The aim of this study was to determine the feasibility and outcomes of early surgical ligation in preterm neonates with hemodynamically significant patent ductus arteriosus (HSPDA) and to investigate predictors for surgical treatment after unsuccessful medical management.n = 49; within 10 days of age) and the late ligation group .Medical records from the neonatal intensive care unit of Hanyang University Seoul Hospital from January 2010 to December 2018 were retrospectively reviewed. 233 preterm neonates weighing less than 1500g with HSPDA were enrolled in our study. Of these preterm neonates, 134 underwent surgical ligation and were subdivided into the early ligation group (p <  0.001). PDA ductal diameter > 2.0 mm (p <  0.001), low Apgar score at 5 min (p = 0.033), and chorioamnionitis (p = 0.037) were the predictors for receiving surgical treatment for PDA. Early ligation was significantly associated with a low incidence of culture-proven sepsis (p = 0.004), mechanical ventilator time > 4 weeks (p = 0.007), necrotizing enterocolitis stage (NEC) ≥ III (p = 0.022), and intraventricular hemorrhage (IVH) grade ≥ III (p = 0.035).The mean gestational age and birth weight were significantly lower in the patent ductus arteriosus (PDA) ligation group than in the Non-ligation group (Early surgical ligation minimizes the adverse effects of HSPDA in predicted preterm neonates who subsequently require surgical treatment for PDA. This result suggests that in preterm neonates weighing less than 1500g with HSPDA that is unresponsive to medical treatment, delayed ductal closure should be avoided to reduce severe NEC, severe IVH, culture-proven sepsis, and facilitate earlier endotracheal extubation. Patent ductus arteriosus (PDA) is one of the most common congenital anomalies in premature neonates –3 and isIf pharmacologic treatment is contraindicated or fails, surgical ligation can be considered. Surgical ligation can be performed at the bedside in the neonatal intensive care unit (NICU) without a high risk of surgical morbidity or mortality . AlthougThe goal of this study was to analyze the feasibility of early surgical ligation (within 10 days of age) in preterm neonates with HSPDA and to investigate parameters that would be helpful for deciding on early surgery.Hanyang University Seoul Hospital is a tertiary referral center for patients with a multidisciplinary PDA team in Seoul, South Korea. All medical records of the NICU at our center from January 2010 to December 2018 retrospectively reviewed to identify preterm neonates weighing less than 1500g. Our institutional review board approved this study, and the need for patient consent was waived .3), as in our previous publication [The direction of treatment for PDA was determined by the neonatologist. Most HSPDA patients were initially treated with 2 or 3 cycles of nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin or ibuprofen. The protocol for indomethacin and ibuprofen treatment is described in Table lication .Table 1The decision to refer a preterm neonate with HSPDA to the department of Thoracic and Cardiovascular Surgery for surgical ligation after failure or due to contraindications of medical therapy was performed by a neonatologist and a pediatric cardiologist specialized in echocardiography. All operations were performed at the NICU bedside with the preterm neonate under general anesthesia. A left transaxillary mini-thoracotomy via the 3rd or 4th intercostal space was used as the PDA approach. The ductus arteriosus was ligated using a single medium or medium-large sized titanium Horizon clip . Immediately after the operation, the attending neonatologist checked with echocardiography to determine whether the PDA ligation was successful.The PDA ligation group comprised patients who underwent surgical ligation, and the Non-ligation group comprised patients who did not undergo surgical treatment. The PDA ligation group was divided into two subgroups: “early ligation (EL)” and “late ligation (LL)”. As mentioned above, the EL group comprised patients who underwent PDA ligation within 10 days of age, and the LL group comprised patients who underwent surgery after 10 days of age.The primary outcome of this study was a comparison of mortality between the PDA ligation and Non-ligation groups and the EL and LL groups. Secondary outcomes were factors associated with PDA surgical ligation and postoperative clinical outcomes such as NEC, BPD, IVH (grade ≥ III), sepsis, retinopathy of prematurity (ROP), and periventricular leukomalacia (PVL).Echocardiography was performed within 3 days of birth, and subsequent echocardiographic parameters were obtained on day 6 (± 1 day), day 9 (± 1 day), and day 14 (± 2 days) to identify symptomatic PDA in preterm neonates. Symptomatic PDA indicated HSPDA, which was defined as a ductal diameter ≥ 1.5 mm, or a ratio of 1.5 or more of the size of the left atrium to the diameter of the aortic root on at least one echocardiography . This definition was based on the description of the previous publication [IVH was classified by Volpe’s grading system . Culturet-tests were used for continuous variables when a normal distribution was found. The Mann-Whitney U test was used for variables with skewed distributions. All tests were two-tailed. Logistic regression analysis was used to determine risk factors between the PDA ligation and Non-ligation groups, and clinical morbidities between the EL and LL groups. Receiver operating characteristic (ROC) curves were constructed for the assessment of significant factors associated with PDA surgical ligation. All p values of less than 0.05 were considered statistically significant. Statistical analysis was performed using SPSS, version 22.0 .Data were expressed as either the mean ± standard deviation or frequency and proportion. Comparisons between groups were performed with chi-square tests and Fisher’s exact tests for categorical variables. Two sample Student’s n = 49, 36.6%) and the LL group . The conditions of 99 neonates improved with medical treatment alone according to the protocol described at Table A total of 233 preterm neonates weighing less than 1500g with HSPDA were ultimately enrolled in our study , while pregnancy-induced hypertension (PIH) was significantly lower in the PDA ligation group than in the Non-ligation group (p = 0.031). Regarding neonate characteristics, gestational age (GA), birth weight, length, head circumference, and Apgar scores at 1 min and 5 min were significantly lower in the PDA ligation group than in the Non-ligation group. In contrast, time on a mechanical ventilator or on oxygen therapy, total parenteral nutrition and hospitalization, and age at PDA closure were significantly higher in the PDA ligation group than in the Non-ligation group. Additionally, PDA size  and the proportion of preterm neonates with PDA ductal diameters larger than 2.0 mm  were significantly different between the PDA ligation and Non-ligation groups.The baseline characteristics of the patients in the PDA ligation and Non-ligation groups are summarized in Table p <  0.001) and body weight at surgical ligation  were significantly different between the EL and LL groups. The baseline maternal characteristics and preoperative status did not differ significantly between the EL and LL groups. Regarding neonate characteristics, cesarean section was significantly higher in the EL group than in the LL group (p = 0.044). In contrast, culture-proven sepsis (p = 0.026), NEC stage ≥ III (p = 0.030), and time on a mechanical ventilator (p = 0.048) were significantly lower in the EL group than in the LL group.The baseline characteristics of the patients in the EL and LL groups are summarized in Table p = 0.576), or between the EL and LL groups (p >  0.999).No patients died during their operations. Two neonates required reoperation due to residual flow of PDA, as diagnosed by immediate postoperative transthoracic echocardiography. The residual flow was corrected with an additional metal clip. Three patients died during the postoperative hospital day. In the LL group, one neonate died 100 days after PDA ligation due to NEC. In the Non-ligation group, two neonates died 12 and 17 days after birth, and the cause of death was sepsis. There were no statistically significant differences in mortality rate between the PDA ligation and Non-ligation groups (p <  0.001), low GA (p = 0.004), low Apgar score at 5 min (p = 0.033), and histologic chorioamnionitis (p = 0.037) remained significant after the analysis was controlled for GA, histologic chorioamnionitis, PIH, Apgar score at 5 min, and PDA ductal diameter > 2.0 mm.The logistic regression analysis for factors associated with PDA surgical ligation is presented in Fig. The ROC curve for the ability to predict PDA surgical ligation showed that PDA ductal diameter > 2.0 mm predicted surgical treatment with an area under the curve ) of 0.650 (0.579–0.721). Histologic chorioamnionitis showed an area under the curve (95% CI) of 0.570 (0.495–0.645), making it statistically significant in relation to the factors associated with PDA surgical ligation Fig. .Fig. 3Rp <  0.1 in the univariate analyses were analyzed by multivariate logistic regression with adjustments for cesarean delivery, weight on PDA ligation and PDA diameter > 2.0 mm. After adjustments were made for confounders, EL was found to be significantly associated with a low incidence of IVH grade ≥ III (p = 0.035), culture-proven sepsis (p = 0.004), NEC stage ≥ III (p = 0.022) and time on a mechanical ventilator > 4 weeks (p = 0.007).The clinical factors that were shown to affect the postoperative clinical outcomes of the patients (EL versus LL) in the multivariate model are shown in Fig. In this retrospective cohort study of preterm neonates with HSPDA that is unresponsive to pharmacological treatment, there was no statistically significant difference in mortality rate between the PDA ligation and Non-ligation groups. PDA ductal diameter > 2.0 mm, low GA, low Apgar score at 5 min, and histologic chorioamnionitis were related to the need for surgical ligation of HSPDA. Additionally, early surgical ligation was not significantly associated with increased mortality among preterm neonates with HSPDA. The LL group was significantly related to an increased risk of NEC (stage ≥ III), IVH (grade ≥ III), culture-proven sepsis and time on a mechanical ventilator > 4 weeks.The role of HSPDA surgical ligation in preterm neonates is still controversial. Although surgical treatment can close HSPDA immediately, multiple postoperative comorbidities such as left recurrent laryngeal nerve injury, bleeding, chylothorax, development of coarctation and acute hemodynamic compromise, can be associated with in-hospital mortality . In addiPDA surgical ligation is a viable option that is safe and effective , and it In this study, histologic chorioamnionitis, which is diagnosed by histologic biopsy of the maternal placenta, showed a significant association with factors related to PDA surgical ligation. The role of infection in maintaining the patency of PDA can be considered . InfectiIn preterm neonates with HSPDA, it is important to determine the optimal timing of surgical ligation , 25. OurAdditionally, sepsis with increased serum levels of inflammatory mediators or prostaglandins can be associated with smooth muscle relaxation of the ductus arteriosus . Thus, aProlonged patency of PDA increases pulmonary circulation that can be injurious to the capillary endothelium and stimulate an inflammatory cascade that results in pulmonary edema, CLD development, and increased ventilator support . EL may This study has several limitations. First, this was a small retrospective study with only 233 patients, and a randomized and prospective trial could not be performed. Thus, the statistical power of the population may be limited. Second, all operations were performed by one cardiac surgeon with a high level of experience in pediatric heart surgery. One goal of future research is to perform a large prospective multicenter study with long-term and close follow-up of preterm neonates with HSPDA that is refractory to pharmacological treatment.Early surgical ligation minimizes adverse effects of HSPDA in predicted preterm neonates who subsequently require surgical treatment for PDA. This result suggests that in preterm neonates weighing less than 1500g with HSPDA that is unresponsive to medical treatment, delayed ductal closure should be avoided to reduce severe NEC, severe IVH, culture-proven sepsis, and facilitate earlier endotracheal extubation. Avoidance of delayed surgical ligation after failure of pharmacologic closure may have beneficial outcomes in terms of postnatal morbidity among preterm neonates with risk factors in relation to HSPDA surgical ligation.


The incidence of childhood obesity and associated comorbidities are on an increasing trend worldwide. More than 340 million children and adolescents aged between 5 and 19 years old were overweight or had obesity in 2016, from which over 124 million children and adolescents (6% of girls and 8% of boys) had obesity.To describe the relationship between pancreas steatosis, body fat and the risk of metabolic syndrome, insulin resistance in Hong Kong Chinese adolescents with both obesity and non‐alcoholic fatty liver disease (NAFLD).U test, multiple linear/binary logistic regression analyses and odds ratios were used.Fifty two adolescents with obesity and NAFLD were analysed (14‐18 years), stratified into fatty and non‐fatty pancreas groups using chemical shift encoded MRI‐pancreas proton density fat fraction P = .006, .016). Pancreas and liver PDFF were both independent predictors of beta cells dysfunction  and metabolic syndrome . Presence of fatty pancreas in obesity was associated with insulin resistance  and metabolic syndrome .Fifty percent had fatty pancreas, 38% had metabolic syndrome and 81% had insulin resistance. Liver proton density fat fraction (PDFF) and VAT were independent predictors of insulin resistance (A significant causal relationship exists between fatty pancreas, fatty liver, body fat and the risk of developing metabolic syndrome and insulin resistance.Fatty pancreas is a common finding in adolescents with obesity, with a prevalence rate of 50% in this study cohort.Liver PDFF and VAT are independent predictors of insulin resistance while pancreas PDFF and liver PDFF are independent predictors of both beta cells dysfunction and metabolic syndrome.Presence of fatty pancreas at imaging should not be considered as a benign finding but rather as an imaging biomarker of emerging pancreatic metabolic and endocrine dysfunction. BMIbody mass indexHOMA‐Bhomeostasis model assessment‐betaHOMA‐IRhomeostasis model assessment‐insulin resistanceNAFLDnon‐alcoholic fatty liver diseaseQUICKIquantitative insulin sensitivity check indexSATsubcutaneous adipose tissueT2DMtype 2 diabetes mellitusVATvisceral adipose tissue1Childhood obesity and its associated comorbidities are increasing.Fatty pancreas has also been associated with metabolic syndrome, which is characterized by central obesity, hypertension, impaired glucose tolerance and dyslipidemia.Interestingly, studies have shown that in people suffering from impaired glucose metabolism there was decreased pancreatic volume and increased pancreatic fat.Chemical shift encoded MRI (CSE‐MRI) is an excellent quantitative method to calculate fat in the body. It is robust, accurate, reproducible, vendor and operator independent method that is able to quantify body, pancreatic and hepatic fat content.22.1This study was a substudy of Chan et al2.2Physical examination and anthropometric measurements were carefully taken at least within 24 hours of performing abdominal MRI scan. These included body weight in kilograms (kg), while the child was in light clothes and bare feet. The height in metres was measured using a flexible non‐stretchable measuring tape with the subject standing upright, extended knees, hips, waist and neck. BMI was calculated as weight (kg) divided by height in metre squared and z‐scores were derived using World Health Organization references.2.3Participants were allowed to be seated in a quiet room for 3‐5 minutes before measurement to reduce anxiety, with the back supported and feet uncrossed on the floor.2.4Laboratory tests were performed following 8 hours of fasting and within 24 hours of performing an abdominal MRI scan. Investigations included: plasma fasting glucose, lipid profile, plasma alanine aminotransferase, aspartate aminotransferase and serum insulin. Homeostasis model assessment‐insulin resistance (HOMA‐IR), Quantitative insulin sensitivity check index (QUICKI) were used to study insulin resistance while Homeostasis model assessment‐beta (HOMA‐B) was used to study pancreatic beta cells dysfunction. HOMA‐IR was calculated as: Fasting insulin (mIU/L) × glucose (mmol/l)/22.5,2.52 for ages above 16 years) plus any two or more: Hypertension (Systolic blood pressure ≥130 mm Hg or Diastolic blood pressure ≥85 mm Hg or treatment with anti‐hypertensive drugs), Dyslipidemia (triglycerides ≥1.7 mmol/L or high density lipoproteins cholesterol levels (HDL‐ch) ≤ 1.0 mmoL/L for ages 10‐16 years or triglycerides ≥1.7 mmoL/L or HDL‐ch ≤1.0 (boys) or ≤1.3 mmoL/L (girls) for ages above 16 years) or impaired glucose (fasting plasma glucose ≥5.6 mmol/L).Metabolic syndrome was defined according to the International Diabetes Federation (IDF) criteria2.6MR imaging was performed in all subjects using a 3.0 T scanner  equipped with 16‐channel SENSE‐XL‐Torso array coil. 3D spoiled chemical‐shift water‐fat mDixon sequence was used /1.0‐1.2 (ms), number of echoes = 6, flip angle = 3°, parallel imaging acceleration = 2, a 15 seconds breath hold technique was employed to acquire co‐registered water, fat, fat‐fraction and T2* image series and was reconstructed with slice thickness/number of slices = 3.0 mm/50. The field of view (FOV) covered the whole abdomen, that is, region from the dome of the diaphragm to the symphysis pubis. Image reconstruction was completed online using Philips mDixon product implementation with the multi‐peak spectral model of fat and T2* correction to increase accuracy and sensitivity.2.72.7.12 were drawn on the head, body and tail of the pancreas thrice in any slice that showed the pancreas clearly (avoiding the pancreatic duct and splenic vein) using RadiAnt DICOM viewer software version 4.6.5, Medixant, Poland as shown in Figure Readers consisted of two radiology staff with , both of whom were blinded to the clinical data. Pancreas proton density fat fraction (PDFF) was measured using the CSE‐MRI pancreas proton density fat fraction images. Three operator‐defined regions of interest (ROIs) set to 1 cm; 15 and 2.7.22 were placed into all nine Couinaud liver segments localized on PDFF maps (obtained in at least two slices) avoiding the hepatic blood vessels, bile ducts and motion artefacts.Reader 1 determined liver PDFF for each participant using the same RadiaAnt viewer. Nine elliptical regions of interest (ROIs) set to 4 cm2.8Pancreatic volumes were measured by Reader 1 using CSE‐MRI out of phase images as the pancreatic boundaries are clearest in these series of images. The pancreas was delineated from the adjacent structures using the splenic vein, superior mesenteric vessels, Inferior vena cava, aorta and the duodenum. ITK‐SNAP version 3.6.02.9Using an in‐house automated validated method2.10U test. Kruskal‐Wallis test was used to compare the fat distribution in the three regions of the pancreas. Interclass correlation coefficient was used to evaluate the inter and intra reader agreement of ROIs with 1 to 2 weeks' interval between measurements. Pearson's correlation coefficients were used to assess linear relationships between variables. To evaluate the causation relationships between variables, multiple linear and binary Logistic regression analyses with correction for multiple comparisons were used. Relative risk was determined by odds ratios. All tests were two‐sided and P‐values <.05 were considered statistically significant. Statistical analyses were performed by using the SPSS statistical package software .Normally distributed data was expressed as means ± SD, unless stated otherwise. Differences between two groups were analysed using Mann‐Whitney 33.12, waist circumference; 103.7 ± 8.7 cm and liver PDFF; 9.8 ± 7.6%) were analysed. The detailed patient characteristics are outlined in Tables P < .0001). Participants were categorized into fatty pancreas group (N = 26) and non‐fatty pancreas group (N = 26). Pancreas PDFF and body weight were significantly different between the two groups (P < .0001 and P = .027). Of note, the fat content was homogenously distributed in all the regions  of the pancreas (P < .05). No significant pancreas PDFF differences were noted between sex (P = .174).Fifty‐two participants  in the fatty pancreas group. 79% of all the participants were found to have insulin resistance, that is, HOMA‐IR ≥2.63.3P = .927) non‐fatty pancreas vs fatty pancreas respectively with intraclass correlation coefficient absolute agreement of 0.936 . To assess the relationship between pancreatic volume and insulin resistance/beta cells dysfunction using HOMA‐IR/ HOMA‐B, the pancreatic volumes were calculated. The mean pancreatic volume of the whole study population was 73.7± 18.6 cm3. No statistically significant differences were noted between the groups (P = .592), with intraclass correlation coefficient absolute agreement of 0.908 .The mean liver PDFF between groups was not statistically different . Pancreas PDFF correlated with body weight, BMI and central obesity , with a borderline correlation with HOMA‐IR (P = .056). SAT correlated with body weight, BMI, BMI z‐score, central obesity, HOMA‐IR and HOMA‐B . VAT correlated with age, BMI, BMI z‐score, central obesity, triglycerides and HOMA‐IR . Summary of the correlation results are shown in Table Pearson correlation coefficient tests showed that liver PDFF correlated with central obesity, BMI, Homeostasis model assessment‐insulin resistance (HOMA‐IR), Homeostasis model assessment‐beta (HOMA‐B), triglycerides, SAT and metabolic syndrome (3.5P < .001), total cholesterol  and plasma fasting glucose  were independent predictors of fatty pancreas after correcting for age, sex, HOMA‐IR, triglycerides, SAT, VAT, LDL‐c, HDL‐c, insulin and central obesity. Multiple linear regression step‐wise analysis showed that VAT and liver PDFF  were the only independent predictors of insulin resistance after correcting for pancreas PDFF, SAT, BMI and pancreatic volume.Multiple linear regression step‐wise analysis showed that BMI  and liver PDFF  were independent predictors of beta cells dysfunction at multiple regression enter method after correcting for age, VAT, SAT, BMI z‐score and BMI. Binary logistic regression showed that liver and pancreas PDFF  were the independent predictors of metabolic syndrome after correcting for VAT, SAT, BMI and central obesity. In order to know the relative risks of developing insulin resistance and metabolic syndrome given that one is a Chinese adolescent with obesity and has both fatty pancreas and fatty liver, we calculated the odds ratios. It was shown that insulin resistance was associated with fatty pancreas with an odds ratio (OR) 1.575  while metabolic syndrome was associated with fatty pancreas with an odds ratio (OR) 1.696 .Pancreas PDFF  cut offs.This study showed that the independent predictors of fatty pancreas are BMI, fasting plasma glucose and total cholesterol, in agreement with a previous study.P = .056) correlation with HOMA‐IR in concordance with previous studies.This study showed that the odds ratio of developing insulin resistance in adolescents with both obesity and fatty pancreas was nearly 2 folds than in those without fatty pancreas, similar to the findings of Singh et alBinary logistic regression showed that both pancreas and liver PDFF were independent predictors of metabolic syndrome similar to other studies.Strangely, no direct correlations among pancreas PDFF, liver PDFF and VAT were noted in our study similar to the findings of van der Zijl et al.Thus, we would recommend “screening” in this population group once the waist circumference and BMI/BMI z‐scores are outside the normal range. Furthermore, as total cholesterol and plasma fasting glucose were found to be independent predictors of fatty pancreas, we would recommend initiating “screening” if these parameters are elevated. Moreover, as the presence of fatty pancreas was as high as 50% in this Hong Kong Chinese cohort with fatty liver, the presence of fatty liver could be an indicator of the presence of fatty pancreas. Since fatty liver and fatty pancreas can be assessed during the same scanning session using chemical shift encoded MRI (CSE‐MRI) PDFF, the assessment of pancreatic fat can be performed in addition to assessment of hepatic fat.For limitation, this study only involved a cohort of adolescents with both obesity and NAFLD without healthy controls. Insulin resistance and beta cells function were not directly measured. Instead we used HOMA‐IR and HOMA‐B, acceptable surrogates to measure insulin resistance and beta cells function respectively. Besides, a relatively small sample size may also reduce the statistical power of our measurements. Finally, our study cohort was predominantly Chinese, therefore caution should be taken in the generalization of the results.In the future, it will be valuable to provide longitudinal follow up for those participants with high risk of developing insulin resistance and metabolic syndrome into their adulthood, to monitor their biochemical profile. With our established quantitative imaging and analysis technique for fat content in abdominal viscera, it would also be interesting to evaluate the change of pancreas. PDFF, liver PDFF and body fat components in participants who might be undergoing life‐modifying intervention or other kinds of medical treatment, to correlate the changes of body fat content with metabolic risks. Additionally, Wong et alIn conclusion, fatty pancreas is a common finding in Chinese adolescents with both obesity and non‐alcoholic fatty liver disease. A significant causal relationship exists between fatty pancreas, fatty liver, body fat and the risk of developing metabolic syndrome and insulin resistance.5The authors declare that they have no conflict of interest.C.C. and W.C. conceptualized the study. S.H. and D.Y. carried out the technical aspect of the experiments. C.C., D.C., H.K.S., M.D. and T.N. were involved in investigation and analysis. D.C. and W.C. sourced the project funding. C.C. wrote the initial draft of the manuscript. All authors revised the manuscript, approved the final manuscript as submitted, and agreed to be accountable for all aspects of the work.


The CELESTIAL, RESORCE, and REACH‐2 trials showed survival benefit of cabozantinib, regorafenib, and ramucirumab, respectively, in hepatocellular carcinoma (HCC) patients treated with sorafenib who had good performance status (ECOG 0‐1) and liver function (Child‐Pugh‐A). This study characterizes subsequent treatments received by HCC patients after sorafenib, and determines the proportion of patients eligible for novel therapies if strict eligibility criteria (SEC) were utilized compared to more liberal modified eligibility criteria .HCC patients who received sorafenib between 2008 and 2017 were included from the Canadian HCC CHORD Database. Patients were classified as eligible or ineligible based on available CELESTIAL, RESORCE, and REACH‐2 trial SEC or MEC. Median overall survival (mOS) was assessed using the Kaplan‐Meier method.P < .001). Using SEC, only 13.1% of patients would be eligible for cabozantinib, regorafenib, or ramucirumab. Expanding eligibility to include patients who meet MEC increased the proportion of eligible patients to 31.7%. Higher ineligibility for regorafenib and ramucirumab was driven by trial‐specific criteria, including sorafenib intolerance (28%) for RESORCE and AFP <400 (58.9%) for REACH‐2.A total of 730 patients were identified; and 172 (23.6%) received subsequent treatment. Patients who received subsequent treatment had longer mOS than those who did not  liver function might still benefit from treatment; therefore, modified eligibility criteria including ECOG 2 and CPB7 patients should be considered in clinical practice. The present retrospective analysis characterizes subsequent treatments received by HCC patients at multiple cancer centers across Canada over the past decade, and assesses their impact on survival in the real‐world setting. We also evaluate which patients in the real‐world would be eligible for novel treatments using SEC from the CELESTIAL, RESORCE, and REACH‐2 clinical trials, and determine the prognostic impact of using modified eligibility criteria (MEC) which would include patients with slightly worse performance status (ECOG 2) and/or limited liver dysfunction (Child‐Pugh‐B7).22.1The HCC Cancer Health Outcomes Research Database (CHORD) consortium is a Canadian research initiative that seeks to pool real‐world data to study outcomes in HCC patients treated with systemic therapy. Standardized data elements are collected from each participating institution and then merged into a central repository. For this study, data were combined from cancer centers in three Canadian provinces: British Columbia, Alberta, and Ontario.Patients with a confirmed diagnosis of HCC who were treated with sorafenib between January 2008 and June 2017 at all British Columbia Cancer Agency cancer centers in British Columbia, all cancer centers in Alberta, and 2 cancer centers in Toronto, Ontario  were retrospectively identified. Clinical, pathologic, laboratory, treatment, and outcome data were collected from the CHORD consortium database. Ethics approval was obtained from each provincial cancer research ethics board or individual participating center as per local institutional guidelines prior to data collection for this study.2.2The type of treatment received by patients after sorafenib was characterized. Localized treatments included stereotactic body radiation therapy (SBRT), transarterial chemoembolization (TACE), transarterial radioembolization (TARE), bland embolization, radiofrequency ablation (RFA), and surgical resection. Systemic therapies included chemotherapy and clinical trial drugs such as multikinase inhibitors, immunotherapy, or other trial drugs. Palliative radiation included radiation treatment to nonlocoregional sites.2.3Patients who met the common clinical trial inclusion/exclusion criteria from the CELESTIAL, RESORCE, and REACH‐2 trials were identified from our database. The common trial inclusion criteria were ECOG performance status 0‐1, Barcelona Clinic Liver Cancer (BCLC) stage B or C, Child‐Pugh‐A, and absence of ascites.Patient charts were also reviewed for trial‐specific inclusion criteria, which were each specific to only one of the clinical trials. RESORCE trial‐specific criteria included sorafenib tolerability (defined as ≥400 mg daily for at least 20 of the 28 days before discontinuation), as well as documented radiographic progression during sorafenib treatment. REACH‐2 trial‐specific criteria included an alpha‐fetoprotein (AFP) level of ≥400 ng/mL. Patients who met these trial‐specific inclusion criteria for each trial and the common inclusion/exclusion criteria listed above were defined as meeting SEC for that specific trial.Patients included in the modified eligibility criteria (MEC) group included those in the SEC group, as well as patients with ECOG 2 performance status and/or limited liver dysfunction (Child‐Pugh‐B7). These patients, while not generally eligible for HCC clinical trials would be regarded by most oncologists as well enough for treatment in the real‐world setting.2.4The Kaplan‐Meier method was used to estimate overall survival (OS) based on subsequent treatment. For assessment of survival outcomes based on trial eligibility, patients were classified as eligible or ineligible based on available CELESTIAL, RESORCE, REACH‐2 clinical trial eligibility criteria (SEC), and also MEC.33.1A total of 730 patients with HCC previously treated with sorafenib were identified. In this cohort, patients were treated with sorafenib for a median duration of 3.4 months, and received a mean dose of approximately 66.1%. Baseline patient characteristics are summarized in Table 3.2A total of 172 (23.6%) patients received subsequent treatment after sorafenib . Patients who met SEC were more likely to receive subsequent treatment than those who did not . Patients who received subsequent treatment had longer median OS than those who did not . Median overall survival was also longer if patients met SEC compared to MEC for the CELESTIAL cabozantinib trial , RESORCE regorafenib trial , and the REACH‐2 ramucirumab trial   Figure . Patient3.5P < .001, and CP HR 1.38, 95% CI 1.09‐1.75, P = .007). Despite controlling for SEC and MEC, there was continued benefit from systemic , localized , and palliative  treatment.In a Cox regression model Table , patientP < .084), whereas inclusion of only patients who discontinued sorafenib for progression would have selected for a poorer prognosis group . The REACH‐2 trial‐specific inclusion criteria of AFP ≥ 400 selected for patients with a poorer prognosis .The trial‐specific inclusion criteria of sorafenib tolerability in the RESORCE trial selected for potentially better prognostic patients  did not receive subsequent treatment. Of those who received treatment after sorafenib, only 13% received systemic therapy and 10% were included in a clinical trial. It is interesting to note that only 13.1% of patients in our study met SEC and would have been eligible for the CELESTIAL, RESORCE, and REACH‐2 trials. Broadening eligibility using MEC, which many physicians would likely use to guide second‐line treatment eligibility in clinical practice, an additional 18.6% of patients could receive subsequent treatment. In addition, this study showed that subsequent treatments appeared to improve survival for patients who met SEC or MEC. In other words, carefully selected patients with performance status ECOG 2 and CP‐B7 liver function may benefit from subsequent treatments.To our knowledge, this is the first study of HCC patients treated in non‐East Asian countries to characterize subsequent treatments after sorafenib. In addition, it is the only study to examine potential eligibility for novel second‐line treatments postsorafenib. Kondo et al previously reported on 71 HCC patients treated at a Japanese medical center who progressed on sorafenib.We found that only a small proportion of HCC patients progressing on sorafenib would be eligible for second‐line regorafenib, cabozantinib, or ramucirumab if strict eligibility criteria (SEC) from their respective clinical trials were followed. In clinical practice, it is likely safe to treat patients with a performance status of ECOG 2 and/or Child‐Pugh‐B liver function with an oral multikinase inhibitor. The SHARP trial comparing first‐line sorafenib to placebo included 8% of patients with a performance status of ECOG 2 and 5% of patients with Child‐Pugh‐B liver function in the sorafenib arm.P < .001). On the other hand, we found potentially better prognosis for patients who demonstrated sorafenib tolerability . The REACH‐2 trial excluded patients with an AFP < 400. We showed in multivariable analysis that patients with an AFP ≥ 400 had worse prognosis , which likely contributed to the shorter survival in patients who met eligibility for REACH‐2.Our study also confirms the relative prognostic impact of the trial‐specific eligibility criteria used in RESORCE and REACH‐2. Patients were required to have evidence of radiographic progression on sorafenib, as well as demonstrated sorafenib tolerability to be eligible for the RESORCE trial. On multivariable analysis, we found that radiographic progression on sorafenib was associated with worse prognosis  Sanofi, Clinical Trials (To Institution) Boston Biomedical. Tam—Honoraria: BMS, Eisai, Ipsen. Research Funding (To Institution): Bayer, Eisai. Clinical Trials Funding (To Institution): AstraZeneca, BMS, Boston Biomedical, Exelixis, Merck. Davies—Clinical trial funding from Merck, BMS. Honoraria/Consulting: Eisai. Knox—Research support: Merck, Roche, AstraZeneca, Ipsen. Consulting: Merck.Andrea S. Fung: Formal analysis, writing original draft, reviewing and editing of manuscript. Vincent C. Tam: conceptualization, data curation, methodology, funding acquisition, supervision, reviewing, and editing. Daniel E. Meyers: Data curation, methodology, reviewing, and editing. Hao‐Wen Sim, Jennifer J. Knox, Valeriya Zaborska, Janine Davies, Yoo‐Joung Ko, Eugene Batuyong, Haider Samawi, and Winson Y. Cheung: Data curation, reviewing, and editing. Richard Lee‐Ying: conceptualization, data curation, formal analysis, methodology, funding acquisition, supervision, reviewing, and editing.


Contingent negative variation (CNV) is a negative cortical wave that precedes a pre‐cued imperative stimulus requiring a quick motor response. It has been related to motor preparation and anticipatory attention. The aim was to ascertain whether the clinical improvement of functional movement disorders after physiotherapy would be associated with faster reaction times and modulation of CNV.Motor performance and CNV were analysed during a pre‐cued choice reaction time task with varying cue validity. Twenty‐one patients with functional movement disorders and 13 healthy controls at baseline were compared. Patients then underwent physiotherapy. At follow‐up after physiotherapy, patients were categorized as clinically improved (responders) or not improved (non‐responders) and retested.P = 0.010], contrary to non‐responders. Simultaneously, responders showed a recovery of CNV after physiotherapy , contrary to non‐responders .At baseline, patients did not generate CNV, contrary to controls [mean amplitude (µV) at the end of preparation to move: patients −0.47  versus controls −2.59 ]. Responders performed faster after physiotherapy [mean natural logarithm (ln) reaction time (RT) (ms): follow‐up 6.112  versus baseline 6.206 , Clinical improvement of functional movement disorders after physiotherapy was associated with faster reaction times and normalization of CNV, which was absent at baseline. These findings suggest that CNV may constitute a useful neurophysiological biomarker related to abnormal attention in functional movement disorders. One of the most characteristic clinical features of functional movement disorders (FMDs) is their alteration with attention: when attention is focused onto movement, movement is impaired; but with distraction, movement typically normalizes . This phThere is some evidence of a pathophysiological role for explicitly directed attention in FMD , 6. TherThe usefulness of a simple pre‐cued reaction time (RT) task, based on the classic Posner paradigm, as a diagnostic biomarker for FMD was previously explored , 6. In tIn this study, the utility of a different potential biomarker was explored: the contingent negative variation (CNV). CNV is a slow negative cortical wave that develops following a pre‐cue which signals that, within a few seconds, an imperative stimulus will arrive, requiring a quick motor response , 8. CNV In people with FMD, it was predicted that excessive attention onto the current state of the limb to be moved and away from the movement’s goal would be associated with an insufficient deployment of anticipatory attention and abnormal motor preparation. This would translate into slower RTs to the imperative cues (thus replicating the findings of previous research)  and a reTherefore, in this study, it was hypothesized that (i) CNV amplitude would be reduced at baseline in comparison with healthy controls; (ii) clinical improvement after physiotherapy would be associated with faster RT and recovery of CNV.A case–control study was performed comparing patients with FMD and healthy volunteers. Patients with FMD were recruited from a pool of patients being enrolled in a randomized feasibility study comparing specialized with standard physiotherapy for FMD . A detaiAssessment of clinical improvement after physiotherapy was based on Clinical Global Impression (CGI), the Physical Function domain of the Short‐Form Health Survey (SF‐36) (version 1) and the Simplified Functional Movement Disorders Rating Scale (S‐FMDRS) , 13, 14.Our behavioural experiment consisted of a Posner‐type pre‐cued choice RT task with varying cue validity , 6, 15, Response time in milliseconds (ms) was calculated for each trial. Trials where the preparation cue accurately predicted the go cue (congruent) were separated from those where the prediction was incorrect (incongruent). RTs were separately averaged across trials for congruent and incongruent trials in each of the two conditions.Continuous EEG was recorded using a 32‐channel ANT‐EEG®  system conforming to the 5% electrode system. Our reference was an average of all electrodes. Trials with prominent artefacts and trials where participants pressed the wrong key or did not press any key were excluded.A more detailed description of the participants, experimental task and EEG recording can be found elsewhere .Statistical Parametric Mapping  and MATLAB®  were used for data processing. Data were downsampled from 2048 to 250 Hz and epoched to frames from −1 to +4 s relative to the onset of the preparation cue. The interval preceding the preparation cue was selected as baseline and baseline‐corrected the epoched frames. Finally, data were averaged over trials for each participant and extracted data from the Cz electrode , which is considered to record CNV with greatest amplitude . The midPre‐processing resulted in four datasets of Cz amplitude as a function of time: (a) 95% trial, right key press (right index finger); (b) 95% trial, left press (left index finger); (c) 50% trial, right press; (d) 50% trial, left press.Statistical analysis was performed using Stata® . Continuous variables were expressed as mean (and standard deviation) if normally distributed or median (and interquartile range) if not normally distributed. Categorical variables were expressed as frequencies and proportions. The normality assumption was assessed by visually inspecting the distribution of the continuous variable and confirmed by Kolmogorov–Smirnov testing.Reaction times (RTs) were non‐normally distributed and were therefore transformed into their natural logarithms (ln), in order to fulfil the normality assumption and thus be able to fit a multilevel mixed effect linear model.Participants could pre‐plan the forthcoming key press in the interval between the appearance of preparation and go cues . CNV amplitude (µV) at the moment of maximum preparation was analysed by restricting our analysis to the last 12 ms preceding the go cue (averaging data from three data points).A baseline comparison was made of patients with FMD and healthy controls.Behavioural results (RTs) for baseline comparison were presented in our previous paper focusing on beta oscillations (see summary below) .For CNV amplitude, the effects of group, predictability and hand, their interactions and an individual level random effect were included.A comparison was carried out of FMD responders and non‐responders to physiotherapy, before and after this intervention.For RT, our analysis was restricted to trials with congruent preparation and go cues, as those were the ones thought to reflect motor preparation. A model was fitted including the effects of time‐point (baseline versus follow‐up), response (responder versus non‐responder) and predictability (95% vs. 50%), their respective interactions and an individual level random effects factor.For CNV amplitude, the effects of group, predictability and hand, their interactions and an individual level random effect were included.Our outcome measures were RT (ms) and CNV amplitude (µV) at the end of preparation to move. Mixed effects multilevel linear modelling allowed the dependence in the data caused by repeated measurements within‐subjects to be taken into account. The following models were fitted.Finally, the relationship between changes in CNV and changes in RT at follow‐up was investigated. The grand average of end‐of‐preparation CNV (µV) and RT (ms) at baseline and at follow‐up was calculated, for each participant. The baseline averages were then subtracted from the follow‐up averages for both parameters. It was planned to regress the average change of RT against the average change of end‐of‐preparation CNV.P < 0.05.Statistical significance was predefined as This study was approved by the local ethics committee. Participants gave their informed written consent to take part in the studies.Twenty‐one patients with FMD and 13 healthy controls were recruited and a baseline assessment was performed. Nine patients with FMD were randomized to undergo specialized physiotherapy and another 12 to receive standard physiotherapy. Groups at baseline were well matched for age, sex and proportion of left‐handed participants (reported elsewhere ).Patients with FMD were evaluated after a mean period of 4.7 weeks SD 1.7) after treatment. Ten patients with FMD were classified as responders and 11 as non‐responders, in accordance with their self‐rated CGI. FMD responders, contrary to non‐responders, showed an increase in SF‐36 and a decrease in S‐FMDRS at follow‐up  was found but not for predictability (P = 0.484), hand (P = 0.496) or the interactions group × predictability (P = 0.459), group × hand (P = 0.245), predictability × hand (P = 0.923) and group × predictability × hand (P = 0.361)  Fig. .P value for the pairwise comparison between FMD and healthy controls was 0.081 [mean FMD −0.47  versus healthy controls −2.59 ]. Importantly, patients with FMD failed to generate the negative wave that defines CNV (P = 0.532 for rejecting the null hypothesis of CNV amplitude being zero), contrary to healthy controls (P = 0.007).After eliminating all non‐significant factors from our model, the P = 0.012). None of the other terms was significant, including response (P = 0.184), time‐point (P = 0.140), predictability (P = 0.755), response × predictability (P = 0.691), time‐point × predictability (P = 0.466) and response × time‐point × predictability (P = 0.498). Responders at follow‐up were unable to take advantage of predictive conditions (95% congruence) to perform faster, compared with non‐predictive conditions (50% congruence) (P = 0.643 for the corresponding pairwise comparison). This specific finding is similar to what has been described elsewhere for patients with FMD at baseline .In order to dissect the significant interaction between response × time‐point, a pairwise comparison analysis was then performed in a model only including response, time‐point and their interaction. In accordance with our predictions, responders performed faster at follow‐up than at baseline . Notably, only responders at follow‐up generated a negative wave at the end of preparation to move .In our predefined model, the effects of response (nt P = 0.81 were n01) Fig. . In ordeIn responders, RT became −41 ms (SD 31) faster at follow‐up, whilst the end‐of‐preparation CNV became −1.97 (SD 2.12) more negative at follow‐up. In contrast, in non‐responders, RT became 12 ms (SD 159) slower and the end‐of‐preparation CNV 0.40 (SD 4.56) more positive at follow‐up.P = 0.004) Here it is reported that CNV is abnormal in people with FMD and that clinical improvement that occurred following treatment is associated with its normalization. In contrast, people with FMD who did not experience clinical improvement with treatment continued to demonstrate abnormal CNV at follow‐up assessment.It has been previously observed that people with FMD are unable to take advantage of highly predictable conditions to prepare for the forthcoming movement and improve performance (i.e. generate faster RTs) , 6. ThisContingent negative variation is related to anticipatory attention and motor preparation , 9. TherOnly one previous study reported suppression of CNV in FMD, in a group of six patients with functional weakness. Suppression of CNV was not observed in a group of 24 participants feigning paralysis, despite similar motor performances, or in a group of 12 healthy subjects .In addition, FMD patients were highly accurate in their performance (95.3% vs. 98.8% in controls) which it is believed is evidence against feigning as an explanation for their lack of CNV Table .et al. observed a decrease in thalamic and basal ganglia single‐photon emission computed tomography activation in response to contralateral limb vibration in seven patients with unilateral functional motor symptoms, which normalized after symptom improvement at follow‐up [It was found that clinical improvement in responders was associated not only with faster RT but also with a recovery of CNV after treatment. The same was not observed in non‐responders, ruling out confounding by a simple retesting effect. Physiotherapy for FMD is based on movement retraining with the aim of restoring normal movement by redirecting the focus of motor attention towards the movement goal and away from movement mechanics , 5. CNV ollow‐up .Our results may help explain rather unusual results from assessment of Bereitschaftspotentials  in people with functional myoclonus . In thesA crucial facet of the data presented here is that CNV relating to movement preparation for right or left arm movement was recorded, but many of the patients did not have symptoms in their arms or, in some patients, only one arm was affected. Despite this, there was no systematic difference in our findings between those with or without clinical involvement of the upper limbs. This fits with our clinical experience that it is very common for functional motor signs to be triggered through the act of physical examination, even in patients who do not complain of specific symptoms in the limb being examined. Indeed this phenomenon is commonly seen in people with non‐motor functional symptoms, e.g. chronic pain, functional sensory loss, chronic fatigue. In such patients, examination of power commonly reveals give‐way patterns of weakness, a positive Hoover’s sign, or flurries of jerks and tremors. This is in accordance with the common co‐occurrence of functional symptoms in different domains  and with neurobiological accounts of functional neurological disorders which make no separation between the mechanism of functional symptoms that occur in different domains. This is important information for the potential use of CNV as a neurophysiological diagnostic biomarker, as it does not require people to have symptoms in the limbs being studied, and it also may be of use in those with non‐motor functional symptoms. This requires further study, but could indicate a more general utility of CNV as a biomarker related to abnormal attention in functional neurological disorder.There are several limitations to our study. It was decided to use data from the lead Cz because this is previously reported to provide CNV with the largest amplitude. Our main interest here was studying FMD responders and non‐responders, which restricted our sample size. Therefore, it was decided to prioritize testing for differences in CNV amplitudes over investigating CNV lateralization, which is obviously not possible with Cz.Patients were dichotomized into responders and non‐responders based on one self‐rated outcome measure (CGI). However, changes in SF‐36  and S‐FMDRS (video rating blinded for time‐point ) after tExperiments with long intervals between preparation and go cues have described an early and late component of CNV. Notwithstanding significant controversy, late CNV was proposed to be more closely related with the BP. Although the rules for decomposing CNV into its early and late components are not ‘set in stone’, foreperiods of at least 3 s duration are often used. Therefore, it is considered that our interval was too short to allow a precise separation of these components.Responders’ RTs in congruent trials overall became faster at follow‐up, contrary to what was observed in non‐responders. However, there was a persistence of some behavioural abnormalities, with patients with FMD remaining unable to take advantage from predictive pre‐cues to perform even faster .Contingent negative variation abnormalities were previously described in other movement disorders, including Parkinson’s disease , writer’In conclusion, a recovery of CNV in the context of a clinical and behavioural improvement after physiotherapy is described. These findings suggest that CNV is a potential candidate biomarker for treatment response in FMD, and indeed may have utility outside the setting of those with FMDs and be useful in functional neurological disorder in general.(i) Research project: conception, MJE, AL, TT, IP, SL, AMM; organization, AMM, IP, TT, GN, SL, MJE; execution, AMM, IP, TT, GN, AM, IP. (ii) Statistical analysis: design, TT, AK; execution, TT, AK; review and critique, TT, AK, MJE, SL, IP, JJF. (iii) Manuscript: writing of the first draft, TT; review and critique, AK, AMM, SL, GN, AM, JJF, IP, AL, MJE.Tiago Teodoro, Akihiro Koreki, Anne Marthe Meppelink, Simon Little, Glenn Nielsen, Antonella Macerollo and Mark J Edwards: no disclosures. Joaquim J Ferreira: stock ownership in medically related fields – none; intellectual property rights – none; consultancies – GlaxoSmithKline, Novartis, TEVA, Lundbeck, Solvay, Abbvie, BIAL, Merck‐Serono, Merz, Ipsen, Biogen, Sunovion Pharmaceuticals, Zambon; expert testimony – BIAL, Novartis; advisory boards – BIAL, Sunovion Pharmaceuticals; employment – Faculdade de Medicina de Lisboa, CNS – Campus Neurológico Sénior; partnerships – none; contracts – none; honoraria – none; royalties – none; grants – GlaxoSmithKline, Grunenthal, Fundação MSD , TEVA, MSD, Allergan, Ipsen, Novartis, Medtronic; other – none. Isabel Pareés: has received honoraria and/or travel expenses from Allergan, Abbvie, Alter, TEVA and Italfarmaco for attending and/or speaking at meetings. Anthony Lang: stock ownership in medically related fields – none; consultancies – Abbvie, Acorda, Biogen, Janssen, Jazz Pharma, Sun Pharma, Kallyope, Merck, Paladin, Theravance and Corticobasal Degeneration Solutions; advisory boards – Jazz Pharma, PhotoPharmics; partnerships – none; honoraria – Sun Pharma, Medichem, Medtronic, AbbVie and Sunovion; grants – Brain Canada, Canadian Institutes of Health Research, Corticobasal Degeneration Solutions, Edmond J Safra Philanthropic Foundation, Michael J. Fox Foundation, the Ontario Brain Institute, National Parkinson Foundation, Parkinson Society Canada, and W. Garfield Weston Foundation; intellectual property rights – none; expert testimony – none; employment –University Health Network, University of Toronto; contracts – none; royalties – Elsevier, Saunders, Wiley‐Blackwell, Johns Hopkins Press and Cambridge University Press; other – none.Table S1. Reaction time (non‐transformed) per group and time‐pointTable S2. Reaction time  per group and time‐pointTable S3. Accuracy per group and time‐pointTable S3. CNV at end of preparation to moveClick here for additional data file.Appendix S1. Specialist physiotherapy for functional motor symptomsClick here for additional data file.


Optimizing quality of life (QoL) is a key priority in the management of heart failure (HF).To investigate ethnic differences in QoL and its association with 1‐year survival among patients with HF.A prospective nationwide cohort  of Chinese (62.3%), Malay (26.7%) and Indian (10.9%) ethnicities from Singapore, QoL was assessed using the Minnesota Living with HF Questionnaire (MLHFQ) at baseline and 6 months. Patients were followed for all‐cause mortality.P < .001. NYHA class was the strongest independent predictor of MLHFQ scores . After multivariable adjustment , ethnicity remained an independent predictor of QoL (P < .001). Crude 1‐year mortality in the overall cohort was 16.5%. A 10‐point increase of the physical component (of MLHFQ) was associated with a hazard  of 1‐year mortality (P = .018) in the overall cohort. An interaction between MLHFQ and ethnicity was found (P = .019), where poor MLHFQ score (per 10‐point increase) predicted higher adjusted mortality only in Chinese .At baseline, Chinese had a lower (better) mean MLHFQ total score (29.1 ± 21.6) vs Malays (38.5 ± 23.9) and Indians (41.7 ± 24.5); Ethnicity is an independent determinant of QoL in HF. Despite better baseline QoL in Chinese, QoL was more strongly related to survival in Chinese vs Malays and Indians. These findings have implications for HF trials that use patient‐reported outcomes as endpoints. We investigated potential interethnic differences in QoL and assessed the relationship of QoL to mortality.22.1Singapore is a highly developed city state. Its national healthcare expenditure constitutes approximately 4.9% of the GDP, which is considerably lower than other developed countries.2.2Data from the Singapore Heart Failure Outcomes and Phenotypes study (SHOP) studyThe demographics of Singapore and HF admissions had been previously described.Baseline patient demographic details and clinical data, such as vital signs and symptoms on physical examination, New York Heart Association (NYHA) functional status, serum biochemistry and hematology, comorbid conditions, medications, and interventions were recorded. Comprehensive two‐dimensional echocardiography was also performed on all eligible patients, using standardized machines at study sites.Health‐related QoL was assessed at baseline, 3 and 6 months following first admission/consultation with the Minnesota Living with Heart Failure Questionnaire (MLHFQ).For socioeconomic status, we used the small areal Socioeconomic disadvantage index (SEDI) described by Earnest et al.3P‐values <.1 were then considered for multivariable adjustments, including any important clinical and demographic factors.Descriptive statistics were used to characterize the study population and ethnic groups. Categorical variables are described as percentages and continuous variables are described as a mean with standard deviations or median (interquartile range) if skewed. The relationship of MLHFQ scores  with independent risk factors was assessed using linear least‐squares regression models. Univariable analyses were first performed on all the baseline variables. Covariates with P value of less than .05 was considered statistically significant. All statistical analyses were performed with STATA/SE v14.0.Multivariable Cox proportional hazards models were used to determine the association of MLHFQ scores  with 1‐year all‐cause mortality. Multivariable adjustments included ethnicity, age, sex, body mass index, systolic blood pressure, diastolic blood pressure, heart rate, biomarkers , NYHA functional class, diabetes, coronary artery disease, atrial fibrillation, hypertension, prior stroke, liver disease, chronic respiratory disease, history of smoking or alcohol usage, evidence‐based medications for HF, and areal socio‐economic disadvantage index (SEDI),Ethics approvals were obtained from the relevant human ethics committees at the investigating sites. The study conforms to the Declaration of Helsinki.44.1P < .001), with the proportions of ≥65 years being 46.1% in Chinese, 30.5% in Malays, and 32.3% in Indians, respectively. No significant difference (P = .149) in areal socio‐economic disadvantage index (as proxy for socio‐economic status) was observed among the three ethnicities, with 72.5% Chinese, 76.7% Malay, and 68.3% Indian, being in the lowest two SEDI quartiles.Baseline characteristics of 1070 HF patients  are summarized in Table P < .001). Comorbid atrial fibrillation was highest in the Chinese (26.5%), but notably the least in Indians (12.2%). CKD was more similarly prevalent in half of Chinese and Malays but less in Indians (44.6%). For lifestyle risk factors, Malays were more likely to be smokers than Chinese and Indians, but Indians were more likely to report alcohol intake than the other ethnicities (P < .001), Table Comorbidities were common in the study population Table : with hiP < .001). Systolic and diastolic blood pressure, heart rate, eGFR, galectin‐3 levels, NT‐proBNP levels, sex, and NYHA class composition did not differ significantly across ethnicities, although more Malay (17.0%) and Indian (24.3%) patients had higher severity of HF (in NYHA class III/IV) compared to Chinese (14.8%).Chinese also had lower BMIs than Malay and Indian patients (P = .002). Indian patients were less likely than Chinese or Malay patients (80.3% vs 88%‐89%) to be on β‐blockers, despite higher prevalence of CAD or hypertension than Chinese or Malay patients (P = .045).A majority of patients took ACE inhibitors or ARBs (70.1%), β‐blockers (87.5%), diuretics (89.6%), and statins (83.4%). Malay patients were more likely to be on statins than Chinese and Indian patients . Left ventricular ejection fraction was not independently associated with QoL.At baseline, mean MLHFQ scores in the entire cohort for the total, physical, and emotional components were 32.9 ± 23.1, 15.4 ± 11.0, and 5.9 ± 6.0, respectively. Chinese had a lower (better) MLHFQ total score (29.1 ± 21.6) compared with Malays (38.5 ± 23.9) and Indians (41.7 ± 24.5); 4.3Of the 21 MLHFQ questions, patients reported the greatest burden in response to “Costing you money for medical care?”  in response to “Costing you money for medical care?”.Among patients in the two lowest SEDI quartiles, 52% reported substantial economic burden of HF (with scores ≥3), with significantly more Malays (41.2%) and Indians (39.3%) than Chinese (29.3%), 4.4β = 12.7 units increment), physical (6.2 units), and emotional (2.3 units), respectively. Ethnicity, higher log NT‐proBNP levels, and comorbidities  were also independently associated with increased MLHFQ scores. Evidence‐based medications and statins were negatively associated with MLHFQ .MLHFQ scores for the total, physical, and emotional components at 6 months were available for 622, 647, and 645 patients, respectively. At 6 months' follow‐up, all ethnic groups showed improvement in QoL, with a cohort‐wide total score change of −11.0 ± 22.5 Tables  and S2. 4.6P = .013). Furthermore, a significant interaction between the MLHFQ total score and ethnicity was found (P = .019), where a poor MLHFQ score predicted higher adjusted mortality (per 10‐unit increment) only in Chinese (HR = 1.18 [95% CI 1.07‐1.30]) for total score, HR =1.44 (95% CI 1.17‐1.75) for physical and HR = 1.45 (95% CI 1.05‐2.00) for emotional scores, respectively.Crude 1‐year all‐cause mortality was 16%, with no significant difference among the ethnicities. Of the three scores: MLHFQ total, physical, and emotional scores, the physical score was the strongest independent predictor of mortality  QoL score had the strongest association with 1‐year adjusted mortality than total and emotional QoL scores. Significant interactions between MLHFQ total and physical scores with ethnicity on 1‐year adjusted mortality were however observed such that Chinese had poorer outcomes than Malays or Indians, independent of NT‐proBNP and contemporary evidence‐based pharmacotherapy for HF. Interestingly, all three ethnic groups reported significant improvement (greatest in Indian patients) in overall QoL, with no significant ethnic difference in QoL at 6 months. This finding suggests that the receipt of medical care ameliorated ethnic differences in QoL for our study subjects.There has been a growing recognition that PROMs are a legitimate measure for monitoring health care outcomes. PROMs can provide insights that, while unobtainable through direct clinical measurements, are nonetheless consistent with those of clinicians.Physical mobility contributed to a significant component of the overall MLHFQ score. In terms of its prognostic utility, we observed a strong (twofold) association of a high (fourth quartile vs first quartile) physical score with 1‐year adjusted mortality in the overall cohort. Findings from several studies with inclusion of the physical domain of the MLHFQ had been inconsistent in terms of its predictive association with mortality.only in the Chinese patients . The significantly older age of the Chinese (63.4 years) vs other ethnicities , higher comorbidity burden (particularly CKD), and the lower uptake of ACEi/ARBs could in part explain the variation. Additionally, there might be residual confounding of unmeasured clinical factors with the outcome examined.Intriguingly, a significant interaction between the overall MLHFQ score and ethnicity with respect to mortality was observed where poor MLHFQ score predicted higher adjusted mortality To begin interpreting these results, we first looked to biochemical factors that may explain the observed ethnic differences in QoL. Other statistically significant ethnic differences in baseline characteristics ‐rates of hypertension, coronary artery disease smoking, and diabetes‐ did not seem to account for the observed differences in QoL. The same is true for systolic blood pressure, levels of log NT‐proBNP, use of alcohol, angiotensin II receptor blocker use, and sex distribution. We must then ask ourselves the following question: what is driving the observed ethnic difference in QoL?5.1.1.In this analysis, areal SEDI—as proxy for socio‐economic status—did not significantly differ among the ethnic groups and as such did not explain any of the variation in QoL seen. Notably, though, >70% of each ethnic group were in the lowest two SEDI  categories. This proportion is higher than would be expected in a random sample of the general population, which may reflect an association between low SES and incident HF. However, our data are limited to prevalent HF. Given the low SES of our cohort, the extreme expense of treating HF, and the high (54.8%) out‐of‐pocket expense for healthcare expenditures in Singapore,5.1.2.Better mean QoL scores in the Chinese at baseline can in part be attributed to the smaller  proportion of patients in NYHA Class III/IV compared to Malays and Indians. The observed ethnic differences in QoL are likely also attributable to ethno‐cultural variance. Notably, the mean MHLFQ total score, 32.9 ± 23.1, in the overall cohort was substantially less severe than those reported in QoL studies focused on Western patient populations, despite the high comorbidity burden.Notably, sexuality, dementia/forgetfulness, and depression are “sensitive” topics which Asians are more hesitant to respond or give neutral responses to . More than 60% of the patients reported no depression in our study, in contrast to the higher prevalence (though consistent with under‐reporting among Asians patients) as suggested in a meta‐analysis of HF patients.5.1.3.Our data suggest that QoL is related to prognosis and that this relationship differs between ethnicities. While the total QoL score was significantly associated with increased mortality hazard in only the Chinese, the physical component was more strongly (twofold) associated with mortality in the overall cohort. This finding is not entirely surprising, since physical symptoms have the simplest and most direct relation to disease course. It is surprising, however, given the fact that QoL does not always align with other risk stratification algorithms. Our findings do suggest, however, that in this cohort improving physical QoL may be correlated with improved prognosis. This is consistent with proven survival benefit of exercise programs in HF. Patients' goal attainment in terms of physical mobility might have implications for rehabilitative medicine for HF patients.The observation of interethnic differences in the relationship of QoL to prognosis in HF calls for an ethnicity‐specific approach with respect to measures aimed at improving QoL. However, it is important to note that these associations may not reflect a fundamental ethnic difference in HF progression. Any discussion of self‐reported QoL measures is incomplete without calling attention to the multitude of factors that influence QoL which could not be controlled for in our analysis. For instance, at the population‐level, structural and historical ethnic and racial biases play a major role in QoL, which has been well‐documented in the literature on racial health inequities in the United States.The study is limited in that global well‐being was not measured with the use of a generic QoL instrument. Additionally, no individual patient socioeconomic variables  were available so areal SEDI had to be used as proxy. Despite these minor limitations, a diverse patient population, comprising both inpatients and outpatients, and the availability of comprehensive clinical information, including NT‐proBNP for adjustment and the use of contemporary pharmacotherapy, enhance the generalizability of this population‐based study.6In this relatively young cohort of HF patients with high multi‐morbidity, ethnic differences in QoL were seen between Chinese, Malay, and Indian patients. Ethnicity was an independent determinant of QoL. Poorer physical QoL strongly predicted 1‐year survival in the overall cohort. Healthcare professionals should be mindful of such factors to educate patients and their family members so as to provide patients with coping skills to better manage HF. Finally, the findings have implications for an individualized approach to the management of HF patients of different ethnicities and for HF trials that use patient‐reported outcomes as endpoints. Patient‐centered values and QoL should in essence be integrated in clinical decision‐making.The authors declare no potential conflict of interest.Table S1 Changes in MLHFQ scores at 6 months, by ethnic groups.Click here for additional data file.Table S2 Baseline characteristics, included vs excluded patients for subanalysis at 6 month's follow‐up.Click here for additional data file.


Some studies have stated that intrauterine insemination (IUI) with controlled ovarian stimulation (COS) might increase the pregnancy rate, while others suggest that IUI in the natural cycle (NC) should be the first line of treatment. It remains unclear whether it is necessary to use COS at the same time when IUI is applied to treat isolated male factor infertility. Thus, we aimed to investigate efficacy of IUI with COS for isolated male factor infertility.A total of 601 IUI cycles from 307 couples who sought medical care for isolated male factor infertility between January 2010 and February 2020 were divided into two groups: NC-IUI and COS-IUI. The COS-IUI group was further divided into two subgroups according to the number of pre-ovulatory follicles on the day of HCG: cycles with monofollicular development (one follicle group) and cycles with at least two pre-ovulatory follicles (≥ 2 follicles group). The IUI outcomes, including clinical pregnancy, live birth, spontaneous abortion, ectopic pregnancy, and multiple pregnancy rates were compared.P = 0.091), and a significant difference was found between the NC-IUI and ≥ 2 follicles group .The clinical pregnancy, live birth, spontaneous abortion, and ectopic pregnancy rates were comparable between the NC-IUI and COS-IUI group. Similar results were also observed among the NC-IUI, one follicle, and ≥ 2 follicles groups. However, with respect to the multiple pregnancy rate, a trend toward higher multiple pregnancy rate was observed in the COS-IUI group compared to the NC-IUI group (8.7% vs. 0, In COS cycles, especially in those with at least two pre-ovulatory follicles, the multiple pregnancy rate increased without a substantial gain in overall pregnancy rate; thus, COS should not be preferred in IUI for isolated male factor infertility. If COS is required, one stimulated follicle and one healthy baby should be the goal considering the safety of both mothers and foetuses.The online version contains supplementary material available at 10.1186/s12958-021-00730-3. Infertility, defined as failure to achieve pregnancy within 12 months of unprotected intercourse or therapeutic donor insemination in women younger than 35 years or within 6 months in women older than 35 years, affects approximately 15% of couples [Intrauterine insemination (IUI) is an effective and frequently used fertility treatment for couples with male factor and unexplained infertility since it is less invasive, less stressful, more easily accepted by patients, and more cost-effective –9. In IUIUI can be performed with or without controlled ovarian stimulation (COS). Some studies stated that IUI with COS might increase the pregnancy rate –14, whil6/mL; motility < 50%; normal morphology < 15%, according to the World Health Organisation (WHO) criteria (4th version). Additionally, since 2014, the diagnosis was changed as follows: total sperm < 39 × 106/ejaculation or sperm concentration < 15 × 106/mL; progressive motility < 32%; and normal morphology < 4%, according to the current WHO criteria (5th version). All diagnoses were based on at least two semen analyses. The study protocol was approved by the institutional ethics committee of Zhongshan City People’s Hospital, and informed consent for their clinical data to be used for research purposes was obtained from all participants.A retrospective study was performed by reviewing the clinical data of 601 IUI cycles from 307 couples who sought medical care for male infertility at the Center for Reproductive Medicine of Zhongshan City People’s Hospital from January 2010 to February 2020. The inclusion criteria were as follows: (1) couples diagnosed with primary or secondary infertility; (2) the female partner had a normal fertility status, characterised by regular menstrual cycles, normal uterine cavity, and positive post-coital test; and (3) there was at least one patent fallopian tube assessed by hysterosalpingography/transvaginal real-time three-dimensional hysterosalpingo-contrast sonography and/or laparoscopy. Couples were excluded if the female partner had bilateral tubal pathology, endometriosis, irregular cycles, polycystic ovarian syndrome, or other endocrine disorders. Of note, in our centre, before 2014, the diagnosis of male infertility was defined as one or more of subnormal semen variables: sperm concentration < 20 × 10Ovarian stimulation drugs included clomiphene citrate (CC), letrozole (LE), human menopausal gonadotropin (HMG), and urine follicle-stimulating hormone . The ovarian stimulation protocols were as follows: (1) CC 50–100 mg/day or LE 2.5–5 mg/day starting from days 3–5 of the menstrual cycle for 5 days; (2) HMG or uFSH 37.5–75 IU/day starting from days 3–5 for a variable duration depending on the response; (3) CC/LE combined with HMG/uFSH: CC 50–100 mg/day or LE 2.5–5 mg/day starting from days 3–5 for 5 days followed by addition of 37.5-75 IU HMG/uFSH for a variable duration depending on the response.Follicle growth was monitored using transvaginal ultrasonography by gynaecologists in the reproductive medicine centre. In both NC and COS cycles, follicle development was monitored from days 8–10, and then repeated every 2 or 3 days based on the follicle size. Couples were advised to cancel the cycle if more than 3 dominant follicles > 16 mm were present. Ovulation was triggered by administering human chorionic gonadotrophin (hCG) 5000–10,000 IU or triptorelin  0.1 mg when at least one follicle of 18 mm or more was seen on transvaginal ultrasonography. If endogenous LH surge occurred , the trigger was omitted. Insemination was performed 36–40 h later.On the day of IUI, semen was processed by density-gradient centrifugation or the swim-up method after liquefaction. The pre- and post-wash semen parameters, such as volume, sperm concentration, progressive motility, and normal sperm morphology, were recorded. The volume of the washed semen sample used for insemination was 0.5 mL. IUI was performed by a gynaecologist in a room adjacent to the laboratory. After IUI, the women underwent bed rest for 30 min.Luteal phase support consisting of 20 mg/d dydrogesterone  was routinely used since the day of ovulation . If pregnancy was confirmed on days 14–16 after IUI by measuring serum β-hCG levels, luteal phase support was continued up to 8 weeks of gestation. In women with positive β-hCG, transvaginal ultrasound examination was performed 2 weeks later to confirm clinical pregnancy. The outcomes of clinical pregnancy were subsequently recorded, including spontaneous abortion, ectopic pregnancy, multiple pregnancy, and live birth. Live birth was defined as the birth of an infant after 28 weeks of gestation with postnatal evidence of life.P < 0.05. According to the study by Cohlen et al. [Statistical analysis was performed using the Statistical Package for Social Sciences . Fisher’s exact test was used to compare categorical data between the groups. The Mann-Whitney U-test was used to compare continuous variables between groups. Statistical significance was set at n et al. , to dete6) and 8.2 ± 2.1 (%), respectively and 17.6 ± 11.0 (× 106) and 4.6 ± 1.4 (%) in 2014 or after. A total of 75 cycles resulted in pregnancy, and 69 babies were delivered. The clinical pregnancy and live birth rates were 12.5 and 11.3%, respectively. Of the 75 pregnancies, 68 resulted in the birth of a single child (n = 67) or twins (n = 1), five pregnancies ended in spontaneous abortion, two pregnancies ended in ectopic pregnancy, and there was one case of heterotopic pregnancy who underwent laparoscopic left salpingectomy at 7 weeks of gestation, and delivered a live baby by caesarean section at 35 weeks of gestation. Neither high-order multiples nor ovarian hyperstimulation syndrome occurred.A total of 307 couples completed 601 IUI cycles. Among them, 265 cycles (194 NC cycles and 71 COS cycles) were completed before 2014, accounting for 44.1%, and the rest (231 NC cycles and 105 COS cycles) were performed in 2014 or after. The mean ± standard deviation (SD) of female age, male age, and duration of infertility were 31.0 ± 4.8, 33.2 ± 5.4, and 2.9 ± 1.9 years, respectively. The mean ± SD total progressive motile sperm counts  and the percentage of normal morphology post-wash before 2014 were 19.5 ± 14.7 (× 10P < 0.001) but not in age of the female or male partner, type of infertility, duration of infertility, and endometrial thickness. The TPMSC and the percentages of normal morphology were also comparable between the two groups.Table P = 0.091, Table P = 0.033). The results are presented in Table The pregnancy outcomes between the two groups, including the clinical pregnancy, live birth, spontaneous abortion, and ectopic pregnancy rates, were also comparable. Although a trend toward higher multiple pregnancy rates was observed in the COS-IUI group (8.7% vs. 0), the difference was not statistically significant . Other parameters were comparable except for the duration of infertility in subgroup TPSMC 5–10 × 106   on the results, only the first cycle was included and further divided into two subgroups: before 2014 and from 2014 onwards. In each subgroup, no significant differences were found in pregnancy outcomes between the NC-IUI and COS-IUI groups . Therefore, we advocate that for male infertility, IUI with COS did not significantly increase the pregnancy and live birth rates, regardless of the diagnostic criteria for male infertility. Moreover, from the perspective of cost-effectiveness, IUI alone is a more cost-effective approach than IUI with COS [An increasing number of studies , 15–17 rwith COS .P = 0.091). However, when we further compared the multiple pregnancy rates between the NC-IUI group and ≥ 2 follicles group, a significant difference was found . Few studies have focused on reporting multiple pregnancies of IUI with or without COS in male infertility.Two patients who received IUI with COS had multiple pregnancies  in our study. A trend toward higher multiple pregnancy rates was observed in the COS-IUI group, when compared to that in the NC-IUI group, but the difference was not statistically significant  is widely used as a source of standard methodology for semen collection, analysis, and preparation. However, other elements of the IUI practice did not change. We also performed an analysis stratified for different criteria to eliminate the potential influence on the results as much as possible.To the best of our knowledge, the present study included the largest number of couples with male infertility to date in which the pregnancy outcomes of IUI were analysed between NC and COS cycles. The findings of the current study suggest that for male infertility, COS in IUI should not be preferred, since in cycles with COS, especially in those with at least two pre-ovulatory follicle cycles, the multiple pregnancy rate increased without substantial gain in the overall pregnancy rate. If COS is required, one stimulated follicle and one healthy baby should be the goal considering the safety of both mothers and foetuses.Additional file 1: Supplemental Table 1. Characteristics of patients and cycles between the NC-IUI and COS-IUI groups stratified by TPSMC.Additional file 2: Supplemental Figure 1. Consort diagram. IUI, intrauterine insemination; NC, natural cycle; COS, controlled ovarian stimulation; *including one heterotopic pregnancy; # two patients gave birth to a single child in the first cycle and planned to have a second child; ## one patient gave birth to a single child in the fourth cycle and planned to have a second child.


Online patient simulations (OPS) are a novel method for teaching clinical reasoning skills to students and could contribute to reducing diagnostic errors. However, little is known about how best to implement and evaluate OPS in medical curricula. The aim of this study was to assess the feasibility, acceptability and potential effects of eCREST — the electronic Clinical Reasoning Educational Simulation Tool.A feasibility randomised controlled trial was conducted with final year undergraduate students from three UK medical schools in academic year 2016/2017 (cohort one) and 2017/2018 (cohort two). Student volunteers were recruited in cohort one via email and on teaching days, and in cohort two eCREST was also integrated into a relevant module in the curriculum. The intervention group received three patient cases and the control group received teaching as usual; allocation ratio was 1:1. Researchers were blind to allocation. Clinical reasoning skills were measured using a survey after 1 week and a patient case after 1 month.n = 148). Of the intervention group, most  agreed eCREST helped them to learn clinical reasoning skills.Across schools, 264 students participated . Cohort two had greater uptake  than cohort one . After 1 week, 99/137 (72%) of the intervention and 86/127 (68%) of the control group remained in the study. eCREST improved students’ ability to gather essential information from patients over controls (OR = 1.4; 95% CI 1.1–1.7, eCREST was highly acceptable and improved data gathering skills that could reduce diagnostic errors. Uptake was low but improved when integrated into course delivery. A summative trial is needed to estimate effectiveness. Clinical reasoning — the thought processes used by clinicians during consultations to formulate appropriate questions — is essential for timely diagnosis of disease –4. ProviOnline patient simulations (OPS) are a specific type of computer-based program that simulates real-life clinical scenarios and could support teaching reasoning skills , 9. TheoThere is currently little empirical evidence to support the use of OPS for assisting clinical reasoning skills teaching. The few studies conducted were not methodologically robust and difficult to interpret due to the poor validity of clinical reasoning outcome measures –20. FurtThis research aimed to inform the design of a summative evaluation of an OPS to support teaching of reasoning skills in medical schools. The development of this OPS, the Electronic Clinical Reasoning Educational Simulation Tool (eCREST), is reported elsewhere . Brieflyidentifying optimal recruitment strategies, measured by student uptake;testing the acceptability to students via student retention and feedback;testing the validity and measuring the possible effect sizes of two clinical reasoning outcome measures.This study sought to obtain evidence as to the feasibility of a trial through:A multicentre parallel feasibility RCT was conducted across three UK medical schools: A, B and C. We followed the CONSORT statement for reporting pilot or feasibility trials . EligiblFeasibility was measured by assessing student uptake by school and cohort. Acceptability was measured by retention rates and a survey adapted from previous studies, consisting of six statements on the perceptions of eCREST , 27.Clinical reasoning was measured using the Flexibility in Thinking (FIT) scale of the Diagnostic Thinking Inventory (DTI), which is a self-reported measure . The FITClinical reasoning was also measured using an observed measure of clinical reasoning by using data from an additional eCREST patient case that students received 1 month after baseline. This measure comprised indicators of three cognitive biases that eCREST sought to influence: the unpacking principle, confirmation bias and anchoring. These were identified by previous clinical reasoning research , 30, 31.The observed measure assessed ‘essential information identified’ by measuring the proportion of essential questions and examinations asked, out of all possible essential examinations and questions identified by experts. This aimed to detect the influence of the unpacking principle on reasoning, as it captured whether the students elicited enough essential information to make an appropriate decision. The ‘relevance of history taking’ was measured by assessing the proportion of all relevant questions and examinations asked, out of the total questions and examinations asked by the student. This aimed to detect susceptibility to confirmation bias by capturing whether they sought relevant information. Finally, it measured ‘flexibility in diagnoses’ by counting the number of times students changed their diagnosis. This reflected how susceptible students were to anchoring, by measuring their willingness to change their initial differential diagnosis. All measures were developed by RP and three clinicians . The content validity of the observed measure of clinical reasoning was tested with two clinicians .Diagnostic choice was captured in the additional patient case. Selection of the most important diagnosis that the student should not have missed was used to assess how well the observed measure of reasoning predicted diagnostic choice.Relevant medical knowledge was measured by 12 single best answer multiple choice questions (MCQs). We hypothesised that greater knowledge is associated with better clinical reasoning skills, consistent with the literature , 35. TheThe trial procedure is outlined in Fig. Uptake was calculated as the percentage of students who registered out of the total number of eligible students. Retention was calculated as the percentage of students who completed T1 and T2 follow-up assessments out of all registered. Acceptability was measured by calculating the percentage of students who agreed with each statement on the acceptability questionnaire. Uptake, retention and acceptability were compared between schools and cohorts using chi-squared tests.Internal consistency of the self-reported clinical reasoning measure was assessed using Cronbach’s alpha. Construct validity of the self-reported and observed clinical reasoning measures was assessed by correlating the reasoning and knowledge outcomes, using Spearman’s rank correlation coefficient. To estimate the predictive validity of the clinical reasoning measures, the self-reported measure and observed measure of clinical reasoning were correlated with diagnostic choice. The analyses were undertaken for the aggregated dataset then separately for the intervention and control groups.p ≤ 0.05 considered statistically significant [Independent t-tests were used to compare mean self-reported clinical reasoning scores between intervention and control groups at T1 and T2. A mixed factorial ANOVA was used to assess change in self-reported clinical reasoning over time, between groups and interaction effects. Logistic regression analyses were conducted to assess the ‘essential information identified’ and the ‘relevance of history taking’. These outcomes were proportional data, so were transformed by calculating the log odds of the outcomes , 37. Gronificant .n = 183/833, 22%) than those in cohort one . Uptake was slightly greater at school B , followed by A  and C . Uptake was similar at schools A  and B  in cohort one. However, uptake was greater at school B  than A  and C  in cohort two. Participant characteristics are shown in Table Across the three UK medical schools, 264 students participated  = 0.65, p = 0.42), or after 1 month, 57 and 55% respectively (χ2 (1) = 0.34, p = 0.56, Fig. n = 47/112, 42%) than at school B  and C , χ2 (2) = 9.58, p = 0.008. Those in cohort one were significantly less likely to stay in the study one-week post baseline  than those in cohort two , χ2 (1) = 11.75, p = 0.001. This was also observed one-month post baseline , χ2 (1) = 13.92, p = 0.000.There was no significant difference detected in retention between the intervention and control groups 1 week after baseline, 72 and 68% respectively (χ2 (2) = 7.5, n = 98, p = .024); eCREST enhanced their overall learning (93.2% vs 64.0%), χ2 (2) = 13.7, n = 98, p = .001) and that they would use eCREST again without an incentive (97.3% vs 52.0%), χ2 (2) = 31.8, n = 98, p = .000).Most students (> 80%) agreed that eCREST helped them learn clinical reasoning skills and that they would use it again without incentives Table . There wrs = 0.13, p = 0.037, n = 240). The observed clinical reasoning measure was positively but not significantly correlated with knowledge. The self-reported clinical reasoning measure at baseline and the observed clinical reasoning measure were positively but not significantly correlated with identification of the most serious diagnosis.The internal consistency of the self-reported clinical reasoning measure was adequate (Cronbach’s α = 0.66). Correlations between self-reported and observed clinical reasoning outcome measures, and knowledge and clinical outcomes are shown in Table p = 0.26) and Time 2 . There was no significant effect of group allocation, (F (1)=0.00, p = 0.97, n = 136) time, (F (2)=0.01, p = 0.99, n = 136) or interaction between group allocation and time, F (2)=0.48, p = 0.62, n = 136.The intervention group had non-significantly higher self-reported clinical reasoning skills than the control group at Time 1  but the extensive demands of medical curricula often result in low uptake of additional resources. Uptake was higher in this study than some previous online learning studies that relied on medical student volunteers and the sample size was ample for the purposes of the feasibility RCT , 42. ThiA further limitation of this study is that it was a complete case analysis, which assumes data were missing at random and those who dropped out were similar to those who remained. It was not possible to follow up those who dropped out to determine whether they had different views of eCREST or different patterns of reasoning. Furthermore, the observed measure of clinical reasoning was only collected at T2 and not at baseline. It is possible that the two groups differed on this measure at baseline. However, no differences in self-reported clinical reasoning were detected between groups at baseline.This feasibility RCT has illustrated the importance of integration into the course when evaluating OPS in medical education. It would be feasible to conduct a summative trial to assess the effectiveness of eCREST on medical students’ clinical reasoning skills in multiple medical schools, if it were appropriately positioned in a curriculum to benefit student learning. Further testing of the validity of using OPS as an outcome measure is needed. Nevertheless, this study provides evidence that OPS can be used to support face-to-face teaching to reduce cognitive biases, which may help future doctors in achieving timely diagnoses in primary care.


II/TeIII‐catalyzed dehydrogenative C−H phenothiazination of challenging phenols featuring electron‐withdrawing substituents under mild aerobic conditions and with high yields is described. These unexpected TeII/TeIII radical catalytic properties were characterized by cyclic voltammetry, EPR spectroscopy, kinetic experiments, and DFT calculations.The Te II/TeIII‐catalyzed dehydrogenative C−H phenothiazination of challenging phenols proceeds under mild aerobic conditions and with high yields. These unexpected TeII/TeIII radical catalytic properties were characterized by cyclic voltammetry, EPR spectroscopy, kinetic experiments, and DFT calculations.A Te After testing and optimizing various retrosynthetic approaches, we eventually established a route through 2,2′‐diiododiphenylamine . We finally selected and optimized a mild O2‐mediated basic oxidation method, for a limited reaction time of 3 hours.2HPO4 was found to be an optimal base in comparison to K3PO4, NaHCO3, or AcOK, although good results were also obtained with K2CO3.PTeZH) was found significantly superior to the Se catalyst candidate (PSeZH). Moreover, while 5 mol % of PTeZH catalyst loading provided encouraging results, 10 mol % was found optimal. The optimized tellurium‐catalyzed conditions are shown in Scheme 3 aa, 97 % isolated).In order to proceed with this objective, selenium and tellurium azine derivatives were targeted as prospective catalysts. e Scheme .13]Pe Scheme . Indeed,t Scheme . This nePe ScheKa down to 7.5, 3 ea, 73 %), with high yields. Challenging functional groups such as ketones, a pyridine, and an aldehyde were moreover well tolerated . Importantly, control experiments omitting the Te catalyst systematically led to very poor conversions, thus highlighting by contrast the strong catalytic role of the TeII organometalloid PTeZH complex  does not perform much better at longer reaction times.Moreover, the non‐catalyzed reaction . Thus, the use of these highly sustainable O2‐based reaction conditions requires the presence of the PTeZH catalyst. Finally, this TeII‐catalyzed method allowed the straightforward scale‐up of the reaction without any loss of yield , therefore demonstrating its robustness.For example, the uncatalyzed method afforded E°(1/2ox)=+0.24, +0.22, +0.24 V, respectively). In contrast, the oxidation potential of the largest congener  deviates significantly from the other three chalcogens, at only +0.08 V.In order to understand this remarkable catalytic effect, the cyclic voltammetry (CV) plots of all four chalcogen congeners are presented in Figure POZH, PSZH, PSeZH, and PTeZH in [D6]benzene at room temperature. The corresponding EPR profiles are shown in Figure XZ.P  delivered a very different EPR signal, which, according to simulations and supporting DFT property calculations, corresponds to a (protonated) radical cation species: .+PTeZH. This difference between tellurium and the other chalcogens presumably arises from a lower oxidation potential (+0.08 V) and subsequent weaker acidity of .+PTeZH compared to the other three chalcomers =+0.22–0.24 V). Indeed, one‐electron oxidation of POZH, PSZH, and PSeZH apparently leads to strongly acidified .+PXZH radical cations, which spontaneously deprotonate at nitrogen to the corresponding persistent neutral radicals. In contrast, the (NPA) charge and spin density of .+PTeZH are significantly shifted from N to Te .This oxidation potential difference for tellurium has important consequences for its reactivity, as will be discussed below. Next, the radical character of each oxidized chalcogenazine congener was investigated by electron paramagnetic resonance (EPR) spectroscopy. The radical species were generated by bubbling air through a solution of . Figure . In contPSZH (X=S) as the reference (krel=1). In those four parallel experiments, POZH was found to be the fastest azine (krel=kX/kS=4.4), and PTeZH the slowest . Moreover, in the latter case, the PSZH initial conversion rate has been multiplied by 4 in comparison to the non‐catalyzed reaction (absence of PTeZH).Next, we measured the relative initial rates of conversion (5 min reaction time) of the various chalcogenazines as N‐substrates, with common phenothiazine PTeZH is a good catalyst in this reaction because it combines a significantly lower oxidation potential compared to PSZH , such that it must oxidize first, with a very reactive neutral N‐centered radical (.PTeZ). Indeed, the H‐atom transfer (HAT) process was calculated to be very favorable from PSZH to .PTeZ. The latter species therefore serves as radical catalyst.+PTeZH, facilitated by the basic reaction conditions and/or peroxide anions resulting from O2 reduction . In all cases, the absence of TeII catalyst leads to dramatically lower conversions. This unexpected catalytic effect essentially arises from a combination of two important properties: a lower oxidation potential of the PTeZH catalyst towards the .+PTeZH radical cation and a significantly higher spin density at the tellurium center compared to the sulfur‐based substrates. It is thus probable that PTeZH will find further applications as radical catalyst[In conclusion, we have demonstrated that a TeThe authors declare no conflict of interest.As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.SupplementaryClick here for additional data file.