remain unclear. Here, we developed an endogenous PPARG reporter system in luminal bladder cancer cells and performed genome-wide CRISPR knockout screening to identify bona fide regulators of PPARG gene expression. Functional validation of the dataset confirmed GATA3, SPT6, and the cohesin complex components SMC1A, and RAD21, as permissive upstream positive regulators of PPARG gene expression in luminal bladder cancer. In summary, this work provides a resource and biological insights to aid our understanding of PPARG regulation in bladder cancer.

Homologous recombination deficiency in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian cancer: a multi-national observational study.

OBJECTIVE: Olaparib plus bevacizumab maintenance therapy improves survival outcomes in women with newly diagnosed, advanced, high-grade ovarian cancer with a deficiency in homologous recombination. We report data from the first year of routine homologous recombination deficiency testing in the National Health Service (NHS) in England, Wales, and Northern Ireland between April 2021 and April 2022. METHODS: The Myriad myChoice companion diagnostic was used to test DNA extracted from formalin-fixed, paraffin-embedded tumor tissue in women with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage III/IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. Tumors with homologous recombination deficiency were those with a BRCA1/2 mutation and/or a Genomic Instability Score (GIS) ≥42. Testing was coordinated by the NHS Genomic Laboratory Hub network. RESULTS: The myChoice assay was performed on 2829 tumors. Of these, 2474 (87%) and 2178 (77%) successfully underwent BRCA1/2 and GIS testing, respectively. All complete and partial assay failures occurred due to low tumor cellularity and/or low tumor DNA yield. 385 tumors (16%) contained a BRCA1/2 mutation and 814 (37%) had a GIS ≥42. Tumors with a GIS ≥42 were more likely to be BRCA1/2 wild-type (n=510) than BRCA1/2 mutant (n=304). The distribution of GIS was bimodal, with BRCA1/2 mutant tumors having a higher mean score than BRCA1/2 wild-type tumors (61 vs 33, respectively, χ2 test p<0.0001). CONCLUSION: This is the largest real-world evaluation of homologous recombination deficiency testing in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. It is important to select tumor tissue with adequate tumor content and quality to reduce the risk of assay failure. The rapid uptake of testing across England, Wales, and Northern Ireland demonstrates the power of centralized NHS funding, center specialization, and the NHS Genomic Laboratory Hub network.

Performance Evaluation and Cyberattack Mitigation in a Blockchain-Enabled Peer-to-Peer Energy Trading Framework.

With the electric power grid experiencing a rapid shift to the smart grid paradigm over a deregulated energy market, Internet of Things (IoT)-based solutions are gaining prominence, and innovative peer-to-peer (P2P) energy trading at a micro level is being deployed. Such advancement, however, leaves traditional security models vulnerable and paves the path for blockchain, a distributed ledger technology (DLT), with its decentralized, open, and transparency characteristics as a viable alternative. However, due to deregulation in energy trading markets, most of the prototype resilience regarding cybersecurity attack, performance and scalability of transaction broadcasting, and its direct impact on overall performances and attacks are required to be supported, which becomes a performance bottleneck with existing blockchain solutions such as Hyperledger, Ethereum, and so on. In this paper, we design a novel permissioned Corda framework for P2P energy trading peers that not only mitigates a new class of cyberattacks, i.e., delay trading (or discard), but also disseminates the transactions in a optimized propagation time, resulting in a fair transaction distribution. Sharing transactions in a permissioned R3 Corda blockchain framework is handled by the Advanced Message Queuing Protocol (AMQP) and transport layer security (TLS). The unique contribution of this paper lies in the use of an optimized CPU and JVM heap memory scenario analysis with P2P metric in addition to a far more realistic multihosted testbed for the performance analysis. The average latencies measured are 22 ms and 51 ms for sending and receiving messages. We compare the throughput by varying different types of flow such as energy request, request + pay, transfer, multiple notary, sender, receiver, and single notary. In the proposed framework, request is an energy asset that is based on payment state and contract in the P2P energy trading module, so in request flow, only one node with no notary appears on the vault of the node.Energy request + pay flow interaction deals with two nodes, such as producer and consumer, to deal with request and transfer of asset ownership with the help of a notary. Request + repeated pay flow request, on node A and repeatedly transfers a fraction of energy asset state to another node, B, through a notary.

Predictors of Advance Care Planning Engagement Among Muslim Americans.

Advance care planning (ACP) enables people to discuss their physical, psychological, social, and spiritual needs before nearing death. Most literature examining the determinants of ACP engagement is limited and does not include minority faith communities in the United States, including Muslim communities. The purpose of this cross-sectional correlational study was to examine ACP engagement determinants among Muslims in the United States. Using the Social Ecological Model, we conceptualized the determinants of ACP engagement into intrapersonal, interpersonal, and community factors. The study self-administered questionnaires were distributed using convenience and snowball techniques. Multiple linear regression was used to predict ACP engagement. The total sample was 148 Muslim adults. The age range was 18 to 79 years. Among all tested factors, being Asian American, knowing a deceased person who had received aggressive or minimal medical treatments near death, being born in the United States, having knowledge and awareness about ACP, and being accepting of the American culture were the determinants of ACP engagement. Engagement in ACP is a multifactorial behavior. Several intrapersonal and interpersonal factors, but none of the community factors, were associated with ACP engagement among Muslim adults. Future ACP interventions targeted toward Muslim Americans should be planned with an understanding of the multifactorial nature of ACP engagement.

Frequency of Nucleophosmin 1 Expression by Immunohistochemistry in Acute Myeloid Leukemia.

Nucleophosmin (NPM1) mutation is one of the most common recurring genetic abnormalities seen in acute myeloid leukemia (AML). Immunohistochemistry serves as a cost effective and simple surrogate testing method for detection of NPM1 mutation. This study was conducted to evaluate the frequency of aberrant cytoplasmic nucleophosmin 1 expression in leukemic blast cells on formalin fixed bone marrow trephine biopsy (BMB) sections and also to correlate this data with the reference molecular method (reverse transcriptase-polymerase chain reaction; RT-PCR and gene sequencing), where available. Immunostains were performed using mouse anti-NPM1 monoclonal antibody on 71 paraffin embedded bone marrow biopsies (BMB) of patients with AML of any French-American-British (FAB) subtype. Results of immunohistochemistry (IHC) were then compared with the reference molecular method. The proportion of NPM1 expression by immunostaining in AML cases was found to be 17%. Twelve of the total 71 cases demonstrated cytoplasmic nucleophosmin (NPMc+) on immunostaining. Eleven of the positive cases that were correlated with the molecular standard demonstrated mutation in exon 12 of NPM1 gene. Cytoplasmic nucleophosmin expression by immunostaining was found to be in complete agreement with the standard molecular method. In a resource restricted setup, the information from this study might help in providing an inexpensive and accurate detection method to facilitate introduction of this marker in diagnostic and prognostic workup of AML especially in patients showing normal karyotype and no common recurrent translocations.

Polyol-assisted hydrothermal synthesis of Mn-doped α - Fe2O3(MFO) nanostructures: Spin disorder-induced magnetism and photocatalytic properties.

Hierarchical nanostructures play an important role in environmental clean-up and sustainability applications. The magnetic and photocatalytic characteristics of flower-like Mn-doped α-Fe2O3 nanostructures were prepared by using a polyol-assisted hydrothermal method. Crystallite sizes are in the range of 35-42 nm, and the existence of 3D hierarchical nanostructures was observed in FESEM pictures. The optical band gap energy varies between 2.08 and 2.16 eV, while XPS examination exposes the ions' charge states and validates Mn3+ inclusion in the Fe3+ lattice. At room temperature, the addition of Mn to α-Fe2O3 results in a spin disorder ferromagnetism and coercivity of about 600 Oe was achieved. Methylene blue (MB) dye solution degraded by 92% when 2.5% Mn doped with α-Fe2O3 under visible conditions for 120 min irradiation time.

Association of combined second trimester maternal serum Homocysteine and Uterine Artery Doppler to predict adverse pregnancy outcome.

Introduction: Disturbances in placentation increase the risk of maternal and fetal complications. Several biochemical and imaging modalities have been studied, but the hunt for a single effective screening test never became a reality as the causes of this complex condition are multifactorial and polygenetic, many of which we are only beginning to discover. Not many studies have been conducted in the developing countries like India and other low resource settings to consider whether it would be worthwhile to combine inexpensive and effective markers together for better prediction of adverse pregnancy outcome.This study primarily aims to investigate the predictability of combined screening with maternal serum homocysteine and second trimester uterine artery Doppler in diagnosis of adverse pregnancy outcome. Methodology: A prospective cohort study which involved 100 women with singleton gestation, meeting the inclusion criteria, attending the inpatient or outpatient of Obstetrics and Gynaecology in Amrita Institute of Medical Sciences, Kerala, a tertiary care centre in Southern India from July 2016 and September 2018 was conducted. Serum Homocysteine estimation (tHcy) was done between 18 and 28 weeks of gestation with informed consent, and uterine artery (UA) Doppler PI which is a non-invasive routine study was done along with targeted second trimester anomaly scan (18-24 weeks) in Fetal Medicine Department. Cutoff values of tHcy and UA PI were computed at 95th (> / = 9.7 mmol/l) and 90th percentile, respectively as reported by Onalan et al. [9] and Nicholaides et al. [4]. Statistical analysis was performed using IBM SPSS version 20.0 software. Chi-square test and diagnostic measures were also used. Results: Of the 100 patients, 15% (n = 15) developed hypertensive disorder. 7% (n = 7) had FGR and 7%(n = 7) had spontaneous preterm birth. 6% (n = 6) neonates had an APGAR score < 7 and 8% neonates (n = 8) required immediate NICU admission. Statistically significant association was found when tHcy and UA PI were used together for the prediction of FGR (p = 0.003), preterm birth (p = 0.002) and low APGAR score at birth (p = 0.009) with a specificity of 83.4%. With regard to PIH, both parameters were found to be statistically significant only when used independently (p = 0.001) but not when used in combination (p = 0.17). Both elevated tHcy and abnormal UA PI used in combination predicted adverse pregnancy outcome like FGR but with a low sensitivity of 14.3% and high specificity of 98.9%. However, when used independently these markers predicted FGR with a better sensitivity (tHcy- 28.6% and UA PI- 44.4%). Conclusion: Findings from this study have been promising with potential clinical implications for the diagnosis and management of high-risk pregnancies. Though the independent role of the two markers in screening various adverse pregnancy outcomes could be proved, their combined use to improve predictivity of more complications warrants further studies on a larger population with appropriate randomisation.