Background and Purpose: Glucose tolerance tests (GTTs) are commonly used in preclinical studies but are poorly standardised. Male mice are often preferred due to more severe phenotypes which may aid in detecting drug effects. Using novel glucose telemetry in undisturbed mice, the effect of different pre-GTT protocols on blood glucose concentrations, GTTs and detection of drug effects were considered. Experimental Approach: Seven male and female C57Bl/6J mice (8-10 weeks) were implanted with HD-XG glucose telemetry devices. Mice were fasted for 16h overnight or 6h in the daytime following a whole cage change, cage change with retention of used bedding or no cage change prior to i.p.GTTs. Glucose tolerance following oral glucose gavage was compared to voluntary ingestion of gels. Using the most refined procedures, 250mg/kg oral metformin and 10nmol/kg i.p. exendin-4 were tested. Key Results: Blood glucose initially increased following cage changing at the start of the fast. For 6h fasting, retaining bedding reduced these initial responses and produced more timely glucose reductions whereas 16h fasts caused pronounced hypoglycaemia. Impaired glucose tolerance in males was exaggerated following 16h fasting or whole cage changes. Refined procedures including voluntarily ingested glucose gels blunted responses but the effects of exendin-4 and metformin were still observable in both sexes. Conclusion and Implications: Variations in GTT protocol can have profound effects on glucose homeostasis. Improved glucose tolerance due to protocol refinement and/or the use of females still allows for detection of drug effects providing evidence that more severe phenotypes are not required when testing drugs.

Experimenters face challenges and limitations while analyzing glycoproteins due to their high flexibility, stereochemistry, anisotropic effects, and hydration phenomena. Computational studies complement experiments and have been used in characterization of the structural properties of glycoproteins. However, recent investigations revealed that computational studies face significant challenges as well. Here, we introduce and discuss some of these challenges and weaknesses in the investigations of glycoproteins. We also present requirements of future developments in computational biochemistry and computational biology areas that could be necessary for providing more accurate structural property analyses of glycopro-teins using computational tools. Further theoretical strategies that need to be and can be developed are discussed herein.

Background: Conservative-surgery (CS) brachytherapy (BT) techniques for local therapy in bladder-prostate rhabdomyosarcoma (BP-RMS) seeks to retain organ function. We report bladder function after high-dose-rate (HDR) BT combined with targeted CS for any vesical component of BP-RMS. Procedure: Prospective cohort of all BP-RMS patients between 2014-19 receiving HDR-BT (Iridium-192, 27.5Gy in 5 fractions) with/without percutaneous endoscopic-polypectomy (PEP) or partial cystectomy (PC). Functional assessment included frequency-volume-chart, voided volumes, post-void residual, flow studies, continence status and ultrasound scanning; abnormalities triggered video-urodynamics. Results: Thirteen patients (10 male), aged 9 months to 4 years (median 23 months), presented with localised fusion-negative embryonal BP-RMS measuring 23-140mm (median 43mm) in cranio-caudal extent. After induction chemotherapy, local treatment consisted of PC+BT in three, PEP+BT in four and BT alone in six. At a median 3½ years (range 1¾-7 years) follow up, all were alive without relapse. At a median age of 6 years (4-9 years), the median bladder capacity was 86% (47%-144%) of that expected for age, including 75% (74-114%) after PC. There was no relation to radiation dose to the bladder. Complications occurred in two: one urethral stricture and one vesical decompensation in a patient with pre-existing high-grade VUR. The remaining patients are dry by day; five with anticholinergic medication for urinary urgency. Three patients are enuretic. Conclusions: Day-time dryness at a median 3½ years after CS-HDR-BT was achieved in 92%, with 85% voiding urethrally, and 62% attaining day-and-night continence aged 4-9 years. We report reduced open surgery, with minimally-invasive percutaneous surgery with HDR-BT or brachytherapy alone being suitable for many.

Although the surgical technique for acute type A aortic dissection markedly improved in the last decade, perioperative mortality and morbidity rates remain dramatically high. Therefore, we introduce the novel “plaster technique” using the single interrupted suture with a felt and plastering the minimum dose of BioGlue® (Cryolife Inc., Kennesaw, GA, USA) into the suture hole in this report. We found that the plaster technique using a felt pledget and minimum dose of BioGlue is effective for fragile aortic walls, as in patients undergoing acute aortic dissection and is a simple, safe, and durable technique to strengthen the suture line.

Favipiravir is one of the repurposed antiviral medications for the treatment of SARS-CoV-2 infection. Since the dosing regimen is a prominent factor for the success of the antiviral therapy, this prospective observational study aimed to characterize the pharmacokinetic characteristics of favipiravir in COVID-19 patients. Adult patients (n=21) hospitalized for mild to moderate COVID-19 with a positive RT-PCR test, and assigned for favipiravir treatment were included. Favipiravir was administered for 5 days, with a loading dose of 3200 mg and a 1200 mg/day maintenance dose. Serial blood samples were collected on Day-2 and Day-4 of the therapy. Laboratory findings of the patients and in-hospital mortality were assessed. Favipiravir concentrations exhibited high variations and a significant decrease during the treatment of COVID-19. The median favipiravir trough concentration (C0-trough) on Day-2 was 21.26 µg/mL whereas it decreased significantly to 1.61 µg/mL on Day-4, the area under the concentration versus time curve decreased from 345.6 µg.h/mL to 108.6 µg.h/mL, respectively. Gender seems significant to affect favipiravir concentrations. Day-2-C0-trough of female patients was significantly higher than male patients. Of the 5 patients that died, 4 were male with a significant increase in ferritin levels from Day-0 to Day-5 compared to surviving patients. In addition, there was a significant decrease in D-dimer and CRP levels in the surviving patients. Our findings indicate that favipiravir concentrations show significant changes during the treatment of COVID-19. Therapeutic drug monitoring may best guide dose adjustments in patients that do not respond to treatment with favipiravir.

Background: Neurally adjusted ventilatory assist (NAVA) is an emerging mode of respiratory support that uses the electrical activity of the diaphragm (Edi) to provide synchronised inspiratory pressure support, proportional to an infant’s changing inspiratory effort. Data on Edi reference values for neonates are limited. The objective of this study was to establish reference Edi values for preterm and term neonates. Methods: This was a prospective observational study of newborn infants breathing spontaneously in room air. The Edi signal was monitored by a specialised intragastric feeding tube with embedded electrodes positioned at the level of the diaphragm. Edi minimums and peaks were recorded continuously for four hours. Results: 24 newborn infants (16 preterm [<37 weeks’ gestation]; 8 term) were studied. All infants were breathing comfortably in room air at the time of study. Edi data were successfully captured in all infants. The mean (±SD) Edi minimum was 3.02 (±0.94) µV and the mean Edi peak was 10.13 (±3.50) µV. In preterm infants the mean (±SD) Edi minimum was 3.05 (±0.91) µV and the mean Edi peak was 9.36 (±2.13) µV. In term infants the mean (±SD) Edi minimum was 2.97 (±1.05) µV and the mean Edi peak was 11.66 (±5.14) µV. Conclusion: Reference Edi values were established for both preterm and term neonates. These values can be used as a guide when using diaphragm-triggered modes on respiratory support in newborn infants.

This paper aims to give a mathematically rigorous description of the corner singularities of the weak solutions for the plane linearized elasticity system in a bounded planar domain with angular corner points on the boundary. The qualitative properties of the solution including its regularity depend crucially on these corner points or such types of boundary conditions. In particular, the resulting expansion of the solutions of the underlying problem involves singular vector functions, inlines, depending on a certain parameter ξμ. We derive the transcendental equations for all ten possible cases of combinations of the boundary conditions generated by the basic four ones in classical elasticity proposing in the two natural directions of the boundary, i.e., tangential and normal direction, respectively, which depends on ξμ . So, a MATLAB program is developed whereby ξμ can be computed, and figures showing their distributions are presented. The leading singular exponents are computed for these combinations of the boundary conditions, wherein critical angles ω_ critical are listed such that for interior angles ω

Conflict of interestThe authors declare no conflicts of interest.

There is an increasing incidence of food allergy identified globally in the paediatric population. Diagnosis of suspected cases by oral food challenge (OFC) is time-consuming and often linked to anxiety in parents and children. There is also a risk of triggering an anaphylaxis reaction between 2.4%-34.1% of challenges triggering anaphylaxis. To reduce the number of OFC carried out in allergy-suspected children, the use of skin prick tests (SPT) is a simpler and less expensive method of diagnosis. Although the predictive value of the SPT remains unclear, hence there is a requirement for further studies on the predictive value of the SPT to provide increased clarity of the essential parameters.

Background: Anaphylaxis is a significant health burden in most Western countries but there is little published data on the incidence and pattern of anaphylaxis in Asia. We aim to determine the incidence rate and pattern of anaphylaxis over the past decade among the paediatric population in Hong Kong. Methods: Medical records of patients presenting with allergy-related symptoms during the period 2010 to 2019 were examined. Paediatric patients aged below 18 years who fulfilled the diagnostic criteria for anaphylaxis laid out by the NIAID/FAAN were analysed. Incidence rates were calculated using population statistics as the denominator. All information pertaining to the anaphylaxis events and patients’ characteristics were retrieved using standardized data collection forms. Results: The overall 10-year estimated incidence of anaphylaxis was 7.70 per 100,000 person-years, with a rising trend of anaphylaxis incidence across time. Food-induced anaphylaxis accounted for the majority of hospital presentation, of which peanut and shellfish were the top food triggers in our population. Comorbid asthma and young age were risk factors associated with wheeze at presentation. Misdiagnosis of anaphylaxis occurred in up to half the anaphylaxis cases and adrenaline was only utilised in 45% of cases. Conclusions: An increasing trend of anaphylaxis incidence over the past decade is evident in Hong Kong children, with a discrepantly low accuracy in diagnosis and suboptimal management of anaphylaxis. There is a pressing need to heighten public and physicians’ awareness of the distinctive features of anaphylaxis in the paediatric age group.

Introduction: Although prolonged respiratory symptoms following SARS-CoV-2 infection have been reported in adults, there is a paucity of literature describing post-acute symptoms in pediatric patients following COVID-19. In this study we describe health data and respiratory findings in pediatric patients presenting with complaints of persistent respiratory symptoms following acute COVID-19 infection. Methods: This study included patients referred to Pulmonary Clinic at the Children’s Hospital of Philadelphia between December 2020 and April 2021 (n=29). Inclusion criteria included a history of SARS-CoV-2 RNA positivity or confirmed close household contact. A retrospective chart review was performed and demographic, clinical, imaging, and functional test data were collected. Results: The mean age at presentation to clinic was 13.1 years (range: 4-19 years). Patients had persistent respiratory symptoms ranging from 1.3 to 6.7 months post-acute infection. Persistent dyspnea and/or exertional dyspnea were present in nearly all (96.6%) of the patients at the time of clinic presentation. Other reported chronic symptoms included cough (51.7%) and exercise intolerance (48.3%). Fatigue was reported in 13.7% of subjects. Many subjects were overweight or obese (62.1%) and eleven subjects had a prior history of asthma. Lung function was normal in most patients. The six-minute walk test (6MWT) revealed exercise intolerance and significant tachycardia in two-thirds of children tested. Conclusion: Exertional dyspnea, cough and exercise intolerance were the most common respiratory symptoms in children with post-acute COVID-19 respiratory symptoms seen in an outpatient pulmonary clinic. Lung function, however, was mostly normal, and exertional intolerance was frequently demonstrated using the 6MWT.

Background: Many European health institutions have appointed multidisciplinary teams for the general management of vascular access to help improve efficiency, patient safety and reduce costs. Vascular access teams (VATs), or infusion teams, are specifically trained groups of healthcare professionals who assess, place, manage and monitor various outcomes and aspects of vascular access care. Objective: To assess the current landscape of vascular access management as a discipline across Europe. Methods: A Faculty of European VAT leads and experts developed a survey of 20 questions which was disseminated across several European countries. Questions focused on respondent and institution profile, vascular access device selection and placement, monitoring and reporting of complications, and access to training and education. The 1449 respondents included physicians, nurses, anaesthetists, radiologists and surgeons from public and private institutions ranging in size. Results: Availability of dedicated VATs vary by country, institution size, and institution type. Institutions with a VAT are more likely to utilise a tool (e.g., algorithm or guideline) to determine the appropriate vascular access device (55% vs 38%, p < 0.0002) and to have feedback on systematic monitoring of complications (40% vs 28%, p = 0.015). Respondents from institutions with a VAT are more likely to have received training on vascular access management (79% vs 53%, p < 0.0001) and indicated that the VAT was a source of support when difficulties arise. Conclusion: The survey results highlight some of the potential benefits of implementing a dedicated VAT including use of a broader range of vascular access devices, increased awareness of the presence of vascular access policies, increased likelihood of recent vascular access training, and increased rates of systematic monitoring of associated complications. The study reveals potential areas for further focus in the field of vascular access care, specifically examining the direct impact of vascular access teams.

Background: Deprescribing interventions have shown to improve medication appropriateness in older people. However, the evidence on the actual benefits and risks of deprescribing in older adults at the end of life are limited. Due to the lack of evidence on the safety and efficacy of medication in these populations, the most appropriate deprescribing approach is unclear. We aimed to conduct a narrative review of research on existing deprescribing guidelines targeted to frail older people at the end of life. Methods: A literature search was conducted in PubMed, Embase, CINAHL and Google Scholar to identify studies from inception to January 2021 on deprescribing guidelines/tools for frail older adults near end-of-life or palliative situation or life-limiting illnesses or limited life expectancy were included. Results: A total of nine studies were included. The deprescribing guidelines used in these studies were helpful to some extent in optimising medications in patients with limited life expectancy and life-limiting illnesses. Some of them have been tested in prospective studies that showed their usefulness in minimising the number of potentially inapproapriate medications. These studies however were not randomised and involved small sample sizes and had little insight into the clinical outcomes of using these tools. Conclusions: The existing tools and guidelines on deprescribing do not represent the end of life care nor address the medication appropriateness among individuals with a specific condition. An explicit and rigorous consensus-based guideline needs to be developed and tested in a well-designed clinical trial to measure clinically significant outcomes

Introduction: To identify the ability to acquire various fetal cardiac views using two-dimensional ultrasound at different gestational age and body mass index (BMI) categories. Material and methods: We performed a prospective observational study among low-risk women with singleton pregnancies attending the University Obstetrics Unit, North Colombo Teaching Hospital, Ragama, Sri Lanka. The ability to obtain satisfactory views for the situs, four chambers (4CH), right and left outflow tracts (ROFT/LOFT), three vessels (3V), aortic arch (AA), ductal arch (DA), and superior and inferior vena cava (SVC/IVC) of fetal heart was studied. Results: A total of 314 eligible pregnant women underwent fetal echocardiography and 288 had complete data. All eight cardiac views were obtained with a 100% success at the gestational age of 18 to 21+6 weeks. All eight cardiac views were satisfactory in more than 97% at the gestational age of 22 to 25+ 6 weeks. BMI was not significantly associated with acquisition of cardiac views at all gestations (Log-rank test, p=0.62). All eight cardiac views were obtained with 50% success at 14 -17+6 weeks and 5.4% success at 11-13+6 weeks. Conclusions: The ability to acquire all fetal cardiac views was best at 18 to 21+6 weeks of gestation, but reasonably successful till 26 weeks. The acquisition of all cardiac views was sub-optimal in early gestations below 18 weeks and for some of the cardiac views after 26 weeks. BMI does not hamper the ability to obtain cardiac views during fetal echocardiography.

Cornual pregnancy is a rare condition that accounts for approximately 2-4% of ectopic pregnancies worldwide. Herein, we report an unstable case of a 32-year-old female with a history of oophorectomy, and salpingectomy who was admitted for a ruptured cornual pregnancy in the left cornu which was successfully managed by laparotomy.

Aims: The putative protective role of esRAGE for cardiac autonomic function (CAF) remain unclear. To address this question, the present study has assessed the relationship of serum AGEs, sRAGE and esRAGE, and tissue AGEs with CAF in a high-risk population without diabetes. Material and methods: Forty eight subjects of mean age 52.7±11.2years and mean BMI 28.4±6.3kg/m2, divided into 2 groups according to glucose tolerance: 16 with normal glucose tolerance (NGT) and 24 with prediabetes, were enrolled. A standard OGTT was performed. The glucose tolerance was defined according to 2006 WHO criteria. Fasting, 120-min glucose, lipids, creatinine and HbA1c were measured. eGFR was calculated (CKD-EPI). Fasting, 120-min insulin (ECLIA method), esRAGE, sRAGE and AGEs (ELISA method) were assessed. HOMA-IR was calculated. Tissue AGEs were assessed by skin autofluorescence (AGE-Reader, DiagnOpticsTM). CAF was evaluated with ANSAR, applying deep breathing, Valsalva and standing. Results: There was a significant decline in CAF in prediabetes in comparison to NGT. Serum and tissue AGEs, sRAGE and esRAGE levels were similar between groups. On the matrix analysis, both sympathetic and parasympathetic activity at baseline and after standing and sympathetic tone during Valsalva were positively related to esRAGE in prediabetes. Multivariate regression analysis showed that esRAGE is an independent contributor to sympathetic, parasympathetic and total autonomic tone in prediabetes accounting for about 28%, 34% and 35% of their variances, respectively. Conclusion: Our results have demonstrated that CAF is decreased in prediabetes. esRAGE, but not sRAGE, is reciprocally related to CAF, probably opposing the negative effects of glycation.

Background: The COVID‑19 pandemic is an ongoing global pandemic. Jerusalem with its 919,400 inhabitants has a wide variety of populations, of which 62% are Jews (36% ultra-orthodox; 64% non-ultraorthodox) and 38% Arabs which were largely affected by the pandemic. The aim of our study was to understand the different presentations, course and clinical outcomes in these different ethnical and cultural groups in Jerusalem in the COVID-19 pandemic. Methods: We performed a cohort study of all COVID-19 patients admitted between March 9 - July 16, 2020 to the two university medical centers in Jerusalem. Patients were divided according to their religion and ethnicity into 3 main groups: 1) Ultra-Orthodox Jews; 2) other (non-Ultra-Orthodox) Jews and 3) Arabs. Results: Six hundred and two patients comprised the study population. Of them the 361 (60%) were Ultra-Orthodox Jews; 166 (27.5%) non-Ultra-Orthodox Jews and 75 (12.5%) Arabs. The Arab patients were younger than the Ultra-Orthodox Jews and the non-Ultra-Orthodox Jews (51±18 year-old vs. 57±21 and 59±19, respectively, p<0.01), but suffered from significantly more co-morbidities. Moreover, hemodynamic shock, ischemic ECG changes and pathological chest x-ray were all more frequent in the Ultra-Orthodox patients as compared the other groups of patients. Being an Ultra-Orthodox was independently associated with significantly higher rate of Major Adverse Cardiovascular Events (MACE) [OR=1.96; 95% CI (1.03-3.71), p<0.05]. Age was the only independent risk factor associated with increased mortality rate [OR=1.10; 95% CI (1.07 - 1.13), p<0.001]. Conclusions: The COVID-19 first phase in Jerusalem, affected different ethnical and cultural groups differently, with the Ultra-Orthodox Jews mostly affected by admission rates, presenting symptoms clinical course and MACE (Acute coronary syndrome, shock, cerebrovascular event or venous thromboembolism). It is conceivable that vulnerable populations need special attention and health planning in time of pandemic, to prevent rapid distribution and severe morbidity.

ABSTRACT Background: Obesity and overweight are significant public health problems due to higher risk for coronary artery disease (CAD). It is very important to determine new predictive markers to identify the CAD risk in obese and overweight. To this aim, we analyzed HDL-C subclass and their paraoxonase-1 (PON-1) activity in obese, overweight and normal weight subjects. Method: 71 newly diagnosed obese, 40 overweight and 30 healthy subjects as a control group were enrolled the study. Serum lipids levels were determined with enzymatic colorimetric method. PON-1 activities and HDL-3 levels were determined by spectrophotometric methods. Non-HDL3-C concentrations were calculated with the subtraction of HDL3-C from total HDL-C. Results: The mean serum levels of total HDL-C, HDL3-C, Non-HDL3-C -C and ApoA1 were higher in control group than obese and overweight groups. There were a statistically significant difference between obese and control group in terms of Lp(a), hsCRP and HOMA index. Higher total PON-1, non-HDL3 PON-1 and HDL3 PON-1 activities were found in the control group compared to obese and overweight groups. Total HDL was weakly negative correlated with the HOMA index, BMI and waist circumference. There was a weak negative correlation between non-HDL3-C and waist circumstance. Conclusion: Abnormal HDL-subgroups pattern and decreased PON-1 activities causes increased risk for CVD in obese and overweight individuals. Therefore determination of HDL subgroups and their PON-1 activity improves risk prediction compared with measuring total HDL-C levels and its PON-1 activity alone. Body weight and insulin resistance appear to have a role in the decreased HDL-C levels and PON-1activity in obese.

Background: Biochemical recurrence (BCR) can be seen in the early or late period after radical prostatectomy (RP). Various models have been developed to predict BCR. Objective: In our study we evaluated accuracy of four pre-operative models (GP score, PRIX, D’Amico risk classification, CAPRA) in predicting BCR after RP in Turkish patients. Methods: Age, preoperative total prostate specific antigen (PSA) values, clinical stages, total number of cores taken in biopsy, number of positive cores, preoperative biopsy Gleason score (GS), follow-up time and presence of BCR after RP were recorded. BCR was defined as a total PSA value > 0.2 ng / dl twice consecutively after RP. Classifications or scoring was performed according to pre-operative models. The 1, 3 and 5 year (yr) BCR-free rates of the patients were determined for each model. Also the accuracy of four predictive models for predicting 1, 3 and 5-yr BCR was evaluated. Results: For all pre-operative models there was statistically significant difference between risk groups in BCR free rates at 1, 3 and 5-yr after RP (p<0.001). The Harrell’s concordance index for 1-yr BCR predictions was 0,802, 0,831, 0,773 and 0,745 for the GP score, PRIX, CAPRA and D’Amico and respectively. For 3-yr BCR predictions it was 0,798, 0,791, 0,723 and 0,714 for the GP score, PRIX, CAPRA and D’Amico and respectively. Finally, The Harrell’s concordance index for 5-yr BCR predictions was 0,778, 0,771, 0,702 and 0,693 for the GP score, PRIX, CAPRA and D’Amico and respectively. Conclusion: In prediction of BCR, accuracy of GP scoring and PRIX seems slightly higher than CAPRA and D’Amico risk classification. Surely our results should be supported by head to head comparisons with in other larger cohorts

Purpose: Incontinence is a condition that can cause significant problems that can affect patients’ quality of social, emotional, psychological and sexual life. The aim of this study was to evaluate the level of anxiety, health anxiety, depression, and somatosensory amplification in patients with urge incontinence. Materials and Methods: The study group consisted of 58 patients that met the inclusion criteria. The control group consisted of 67 volunteer participants that did not have physical or psychiatric illness and incontinence complaints. All participants filled out sociodemographic data form, Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Somatosensory Amplification Scale (SSAS), and Health Anxiety Inventory (HAI). Results: The mean duration of incontinence in patients with urge incontinence was 16.55 ± 10.03 months. The mean age in urge incontinence group and the control group were 40.98 ± 9.58 and 39.1 ± 7.89 years, respectively. The mean values of SSAS, HAI, and BAI scores in the incontinence group were significantly higher than the control group (p <0.001), but there was no significant difference between the groups in terms of BDI scores. The linear regression analysis indicated that HAI and BAI significantly affected SSAS (p = 0.025 and 0.019, respectively). Conclusions: Anxiety, health anxiety and somatosensory amplification are more common in patients who report urge incontinence. For these reasons, we believe that psychiatric evaluation should be included in the diagnosis and treatment process of patients presenting with urgency and incontinence symptoms. Keywords: Incontinance, Somatosensory Amplification, Beck Depression Inventory, Beck Anxiety Inventory, Urgency.

Scabies may present with unusual features like vesicles, pustules, and bullae. In the setting of an already burdened health sector, careful history taking is of utmost importance in order to avoid unnecessary and expensive investigations to reach a diagnosis.

Objective: To investigate the association between hysterectomy with conservation of one or both adnexa and ovarian and tubal cancer. Design: Prospective cohort study. Setting: 13 NHS Trusts in England, Wales and Northern Ireland. Population: 202,506 postmenopausal women recruited between 2001-2005 to the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) and followed up until 31 December 2014. Methods: Multiple sources (questionnaires, hospital notes, Hospital Episodes Statistics, national cancer/death registries, ultrasound reports) were used to obtain accurate data on hysterectomy (with conservation of one or both adnexa) and outcomes censored at bilateral oophorectomy, death, ovarian/tubal cancer diagnosis, loss to follow-up or 31 December 2014. Cox proportional hazards regression models were used to assess the association. Main outcome measures: Invasive epithelial ovarian and tubal cancer (WHO 2014) on independent outcome review. Results: Hysterectomy with conservation of one or both adnexa was reported in 41,912 (20.7%; 41,912/202,506) women. Median follow up was 11.1years (IQR 9.96-12.04), totalling >2.17million women-years. Among women who had undergone hysterectomy, 0.55% (231/41912) were diagnosed with ovarian/tubal cancer, compared with 0.59% (945/160594) of those with intact uterus. Multivariable analysis showed no evidence of an association between hysterectomy and invasive epithelial ovarian/tubal cancer (RR=0.98, 95%CI 0.85-1.13, p=0.765). Conclusions: This large cohort study provides further independent validation that hysterectomy is not associated with alteration of invasive epithelial ovarian and tubal cancer risk. This data is important both for clinical counselling and for refining risk prediction models.

Phenotypic integration and developmental canalization have been hypothesized to constrain the degree of phenotypic plasticity, but there is little evidence for the relationships among the three processes in different environments, especially for plants under natural conditions. To address this issue, we conducted a field experiment by subjecting plants of Abutilon theophrasti to low, medium and high densities, under infertile and fertile soil conditions, measured a variety of traits and analyzed canalization (coefficient of variation [CV]), integration (coefficient of integration [CI] and the number of significant correlations of a trait with other traits [NC]), and plasticity (REL RDPIs and ABS RDPIs) in these traits and their relationships at two stages of plant growth. Our results showed an increase in mean CV, NC and ABS RDPIs of traits with density, and the positive correlations between trait NC and ABS RDPIs became stronger with higher densities but weaker over time in fertile soil, while correlations among trait CV, NC and ABS RDPIs became stronger over time in infertile soil. Results suggested shared or cooperation mechanisms among phenotypic integration, canalization and plasticity. Soil conditions and growth stage may affect responses of these correlations to density via modifying plant size and competition strength. The attenuated canalization and enhanced integration may be helpful for the production of plasticity, especially under intense competition.

Background and purpose: Cancer patients are always complicated with vein thromboembolism, thus the combination of anticoagulants with anti-cancer drugs has profound foundations. This study aimed to assess the safety of rivaroxaban comminating with three tyrosine kinase inhibitors (TKIs) in cancer patients. Experimental Approach: The inhibition of three TKIs on CYP2J2- and CYP3A4-mediated rivaroxaban metabolism was first screened and then reversible and mechanism-dependent inhibitory kinetic constants were determined. Molecular docking was conducted to reveal the interactions between TKIs and CYP2J2 and CYP3A4. Finally, pharmacokinetic parameters of cancer patients were used to assess the safety. Key Results: Imatinib and gefitinib significantly reversibly inhibited CYP2J2- and CYP3A4-mediated rivaroxaban metabolism, while sunitinib only showed reversible inhibition of CYP3A4, not CYP2J2. Three TKIs also showed time-dependent inactivation of CYP3A4. Notably, sunitinib had the strongest inactivation effect on CYP3A4 than the other TKIs with a 4.00-fold IC50 shift, however, a slight effect on CYP2J2. Docking simulations revealed the relation of inhibitory activity to ChemScore. Additionally, drug-drug interaction risks of combinations were assessed using pharmacokinetic data of cancer patients. Imatinib, which showed the strongest inhibition, was predicted to cause a 114–244% increase in rivaroxaban exposure. Conclusion and Implications: Imatinib was predicted to have a moderate DDI risk when was combined with rivaroxaban. These results provide evidence for medication guidance when combining rivaroxaban with TKIs for cancer patients, and also give new insight for the DDI assessment involving rivaroxaban.