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Background. Third-generation aromatase inhibitors (AIs) are the mainstay of treatment in hormone receptor (HR)-positive breast cancer. Even though it is considered to be a well-tolerated therapy, AI-induced musculoskeletal symptoms are common and may be accused for treatment discontinuation. Recently, selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors changed the therapeutic setting, and currently, ribociclib, palbociclib, and abemaciclib are all approved in combination with nonsteroidal AIs in patients with ER-positive, HER2-negative advanced or metastatic breast cancer. This systematic review aims to identify the frequency of aromatase inhibitor-associated musculoskeletal syndrome (AIMSS) in the adjuvant setting in patients under AI monotherapy compared to patients under combination therapy with AIs and CDK4/6 inhibitors and demonstrate the underlying mechanism of action. Methods. This study was performed in accordance with PRISMA guidelines. The literature search and data extraction from all randomized clinical trials (RCTs) were done by two independent investigators. Eligible articles were identified by a search of MEDLINE and ClinicalTrial.gov database concerning the period 2000/01/01–2021/05/01. Results. Arthralgia was reported in 13.2 to 68.7% of patients receiving AIs for early-stage breast cancer, while arthralgia induced by CDK4/6 inhibitors occurred in a much lower rate [20.5–41.2%]. Bone pain (5–28.7% vs. 2.2–17.2%), back pain (2–13.4% vs. 8–11.2%), and arthritis (3.6–33.6% vs. 0.32%) were reported less frequently in patients receiving the combination of CDK4/6 inhibitors with ET. Conclusions. CDK4/6 inhibitors might have a protective effect against joint inflammation and arthralgia occurrence. Further studies are warranted to investigate arthralgia incidence in this population.

Motorway users have various opinions about the types of smart motorways. Motor-way utilization can be affected if road users have a negative perception towards certain types of smart motorway, particularly on the topic of safety. There are three types of smart motorways in the UK. These are Controlled, Dynamic and All-Lane Running. This study focuses on the comparison of ALR and DHS smart motorways as ALR smart motorways are aiming to replace and improve upon DHS smart motorways. The aim of this project is to understand how the general population perceive smart motorways in the UK. This aim will be achieved through answering a series of these research questions: (1) How does existing knowledge of smart motorways effect perception of smart motorways; (2) How does age effect perception of smart motorways; (3) How does car ownership affect perception of smart motorways? Data were collected using an online survey disseminated to the UK vehicle and non-vehicle drivers via social media and advertisements. Descriptive statistics and cluster analysis were used to analyse the dataset and find similarity clusters. The primary research shows that ~57% of the survey respondents had never heard of or did not know the meaning of the 3 different types of smart motorway and only ~13% of respondents fully understand the different types. Car owners in both cluster analysis models show substantial variation in the results of the comfort / smart motorway choice variables. Greater knowledge and awareness about smart motorways is required to improve the perception of smart motorways. It would seem that this is particularly true for all-lane running smart motorways which are both the newest and most physically different type of smart motorway with their removal of the hard shoulder.

Background: Immune checkpoint inhibitors (ICIs) have been widely implemented in the treatment of solid tumors. Although epithelial ovarian carcinoma is considered as scarcely immunogenic, the presence of tumor-infiltrating T lymphocytes (TILs) in the ovarian tumor microenvironment (TME) could increase sensitivity to immune checkpoint inhibitors (ICIs). Combinations of ICIs with chemotherapy, anti-VEGF compounds and PARP inhibitors are under evaluation in ovarian cancer. Recently, a Phase II study evaluated the efficacy of Pembrolizumab in Combination with bevacizumab and oral cyclophosphamide in patients with recurrent platinum-sensitive, platinum-resistant, or refractory epithelial ovarian cancer.Methods: Herein, we present a retrospective study of all patients who received pembrolizumab in combination with bevacizumab and oral cyclophosphamide for recurrent platinum-resistant heavily pretreated ovarian cancer in the Oncology Unit of Alexandra University Hospital.Results: Median age at diagnosis was 54.5 years (SD; 8.9; range: 44–72). All patients were diagnosed with high-grade serous ovarian carcinoma (HGSC). Initial disease stage was FIGO IIIC (8/10; 80%), IIIB (1/10; 10%) and IIC (1/10; 10%)). Patients were heavily pretreated with a median of 6 (range: 4–9) prior lines of systemic therapy. All patients have experienced disease progression on first-line platinum-based chemotherapy and median PFS to first-line treatment was 20.1 months (95%CI; 11.4 – 28.7). Patients received a median of 4 cycles of pembrolizumab in combination with cyclophosphamide and bevacizumab (range 2-11). ORR was 20% (2/10) with two patients achieving partial response (PR) and two patients achieving stable disease (SD) while disease control rate (DCR) was 40% (4/10). Median PFS was 2.7 months (95%; 0.6 – 4.8) and 6-month PFS rate 20%. Conclusions: Though our data reflect a small population, we here demonstrate that the combination of pembrolizumab with bevacizumab and oral cyclophosphamide is an effective alternative in platinum-resistant recurrent ovarian carcinoma. This novel combination provides a promising alternative in heavily pretreated patients that have otherwise limited treatment options.

Background: There is limited data on the optimal time interval between the last dose of neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) in high-grade serous ovarian carcinoma (HGSC). Methods: We retrospectively identified patients with stage IIIC/IV HGSC who received NACT followed by IDS during a 15-year period (January 2003–December 2018) in our Institution. Results: Overall, 115 patients with stage IIIC/IV HGSC were included. The median age of diagnosis was 62.7 years (IQR: 14.0). A total of 76.5% (88/115) of patients were diagnosed with IIIC HGSC and 23.5% (27/115) with IV HGSC. Median PFS was 15.7 months (95% CI: 13.0–18.5), and median OS was 44.7 months (95% CI: 38.8–50.5). Patients were categorized in groups according to the time interval from NACT to IDS: 6 weeks (group D). Patients with a time interval IDS to NACT ≥4 weeks had significantly shorter PFS (p = 0.004) and OS (p = 0.002). Median PFS was 26.6 months (95% CI: 24–29.2) for patients undergoing IDS 4 week time interval NACT to IDS groups (p = 0.002). On multivariate analysis, the short time interval (

Cancer-associated retinopathy (CAR) is a rare paraneoplastic disorder mediated by auto-antibodies that cross-react with retinal antigens leading to gradual visual defects. Early diagnosis and initiation of treatment is crucial to avoid permanent visual loss. Although most patients with CAR respond to intravenous steroids and intravenous immunoglobulin (IVIG), there are some cases refractory to the aforementioned treatment strategies. The present study describes a case of CAR in a patient with ovarian cancer that was initially resistant to most treatment regimens (chemotherapy, steroids, IVIG). Treatment with rituximab at 375 mg/m(2) and oral cyclophosphamide was administered and the patient showed marked improvement of visual acuity. Electroretinogram showed a 40 and 10% improvement in scotopic and photopic vision, respectively. Notably, at the most recent follow up, the patient was still in remission. In conclusion, treatment with intravenous rituximab and oral cyclophosphamide is a promising treatment option for those cases of CAR that do not respond to steroids, immunomodulatory agents and IVIG.

The use and shareability of Clinical Quality Language (CQL) artefacts is an important aspect in enabling the exchange and interoperability of clinical data to support both clinical decisions and research in the medical informatics field. This paper, while basing on use cases and synthetic data, developed purposeful CQL reusable libraries to showcase the possibilities of multidisciplinary teams and how CQLs could be best used to support clinical decision making.

Over 50% of breast tumors harbor alterations in one or more genes of the phosphatidylinositol 3-kinase (PI3K) pathway including PIK3CA mutations (31%), PTEN loss (34%), PTEN mutations (5%) and AKT1 mutations (3%). While PI3K and mTOR inhibitors are already approved in advanced breast cancer, AKT inhibitors have been recently developed as a new therapeutic approach. Capivasertib (AZD5363) is a novel, selective ATP-competitive pan-AKT kinase inhibitor that exerts similar activity against the three AKT isoforms, AKT1, AKT2, and AKT3. Preclinical studies demonstrated efficacy of capivasertib in breast cancer cell lines as a single agent or in combination with anti-HER2 agents and endocrine treatment, especially in tumors with PIK3CA or MTOR alterations. Phase I/II studies demonstrated greater efficacy when capivasertib was co-administered with paclitaxel, fulvestrant in hormone receptor (HR)-positive, HER2-negative breast cancer or olaparib. The recommended phase II dose of capivasertib as monotherapy was 480 mg bid on a 4-days-on, 3-days-off dosing schedule. Toxicity profile proved to be manageable with hyperglycemia (20-24%), diarrhea (14-17%) and maculopapular rash (11-16%) being the most common grade ≥3 adverse events. Ongoing Phase III trials of capivasertib in combination with fulvestrant (CAPItello-291), CDK4/6 inhibitor palbociclib (CAPItello-292) and paclitaxel (CAPItello- 290) will better clarify the therapeutic role of capivasertib in breast cancer.

Motorway users have various opinions about the types of smart motorways. Motorway utilization can be affected if road users have a negative perception of certain types of smart motorways, particularly on the topic of safety. There are three types of smart motorways that can be found in the UK. These are Controlled Smart Motorways (CSM), Dynamic Hard Shoulder (DHS), and All-Lane Running (ALR). This study focuses on the comparison of ALR and DHS smart motorways as ALR smart motorways are developed to replace and improve upon DHS smart motorways.

Background. Third-generation aromatase inhibitors (AIs) are the mainstay of treatment in hormone receptor (HR)-positive breast cancer. Even though it is considered to be a well-tolerated therapy, AI-induced musculoskeletal symptoms are common and may be accused for treatment discontinuation. Recently, selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors changed the therapeutic setting, and currently, ribociclib, palbociclib, and abemaciclib are all approved in combination with nonsteroidal AIs in patients with ER-positive, HER2-negative advanced or metastatic breast cancer. This systematic review aims to identify the frequency of aromatase inhibitor-associated musculoskeletal syndrome (AIMSS) in the adjuvant setting in patients under AI monotherapy compared to patients under combination therapy with AIs and CDK4/6 inhibitors and demonstrate the underlying mechanism of action. Methods. This study was performed in accordance with PRISMA guidelines. The literature search and data extraction from all randomized clinical trials (RCTs) were done by two independent investigators. Eligible articles were identified by a search of MEDLINE and ClinicalTrial.gov database concerning the period 2000/01/01–2021/05/01. Results. Arthralgia was reported in 13.2 to 68.7% of patients receiving AIs for early-stage breast cancer, while arthralgia induced by CDK4/6 inhibitors occurred in a much lower rate [20.5–41.2%]. Bone pain (5–28.7% vs. 2.2–17.2%), back pain (2–13.4% vs. 8–11.2%), and arthritis (3.6–33.6% vs. 0.32%) were reported less frequently in patients receiving the combination of CDK4/6 inhibitors with ET. Conclusions. CDK4/6 inhibitors might have a protective effect against joint inflammation and arthralgia occurrence. Further studies are warranted to investigate arthralgia incidence in this population.

Undoubtedly, the development of COVID-19 vaccines displays a critical step towards ending this devastating pandemic, considering their protective benefits in the general population. Yet, data regarding their efficacy and safety in cancer patients are limited. Herein we provide the initial analysis of immune responses after the first dose of vaccination in 21 breast cancer patients receiving cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors. The levels of neutralizing antibodies post vaccination were similar to the matched healthy controls, whereas no safety issues have been raised. Further exploration is needed to reduce the uncertainty of SARS-CoV-2 immunity among cancer patients under treatment.

Uterine serous carcinoma accounts for 3–10% of endometrial cancers, but it is the most lethal histopathological subtype. The molecular characterization of endometrial carcinomas has allowed novel therapeutic approaches for these patients. We undertook a retrospective analysis of patients with uterine serous carcinomas treated in our hospital within the last two decades to identify possible changes in their management. The patients and their characteristics were evenly distributed across the two decades. Treatment modalities did not change significantly throughout this period. After adjuvant treatment, patients’ median disease-free survival was 42.07 months (95% CI: 20.28–63.85), and it did not differ significantly between the two decades (p = 0.059). The median overall survival was 47.51 months (95% Cl: 32.18–62.83), and it significantly favored the first decade’s patients (p = 0.024). In patients with de novo metastatic or recurrent disease, median progression-free survival was 7.8 months (95% Cl: 5.81–9.93), whereas both the median progression-free survival and the median overall survival of these patients did not show any significant improvement during the examined time period. Overall, the results of our study explore the minor changes in respect of uterine serous carcinoma’s treatment over the last two decades, which are reflected in the survival outcomes of these patients and consequently underline the critical need for therapeutic advances in the near future.

Background: High grade serous ovarian carcinoma (HGSOC) is the most lethal type of epithelial ovarian cancer, with a prevalence of germline BRCA1/2 mutations as high as 20%. Our objective is to determine whether the location of mutations in the different domains of the BRCA1/2 genes affects the clinical outcome of HGSOC patients. Methods: A total of 51 women with BRCA1 or BRCA2 mutated ovarian cancer were identified. Progression-free survival (PFS) and overall survival (OS) were analyzed. Results: In our study cohort, 35 patients were carriers of germline mutations in BRCA1 and 16 in BRCA2. The median PFS time following completion of the primary therapy was 23.8 months (95% CI 20.1–27.5) and the median OS was 92.9 months (95% CI 69.8–116.1) in all BRCA carriers. After multivariate analysis, no significant association among the location or type of BRCA1/2 mutation with PFS or OS was identified. Notably, significant differences in PFS between carriers of identical mutations in the same BRCA gene were detected. Conclusions: Among HGSOC patients, BRCA1/2 carriers with mutations in different locations of the genes show no significant difference in survival outcomes, in terms of PFS and OS, suggesting the potential effect of other genetic abnormalities and co-contributing risk factors.

Background Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) is the recommended approach in patients with advanced epithelial ovarian cancer (EOC). However, most patients eventually relapse despite the initial high response rate to chemotherapy. Neutrophil-to-lymphocyte ratio is a well-known biomarker that reflects severe inflammation, critical illness, and mortality in various diseases. Chemotherapy response score (CRS) and neutrophil-to-lymphocyte ratio (NLR) have been identified as potential biomarkers of platinum resistance and disease prognosis. We retrospectively evaluated 132 patients with stage IIIc or IV ovarian/fallopian tube/primary peritoneal cancer who had received NACT followed by IDS from 01/01/2003 to 31/12/2018. CRS was assessed on omental specimens collected from IDS according to ICCR guidelines. Results Median age was 64.57 years (SD: 9.72; range 39.2–87.1). Most ovarian tumors were serous epithelial (90.9%; 120/132). An elevated NLR (defined as > 3) was observed in 72% (95/132) of patients in contrast with 28% (37/132) of patients characterized by low NLR status. Median PFS (mPFS) and median overall survival (mOS) were 13.05 months (95% CI: 11.42–14.67)) and 34.69 months (95% CI: 23.26–46.12) respectively. In univariate analysis, CRS3 score was significantly associated with prolonged mPFS (CRS1/2: 12.79 months vs CRS3: 17.7 months; P = 0.008). CRS score was not associated with mOS (P = 0.876). High NLR was not significantly associated with mPFS (P = 0.128), however it was significantly associated with poor mOS (P = 0.012). In multivariate analysis, only performance of surgery maintained its statistical significance with both PFS (P = 0.001) and OS (P = 0.008). Conclusion NLR could serve as a useful predictor of OS but not PFS in ovarian cancer patients receiving NACT. In accordance with our previous study, CRS score at omentum was found to be associated with PFS but not OS in ovarian cancer patients treated with NACT and IDS., Research highlights Biomarkers that would predict response to neoadjuvant chemotherapy in advanced ovarian cancer patients are eagerly needed: • Neutrophil to Lymphocyte Ratio (NLR) is an indicator of systemic inflammatory response to the malignancy. • NLR was evaluated in 132 patients undergoing Neoadjuvant Chemotherapy for advanced ovarian cancer. • Elevated NLR was associated with worse prognosis. • No association between NLR and response to chemotherapy was noted.

Background Tumor protein 53 (TP53) gene mutations are identified in up to 37% of breast tumors especially in HER-2 positive and basal-like subtype. Previous studies have indicated TP53 mutations as a prognostic biomarker in breast cancer. However, most of these studies performed immunohistochemistry (IHC) for the detection of TP53 mutations. Aim The purpose of our study is to evaluate the role of TP53 somatic mutations detected via next-generation sequencing (NGS) as a potential prognostic marker in patients with breast cancer. Materials and methods 82 female patients with Stage I-III breast cancer underwent NGS in paraffin blocks and blood samples during the period 25/09/2019 through 25/05/2021. 23 cases of somatic TP53 mutations and 23 cases of healthy controls were matched on age at diagnosis, menopausal status, histological subtype, histological grade, ki67 expression and disease stage. Results Mean age at diagnosis was 52.35 (SD; 11.47) years. The somatic TP53 mutation NM_000546.5:c.824G>A p.(Cys275Tyr) was most frequently detected. Co-existence of PIK3CA mutation was a common finding in somatic TP53-mutant tumors (4/23; 17.4%). Disease-free survival was shorter in TP53-mutated cases (16.3 months vs. 62.9 months). TP53 pathogenic somatic mutations were associated with a 8-fold risk of recurrence in the univariate Cox regression analysis (OR = 8.530, 95% CI: 1.81-40.117; p = 0.007). Conclusions Our case-control study suggests that TP53 somatic mutations detected by next-generation sequencing (NGS) are associated with an adverse prognosis in breast cancer.

The research that studies the improvement of elementary school students' science knowledge and the development of elementary students' abilities to use the scientific and engineering practices is restricted. The purpose of this research is to study the effects of an instructional intervention on the knowledge of the students of elementary school about electromagnets and their abilities to design science investigations. Instructional material about electromagnets was developed, based on an inquiry-based approach using the scientific and engineering practices, which was applied to 76 students of elementary school (12 years old). To evaluate the students' knowledge of electromagnets as well as their abilities to design science investigations, a questionnaire was developed which was completed by the students both before and after the instructional intervention. The data of the research were the answers of the students to the questionnaires. The data analysis showed that the students' knowledge about electromagnets as well as their abilities to design science investigations was improved, through the instructional intervention for electromagnets.

Objective Gastroschisis is a full-thickness congenital defect of the abdominal wall through which intestines and other organs may herniate. In a prior analysis, attempted vaginal delivery with fetal gastroschisis appeared to increase through 2013, although cesarean delivery remained common. The objective of this analysis was to update current trends in attempted vaginal birth among pregnancies complicated by gastroschisis. Study Design We performed an updated cross-sectional analysis of live births from 2014 and 2020 using data from the U.S. National Vital Statistics System and evaluated trends in attempted vaginal deliveries among births with gastroschisis. Trends were evaluated using joinpoint regression. We constructed logistic regression models to evaluate the association between demographic and clinical variables and attempted vaginal delivery in the setting of gastroschisis. Results Among 5,355 deliveries with gastroschisis meeting inclusion criteria, attempted vaginal delivery increased significantly from 68.9% to 75.1%, an average annual percent change of 1.7% (95% confidence interval [CI], 0.8–2.5). Among gastroschisis-complicated pregnancies, patients 35 to 39 years old (adjusted odds ratio [aOR], 0.53; 95% CI, 0.37–0.79) and Hispanic race/ethnicity (aOR, 0.69; 95% CI, 0.58–0.62) were at lower likelihood of attempted vaginal delivery in adjusted analyses. Conclusion These findings suggest that vaginal delivery continues to increase in the setting of gastroschisis. Further reduction of surgical delivery for this fetal defect may be possible. Key Points

In this research work, the development and application of a distributed rainfall – runoff model, to be used in flood related simulations was performed. The model utilizes the time–area diagram theory in order to calculate and route the runoff of each grid to the basin’s outlet. The selected study area is the upper part of the Alfeios river basin, the Karitaina basin, located in southern Greece, while historic rainfall data from regional rain gauges were used, which were interpolated through GIS tools into spatially gridded rainfall fields, with a one-hour temporal scale. The performance of the distributed model was evaluated through its comparison with two lumped models, one based on GIS techniques and the other one based on the unit hydrograph derived from historical rainfall-runoff events. Finally, the abovementioned models were also compared and evaluated with the observed hydrograph of the studied event. The results showed that the distributed model performed well considering that no calibration has been carried out regarding the hydrological losses.

Here the authors examine whether bell sounds can have an impact onambient aerosol levels and size distribution under atmospheric conditions.The authors present calculation results for acoustic coagulation by churchbell sounds for a range of ambient aerosol types. The results show thatfor orthokinetic sonic agglomeration, while the frequency spectrum ofchurch bells is ideal for causing coagulation of ambient aerosols, the soundpressure level (SPL) becomes too low for an effect. However, for verypolluted conditions, at extremely short distances from the bell dust aerosolscan readily undergo sonic coagulation.

BACKGROUND There is limited data on the optimal time interval between the last dose of neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) in high-grade serous ovarian carcinoma (HGSC). METHODS We retrospectively identified patients with stage IIIC/IV HGSC who received NACT followed by IDS during a 15-year period (January 2003-December 2018) in our Institution that is certified by the European Society of Gynecologic Oncology (ESGO) as a center of excellence for the treatment of ovarian cancer. RESULTS Overall, 115 patients with HGSC stage IIIC/IV were included. Median age of diagnosis was 62.7 years (IQR: 14.0). 76.5% (88/115) of patients were diagnosed with IIIC HGSC and 23.5% (27/115) with IV HGSC. Median PFS was 15.7 months (95% CI: 13.0–18.5) and median OS was 44.7 (95% CI: 38.8–50.5). Patients were categorized in groups according to time interval from NACT to IDS (6 weeks (group D). Patients with a time interval IDS to NACT ≥ 4 weeks had significantly shorter PFS (p = 0.004) and OS (p = 0.002). Median PFS was 26.6 months (95% CI: 24–29.2) for patients undergoing IDS p = 0.004). Accordingly, median OS was 66.3 months (95% CI: 39.1–93.4) versus 39.4 months (95% CI: 31.8–47.0) in the 4 week time interval NACT to IDS groups (p = 0.002). On multivariate analysis, short time interval (p = 0.004) and OS (p = 0.003). CONCLUSION We have demonstrated that performing IDS within 4 weeks after NACT may be associated with better survival outcomes. Multidisciplinary coordination of ovarian cancer patients is required to avoid any unnecessary delays.

Archäologie im Rheinland, 2012(2013)

Cardiovascular disease is the leading cause of death worldwide. Given the increased availability of radiopharmaceuticals, improved positron emission tomography (PET) camera systems and proven higher diagnostic accuracy, PET is increasingly utilized in the management of various cardiovascular diseases. PET has high temporal and spatial resolution, when compared to Single Photon Emission Computed Tomography. In clinical practice, hybrid imaging with sequential PET and Computed Tomography acquisitions (PET/CT) or concurrent PET and Magnetic Resonance Imaging are standard. This article will review applications of cardiovascular PET/CT including myocardial perfusion, viability, cardiac sarcoidosis/inflammation, and infection.

Computable knowledge artefact development is challenging and often culminates in the development of unique single usage solutions. Libraries of computable knowledge artefacts have the possibility to enhance the Learning Health System in order to improve the benefits of innovation and the decision making of clinicians. This paper aims to discuss the process of creating the use cases and the tutorial material that would enable students to both understand how the interaction between the dataset and the outcome occurs as well as how HL7 Clinical Quality Language can be used to create artefacts of re-usable code.

The administration of a third dose of a vaccine against SARS-CoV-2 has increased protection against disease transmission and severity. However, the kinetics of neutralizing antibodies against the virus has been poorly studied in cancer patients under targeted therapies. Baseline characteristics and levels of neutralizing antibodies at specific timepoints after vaccination were compared between patients suffering from breast, ovarian or prostate cancer and healthy individuals. Breast cancer patients were treated with cyclin D kinase 4/6 inhibitors and hormonal therapy, ovarian cancer patients were treated with poly (ADP-ribose) polymerase inhibitors and prostate cancer patients were treated with an androgen receptor targeted agent. Levels of neutralizing antibodies were significantly lower in cancer patients compared to healthy individuals at all timepoints. Antibodies’ titers declined over time in both groups but remained above protective levels (>50%) at 6 months after the administration of the second dose. The administration of a third dose increased neutralizing antibodies’ levels in both groups. The titers of protective against SARS-CoV-2 antibodies wane over time and increase after a third dose in cancer patients under treatment.

Computable knowledge artefact development is challenging and often culminates in the development of unique single usage solutions. Libraries of computable knowledge artefacts have the possibility to enhance the Learning Health System in order to improve the benefits of innovation and the decision making of clinicians. This paper aims to discuss the process of creating the use cases and the tutorial material that would enable students to both understand how the interaction between the dataset and the outcome occurs as well as how HL7 Clinical Quality Language can be used to create artefacts of re-usable code.

BackgroundGermline BRCA1/2 mutations are identified in 13-15% of ovarian cancers, while an additional 5-7% of ovarian cancers harbor somatic BRCA1/2 mutations. Beyond these mutations, germline or somatic aberrations in genes of the homologous recombination (HR) pathway such as RAD51B/C/D, PALB2, ATM, BRIP1 may confer an HR deficiency in up to 50% of ovarian tumors. Next-generation sequencing (NGS) is a high-throughput massive parallel sequencing method that enables the simultaneous detection of several mutations in entire genomes.MethodsWe performed NGS analysis in 86 patients with ovarian cancer treated in the Oncology Department of Alexandra University Hospital in order to identify the molecular landscape of germline and somatic mutations in ovarian cancer.ResultsThe genes with the highest number of pathogenic somatic mutations in high grade serous carcinoma (HGSC) patients were TP53 [68%; 34/50] and BRCA1 [22%; 11/50] followed by somatic mutations in RB1 [2%; 1/50], NF1 [2%; 1/50], BRCA2 [2%; 1/50], AKT1 [2%; 1/50], RAD50 [2%; 1/50], PIK3CA [2%; 1/50] genes. Of note, the most common TP53 genetic polymorphism was c.524G>A p.Arg175His in exon 5. Variants of unknown significance (VUS) detected in HGSC included ROS1 [26%; 13/50], RAD50 [6%; 3/50], BRCA2 [6%; 3/50], NOTCH1 [6%; 3/50], TP53 [6%; 3/50], AR [6%; 3/50]. As for germline mutations, BRCA1 [8/30; 27%] and BRCA2 [4/30; 13%] were the most common genes bearing pathogenic alterations in HGSC, while VUS germline mutations commonly affected HRR-related genes, including ATM (c.7816A>G), BRIP (c.2327 C>A), CHEK2 (c.320-5T>A).ConclusionOverall, genetic testing should be offered in most patients with ovarian cancer to identify mutations in HRR genes and determine the population that would be susceptible to poly ADP ribose polymerase (PARP) inhibitors.

The COVID pandemic has transformed our approach to patient care, research, and training in cardio-oncology. While the early phases of the COVID pandemic were exceptionally frightening, we now can reflect on the innovative changes that brought more effective and patient-centered care to our doorsteps: expansion of telemedicine, integration of digital health, wider adoption of cardiac biomarkers, consolidation, and coordination of cardio-oncology testing. Normally, it takes years for health care systems to adopt new technology or modify patient care pathways; however, COVID pushed healthcare providers and the health systems to change at warp speed. All of these innovations have improved our efficacy and provided a more "patient-centered" approach for our cardio-oncology patients. The changes we have made in cardio-oncology will likely remain well beyond the pandemic and continue to grow improving the cardiovascular care of oncology patients.

Background Obesity and high body mass index (BMI) are associated with increased incidence of multiple myeloma (MM). MM usually evolves from a precursor asymptomatic disease, namely monoclonal gammopathy of undetermined significance (MGUS). MGUS progresses to MM at a 1% annual rate; however, risk factors predisposing to MGUS are not completely understood. We conducted a systematic review to assess the relationship between obesity and high BMI with MGUS prevalence and progression to MM. To our knowledge, this is the first systematic review evaluating the role of obesity in MGUS. Patients and Methods We searched the Medline database and ClinicalTrials.gov for studies investigating BMI and obesity association with MGUS incidence and progression. The algorithm consisted of a predefined combination of the words “obesity,” “obese,” “body mass index,” “overweight,” “diet,” “nutrition,” “food,” “dietary,” “adiponectin,” “monoclonal gammopathy,” and “MGUS”. Results Overall, 12 articles were retrieved, including 11 eligible articles and 1 clinical trial. More than 57,068 patients were evaluated in this systematic review. Discrepancies between the identified studies were noted. Multiple studies support the notion that obesity or high BMI are positively linked to MGUS prevalence and transition to MM. In contrast, other studies revealed no such association. Visceral adipose tissue metabolic activity and decreased adiponectin concentrations were identified as biomarkers of MGUS progression to MM. Conclusion Obesity and increased BMI seem to be implicated both in MGUS development and progression to MM. Further studies should be designed to confirm this hypothesis.

OBJECTIVE Several studies have evaluated the differences in duration of latency and clinical outcomes between singleton and twin pregnancies after preterm premature rupture of membranes (PPROM); however, these data are limited to single-institution analyses and based on small sample sizes. The aim of this study was to assess differences in latency and clinical outcomes in singletons versus twin gestations affected by PPROM in a large, diverse cohort of women. STUDY DESIGN This is a secondary analysis of a multicenter trial of magnesium for neuroprotection in women at high risk of preterm birth. Our study included women with PPROM ≥ 24 weeks with singleton and twin gestations. We compared singleton versus twin gestation and our primary outcome was duration of latency after PPROM. Secondary outcomes included selected perinatal and neonatal outcomes including long-term neurodevelopmental outcomes. We fit a linear regression model to assess independent risk factors for latency duration. RESULTS Our study included 1,753 women, 1,602 singleton gestations (91%) and 151 twin gestations (9%). The median latency period was significantly shorter in twins (4 [interquartile range, IQR: 1-10] vs. 7 [IQR: 3-16] days, p

Objective This study was aimed to review 4 weeks of universal novel coronavirus disease 2019 (COVID-19) screening among delivery hospitalizations, at two hospitals in March and April 2020 in New York City, to compare outcomes between patients based on COVID-19 status and to determine whether demographic risk factors and symptoms predicted screening positive for COVID-19. Study Design This retrospective cohort study evaluated all patients admitted for delivery from March 22 to April 18, 2020, at two New York City hospitals. Obstetrical and neonatal outcomes were collected. The relationship between COVID-19 and demographic, clinical, and maternal and neonatal outcome data was evaluated. Demographic data included the number of COVID-19 cases ascertained by ZIP code of residence. Adjusted logistic regression models were performed to determine predictability of demographic risk factors for COVID-19. Results Of 454 women delivered, 79 (17%) had COVID-19. Of those, 27.9% (n = 22) had symptoms such as cough (13.9%), fever (10.1%), chest pain (5.1%), and myalgia (5.1%). While women with COVID-19 were more likely to live in the ZIP codes quartile with the most cases (47 vs. 41%) and less likely to live in the ZIP code quartile with the fewest cases (6 vs. 14%), these comparisons were not statistically significant (p = 0.18). Women with COVID-19 were less likely to have a vaginal delivery (55.2 vs. 51.9%, p = 0.04) and had a significantly longer postpartum length of stay with cesarean (2.00 vs. 2.67days, p Conclusion COVID-19 symptoms were present in a minority of COVID-19-positive women admitted for delivery. Significant differences in obstetrical outcomes were found. While demographic risk factors demonstrated acceptable discrimination, risk prediction does not capture a significant portion of COVID-19-positive patients. Key Points

National Health Service (NHS) policy suggests that increasing usage of electronic personal health records (PHR) by patients will result in cost savings and improved public health, especially for people with long-term conditions. PHR design features are inevitably important, since a good PHR design should make the users achieve their health goals effortlessly, which is understandable and usable. Three original theoretical models were developed using realist evaluation, one per long-term condition cohort, describing the interaction between the PHR design features and the patient and disease specific factors, to help determine what works for whom in what circumstances.

BACKGROUND: Dose-dense sequential chemotherapy with anthracyclines and taxanes achieved an 18% reduction of recurrence risk in early breast cancer (BC). The optimal chemotherapy schedule and interval between cycles remain under investigation. METHODS: Overall, 990 patients were randomised to receive either three cycles of epirubicin (E, 110 mg/m(2)) every 2 weeks followed by 3 cycles of paclitaxel (T, 200 mg/m(2)) every 2 weeks followed by three cycles of intensified CMF (Control Arm A, E-T-CMF) that was previously used in BC or three cycles of epirubicin followed by three cycles of CMF followed by nine consecutive weekly cycles of docetaxel (wD) 35 mg/m(2) (Arm B, E-CMF-wD) or nine consecutive weekly cycles of paclitaxel (wT) 80 mg/m(2) (Arm C, E-CMF-wT). Trastuzumab was administered for HER2-positive disease. RESULTS: At a median follow-up of 13.3 years, 330 disease-free survival (DFS) events (33.3%) were reported. DFS and overall survival (OS) did not differ between patients in the combined B and C arms versus arm A either in the entire cohort (HR = 0.90, P = 0.38 and HR = 0.85, P = 0.20) or among trastuzumab-treated patients (HR = 0.69, P = 0.13 and HR = 0.67, P = 0.13). Thirty-four patients (3.4%) developed secondary neoplasms. CONCLUSIONS: Overall, no significant differences in survival were found amongst the studied regimens after a long-term observational period. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12610000151033.

Considering that COVID-19 could adversely affect cancer patients, several countries have prioritized this highly susceptible population for vaccination. Thus, rapidly generating evidence on the efficacy of SARS-CoV-2 vaccination in the subset of patients with cancer under active therapy is of paramount importance. From this perspective, we launched the present prospective observational study to comprehensively address the longitudinal dynamics of immunogenicity of both messenger RNA (mRNA) and viral vector-based vaccines in 85 patients treated with immune checkpoint inhibitors (ICIs) for a broad range of solid tumors. Despite the relatively poor humoral responses following the priming vaccine inoculum, the seroconversion rates significantly increased after the second dose. Waning vaccine-based immunity was observed over the following six months, yet the administration of a third booster dose remarkably optimized antibody responses. Larger cohort studies providing real-world data with regard to vaccines effectiveness and durability of their protection among cancer patients receiving immunotherapy are an increasing priority.

Treatment of elderly patients with neoplasia is challenging. Age is a known prognostic factor in ovarian cancer but the optimal treatment of elderly patients has not been determined. We undertook a retrospective analysis to determine clinical practice in advanced-stage ovarian cancer patients older than 70 years of age. Methods: Medical records of women with high-grade serous ovarian cancer, stage III and IV were retrospectively analyzed. Results: A total of 735 patients were identified with a median age of 61.5 years. 22.4% among them were older than 70 years of age at diagnosis. First-line Progression-Free Survival (PFS) and Overall Survival (OS) were significantly worse in elderly patients in comparison to the younger ones [mPFS 11.3 months vs., 14.8 months, (p &lt, 0.001) and mOS 30.2 months vs. 45.6 months (p &lt, 0.001)]. However, elderly patients were characterized by worse ECOG-Performance Status and they were more frequently treated with Neoadjuvant Chemotherapy followed by Interval Debulking Surgery, while often they were more frequently denied debulking surgery compared to patients under 70 years of age. Moreover, elderly patients received more frequently monotherapy with platinum as frontline treatment. In contrast, there was no significant difference in the outcome of the debulking surgery in comparison to the younger patients or the frequency that gBRCA test was performed. Age over 70 years did not retain its significance for either Progression-Free Survival or Overall Survival when adjusted for all other reported prognostic factors. Conclusion: Elderly ovarian cancer patients have a worse prognosis. Comprehensive geriatric assessment should be performed for the optimal treatment of these patients.

Bromodomain and extra-terminal (BET) proteins are epigenetic readers that bind to acetylated lysines of histones and regulate gene transcription. BET protein family members mediate the expression of various oncogenic drivers in ovarian cancer, such as the MYC and Neuregulin 1 (NRG1) genes. BRD4, the most thoroughly studied member of the BET family, is amplified in a significant subset of high-grade serous carcinomas (HGSC) of the ovary. It has been reported that BET inhibitors can attenuate the proliferation and dissemination of ovarian cancer cells by inhibiting oncogenic pathways, such as the FOXM1 and JAK/STAT pathways. BET inhibition can re-sensitize resistant ovarian cancer cells to already approved anticancer agents, including cisplatin and PARP inhibitors. This synergism was also confirmed in vivo in animal models. These and other preclinical results provide a promising basis for the application of BET inhibitors in ovarian cancer treatment. Currently, Phase I/II clinical trials explore the safety and efficacy profiles of BET inhibitors in various solid tumors, including ovarian tumors. Here, we review current knowledge on the molecular effects and preclinical activities of BET inhibitors in ovarian tumors. BET proteins have emerged as new druggable targets for ovarian cancer. BET inhibitors may enhance antitumor activity when co-administered with conventional treatment regimens. Results from ongoing Phase I/II studies are anticipated to confirm this notion.

ImportanceReducing rates of unnecessary cesarean deliveries is both a national and a global health objective. However, there are limited national US data on trends in indications for low-risk cesarean delivery.ObjectiveTo determine temporal trends in and indications for cesarean delivery among patients at low risk for the procedure over a 20-year period.Design, Setting, and ParticipantsThis cross-sectional study analyzed 2000 to 2019 delivery hospitalizations using the National Inpatient Sample. Births at low risk for cesarean delivery were identified using a definition from the Society for Maternal-Fetal Medicine and additional criteria. Temporal trends in cesarean birth were analyzed using joinpoint regression to estimate the average annual percentage change (AAPC) with 95% CIs. Data analysis was performed from August 2022 to January 2023.ExposureThis analysis evaluated cesarean birth trends in a population at low risk for this procedure over a 20-year period.Main Outcomes and MeasuresIn addition to overall cesarean birth risk, cesarean deliveries for nonreassuring fetal status and labor arrest were individually analyzed.ResultsOf an estimated 76.7 million delivery hospitalizations, 21.5 million were excluded according to the Society for Maternal-Fetal Medicine definition, and 14.7 million were excluded according to additional criteria. Of the estimated 40 517 867 deliveries included, 12.1% (4 885 716 deliveries) were by cesarean delivery. Cesarean deliveries among patients at low risk for the procedure increased from 9.7% to 13.9% between 2000 and 2009, plateaued, and then decreased from 13.0% to 11.1% between 2012 and 2019. The AAPC for cesarean delivery was 6.4% (95% CI, 5.2% to 7.6%) from 2000 to 2005, 1.2% from 2005 to 2009 (95% CI, −1.2% to 3.7%), and −2.2% from 2009 to 2019 (95% CI, −2.7% to −1.8%). Cesarean delivery for nonreassuring fetal status increased from 3.4% of all deliveries in 2000 to 5.1% in 2019 (AAPC, 2.1%; 95% CI, 1.7% to 2.5%). Cesarean delivery for labor arrest increased from 3.6% in 2000 to a peak of 4.8% in 2009 before decreasing to 2.7% in 2019. Cesarean deliveries for labor arrest increased during the first half of the study (2000-2009) for the active phase (from 1.5% to 2.1%), latent phase (from 1.1% to 1.5%), and second stage (from 0.9% to 1.3%) and then decreased from 2010 to 2019, from 2.1% to 1.7% for the active phase, from 1.5% to 1.2% for the latent phase, and from 1.2% to 0.9% for the second stage.Conclusions and RelevanceCesarean deliveries among patients at low risk for cesarean birth appeared to decrease over the latter years of the study period, with cesarean deliveries for labor arrest becoming less common.