Breast cancer resistance protein (BCRP) and multidrug resistance protein 4 (MRP4) are involved in uric acid excretion in humans and mice. Despite evidence suggesting that renal proximal tubular epithelial cells participate in uric acid excretion in chickens, the roles of BCRP and MRP4 therein remain unclear. This study evaluated the relationship between BCRP and MRP4 expression and renal function in chickens.Sixty laying hens were randomly divided into four treatment groups: a control group (NC) fed a basal diet; a sulfonamide-treated group (SD) fed the basal diet and supplemented with sulfamonomethoxine sodium via drinking water (8 mg/L); a fish meal group (FM) fed the basal diet supplemented with 16% fishmeal; and a uric acid injection group (IU) fed the basal diet and intraperitoneally injected with uric acid (250 mg/kg body weight). The results showed that serum uric acid, creatinine, and blood urea nitrogen levels were significantly higher in the SD and IU, but not FM, than in the NC groups. Renal tubular epithelial cells in the SD and IU groups were damaged. Liver BCRP and MRP4 mRNA and protein levels were significantly decreased in the SD and IU groups, but slightly increased in the FM group. In the SD group, BCRP and MRP4 were significantly increased in the ileum and slightly increased in the kidney. In the FM group, BCRP and MRP4 were significantly increased in the kidney and slightly increased in the ileum. In the IU group, BCRP and MRP4 were significantly increased in the kidney and ileum. BCRP and MRP4 expression in the jejunum was not affected by the treatments.Together, these results demonstrate that BCRP and MRP4 are involved in renal and intestinal uric acid excretion in chickens and that BCRP is positively related to MRP4 expression. Further, impairment of renal function results in an increase in serum uric acid as well as a compensatory increase in BCRP and MRP4 in the ileum; however, under normal renal function, renal BCRP and MRP4 are the main regulators of uric acid excretion. Uric acid is the final product of purine metabolism. Dietary , geneticMRP4 expression by short hairpin-mediated RNA interference. The net transepithelial transport of uric acid decreases when BCRP is knocked down [Uric acid excretion involves several uric acid transporters, such as breast cancer resistance protein (BCRP) , urate aked down , though BCRP is a high-capacity uric acid transporter that physiologically mediates renal and extra-renal  uric acid excretion; its dysfunction leads to hyperuricemia . ExtensiUricase in the mouse liver can convert uric acid into allantoin; however, human and chickens livers lack uricase . Accordin = 15 per group). The control group (NC) was fed a basal diet. The sulfonamide-treated group (SD) was fed the basal diet, and sulfamonomethoxine sodium soluble powder  was added to the drinking water (8 mg/L). The fish meal group (FM) was fed the basal diet supplemented with 16% fishmeal (crude protein 27.6%) . The injection uric acid group (IU) was fed the basal diet and received uric acid (250 mg/kg body weight) via intraperitoneal injection every day; the uric acid  was suspended in 0.5% carboxymethyl cellulose-Na solution . All chickens were reared in cages at 25–30 °C and were allowed ad libitum access to feed and water. The basal diet was prepared based on nutritional requirements outlined by the National Research Council (1994) and contained 204.3 g/kg of crude protein, 11.5 g/kg of calcium, 4.2 g/kg of phosphorus, and 12.11 MJ/kg of metabolic energy. The experiment lasted for 3 weeks. At the end of the experiment (41 days of age), blood samples of 10 chickens from each group were collected from the jugular vein after a 12-h fasting. After clotting for approximately 30 min at room temperature, the blood was centrifuged at 3500×g for 10 min at 4 °C in a cryogenic centrifuge  to obtain serum. The serum was stored at − 20 °C. Six chickens from each group were euthanized by decapitation. The liver, kidney, jejunum, and ileum were collected and divided into two portions, and then stored in 4% paraformaldehyde and liquid nitrogen, respectively. Renal cortex tissues were collected and fixed in 2.5% glutaraldehyde for transmission electron microscopy (TEM).Seventy 20-day-old Isa brown laying hens  were purchased from Anhui Poultry Industry Co., Ltd. (China). Sixty healthy chickens were selected and were randomly divided into four treatment groups  were ground in liquid nitrogen and RNA was extracted using Trizol  based on published paper [g for 15 min. Thereafter, 500 μl of the resulting supernatant was taken and then 500 μl of isopropanol was added followed by centrifugation at 12,000 g for 10 min. Next, the resulting supernatant was discarded and then 500 μl of 80% ethanol was added to the sample followed by centrifugation at 7500 g for 5 min, after which the supernatant was discarded. RNA concentrations were determined on a NanoVue Plus instrument . For each sample, 500 ng of total RNA was reverse transcribed . QPCR was performed using an Arktik thermal cycler , and the cycle conditions were as follows: 2 min at 95 °C, 40 cycles of 15 s at 95 °C, 1 min at 60 °C, 30 s at 60 °C, 60–95 °C in 0.2 °C s− 1, and 10 s at 20 °C. Primers targeting chicken BCRP and MRP4 are listed in Table Tissues from the liver, kidney, jejunum, and ileum  of each sample was normalized to that of 18S rRNA. The mRNA relative expression levels were normalized to the average level of the NC group. The calculation procedures were as follows: −ΔCt = − (Target gene Ct - Reference gene Ct), 2−ΔΔCt = 2(−ΔCt(Target gene) - − ΔCt(control group gene)). For BCRP gene, Ct values < 21.0 or > 26.0 were excluded; for MRP4 gene, Ct values < 24.0 or > 29.0 were excluded; and for 18S rRNA gene, Ct values < 11.0 or > 16.0 were excluded.The QPCR data were analyzed using the 2n = 3 chickens for each group) using RIPA cell lysis buffer  and protein phosphatase inhibitor . Protein concentrations were determined using a BCA protein concentration assay kit . Proteins were electrophoresed using an electrophoresis apparatus . The following antibodies were used: anti-BCRP , anti-MRP4 , anti-β-actin , and goat anti-rabbit IgG . Immunocomplexes were visualized using a western blotting detection kit  and blots were imaged using a ChemiDoc MP Imaging System . Band densities were analyzed by Image-Pro Plus 6.0 and were normalized to those of β-actin. The protein relative expression levels were normalized to the average level of the NC group.Total protein was extracted from the liver, kidney, jejunum, and ileum  and anti-MRP4 1:300) antibodies, as described by Liu et al. . Goat an0 antibodBCPR and MRP4 by Pearson’s correlation coefficients. P < 0.05 was regarded statistically significant. Statistical analyses were performed using SPSS Statistics . Graphs and scatter plots were generated using GraphPad Prism .The sample size was determined according to previous studies , 31, 32.P = 0.01) and creatinine and BUN levels were significantly higher (P < 0.01) in the SD group than in the NC group. Serum uric acid, creatinine, and BUN levels were significantly higher in the IU group than in the NC group (P < 0.01); however, there were no significant differences between the FM and NC groups.As shown in Table TEM revealed that the ultrastructure of renal tubular epithelial cells in the NC and FM groups Fig. A, C was P < 0.01), lowly expressed in the liver, and minimally expressed in the kidney (P < 0.01). MRP4  and were lower than those in the jejunum and ileum (P < 0.01). Immunohistochemical staining showed that BCRP and MRP4 were expressed in the liver cells, renal apical membrane, intestinal smooth muscle cells, and intestinal villi . Renal MRP4 mRNA expression was also significantly increased in the IU group as compared to that in the NC group (P < 0.05). Although BCRP mRNA level was slightly increased in the kidney, it was not significantly different from that in the NC group. Similar to their expression in the kidney, the expression of BCRP and MRP4 in the ileum was significantly increased in the SD and IU groups (P < 0.05). In the FM group, renal BCRP and MRP4 mRNA levels were significantly increased (P < 0.05 for both), ileal BCRP and MRP4 mRNA levels were slightly increased, and liver BCRP and MRP4 mRNA levels showed no obvious difference. BCRP and MRP4 mRNA levels in the jejunum showed a decreasing trend in the three experimental groups, though the differences were not significant.P < 0.05). In the SD group, BCRP and MRP4 protein levels were slightly increased in the kidney and were significantly increased in the ileum . In the IU group, BCRP and MRP4 protein levels were significantly increased in the kidney and ileum . In the FM group, BCRP and MRP4 protein levels were significantly increased in the kidney , ileal BCRP protein levels were slightly increased, and ileal MRP4 protein levels were significantly increased (P < 0.05), whereas there was no significant difference in the liver level compared to the control group. BCRP and MRP4 protein levels in the jejunum did not differ significantly in the three experimental groups.Western blotting results showed that BCRP and MRP4 protein expression levels in the liver, kidney, jejunum, and ileum of each group were consistent with the mRNA expression levels Fig. . In the P < 0.05). In the FM group, liver expression levels were similar to those in the NC group. Renal and ileal BCRP and MRP4 expression levels were significantly increased (P < 0.01) in all experimental groups, except in the SD group, where renal MRP4 expression was slightly increased, whereas jejunum BCRP and MRP4 levels were lower than those in the NC group.Finally, we used immunohistochemistry to evaluate BCRP and MRP4 protein expression levels in the liver, kidney, jejunum, and ileum in each group. As shown in Fig. BCRP and MRP4 expression, BCRP and MRP4 mRNA expression levels of each sample were used for correlation analysis. As shown in Fig. BCRP mRNA expression was positively correlated with MRP4 mRNA expression in the liver, kidney, jejunum, and ileum (P < 0.01).To determine the relationship between BCRP and MRP4 are uric acid transporters present in various organs, such as the human liver, kidney, and intestines, and can be expressed in heterogeeous systems for uric acid transport , 12, 33.The kidney are recognized as the main regulators of serum uric acid, and the excretion of renal uric acid is determined by the balance between uric acid reabsorption and re-secretion . In humaIn this study, serum uric acid, creatinine, and BUN levels were significantly increased in the SD and IU groups compared with those in the NC group, and renal tubular epithelial cells were damaged. In the SD group, sulfonamide crystallization may have blocked the renal tubules and caused renal damage , therebySerum uric acid levels in the SD and IU groups were significantly higher than those in the NC group, whereas liver BCRP and MRP4 expression levels were significantly lower. In the FM group, serum uric acid levels were not altered, and liver BCRP and MRP4 expression levels were slightly increased. These results indicate that changes in liver BCRP and MRP4 expression are inversely correlated with changes in serum uric acid levels. Previous studies have shown that BCRP and MRP4 are expressed as uric acid efflux proteins in the basolateral membrane of hepatocytes . The finBCRP is positively related to MRP4 mRNA expression, the potential interaction between BCRP and MRP4 remains to be elucidated. In addition, this study considered only two transporters and thus other transporters involved in chicken uric acid excretion should be studied. In addition, the expression of BCRP and MRP4 in other tissues needs to be studied in the future.This study had some limitations. The mechanisms underlying the relationship between changes in serum uric acid levels and liver, kidney, and intestinal BCRP and MRP4 levels remain unclear. Although BCRP is positively related to MRP4 mRNA expression. When renal function is impaired, BCRP and MRP4 expression in the ileum exhibit compensatory increases; however, when renal function is normal, renal BCRP and MRP4 are the main regulators of uric acid excretion with ileal BCRP and MRP4 expression having no significant influence. Mechanistic insights into the roles of BCRP and MRP4 in chicken uric acid secretion remain to be investigated in future studies.Our results show that BCRP and MRP4 participate in renal and intestinal uric acid excretion in chickens and that


Lung cancer is a leading cause of morbidity and mortality worldwide. Radiotherapy for lung cancer is beneficial in both the radical and palliative settings, and technologic advances in recent years now afford an opportunity for this treatment to be more targeted than ever before. Although the delivery of more accurate forms of radiotherapy has minimized the risks of side-effects, how to utilize this treatment to optimize outcomes remains questionable. This study aimed to evaluate the accuracy of cone beam computed tomography (CBCT) image registration used in image-guided radiotherapy, providing reasonable guidance for clinic application of CBCT in lung cancer.A total of 53 patients with lung carcinoma including 34 central and 19 peripheral lesions were collected in this study. Varian-IX linear accelerator on-board imaging (OBI) system was used to acquire CBCT scans in three-dimensional (3D) conformal radiotherapy before delivery. Different regions  were manually registered, and the position deviation and the registration time were analyzed.P > 0.05). However, registration time (s) between whole lung registration group, tumor registration group, vertebral body registration group, affected lung registration group, and artificial registration group, was 3.651 ± 0.867 s, 1.144 ± 0.129 s, 1.226 ± 0.126 s, 2.081 ± 0.427 s, 179.491 ± 71.975 s, respectively. The differences were significant (P < 0.05). The registration differences between small tumor group and large tumor group were not statistically significant (P > 0.05).It was suggested that 34 cases belonged to central type and 19 cases belonged to peripheral type. The volume of left lung and right lung was 1242.98 ± 452.46 cc, 1689.69 ± 574.31 cc, respectively. Tumor size was 6.65 ± 3.87 cm in diameter, and 129.67 ± 136.48 cc in volume. The percentage of left lung and right lung was 6.17 ± 1.24%, 4.74 ± 0.38%, respectively. The position deviation value and absolute value of image registration methods of X, Y and Z axis were not significant (The automatic image matching of OBI is accuracy and high reliability in recognition of offset error. Registering body or ipsilateral structure is recommended to be used in CBCT for lung cancer. Lung cancer with high incidence and mortality rate is the first malignant tumors in China, which is induced by interaction between genetic and environmental factors . RadiothIn this study, the accuracy, advantages and disadvantages of different registration sites were compared by CBCT images and planned CT images in 53 patients with lung cancer, in order to provide reference for clinical application of CBCT.From October 2017 to May 2018, all 53 cases diagonozed with lung cancer patients were collected in Third Hospital of Herbei Medical Universitiy, Shijiazhuang, China. All patients took supine position with head cushion B pillow and both hands embracing the head, and were fixed with thermoplastic body membrane. Chest CT scanning ranged from the cricothyroid membrane to the lower edge of the diaphragm was done using Siemens Somotom-sensation Plus-16 spiral CT scanner, and the scanned images were transmitted to the Computerized Medical Systems (CMS) treatment planning system. Among 53 patients, 34 cases belonged to central type and 19 cases belonged to peripheral type.Inclusion criteria: Histological or cytological diagnosis of lung cancer; having no self-reported history of any malignant tumor; willing and able to give written informed consent; and no active or chronic infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C.Exclusion criteria: received any chemotherapy or radiotherapy prior to surgery; pregnant or breast feeding patients; a history or presence of other malignancy; and clinically significant autoimmune disease.The OBI linear accelerator of Warian IX was used as the IGRT system to acquire onboard CBCT images before patient treatment delivery. The image acquisition parameters were 120 kV, 528 mA, clockwise gantry rotation from 180° to 180°, fast scan, gantry speed 360°/min, collimator cassette M20, F1 filter, and 330 frames. CBCT scans were performed for the first time in routine for patients, and then 1–2 times a week. The CBCT images scanned by each patient during the first treatment were taken as the object of study and studied offline.Most scholars believe that gray-level registration with shift deviation less than 0.1 mm has higher accuracy , so thisP < 0.05 was considered as a statistically significant difference.The statistical analysis was performed on different registration methods using the one-way analysis of variance (ANOVA) followed by Post hoc analysis using two independent sample t-test using statistical product and service solutions (SPSS) software . Data were expressed as mean ± standard deviation (SD). General information of the patients was shown in Table P > 0.05). In contrast, registration times were significantly different for whole lung registration (3.651 ± 0.867 s), tumor registration (1.144 ± 0.129 s), vertebral body registration (1.226 ± 0.126 s), affected lung registration (2.081 ± 0.427) and artificial registration (P < 0.05).A total of 265 sets of registration data were collected from 53 patients, and the deviation and absolute values of image registration methods of different parts on X, Y and Z axis were demonstrated in Table P > 0.05)  provides the basis for precise treatment of intensity-modulated radiotherapy, and kV X-ray imaging is used frequently during a course of radiation therapy to improve the precision and accuracy of the delivery of the treatment of lung cancer . IGRT caImage registration with tumor as marker point was first put into CBCT clinical application in a previous study. If there is a significant difference in density between tumor and surrounding lung tissue, the tumor itself has the basic conditions as a registration marker . HoweverNakamura et al. (2015) demonstrated that the accuracies of correlation models derived using the shortest modeling period of 20 s are almost identical to those obtained over the longest modeling period of 40 s . In termIn summary, the automatic matching function of OBI system is precise in chest application, accurate in the identification of offset error and high in reliability. This method shows advantages such as the smaller registration range, the more accurate organization registration, and the less care for the outside of the registration frame, but has disadvantages such as small selection of registration areas, and large deviation value for peripheral lung cancer. Considering the registration time and other factors, it is recommended to choose the affected lung or whole lung as the registration area. However, there are still limitations. First, the cases involved in this study are limited, so individual difference has a great influence on the data. In addition, through comprehensive analysis, the tumor in the course of treatment may be reduced, and some tumors and surrounding tissues do not have obvious density differences, resulting in registration difficulties.


Studies on the effects of weight loss are however needed. This study aimed to prospectively study the effects of weight loss treatment with very low energy diet (VLED) on disease activity in patients with PsA (CASPAR criteria) and obesity  was taken during 12–16 weeks, depending on pre-treatment BMI. Afterwards, an energy-restricted diet was gradually reintroduced. Weight loss treatment was given within a structured framework for support and medical follow-up.Treatment with conventional synthetic and/or biologic disease-modifying anti-rheumatic drugs was held constant from 3 months before, until 6 months after baseline.Patients were assessed with BMI, 66/68 joints count, Leeds enthesitis index, psoriasis body surface area (BSA), questionnaires and CRP at baseline, 3 and 6 months. Primary outcome was the percentage of patients reaching minimal disease activity (MDA) and secondary outcomes were reaching Psoriatic Arthritis Response Criteria (PsARC) and American College of Rheumatology (ACR) response criteria.Totally 41/46 patients completed the study, 63% women, median age 54 years (IQR 48–62). At baseline increased BMI was associated with higher disease activity and poorer function.p = 0.002). PsARC was reached by 46.3%. The ACR 20, 50 and 70 responses were 51.2%, 34.1% and 7.3% respectively.The median weight loss was 18.7 kg (IQR 14.6–26.5) or 18.6% (IQR 14.7–26.3) of the baseline weight. A majority of the disease activity parameters improved significantly after weight loss, including 68/66 tender/swollen joints count, CRP, BSA, Leeds enthesitis index, HAQ and patient VAS for global health, pain and fatigue. A larger weight loss resulted in more improvement in a dose-response manner. The percentage of patients with MDA increased from 29 to 54%,  contains supplementary material, which is available to authorized users. Both psn 30–45% –10. Patin 30–45% –13. Chron 30–45% –16.Although the associations between PsA and obesity, BMI and disease activity are well known, there is to the best of our knowledge only one prior interventional study which has prospectively assessed the effects of weight loss treatment in PsA .The aim of this study was to determine the effects of weight loss treatment with very low energy diet (VLED) on the disease activity in joints, entheses and skin in patients with PsA and obesity. The primary endpoint of the study was the percentage of patients reaching minimal disease activity (MDA) after 6 months weight loss treatment. Secondary endpoints were the percentage of patients reaching American College of Rheumatology (ACR) and Psoriatic Arthritis Response Criteria (PsARC).Patients with PsA and obesity registered at the Rheumatology clinics of Sahlgrenska University hospital and the hospitals of Alingsås and Borås were invited to participate.2 and age 25–75 years were eligible for inclusion [Patients with PsA fulfilling the Classification for Psoriatic Arthritis (CASPAR) criteria, with a BMI ≥ 33 kg/mnclusion . If usinAll the patients in the study gave their written informed consent. The study was approved by the Regional Ethics Committee in Gothenburg and carried out in accordance with the Helsinki Declaration.2, a rigorous energy restriction is needed for optimal weight loss [2), the participants followed an initial period of 12 or 16 weeks on strict VLED. In addition, non-energy-containing beverages were allowed at libitum. During VLED, the mean weight loss usually is 1–2 kg per week. Adherence to treatment was controlled by measuring the body weight of the patients regularly. Absent or limited weight loss was considered a sign of poor adherence to the diet.Weight loss treatment with VLED  is an effective and established method in clinical use in Sweden. In severe obesity, BMI ≥ 35.0 kg/mght loss . The VLEAfter the strict period, food was gradually reintroduced during a period of 12 weeks. Each patient was instructed to follow an energy-restricted diet based on individual energy requirements for weight stability reduced by 30% to achieve further weight loss. The side effects of the VLED treatment are mostly mild to moderate and transient and ceases when the strict period is ended. The most prevalent side effects are headache, nausea, obstipation, dryness of skin and hair loss . The treAll examinations were done at baseline, after 3 months and 6 months. No blinding of assessors was made. Body height and weight were measured with a calibrated ruler and digital scale. Waist circumference was measured with a tape measure in centimetres midway between the lower rib and iliac crest. Joints were examined with 66/68 swollen/tender joints count and entheses with Leeds enthesitis index . The extThe primary endpoint minimal disease activity (MDA) is defined as meeting five of the seven following criteria: tender joint count 68 ≤ 1, swollen joint count 66 ≤ 1, psoriasis body surface area ≤ 3%, patient pain VAS ≤ 15 mm, patient global disease activity VAS ≤ 20 mm, HAQ ≤ 0.5 and tender entheseal points ≤ 1 .Secondary endpoints were the number of patients reaching the PsA Response Criteria (PsARC) and the American College of Rheumatology (ACR) 20, 50 and 70 criteria for treatment response. The PsARC is defined as improvement in at least two of the following four areas: ≥ 20% improvement in physician’s global VAS, ≥ 20% improvement in patient global disease activity VAS, ≥ 30% improvement in 66 swollen joint count, ≥ 30% improvement in 68 tender joint count. Improvement in the swollen or tender joint counts is mandatory, and there should be no worsening of any component , 29. TheBlood samples were analysed for haemoglobin (Hb), white blood cell count (WBC), platelet count (PLT) and C-reactive protein (CRP) using standard laboratory techniques at Sahlgrenska University Hospital.rS). All tests were two-tailed, and p ≤ 0.05 was considered statistically significant.Statistical analyses were made using SPSS Statistics version 25 . Descriptive statistics are presented as median and interquartile range (IQR) and range. Wilcoxon signed rank test was used to compare continuous related samples and McNemar test to compare categorical related samples. Correlations were calculated using Spearman’s correlation  dropped out before the 6 months visit .A total of 41 patients completed the study, 63% women. The median baseline age was 54 (IQR 48–62) years. The characteristics of the study population are shown in Table rS = 0.312, p = 0.047 to rS = 0.483, p = 0.001)  to 29.7 kg/m2 (IQR 26.2–31.5) (p < 0.001) and waistline circumference was reduced from median 116 cm (IQR 112–122) to 95.5 cm (89–103) (p < 0.001).All the patients lost weight, from a minimum of 8.5 to a maximum of 40.2 kg. The median weight loss from baseline to the 6 months visit was 18.7 kg (IQR 14.6–26.5), corresponding to a loss of in median 18.6% (IQR 14.7–26.3) or min–max range 8–35% of baseline weight. BMI decreased from median 35.2 kg/mn = 12) at baseline to 53.7% (n = 22) at 6 months (p = 0.002). Regarding the secondary endpoints, PSARC was reached by 46.3% (n = 19) of the patients and ACR 20, 50 and 70 responses by 51.2% (n = 21), 34.1% (n = 14) and 7.3% (n = 3) respectively  and ACR 20, 50 and 70 response by 62.1% (n = 18), 37.9% (n = 11) and 6.9% (n = 2) respectively of patients in this group. Disease activity and function before and after weight loss treatment in patients who did not have MDA at baseline is displayed in Additional file A sub-analysis on the 29 patients who did not already have MDA at baseline, showed that PsARC was reached by 51.7%  and Δ-HAQ , but not with other Δ-values of disease activity. In addition, the ACR 20 response rate was significantly higher in patients with a weight loss ≥ median 18.6% (n = 21) compared with < 18.6% (n = 20) . Similarly, a trend towards higher ACR 50 response rate was observed in patients with a weight loss ≥ 18.6% compared with < 18.6% . The percentage reduction in waist circumference was also significantly correlated with the reduction in DAS28CRP  .The weight loss in percentage of baseline weight was positively correlated with Δ-DAS28CRP (n = 34) answered “much easier than expected” or “easier than expected”. The patients generally scored their experience of the transition from VLED to normal food as harder. The median score was 4 (IQR 2–6) and totally 56% (n = 23) answered “as expected” or “harder than expected”  and 10 (very hard to implement), the median score was 2 IQR 1–3.5). When asked to score their experience of the VLED treatment in comparison to what they had expected, 83% (.5. When p = 0.002). PSARC was reached by 46% of the patients, and the ACR 20, 50 and 70 responses were 51%, 34% and 7% respectively. As a comparison, randomized controlled trials of TNF inhibitors on PsA have typically reported ACR 20 and 50 responses of 50–60% and 30–40% respectively, whereas the reported ACR 20 and 50 responses to placebo have been 15–25% and 0–5% [This study aimed to prospectively investigate the association between VLED weight loss treatment and disease activity in patients with PsA and obesity. We found significant improvement of the disease activity in joints, entheses and skin, reduction of CRP, PLT and parameters assessing function at the 6 months follow-up. The primary endpoint, patients with MDA, increased from 29.3% at baseline to 53.7% at 6 months , interleukin (IL)23, IL17, IL6 and IL1β are all key cytokines in the pathogenesis of PsA. The white adipose tissue (WAT) can produce the same cytokines  in addition to both pro-inflammatory adipokines  and adipokines viewed as primarily anti-inflammatory  . In obesΔARE and DBA/1 mice) have provided further proof for the importance of mechanical stress, by showing that unloading of the hind limb or tail suspension prohibited enthesitis and new bone formation in these mice [Biomechanical stress may be another factor linking obesity with PsA. PsA is characterized by enthesitis, which is a chronic inflammation at attachment sites of tendons and ligaments, anatomical locations often subject to mechanical stress . The weiese mice .Behavioural factors can also be a link between PsA and obesity. Pain and skin disease can induce a vicious cycle of lowered physical activity and over-eating, leading to obesity and further reduction of the mobility and physical activity , 45. EffThe reduced disease activity seen in the PsA patients after the VLED treatment in the present study could be due to a combination of mechanisms: metabolic effects associated with dietary energy restriction, reduction of pro-inflammatory mediators produced by the WAT, reduced loading of joints and entheses, especially in the back and lower limbs and reduced pain sensitivity. In situations of negative energy balance cells switch to utilize non-hepatic glucose, ketone bodies and free fatty acids as energy source . This haObesity is associated with increased pain sensitivity in inflammatory rheumatic diseases, osteoarthritis and fibromyalgia . In the p < 0.001) [There is one prior study which has prospectively studied the effects of weight loss in patients with PsA and obesity or overweight starting treatment with a TNF-inhibitor. After 6 months treatment, the patients with a successful weight loss (≥ 5%) had a higher rate of achieving MDA than those without a successful weight loss  . The pat< 0.001) , 52. Pos< 0.001) , 54.There are some limitations of the study. First, the present study lacks a control group. The success of the weight loss treatment is reliant on the patients’ determination to follow the given instructions and refrain from intake of energy-containing foods and beverages other than the VLED and non-caloric beverages during the initial strict period of 12–16 weeks. To be effective, VLED treatment must be based on the patients’ active decision and randomization between VLED and care-as-usual was therefore considered unsuitable. Second, no blinding of the assessors was made. Third, a high disease activity was not an inclusion criterion of the study, which may have affected the results. In fact, 29% of the patients had already MDA at baseline. Nevertheless, the study was able to show significant association between weight loss and reduced disease activity. Fourth, no documentation of the side effects  was done; hence, no exact data on the occurrence can be presented. No serious adverse event occurred however during the study. Fifth, the study was relatively short in duration, and it is indeed a great challenge to achieve long-term weight loss. The patients will however be followed during 24 months.Strengths of the present study are the prospective design and the powerful intervention that resulted in a substantial weight loss due to excellent adherence to the dietary regime. The study demonstrates that adding a weight loss treatment to the conventional pharmacologic treatment in patients with PsA and obesity may lead to benefits including lowering of several measures of disease activity along with the weight reduction.Weight loss treatment with VLED in patients with PsA and obesity was associated with significant improvement of disease activity in joints, entheses and skin at 6 months follow-up. A larger weight loss resulted in more improvement in a dose-response manner. The treatment was effective, safe and well tolerated. In addition, we could demonstrate association between higher BMI and increased disease activity at baseline. The patients will be followed during 24 months to study long-term treatment effects. The study supports the hypothesis that obesity is involved in the pathophysiology of PsA.Additional file 1:Table S1. Disease activity and function before and after weight loss treatment in the 29 patients with PsA who did not have minimal disease activity at baseline. (DOCX 16 kb)


Here, we perform a genome‐wide in silico prediction of SR rescuer genes by analyzing tumor transcriptomics and survival data of 10,000 TCGA cancer patients. Predicted SR interactions are validated in new experimental screens. We show that SR interactions can successfully predict cancer patients’ response and emerging resistance. Inhibiting predicted rescuer genes sensitizes resistant cancer cells to therapies synergistically, providing initial leads for developing combinatorial approaches to overcome resistance proactively. Finally, we show that the SR analysis of melanoma patients successfully identifies known mediators of resistance to immunotherapy and predicts novel rescuers.Most patients with advanced cancer eventually acquire resistance to targeted therapies, spurring extensive efforts to identify molecular events mediating therapy resistance. Many of these events involve  Recent experimental and clinical studies have successfully characterized tumor‐specific molecular signatures of resistance to targeted therapies through DNA and RNA sequencing (Jones synthetic rescue (SR) interactions  is compensated by altered activity (downregulation or upregulation) of another, rescuer gene , thus mediating drug resistance. Both primary and adaptive resistance could be mediated by SR mechanisms.To this end, we have set out to predict et al, in vitro screens to identify clinically relevant synthetic lethal (SL) interactions. An SL gene pair when co‐inactive exhibits negative selection as it decreases tumor fitness. ISLE harnesses this principle to identify gene pairs whose co‐inactivation is depleted in in vitro and patient tumors. As this fitness reduction is expected to result in better patient survival, ISLE further refines SL prediction by integrating patients’ clinical information. While SL interactions  DDet al, in silico approach termed “IdeNtification of ClinIcal Synthetic Rescues in cancer” (INCISOR), which is specifically geared to identify SR interactions. Broadly, INCISOR combines multiple lines of evidence—experimental, tumor transcriptomics, survival information, and gene phylogeny—to ascertain whether a gene pair is likely to be SR. Here, we describe the specific steps of INCISOR for predicting DU‐SR interactions, where the rescue event is mediated by over‐expression : By analyzing TCGA gene expression and somatic copy number alterations (SCNA) of 8,749 patients across 28 cancer types, INCISOR selects candidate SR pairs from step 1 that are observed in their rescued state  significantly more than expected. This enrichment testifies to a positive selection of samples in the rescued state, a key property of SR interactions. P‐value of enrichment was corrected for multiple hypotheses tested.Patient survival screening: Analogous to ISLE, this step further selects those candidate SRs whose rescued state in TCGA tumor samples exhibits worse patient's survival, as the reduced survival can serve as an indicator of increased tumor fitness. INCISOR uses a stratified Cox proportional hazard model to establish this relationship. We systematically control for confounding factors including cancer type, sex, age, genomic instability, tumor purity  patient data from TCGA to identify the breast cancer‐specific DU‐ and DD‐SR interactions. The resultant breast cancer SR network is shown to be predictive of breast cancer patients’ survival and to a lesser extent, to be predictive of patients’ drug response across different cancer types  genes in an experimental screen in a head and neck cancer cell line (HN12) and experimentally identified the (DD) rescue events occurring due to a subsequent mTOR inhibition by rapamycin treatment . We further confirmed the ability of predicted SR interactions to predict resistant tumor sensitization in a large published patient‐derived cell line collection  first, DNMT1 epigenetically silences E‐cadherin  annotations of rescuers are similar to GO annotations of their partners  with similar degree distribution as the DU‐SR network, and (ii) GO similarity in a network generated by randomly shuffling the interactions between gene pairs of the DU‐SR network (P < 1E‐10). Second, DU‐SR rescuer genes are significantly closer (P < 1E‐46 and P < 3E‐10 compared to the random network and the shuffled network) to their predicted partners in the human protein interaction (PPI) network  protein interactions are enriched in cancer drivers  to their predicted partner gene in the STRING network. Moreover, the observed functional similarities between DU‐SR pairs are not merely due to co‐expression between gene partners; shuffled DU‐SR gene pairs with similar co‐expression levels as those of predicted DU‐SR pairs exhibit significantly less GO similarity (P < 5E‐05). An analogous functional similarity was also observed for gene pairs in the DD‐SR network  28 FDA‐approved cancer drugs (for which treatment response data are available in the TCGA collection). To remove any potential circularity, during the identification of SR interactions of targets of a given drug, we removed from TCGA patients who were administered with that drug . Please note that INCISOR can only predict response to drugs whose gene targets are known.We next evaluated INCISOR's ability to predict response of patients to cancer drug treatments  from the INCISOR pipeline as they are conducted in in vitro systems lacking an immune component . More specifically, our results provide evidence in humans that support the mice findings, that gene inactivation of IFNGR1, RABEPK, and MIF induces tumors resistant to PD1 blockade and gene inactivation of PDIA3, STUB1, CDC7, UBQLN1, NCSTN, GNG12, and GPI co‐simulates immune response to PD1 blockade in melanoma. Interestingly, we identify CTLA4 as a DU rescuer of anti‐PD1 therapy, supporting the rationale of their combination. Other notable upregulated DU rescuers of PD1 are the immune checkpoint genes VTCN1 and TOP2A. The latter suggest combinations involving DNA topoisomerase inhibitors such as Doxorubicin and Epirubicin with anti‐PD1 as a potential combination therapy. Analogously, top predicted DU (DD) rescuers of anti‐CTLA4 therapy were upregulated (downregulated) in post‐treatment tumor biopsies derived from patients treated with anti‐CTLA4 therapy , which are known to interact with MHC1 and facilitate cell death  rescuers of anti‐PD1 therapy  are uprein vitro experiments to validate our predictions. The paucity of known rescue interactions in the literature further underscores the importance of developing tools like INCISOR. Overall, INCISOR attained precision levels of an average 48%  in the identification of true SR interaction across all published and new experiments. Finally, we show that SR mediates both primary and adaptive resistance in patients: e.g., we show that the pre‐treatment expression data of TCGA tumors are predictive of their response to drug treatments . Consequently, our results demonstrate that a given cancer drug may be effective in cells where its predicted rescuer is in its wild‐type state but may become resistant as it is over‐expressed. As expected, as SL interactions predict patient‐specific primary vulnerabilities, while SR interactions predict a therapy resistance overcoming such vulnerabilities, we found no overlap between predicted DU‐SR interactions and SL interactions, predicted by a similar data mining approach ISLE : Mining large‐scale in vitro shRNA and drug response datasets, INCISOR examines all possible gene pairs to identify putative SR. The screen adopts an analogous approach . Specifically, we model the effect of a vulnerable gene knockdown (y) on cell proliferation as a linear mixed‐effects model of its rescuer expression (g) and cancer type, where g is modeled as fixed effect and cancer type is modeled as random effect as follows: To determine this association between V and R while controlling for cancer types of cell lines used in the screens, INCISOR uses a linear mixed‐effects (46) model. cancer_type) to represent the random effect of the confounding cancer type. In the case of shRNA screens, y represents gene essentiality of the vulnerable and in the case of drug screens y represents the IC50 of a drug that inhibits the vulnerable gene. y is quantile normalized to N and parameter is estimated using the lme4 software (46). The P‐value of the fixed effect was estimated using ANOVA. P‐values were adjusted for multiple hypotheses by calculating the false discovery rate considering the number of hypotheses (pairs) tested in each screen.Here, we follow the standard notation  We first calculated the adjusted P‐value within each dataset and then applied multiple hypothesis correction on the adjusted P‐value for each pair tested. (ii) We also tried the Fisher's method : This screen mines gene expression and SCNA data of the input tumor samples to identify vulnerable gene (V) and rescuer gene (R) pairs having the property that tumor samples in the non‐rescued state  appear significantly more than anticipated (testifying to the positive selection of rescued state of the pairwise interaction). The significance of the enrichment/depletion of rescued/non‐rescued state is determined via a hypergeometric test followed by standard false discovery rate correction. A gene is defined as inactive  if its expression level is less (greater) than the 33rd percentile (67th percentile) across samples for each cancer type (to control for cancer type). Otherwise, it is considered to have a normal activation level. Out of total N tumor samples, if n1 (n2) is the number of samples in the rescued/non‐rescued state using specific activation level of gene R (V) independently, k is the number of samples in the activity state using both genes R and V, the significance of enrichment/depletion of the observed number of samples in the rescued/non‐rescued state is determined using hypergeometric test: hypergeometric . Enrichment/depletion of the activity state using SCNA is set analogously. Pairs significant (FDR < 0.05) in both SCNA and mRNA are passed on to the next screen.Clinical screening : This step selects a gene pair as SR if it has the property that tumor samples in rescued state  exhibit significantly poorer patient's survival and samples in non‐rescued state tumors exhibit better survival than rest of the other samples. Specifically, INCISOR uses a stratified Cox proportional hazard model to check such observed associations of SR rescued/non‐rescued state are significantly larger compared to the expected additive survival effect of their individual genes, while controlling for confounding factors including cancer type, sex, age, genomic instability, tumor purity, and race :g is the hazard function (defined as the risk of death of patients per unit time), and h0g(t) is the baseline hazard function at time t of the gth stratification. The model contains six covariates: (i) I: indicator variable representing if the patient's tumor is in the activity state A, (ii) g(V) and (iii) g(R): gene expression of V and R, (iv) age: age of the patient, (v) GII: genomic instability index of the patient, and (vi) TP: tumor purity. The βs are the unknown regression coefficient parameters of the covariates, which quantify the effect of covariates on the survival.SCNA‐based conditional essentiality is determined analogously. Putative SR pairs significant either in shRNA screen or in drug response screen either using gene expression or SCNA are referred as putative SR. We apply the standard FDR correction . The βs are determined by standard likelihood maximization  followed by a likelihood ratio test and Wald's test .The et al  ABPhylogenetic profiling screening: We further filter and select SR pairs composed of genes having high phylogenetic similarity, motivated by the findings of Srivas et al  hypotheses. We have adjusted the P‐value using Benjamini–Hochberg and apply FDR < 0.2 accordingly, to identify 2878319 putative (DU) shRNA screen‐derived interactions. In the case of drug response, the hypothesis space is smaller, with 221(number of drugs) × 19001 KDs. We again applied a FDR < 0.2 threshold and identified 354K putative drug‐SR interactions. The first step ends up identifying 3 million (DU) SR candidates; the second step identified 1.2 million pairs; and the third step reduced selected 9,021 pairs, followed by 1,033 interactions in the final step.To process half a billion gene pairs for around 9,000 patient tumor samples in a reasonable time, the most computationally intensive parts of INCISOR are coded in C++ and ported to R. Further, INCISOR uses open Multiprocessing (OpenMP) programming in C++ to use multiprocessor in large clusters. Also, INCISOR performs coarse‐grained parallelization using R‐packages “parallel” and “foreach”. Finally, INCISOR uses Terascale Open‐source Resource and QUEue Manager (TORQUE) to uses more than 1,000 cores in the large cluster to efficiently infer genome‐wide SR interactions.rescued state is defined as co‐inactivation of vulnerable (V) and rescuer gene (R); and non‐rescued state is defined as underactive gene V and active gene R  Phylogenetic screen: It remains the same as the case of DU identification .The four types of SR networks for pan‐cancer were created using si be the absolute of log ratio of SCNA of gene i in a sample relative to normal control, GII of the sample is given as . The final INCISOR interaction‐score for a gene pair i is given as: ri(k) represents the rank normalized value of the kth screen of INCISOR.INCISOR evaluates each of the candidate SR gene pairs based on the strength of their SR interactions. We define et al, et al, et al, The drugs were mapped to their targets based on the mapping reported in CCLE, CTRP, and DrugBank  of DU rescuer genes upregulated of its drug targets  in the patient sample. To predict the response of TCGA patients treated, we evaluated the association of C with the patients’ survival using stratified Cox model, which also controls for confounding factors  as follows: g, h0g, βs age, and GII are defined as in the equation C, age, and GII are quantiles normalized to N. The significance of β1, which is the coefficient of C, is determined by comparing the likelihood of the model with the NULL Cox model, which is similar to C, followed by likelihood ratio and Wald's tests , and their significance is determined using Wilcoxon rank sum test.We evaluated the performance of our prediction vs. TCGA drug response based on patient tumor size following the treatment. Based on RECIST drug response profile of 3,872 patients in TCGA, which were annotated into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD), we divided the samples into responders (CR and PR) vs. non‐responders (PD and SD). To determine the ability of SR to predict drug response of each drug, we compared the fraction of the DU rescuers (of the drug's targets) upregulated in patients’ tumors . If AUC > 0.5 and mean fraction of over‐expressed rescuers was higher in responders compared to non‐responders (1‐AUC) was used as the final estimate of AUC.et al . Cells were propagated in the presence or not of a drug for an additional 12 doublings before the final PD13 sample was taken. shRNA barcode was PCR‐recovered from genomic samples and samples sequenced to calculate the abundance of the different shRNA probes. From these shRNA experiments, we obtained cell counts for each gene knockdown at the following two time points: (i) post‐shRNA infection , and (ii) shRNA treatment followed by either rapamycin treatment  or control .et al, et al, P < 0.05) after adjusting for multiple hypothesis. Next, we applied INCISOR to TCGA to specifically predict DD‐SR interactions between 2,214 genes tested and mTOR as DD rescuer. Each gene pairing  was quantified using INCISOR interaction score. The score was used to estimate precision and recall.Significant experimental (DD) rescue event was determined by using Mageck . INCISOR predicted 5 DU‐SR interactions between these oncogenes. Two different inhibitors (rapamycin and INK128) were included for mTOR, and one inhibitor each for PIK3CA, KIT/SRC, AKT, and PTK2 was included in the experiment. This resulted in seven combinations tested . Dasatinib, Erlotinib, BYL719, and INK128 were purchased from Selleckchem . Vita‐Blue Cell Viability Reagent was purchased from Biotools . CAL33, HN12, Detroit 562, and SCC47 cell lines were cultured in 96‐well plate and then treated with drugs for 48 hours (Raw Data in ® siRNA human mTOR SASI_Hs02_00338641 and SASI_Hs01_00203144). Cells were cultured in 96‐well plate, transfected with Lipofectamine RNAiMAX reagent  for 24 h; then, cells were treated with drugs for another 48 h (Raw Data in 3VO4 and 1 mM NaF). Equal amounts of total proteins were subjected to SDS–polyacrylamide gel electrophoresis. Primary antibodies used were from Cell Signaling Technology , PI3KCA , pAKT , AKT , pmTOR , mTOR , pS6 , S6 , and GAPDH , the latter as a protein loading control.siRNAs for non‐targeting control and PIK3CA were purchased from GE Healthcare . siRNAs for mTOR were purchased from Sigma  siRNA‐treated cells to drug treatment was quantified as a change in cell counts relative to the cell counts following the respective siRNA inhibition alone. Next, using this normalized response, DRC was estimated for both targeted and untargeted siRNAs using DRC R‐package. Percentage increase in sensitivity of the primary therapy y‐axis,  due to tet al, Drug screening was performed using automated liquid handling in a 1536‐well plate format  using a 4× objective. Cell nuclei enumeration was performed using the MetaXpress software, and count accuracy was routinely checked visually during acquisition. The screening was conducted in two replicates  and five concentrations of each rescuer inhibitor (two replicates)), Fa‐CI analysis is not feasible. The drug dose tested is provided in et al, et al, Cellcount(X) denotes cell count following the treatment of X. R(C) denotes rescuer inhibitor at dose C. The effect size of synergism at dose C of rescuer inhibitor was estimated as Synergism=Ratio(Y)/Ratio(X). This calculation is separately done for each of two replicates of R dose, generating 10 data points (5 dose × 2 replicate) for each rescuer inhibitor.We used Bliss independence model =medianRatio(Y)Ratio(X). Significance of synergism of R was estimated by a Wilcoxon rank sum test comparing Ratio(Y) and Ratio(X) of the 10 data points of R. Finally, R was estimated to be significantly synergistic with Decitabine, if Synergism(R)>1.25 and P‐value adjusted for multiple hypothesis corrections is < 0.05 <0.75 and P‐value adjusted for multiple hypothesis corrections is < 0.05  network compiled from  and indirect  associations. The comparison control networks were made analogous manner as in case of GO similarity described above.For the DD‐SR network, GO similarity, PPI distance, and STRING database distance were estimated analogously .et al, et al, To identify DU‐SR interactions likely to be mediated by PPI interactions, we applied INCISOR on the human PPI network compiled from  from INCISOR because the dataset used in step 1 was conducted in in vitro models that are deficient of the immune system. Next, we applied the INCISOR to the TCGA to identify the DU and DD rescuers of PD1/PDL1 and CTLA4 downregulation. We call an SR identified by INCISOR as clinically significant if the interaction shows association with survival either in pan‐cancer or melanoma cohort in TCGA patient dataset.To identify rescuers of immune checkpoints, we removed filtering step 1  anti‐PD1 or anti‐PDL1 , (ii) anti‐CTLA‐4, and (iii) combination of anti‐PD1 and anti‐CTLA‐4. Patients were consented for tissue acquisition per Institutional Review Board (IRB)‐approved protocol  and The Wistar Institute (Illumina NextSeq 500). BAM files of raw RNA‐seq data were used to summarize read counts by featureCounts . The more extended version of the code is available on GitHub (https://github.com/vinash85/INCISOR).We have included the code as ADS, JSL, and ER conceived and designed the research. ADS, JSL, JSG, CB, and ER designed the experimental procedure. ADS and JSL performed the computational analysis and statistical computations. ZW and RI‐B performed the experiments. GZ, TT, ZW, BM, NUN, OP, AAF, AA, TM, GK, PG, RKE, LJD, DTF, LJ‐A, AW, KC, SGP, WR, KG, GB, SH, MH, CB, JL, and KF collected data used in the paper. All co‐authors wrote the paper.The authors declare no conflict of interests.AppendixClick here for additional data file.Dataset Tables EV2–EV26 and EV28–EV35Click here for additional data file.Code EV1Click here for additional data file.Cytoscape_networkClick here for additional data file.Review Process FileClick here for additional data file.


Supraglottic jet oxygenation and ventilation (SJOV) can effectively maintain adequate oxygenation in patients with respiratory depression, even in apnea patients. However, there have been no randomized controlled clinical trials of SJOV in obese patients. This study investigated the efficacy and safety of SJOV using WEI Nasal Jet tube (WNJ) for obese patients who underwent hysteroscopy under intravenous anesthesia without endotracheal intubation.2, PETCO2, BP, HR, ECG and BIS were continuously monitored during anesthesia. Two-Diameter Method was deployed to measure cross sectional area of the gastric antrum (CSA-GA) by ultrasound before and after SJOV in the WNJ SJOV Group. Episodes of SpO2 less than 95%, PETCO2 less than 10 mmHg, depth of WNJ placement and measured CSA-GA before and after jet ventilation in the WNJ SJOV Group during the operation were recorded. The other adverse events were collected as well.A single-center, prospective, randomized controlled study was conducted. The obese patients receiving hysteroscopy under intravenous anesthesia were randomly divided into three groups: Control group maintaining oxygen supply via face masks , the WNJ Oxygen Group with WNJ  and the WNJ SJOV Group with SJOV via WNJ . SpOETCO2 < 10 mmHg, SpO2 < 95% in the WNJ SJOV group dropped from 36 to 9% (P = 0.009),from 33 to 6% (P = 0.006) respectively,and the application rate of jaw-lift decreased from 33 to 3% (P = 0.001), and the total percentage of adverse events decreased from 36 to 12% (P = 0.004). Compared with the WNJ Oxygen Group, the use of SJOV via WNJ significantly decreased episodes of SpO2 < 95% from 27 to 6% (P = 0.023), PETCO2 < 10 mmHg from 33 to 9% (P = 0.017), respectively. Depth of WNJ placement was about 12.34 cm in WNJ SJOV Group. There was no significantly difference of CSA-GA before and after SJOV in the WNJ SJOV Group (P = 0.234). There were no obvious cases of nasal bleeding in all the three groups.A total of 102 patients were enrolled, with two patients excluded. Demographic characteristics were similar among the three groups. Compared with the Control Group, the incidence of PSJOV can effectively and safely maintain adequate oxygenation in obese patients under intravenous anesthesia without intubation during hysteroscopy. This efficient oxygenation may be mainly attributed to supplies of high concentration oxygenation to the supraglottic area, and the high pressure jet pulse providing effective ventilation. Although the nasal airway tube supporting collapsed airway by WNJ also plays a role. SJOV doesn’t seem to increase gastric distension and the risk of aspiration. SJOV can improve the safety of surgery by reducing the incidence of the intraoperative involuntary limbs swing, hip twist and cough.Chinese Clinical Trial Registry. Registration number, ChiCTR1800017028, registered on July 9, 2018. It is estimated that more than 100,000 patients receive hysteroscopy each year in China. Usually, hysteroscopy is accomplished under intravenous (IV) anesthesia or sedation without endotracheal intubation, primarily with IV propofol and remifentanil . RemediaThis study was approved by the local Ethics Committee of Peking University People’s Hospital (No. 2018PHB036–01). Informed written consent was obtained from the obese patients who underwent hysteroscopy between July and September 2018. This study adhered to the Consolidated Standards of Reporting Trials (CONSORT) guidelines.2 reduction in WNJ SJOV group and WNJ oxygen group compared to that in control group by the preliminary test. With a standard deviation of 0.8, and bilaterally equal to 0.05, or even 0.2 (power = 0.8), estimated value of each group should be 34 cases (n = 2(μα + μβ)2σ2/δ2 with 20% shedding rate). The randomization was performed by random number table from the SPSS23.0, and the blinding was completed by one medical student and two anesthesiologists. Patients were labeled with WNJ SJOV, WNJ or Control by One anesthesiologist, and the other anesthesiologist administered the intravenous anesthesia and maintained oxygenation. The flow diagram of this study was shown in Fig. Patients were randomized to the mask oxygen group (Control Group) maintaining oxygen absorption via face mask , the WNJ oxygen group with WNJ  and the WNJ SJOV group with SJOV via WNJ . The Sample Size was calculated by SAS, considering at least a 90 and 60% reduction in patients with SpO2; (3) Fasting for 8 h and no water for 4 h before surgery; (1) ASA class: I-II classes. Exclusion criteria were as follows: (1) Epistaxis; (2) Nasal stenosis; (3) Long-term use of anticoagulants; (4) Rhinitis episodes; (5) Severe reflux disease; (6) History of severe respiratory, cardiovascular and cerebrovascular diseases.In-patients receiving routine hysteroscopy under IV anesthesia with propofol and remifentanil were recruited. Inclusion criteria were as follows: (1) 18 yrs. < age < 65 yrs.; (2) BMI > 30 kg/m2 was maintained above 95%. A dose of ephedrine (3–6 mg) was administered as needed in order to maintain the mean arterial pressure above 55 mmHg. Remedial measures were executed immediately in the setting of oxygen saturation (SpO2) < 95%, including adjusting the WNJ position  in the WNJ SJOV group and the WNJ oxygen group, and taking jaw-lift maneuver in the three groups. Mask pressurized ventilation was used to provide oxygen only when SpO2 < 90% happened in all the three groups.Induction of anesthesia was conducted by IV injection of propofol 1.5–2 mg/kg) and remifentanil (0.5 μg/kg). Anesthesia was maintained by continuous IV infusion of propofol (3-5 mg/kg/h) and remifentanil (0.05–0.08μg/kg/ min). After anesthesia induction, the face mask in control group, the WNJ in WNJ oxygen group and WNJ SJOV group were placed appropriately straightway. Before putting WNJ into the unobstructed nostril of patients, a paraffin oil cotton swab was used to clear the nasal cavity and about 1 ml lidocaine ointment was smeared on the tip of WNJ , mean blood pressure (MBP), heart rate (HR), electrocardiogram (ECG) and BIS. SpO2 < 95% and PETCO2 < 10 mmHg were considered hypoxic adverse event and hyperventilation, respectively [We continuously monitored following parameters during the anesthesia: pulse SpOectively , 12.Fig2 less than 95% and PETCO2 less than 10 mmHg during the operation were recorded. The other adverse events such as hip twist, cough, nasal bleeding and remedial interventions such as jaw-lift, pressure mask, depth of WNJ placement were also noted. Types and time of surgery, recovery time of anesthesia, dose of anesthetics, measured CSA-GA before and after jet ventilation in the WNJ SJOV group were also recorded.Episodes of SpO2 less than 95%, PETCO2 less than 10 mmHg, hip twist, nasal bleeding, and patients requiring jaw-lift, pressured mask ventilation, as well as other perioperative adverse reactions were all analyzed withchi-square test and Fisher’s exact test. All data was analyzed with SPSS23.0 statistical software . A value of p < 0.05 was considered the difference was statistically significant.The measurement data was expressed as mean ± SD and the count data was presented as the number and percentage. Kruskal-wallis single factor ANOVA test was used to compare the difference of time of surgery, recovery time of anesthesia, dosage of anesthetics between different groups. The data about depth of WNJ placement between the WNJ SJOV and the WNJ oxygen groups was analyzed by Wilcoxon rank sum test. Independent sample t-test was used for comparing the CSA-GA and ESV before and after jet ventilation in the WNJ SJOV group. Categorical variables as the cases of SpOA total of 102 patients were enrolled. One patient in the control group was excluded because of stuffy nose due to catching a cold, and another patient in WNJ oxygen group was removed because of change of the operative mode during operation. All the patients tolerated the hysteroscopy well. There were no serious adverse events .The clinical characteristics of patients was represented in Table ETCO2 during SJOV. Compared with the Control Group, the incidence of PETCO2 < 10 mmHg,SpO2 < 95% in the WNJ SJOVgroup dropped from 36 to 9% (P = 0.009), from 33 to 6% (P = 0.006) respectively, and the application rate of jaw-lift decreased from 33 to 3% (P = 0.001), and the total percentage of adverse events decreased from 36 to 12% (P = 0.004). Compared with the WNJ Oxygen Group, the use of SJOV via WNJ significantly decreased episodes of SpO2 < 95% from 27 to 6% (P = 0.023), PETCO2 < 10 mmHg from 33 to 9% (P = 0.017), respectively. There were no significant differences in episodes of SpO2 < 95% and PETCO2 < 10 mmHg between the WNJ Oxygen Group and the Control Group (P = 0.789 and P = 1.000).  during operation in this study. One occurred in WNJ oxygen group, the other two cases happened in WNJ SJOV group. On the second day after surgery, these three patients had no other symptoms except feeling slight dry and itching in the throat.P = 0.420 and P = 0.348). However, compared with the Control Group, SJOV could slightly decrease the incidence of cough from 9 to 3% (P = 0.356) and hip twist from 6 to 0% (P = 0.239) .(Table P = 0.234 and P = 0.777). .Table . The chaP = 0.002, P < 0.001).Compared with the Control Group and the WNJ Oxygen Group, respectively, the dosage of propofol in the WNJ SJOV Group increased significantly  is a new approach to enhance oxygenation . THRIVE Jostrand from Sweden first introduced the technology of using 60 to 100 breaths per minute, which was called high frequency positive pressure ventilation (HFPPV) . Klein sETCO2 can also be monitored [In addition to observing chest fluctuation, Ponitored  [Fig. 2 could provide adequate ventilation, although it is less effective than transtracheal jet ventilation (TTJV). However, WNJ SJV could significantly reduce the complications of TTJV, such as barotrauma. WNJ SJV within 25 min did not increase incidence of postoperative laryngopharyngeal pain, cough and ability of discharge of sputum, suggesting that this technique may not produce inflammatory reaction caused by damage of airway mucosa and throat soft tissue.Although the mechanisms about the respiratory depressant effect of propofol have not been fully explained, it is clear that propofol causes the respiratory depressant effect in a dose-dependent manner . When maAlthough it had been reported that SJV can maintain 1 h oxygenation, but it was not suitable for longer time application . ApproprThe shortcomings of this trial are reflected in the small sample size, which cannot fully reflect the real situation of adverse reactions. The position of the patient during ultrasound examination is not the optimal position.SJOV can effectively and safely maintain adequate oxygenation in obese patients under intravenous anesthesia without intubation during hysteroscopy. This efficient oxygenation may be mainly attributed to supplies of high concentration oxygen to the supraglottic area, and the high pressure jet pulse providing effective ventilation. Although the nasal airway tube supporting collapsed airway by WNJ also plays a role. SJOV doesn’t seem to increase gastric distension and the risk of aspiration. SJOV can improve the safety of surgery by reducing the incidence of the intraoperative involuntary limbs swing, hip twist and cough.


In this paper, the dispersion of carbon nanotube (CNT) in ethylene vinyl acetate (EVA) is demonstrated to be significantly improved by the addition of octadecylamine (ODA)-grafted graphene oxide (GO) (GO–ODA). Compared to the CNT/EVA composite, the resultant GO–ODA/CNT/EVA (G–CNT/EVA) composite shows simultaneous increases in tensile strength, Young’s modulus and elongation at break. Notably, the elongation at break of the G–CNT/EVA composite still maintains a relatively high value of 1268% at 2.0 wt % CNT content, which is more than 1.6 times higher than that of CNT/EVA composite (783%). This should be attributed to the homogeneous dispersion of CNT as well as the strong interfacial interaction between CNT and EVA originating from the solubilization effect of GO–ODA. Additionally, the G–CNT/EVA composites exhibit superior electrical conductivity at low CNT contents but inferior value at high CNT contents, compared to that for the CNT/EVA composite, which depends on the balance of CNT dispersion and the preservation of insulating GO–ODA. Our strategy provides a new pathway to prepare high performance polymer composites with well-dispersed CNT. Carbon nanotube (CNT) has been regarded as a very promising nanofiller for polymer matrices to achieve high performance and multifunction, due to its extraordinary mechanical, electrical, and thermal properties ,5,6,7,8.Recently, there are growing efforts on controlled surface modification of CNT to realize well dispersion through covalent or noncovalent approaches ,24,25,26In the current study, octadecylamine (ODA) grafted GO (GO–ODA) was synthesized to assist the dispersion of CNT in ethylene vinyl acetate (EVA), because CNT-based EVA composites are widely used for various applications such as packaging films, adhesives, antistatic field and electromagnetic shielding in view of their excellent flexibility, durability, and chemical resistance ,38,39. S3 and the melt flow rate is 25 g/(10 min) . Graphene oxide (GO) was prepared from expanded graphite, which was provided by Qingdao Haida Graphite Co., Ltd.  with an expansion rate of 200 mL/g, by the modified Hummers method, as described in our previous work [2/g, and 90% carbon purity, was supplied by Nanocyl S.A., . ODA, xylene, deionized water and anhydrous ethanol were supplied by Chengdu Kelong Chemical Reagent Factory, Chengdu, China. All these chemicals were analytical reagent and used without further purification. The commercially available EVA containing 28 wt % of vinyl acetate was kindly provided by Beijing Dongfang Petroleum Chemical Co. . The density is 0.92 g/cmous work . CNT  in a three-neck flask. The mixture was refluxed with intensified mechanical stirring for 24 h at 85 °C and filtrated by a PTFE membrane (0.2 μm pore size). The filtrated powder was then washed thoroughly with ethanol and filtered to remove the remaining ODA. Finally, the mixture was dried in a vacuum oven overnight at 60 °C for 48 h.via ultrasonication for 30 min, then CNT was added to GO–ODA dispersion (1:1 weight ratio) and further ultrasonicated for 60 min. Meanwhile, EVA was completely dissolved in hot xylene (75 °C) by mechanical stirring for 60 min. Subsequently, GO–ODA/CNT/xylene dispersion was poured into the EVA/xylene solution and the mixture was continuously stirred for 30 min at 75 °C. Afterwards, the mixture was recovered by flocculation with ethanol, followed by filtering and drying in a vacuum oven (60 °C) for 48 h. Finally, the dried mixture was compression molded under the pressure of 10 MPa at 160 °C, after preheating for 5 min. The resultant GO–ODA/CNT/EVA composites were marked as G–CNT/EVA composites. For comparison, the CNT/EVA composites were also prepared under the same processing conditions.The schematic representation for the preparation of GO–ODA/CNT/EVA composites is illustrated in −1 spectral resolution on a Nicolet 6700 FTIR spectrometer  in transmission mode. GO or GO–ODA was ground with KBr and pressed into KBr disks for FTIR measurements. X-ray diffraction (XRD) data was collected with a DX-1000 diffractometer  using CuKa irradiation at 40 kV in a scanning range from 2° to 30°. Water contact angle was measured by using a DSA 30 KRUSS drop shape analyzer . Thermogravimetric analysis (TGA) was carried out to evaluate the thermal stability of GO and GO–ODA on a NETZSCH 209F1 , at a heating rate of 10 °C/min over 40–600 °C under nitrogen atmosphere. Scanning electron microscopy (SEM) images were taken by a field emission SEM  at an accelerating voltage of 20 kV. The specimens were cryo-fractured in liquid nitrogen and the fracture surfaces were coated with a thin layer of gold before morphological observation. The volume conductivity of the composite above 10−6 S/m was carried out on a four-point probe instrument  and the volume conductivity below 10−6 S/m was measured with a Keithley electrometer Model 4200-SCS . Tensile test was performed on an Instron universal test instrument  at room temperature. The loading rate was 100 mm/min and the gauge length was 20 mm. More than five samples were tested to calculate the average value and standard deviations.Fourier-transform infrared spectroscopy (FTIR) spectra were recorded with a 2 cm−1, corresponding to C=O in carboxyl group, C=C in aromatic ring, C−OH stretching and C–O–C in epoxide, respectively [−1 is assigned to the hydroxyl groups. When it comes to GO–ODA, the existence of the octadecyl chain is clearly demonstrated because of the emerging peaks at 2919 cm−1 and 2850 cm−1 (–CH2 stretching in the octadecyl chain) as well as the peak at 720 cm−1 [−1 (N–H bending of amide) and 1470 cm−1 (C–N stretch of amide) in GO–ODA also indicate the presence of amide-carbonyl bond between ODA molecule and GO. All these results affirm the intercalation and chemical reaction of ODA with GO, which is in line with the reported in the literature [FTIR spectra were performed to determine the chemical changes that occurred during the refluxing of ODA and GO. As shown in ectively . The bro720 cm−1 ,42. Furt720 cm−1 . The newterature ,43. The terature .The dispersion of nanofillers has a direct correlation with the mechanical, electrical, and other properties of nanofiller/polymer composites. The fractured surface of the CNT-based EVA composite was observed with SEM to assess the CNT dispersion, as shown in −8 S/m, satisfying the antistatic criterion for commercial application [−12 S/m). As the CNT loading rises to 0.5 wt %, the electrical conductivity of the G–CNT/EVA composites increases to 4.9 × 10−6 S/m, which is still higher than that of CNT/EVA composites. However, with further increasing CNT loadings to 1.0 wt % and 2.0 wt %, it can be seen that the electrical conductivities of CNT/EVA composites exceed that of the G–CNT/EVA composites. The main reasons for the interesting phenomenon can be found in the following two aspects. The first aspect is that the incorporation of GO–ODA can significantly improve CNT dispersion in EVA matrix due to π–π stacking interaction between GO–ODA and CNT. This contributes to the formation of inter-connected CNT networks. The second aspect is that the abundant presence of insulating GO–ODA between the adjacent CNTs will increase their contact resistance and thus hinder the electronic transport of CNTs in EVA. To provide visual demonstration of the conductive networks in the G–CNT/EVA and CNT/EVA composites, schematic representations are shown in lication . Such va−8 S/m, satisfying the antistatic criterion for commercial application. The concept of dispersing CNT by using hydrophobic GO–ODA in our work can be easily extended to other CNT-based polymer systems, which paves the way to develop such composites with excellent properties.We demonstrate a facile and effective approach to realize the homogeneous dispersion of CNT in EVA matrix, by using GO–ODA as a compatilizer. The resultant G–CNT/EVA composites show superior mechanical properties in comparison with the CNT/EVA composites, which could be attributed to the uniform dispersion of CNT in EVA matrix and the strong interfacial interaction between CNT and EVA, originating from the solubilization effect of GO–ODA. At a very low CNT content of 0.2 wt %, the electrical conductivity of G-CNT/EVA already reaches 6.9 × 10


In Ontario, FOLFIRINOX (FFX) and gemcitabine + nab‐paclitaxel (GnP) have been publicly funded for first‐line unresectable locally advanced pancreatic cancer (uLAPC) or metastatic pancreatic cancer (mPC) since April 2015. We examined the real‐world effectiveness and safety of FFX vs GnP for advanced pancreatic cancer, and in uLAPC and mPC.Patients receiving first‐line FFX or GnP from April 2015 to March 2017 were identified in the New Drug Funding Program database. Baseline characteristics and outcomes were obtained through the Ontario Cancer Registry and other population‐based databases. Overall survival (OS) was assessed using Kaplan‐Meier and weighted Cox proportional hazard models, weighted by the inverse propensity score adjusting for baseline characteristics. Weighted odds ratio (OR) for hospitalization and emergency department visits (EDV) were estimated from weighted logistic regression models.P = .0001; Hospitalization: OR = 0.76, P = .002), whereas the risk of febrile neutropenia‐related hospitalization was significantly higher . Outcomes for uLAPC and mPC were similar.For 1130 patients , crude median OS was 9.6 and 6.1 months for FFX and GnP, respectively. Weighted OS was improved for FFX vs GnP . Less frequent EDV and hospitalization were observed in FFX  than GnP . More frequent febrile neutropenia‐related hospitalization was observed in FFX (5.8%) than GnP (3.3%). Risk of EDV and hospitalization were significantly lower for FFX vs GnP (EDV: OR = 0.68, In the real world, FFX had longer OS, less frequent all‐cause EDV and all‐cause hospitalization, but more febrile neutropenia‐related hospitalization compared to GnP. In the real world, implementation of universal public funding of FOLFIRINOX for metastatic pancreatic cancer was associated with improved overall survival, less frequent all‐cause emergency department visits, less frequent all‐cause hospitalization, but increased febrile neutropenia‐related hospitalization compared to patients treated with gemcitabine + nab‐paclitaxel. Expanding funding to include unresectable locally advanced pancreatic cancer was associated with a similar trend in benefits, but with improved absolute survival. Incidence of grade ≥3 treatment‐emergent adverse events (AEs) and all grade treatment‐emergent AEs was greater in patients receiving GnP, with a 3% rate of febrile neutropenia in the GnP group.The phase III MPACT trial compared GnP to gemcitabine monotherapy in patients with previously untreated metastatic adenocarcinoma of the pancreas (mPC), age ≥18 years, and Karnofsky performance status (KPS) 70 or greater.The PRODIGE/ACCORD 11 trial compared FFX against gemcitabine in patients with mPC and Eastern Cooperative Oncology Group performance status (ECOG PS).For mPC, the American Society of Clinical Oncology (ACSO) recommends FFX for patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1, favorable comorbidity profile, patient preference, and a support system for aggressive medical therapy, and access to chemotherapy port and infusion pump management services.. Furthermore, the ACCORD trial was conducted only in France, whereas the MPACT trial involved centers internationally. Direct comparisons of FFX and GnP are not expected. Results from indirect comparisons, however, have been conflicting. In one Bayesian meta‐analysis, a trend toward improvement in OS for FFX was found compared to GnP probabilistically, with no obvious difference in toxicities.Although the pivotal trials of both FFX and GnP have shown both treatments improve OS, PFS as well as response rate, distinctive patient populations, and differences in trial design limit the generalizability of indirect comparisons22.1Ontario publicly funded FFX as a first‐line treatment for mPC as of November 7, 2011 and for uLAPC as of April 17, 2015. GnP as a first‐line treatment for patients with mPC or uLAPC was publicly funded as of April 17, 2015. Second‐line oxaliplatin and nano‐liposomal irinotecan were not funded in Ontario during our study period.2.2The study protocol was approved by the institutional ethics committee of Sunnybrook Health Sciences Centre. Patients who received FFX or GnP as first‐line treatment were identified from the New Drug Funding program (NDFP) database. Patients whose first chemotherapy treatment occurred between April 17, 2015  to March 31, 2017 were included in the study. Patients who received FFX as first‐line treatment for mPC before April 17, 2015 were excluded to create a more comparable contemporary cohort to compare FFX vs GnP.Baseline characteristics and outcomes were obtained through data linkage of patient's receiving FFX or GnP to the Ontario Cancer Registry (OCR), Cancer Activity Level Reporting (ALR), Discharge Abstracts Database (DAD), the National Ambulatory Care Reporting System (NACRS), and the Registered Persons Database (RPDB) by patients’ unique health card number. Canadian 2016 Census data were used to obtain patients’ rural/urban status and neighborhood income quintiles based on postal code of patients’ residence. Details see Appendix Data sources and Appendix Figure 2.3Our primary effectiveness outcome was OS, defined as the time from date of first‐line treatment to death or end of follow‐up if censored. Patients were followed up to Aug. 31, 2017. Our safety outcomes included all‐cause hospitalization, all‐cause emergency department (ED) visits and hospitalizations for febrile neutropenia during the treatment period.2.4Descriptive statistics were used to summarize baseline characteristics. Age was calculated at patients’ first treatment. Patients’ postal code, ECOG PS, and mPC indicator were obtained when patients were enrolled to receive treatment. Previous adjuvant gemcitabine and previous radiation treatment were defined as any adjuvant gemcitabine or radiation prior to patients’ first treatment on FFX or GnP. Previous pancreatic resection and Charlson comorbidity index were calculated using DAD data looking back 2 years from patients’ first treatment.t‐test for continuous variables and chi‐square test for binary or categorical variables.Propensity score analysis using inverse probability of treatment weighting (IPTW) was conducted to account for potential confounders when comparing between FFX and GnP. The IPTW method can remove systematic differences between FFX and GnP on observed characteristics to a comparable degree compared to propensity score matching, without having to reduce the current sample size to estimate the average treatment effect.OS was assessed using Kaplan‐Meier survival curves, log‐rank test, and Cox proportional hazard models weighted by the inverse propensity score. For safety outcomes, binary outcomes of all‐cause ED visit, all‐cause hospitalization, and hospitalization for febrile neutropenia during treatment periods were defined, and the weighted odds ratios for all‐cause hospitalization and ED visit during treatment periods were estimated from weighted (IPTW) logistic regression models.All analyses were done in the main cohort and the mPC and uLAPC subcohorts, separately.P values <.05 were considered statistically significant. SAS version 9.4  was used to conduct the analyses.All two‐sided 2.5Two sensitivity analyses were performed to examine the robustness of our results. First, multivariable analyses were conducted adjusting the same potential confounders used in the calculation of propensity score. Multivariable proportional hazards model was adopted to estimate an adjusted hazard ratio for OS and multivariable logistic regression models were adopted to estimate the adjusted odds ratio of all‐cause hospitalization or all‐cause ED visits during the treatment period. Second, we counted the number of all‐cause hospitalizations, number of all‐cause ED visits, and hospitalizations for febrile neutropenia during the patients’ treatment periods, and adopted negative binomial models to estimate the rate ratio (RR) of all‐cause hospitalization, all‐cause ED visits and hospitalization for febrile neutropenia accounting for differences in patients’ treatment periods. Univariate analyses were conducted for proportional hazards model, logistic regression, and negative binomial models as well.33.1The data source and the creation of the study population are shown in Appendix Figures 3.2Baseline characteristics of the study population by treatment group are shown in Table Weighted standardized difference on all baseline characteristics were calculated for the overall cohort Table , mPC subA total of 139 (12.3%) patients of 1130 had subsequent treatments. Of these patients, 129 (92.8%) had initial FFX and 10 (7.2%) had initial GnP. For patients who had initial FFX, 95 (73.6%) proceeded to subsequent gemcitabine and 34 (26.4%) proceeded to subsequent GnP. For patients who had initial GnP, nine (90%) proceeded to subsequent gemcitabine and one (10%) proceeded to subsequent FFX.3.3Patients were followed up until Aug. 31, 2017 with average follow‐up of 8 months and maximum follow‐up time of 28 months. Crude median survival was 9.6 and 6.1 months for patients who received FFX and GnP, respectively. In 334 patients with uLAPC, crude median survival was 13.2 and 8.1 months for FFX and GnP groups; in 796 patients with mPC, crude median survival was 8.2 and 6.1 months for FFX and GnP groups. Kaplan‐Meier curves for overall cohort, mPC and uLAPC subcohorts are shown in Figure 3.4P = .0001; whereas for hospitalization was 0.76 , P = .002. Risk of febrile neutropenia‐related hospitalization was significantly higher for FFX vs GnP group, with weighted OR (95% CI) of 2.12 , P = .001.We excluded 104 patients who were continuing first‐line treatment after July 31, 2017. In the overall cohort, less frequent ED visits and hospitalizations were observed in FFX group  compared to GnP group . More frequent febrile neutropenia‐related hospitalization was observed in FFX (5.8%) compared to GnP patients (3.3%). After applying IPTW, risk of ED visit and hospitalization were significantly lower for FFX vs GnP group. The weighted OR (95% CI) for ED visit was 0.68 , P = .0001, whereas the risk of febrile neutropenia‐related hospitalization was significantly higher for FFX vs GnP patients with weighted OR (95% CI) of 2.10 , P = .008. There is no significant difference of risk of ED visit and hospitalization for febrile neutropenia between FFX and GnP group in the uLAPC subcohort, but the risk of all‐cause hospitalizations for FFX patients was significantly lower with weighted OR (95% CI) of 0.62 , P = .003. Similar trends were observed from multivariable adjusted logistic regression  compared to GnP group  in the mPC subcohort. After applying IPTW, risk of ED visits was significantly lower for FFX vs GnP patients. The weighted OR (95% CI) for ED was 0.63 , The results of the rate ratio regression sensitivity analyses are congruent with the results of binominal logistical regressions with respect to ED visits and hospitalization. In the overall cohort, significantly less frequent ED visits, less all‐cause hospitalizations and more febrile neutropenia related hospitalizations were observed in patients who received FFX compared to GnP; weighted RR were 0.78 , 0.71 , and 2.65  for ED visits, all‐cause hospitalizations, and febrile neutropenia related hospitalizations, respectively. For details see Appendix Table In the advanced pancreatic cancer patients who received treatments, the common diagnosis of hospitalization during treatment included the following: malignant neoplasm of pancreas (16.84%), palliative care (7.95%), obstruction of bile duct (4.77%), acute pancreatitis (2.56%), neutropenia (2.39%), other and unspecified intestinal obstructions (1.97%), unspecified fever (1.87%), unspecified sepsis (1.80%), cholangitis (1.69%), pulmonary embolism (1.52%), mechanical complication of GI prosthetic devices, implants, and grafts (1.49%), and unspecified pneumonia (1.45%). These causes are consistent with symptoms and complications of pancreatic cancer and side‐effects of chemotherapy treatment.4In this large real‐world population‐based study of the most populous province in Canada where FFX and GnP are universally publicly funded for both metastatic and locally advanced pancreatic cancer, OS was better among patients who received first‐line FFX compared with GnP for advanced pancreatic cancer. This remained true for not only all advanced pancreatic cancer, but the mPC and uLAPC subcohorts. The adjusted risk of mortality decreased by 27% for patients who received FFX compared with GnP for all advanced pancreatic cancer patients. FFX appeared to lead to less frequent all‐cause ED visits and all‐cause hospitalization, but more hospitalizations for febrile neutropenia.Compared to the PRODIGE/ACCORD 11 and MPACT trials which both included only mPC patients, median OS for mPC was lower for both FFX and GnP in our real‐world study .P = .003).P = .1824).In a recently published adjuvant trial, FFX significantly improved OS compared to gemcitabine .In a single‐center study in South Korea, mPC patients receiving GnP actually demonstrated significantly longer OS than those receiving FFX at 11.4 months vs 9.6 months .At the time of this study, laboratory data were not available in Ontario, thus we are unable to comment on the effect of missing covariates such as baseline carbohydrate antigen 19‐9 (CA19‐9) and neutrophil‐lymphocyte ratio (NLR), high levels of which have both been significantly correlated with worse OS.In the real world, implementation of universal public funding of FFX for mPC was associated with improved OS compared to patients treated with GnP. In addition, patients treated with FFX had less frequent all‐cause ED visits and all‐cause hospitalization but increased febrile neutropenia‐related hospitalization. Expanding funding of FFX to include uLAPC was associated with a similar trend in benefits, but with improved absolute survival.Brandon Meyers: Speakers bureau—Celgene.Kelvin K. W. Chan, Sierra Cheng, Ruby Redmond‐Misner, Jaclyn Marie Beca, Wanrudee Isaranuwatchai, Lucy Qiao, Craig Earle, Scott R. Berry, James Joseph Biagi, Stephen Welch, Brandon M. Meyers, Nicole Mittmann, Natalie Coburn, Jessica Arias, Deborah Schwartz, Wei Fang Dai, Scott Gavura, Robin McLeod, and Erin Diane Kennedy involved in data interpretation, reviewing, and editing of the manuscript. Kelvin K. W. Chan, Helen Guo, and Lucy Qiao also involved in methodology. Sierra Cheng and Helen Guo also performed writing of the original draft. Helen Guo and Lucy Qiao also involved in formal analysis. Click here for additional data file.


Drug consumption increases with age, but there are few comparisons of drug use between old people living at home or in a nursing home. To identify areas of concern as well as in need for quality improvement in the two settings, we compared drug use among people aged ≥70 years living at home or in a nursing home.Cross-sectional observational study from Oslo, Norway. Information about drug use by people living at home in 2012 was retrieved from the Norwegian Prescription Database. Drug use in nursing homes was recorded within a comprehensive medication review during November 2011–February 2014. Prevalence rates and relative risk (RR) with 95% confidence intervals were compared between uses of therapeutic groups with prevalence rates of ≥5%. Drug use was compared for the total population and by gender and age group.n = 2313) were more likely than people living at home  to use antidementia drugs (RR = 5.7), antipsychotics (RR = 4.0), paracetamol (RR = 4.0), anxiolytics (RR = 3.0), antidepressants (RR = 2.8), dopaminergic drugs (RR = 2.7), antiepileptic drugs (RR = 2.4), loop diuretics (RR = 2.3), cardiac nitrates (RR = 2.1) or opioids (RR = 2.0). By contrast, people living in a nursing home were less commonly prescribed statins (RR = 0.2), nonsteroidal antiinflammatory drugs (NSAIDs) (RR = 0.3), osteoporosis drugs (RR = 0.3), thiazide diuretics (RR = 0.4), calcium channel blockers (RR = 0.5) or renin–angiotensin inhibitors (RR = 0.5). Each of the populations had only minor differences in drug use by gender and a trend towards less drug use with increasing age (p <  0.01).Older people (both genders) in nursing homes (Drug use by older people differs according to care level, and so do areas probably in need for quality improvement and further research. In nursing home residents, this relates to a probable overuse of psychotropic drugs and opioids. Among older people living at home, the probable overuse of NSAIDs and a possible underuse of cholinesterase inhibitors and osteoporosis drugs should be addressed. With the aging of populations, substantially more people are living with multi-morbidity , 2, demeDirect comparisons of morbidity between older persons living at home and in nursing homes are lacking, but cognitive impairment, neuropsychiatric symptoms, Parkinson’s disease and stroke are all more prevalent in nursing home residents than among those living in the community . In NorwOlder people use more drugs than any other group, although the scientific evidence for drug efficacy and safety is limited, particularly for those older than 80 years. In Norway, people older than 67 years represent about 15% of the population but use 45% of all prescription drugs , antipsychotics (RR = 4.0), paracetamol (RR = 4.0), anxiolytics (RR = 3.0), antidepressants RR = 2.8), dopaminergic drugs (RR = 2.7), antiepileptic drugs (RR = 2.4), loop diuretics (RR = 2.3), cardiac nitrates (RR = 2.1) or opioids (RR = 2.0) , nonsteroidal antiinflammatory drugs (NSAIDs) (RR = 0.3), osteoporosis drugs (RR = 0.3), thiazide diuretics (RR = 0.4), calcium channel blockers (RR = 0.5) or renin–angiotensin drugs (RR = 0.5) . For people living in a nursing home, a negative trend in the percentage of people using the drug with increasing age (p <  0.01) was observed for paracetamol, antiepileptic drugs, dopaminergic agents, antipsychotics, anxiolytics, antidepressants, antidementia drugs, cardiac glycoside and nitrates, loop diuretics, statins and antidiabetics . We assumed that institutionalization is a proxy for frailty and a high prevalence of dementia, and we have not differentiated between robust and frail older people living at home. Drug use was investigated in terms of the prevalence of use, but we did not have access to the prescribed daily dosages or how often drugs intended for prn actually were used. Despite these limitations, we consider that our data are representative for each of the populations and have acceptable validity for identifying the most significant differences in drug use patterns between older people residing in the two settings. The prevalence rates of drug use for those living at home differed only marginally between data captured over 3 or 12 months, thus being comparable with the point prevalence data for those living in nursing homes. We included drug use data from more than half of the nursing home population in Oslo and the entire population living at home in the municipality. The patient demographics and findings in our study are also consistent with our clinical experience and with data reported in other studies , 18, 19.This study substantiates that older people living in a nursing home and at home represent two different pharmacologically realities. Further research should investigate when the changes in drug prescription occur in the process of institutionalization or if the two settings may have different therapeutic cultures that partly may explain their different prescription practices. In Norway, the inclusion of prescription data from nursing homes in the NorPD would enable monitoring their drug use over time and follow up on changes in drug use patterns.