The presence of pancreatic lesions in patients with autoimmune pancreatitis requires histological diagnosis (percutaneous or endoscopic biopsy) to exclude malignancy. A nonspecific histology after endoscopic or percutaneous biopsy of a pancreatic lesion may require surgical excision and definite histology. The presence of pancreatic lesions in patients with autoimmune pancreatitis requires histological diagnosis (percutaneous or endoscopic biopsy) to exclude malignancy. A nonspecific histology after endoscopic or percutaneous biopsy of a pancreatic lesion may require surgical excision and definite histology. Here, we report the case of an 81‐year‐old man with symptomatic BD‐IPMN associated with PanIN and IgG4 AIP.We report a case of symptomatic branch‐duct intraductal papillary mucinous neoplasm (BD‐IPMN) of the pancreas having radiological worrisome features, associated with areas of type 1 and type 2 pancreatic intraepithelial neoplasia (PanIN) in the context of a type 1 autoimmune pancreatitis (AIP).29/L with 78.9% neutrophils, and C‐reactive protein (CRP) was 13 mg/L. Liver function tests indicated extrahepatic biliary obstruction with alanine aminotransferase 78 U/L, total bilirubin 8.9 mg/dL, and direct bilirubin 6.4 mg/dL. Blood levels of pancreatic amylase were high (135 U/L) and serum autoimmune antibody tests were positive (IgG4 154 mg/dL). CA 19‐9 was normal (<37 U/mL), whereas CEA was >100 ng/mL (153 U/L).In January 2019, an 81‐year‐old Caucasian man was admitted to our surgical department for acute onset of jaundice and abdominal pain. His past medical history revealed hypertension treated with beta blockers; no smoking, alcohol, or drug abuse; weight loss >15 kg in the last three months. No family history of pancreatic neoplasms was reported. At‐home treatments included esomeprazole 40 mg/d and fondaparinux 2.5 mg/d. Physical examination showed normal cardiac conditions  and no abnormal findings in the chest or abdomen. White blood cell count was 11.4 × 10Abdominal ultrasonography (US) revealed a 30‐mm hypoechoic lesion in the pancreatic head and uncinate process, causing abrupt interruption and upstream dilatation of the main pancreatic duct (MPD). The lesion was further investigated by contrast‐enhanced computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP). Both CT and MRI findings supported the diagnosis of pancreatic BD‐IPMN in the context of a chronical pancreatitis Figure : focal cAn endoscopic retrograde cholangiopancreatography (ERCP) was performed for jaundice palliation, with stenting of the common bile duct (CBD). Endoscopic ultrasound‐guided fine‐needle aspiration (EUS‐FNA) was carried out to obtain a histological characterization of the pancreatic lesion: the histological examination showed nonspecific cellular atypia (of undetermined significance). Due to the symptoms and the radiological worrisome features of the pancreatic cystic lesion,After the resection of the pancreas, the bile duct and the duodenum at 40 mm from the pylorus, restoration of gastrointestinal continuity was performed using the first jejunal loop (Child reconstruction). Firstly, we performed a termino‐lateral pancreaticojejunostomy (PJ) using also a 7 Fr endo‐Wirsung catheter, that was externalized through the Witzel tunneling technique. Secondly, we carried out an end‐to‐side hepaticojejunostomy (HJ) at least 40 mm from the PJ, using a single layer of interrupted, closely spaced, synthetic, nonabsorbable sutures. Finally, we performed a termino‐lateral antecolic isoperistaltic duodenojejunostomy using interrupted, synthetic, absorbable sutures. An intraoperative histopathological examination (frozen section) of the pancreatic and CBD margins was carried out, both to assess the radicality of resection and to exclude the presence of malignancy in the resection margins: no neoplastic abnormalities were found in the examined tissue. The gallbladder was removed. Lymph nodes of the lymphatic stations 8a, 12a, 12p, 12b, 6, 4d, 8p, and 9 were taken with the specimen. Two Penrose‐type surgical drains were positioned: one on the left side to protect pancreatojejunostomy, and the other on the right side to protect hepaticojejunostomy.Nasogastric tube was removed on postoperative day (POD) 1, and clear liquids were allowed on POD 2. Blood glucose was monitored since POD 1, and amylase levels in the drainage liquids were measured on POD 1 and 5. Postoperative course was characterized by a grade A pancreatic fistula ,2.1Macroscopic and microscopic pathological examination of the pancreatic head revealed the presence of a BD‐IPMN having a main diameter of 30 mm, without intramural nodules or increased wall thickness Figure A. The BD2.2Immunohistochemical (IHC) analysis was performed as described elsewhere.3In this report, we describe a rare case of pancreatic BD‐IPMN causing jaundice and abdominal pain, which was associated with PanIN and developed on a chronic IgG4 AIP. To our knowledge, this is the first description of such an association in the literature.AIP is a distinct form of chronic pancreatitis with an autoimmune pathogenesis,Pancreatic intraepithelial neoplasia (PanIN) can be associated with AIP and can be defined as a preneoplastic lesion in chronic pancreatitis. Some authors consider PanIN as a common precursor of PDAC, even if it can be described as a noninvasive epithelial microscopic neoplasia. PanIN arises from smaller pancreatic ducts and is classified as PanIN‐1, PanIN‐2, and PanIN‐3. PanIN‐1 has characteristic columnar epithelial cells and basally oriented uniform nuclei.Pancreatic IPMN is defined as a tumor of the pancreatic duct that produces mucin. Four histologic subtypes of this neoplasm have been described: gastric type, intestinal type, pancreatobiliary type, and oncocytic type.The risk of malignancy in pancreatic neoplasms that produce mucin is an important factor that should be properly stratified. Recent guidelinesIn conclusion, in the context of an AIP, the presence of a pancreatic lesion requires histological definition. Delaying surgery may compromise successful tumor resection, due to metastasis development or vascular involvement. In order to rule out the malignant nature of a pancreatic lesion, a percutaneous, or endoscopic biopsy is absolutely mandatory.The authors have no conflicts of interest to declare.GL: contributed to the conception and design of the study, in the provision of study materials of patients, in the surgical management of patients, in the data analysis and interpretation, in the manuscript writing. LR, AG, BP and ML: contributed in medical oncology patients’ management. GC and FMW: contributed in Histopathological and Immunohistochemical analysis. ADS and VV: contributed in radiological evaluations. MS and FC: contributed in data analysis and interpretation. All authors participated in the collection and/or assembly of data. All authors read, revised and approved the final manuscript.


To identify predictors of length of stay (LOS) after total hip arthroplasty (THA) in an enhanced recovery after surgery (ERAS) program and evaluate the safety and cost‐efficiency of the ERAS program with reduced LOS for unselected patients in a Chinese population.A total of 311 consecutive, unselected patients undergoing primary THA at a single institution were retrospectively reviewed and divided into two groups: LOS ≤ 3 and LOS > 3 group. All patients were managed with the same ERAS protocol and went back home after discharge. Multivariate logistic regression analysis was used to determine independent risk factors for LOS > 3. Harris Hip Score at 90‐day follow‐up, 90‐day readmission rate, and hospitalization costs were compared between two groups.Multivariate regression analysis identified female gender (odds ratio [OR] = 2.623), living alone (OR = 4.127), and primary osteoarthritis of hip (OR = 3.565) to be correlated with LOS > 3. Preoperative hemoglobin (HB), postoperative HB, drain use, blood transfusion, diabetes, respiratory disease, osteoporosis, number of comorbidities, and CCI score showed no significant influence on LOS after adjusting for other risk factors in the multivariate model. Harris Hip Score and readmission rate at 90‐day follow‐up showed no significant differences between two groups. Patients in LOS > 3 group had approximately 3948.6 Chinese yuan higher hospital costs.Female gender, living alone, and primary osteoarthritis of hip were identified as independent risk factors for prolonged LOS. The experience from our institution suggested aggressive management of comorbidities in the ERAS program can minimize the influence of comorbidities on LOS. The safety, efficiency, and costs‐saving benefits of the ERAS program with reduced LOS for unselected patients was confirmed in this study. Total hip arthroplasty (THA) is the most effective and commonly used procedure for end‐stage hip disease. As the number of primary THA is expected to increase steadily, the financial burden of primary THA is projected to rise over the next 10 yearsIn the ERAS program, identifying the preoperative patient demographics related to prolonged LOS is of vital importance. It helps to optimize patient selection and predict risk stratification preoperatively. If patients undergoing THA present a predisposition for delayed discharge preoperatively, enhanced care and extended functional rehabilitation should be implemented, and the rehabilitation protocol and discharge planning for them may be changed. Determination of the perioperative risk factors for delayed discharge helps to optimize the perioperative managements for the THA patients and further improve surgical techniques. In addition, recognizing risk factors for prolonged LOS helps establish patients' expectations and provide increased patient satisfaction.Many predictors of LOS in the ERAS program for THA procedure have been identified. Older ageIt was previously demonstrated that, in the United States, shorter LOS was closely related to lower hospital costs for THA in the ERAS programThe purpose of this study was to: (i) identify perioperative predictors of LOS after THA in a Chinese population; (ii) evaluate the cost‐efficiency of the ERAS program for THA; and (iii) evaluate the safety and efficiency of the ERAS program with reduced LOS for unselected patients undergoing THA.The institutional review board of our hospital approved this retrospective study and all patients provided informed consent for participation. We retrospectively reviewed 313 consecutive, unselected patients undergoing primary unilateral THA between January 2017 and June 2018 at our institution. All surgeries were performed by one experienced surgeon (ZK‐Z), performing over 600 total joint arthroplasties per year for over 10 years. The entire series of 313 patients were managed with the same ERAS protocol, which were performed by the same surgical, nursing, anesthesia, and physiotherapy team. General anesthesia and posterolateral approaches were used in the entire series of 313 patients. There were no exclusion criteria; however, two patients who were lost to follow‐up after surgery were excluded from this study. The remaining 311 patients completed the 3‐month follow‐up and were enrolled in this study.The flow chart of the ERAS program is presented in Fig. 1/FVC was used to evaluate the pulmonary function and patients with FEV1/FVC over 50% were judged to be safe for THA surgery. Respiratory muscle training was used to improve pulmonary function and efficiency of cough. Erythropoietin and chalybeate were used in patients with anemia both pre‐ and post‐operatively, and the preoperative HB should be over 100 g/L. Patients diagnosed with coronary heart disease or with angina should undergo myocardial perfusion imaging test, and the myocardial blood flow over 90% was judged to be safe for THA surgery.Patients with comorbidities were strictly assessed to determine if they were eligible for the surgery. Once a patient was confirmed to undergo THA, aggressive management of comorbidities was undertaken to optimize patient status, which ensures the safety of surgery and rapid rehabilitation after surgery. For example, blood pressure and glucose were controlled to be steady perioperatively. Blood pressure below 140/90 mmHg and postprandial glucose below 12.0 mmol/L were judged to be acceptable for surgery. FEVPostoperative LOS was defined as the number of nights stayed in hospital after surgery. The target postoperative LOS in our institution was 3 dayspre−Hctpo)/Hctmean. Hctpre and Hctpo was the preoperative and postoperative hematocrit level, respectively. Hctmean was the average of Hctpre and Hctpo. Estimated blood volume (EBV) was calculated according to Nadler et al.woman (L) = height (m)3 × 0.356 + body weight (kg) × 0.033 + 0.183; EBVman (L) = height (m)3 × 0.367 + body weight (kg) × 0.032 + 0.604.Patient demographics of age, gender, BMI, preoperative Harris Hip Score (HHS), operation history of involved hip and diagnosis were collected from clinical records. Living alone was defined as living without any partner in the last 6 months. Surgical factors, including use of catheters, use of drains, and blood transfusions, were collected from operation records and clinical records. Intraoperative estimated blood loss (EBL) was calculated according to GrossExisting comorbidities which were diagnosed prior to admission were documented in the clinical records in detail. Comorbidities diagnosed perioperatively were also recorded. American Society of Anesthesiologists (ASA) score, Charlson Comorbidity Index (CCI), and number of comorbidities were recorded to assess the general health status of patients and the presence and severity of comorbiditiesThe hip function at 90‐day (3‐month) follow‐up was evaluated by one observer, who had not participated in the operation and clinical care of these patients, using HHS . At 90‐day follow‐up, patients were asked specifically if they had readmitted into hospital after discharge. Information about readmission into our institution was routinely documented and collected. Complications causing readmission, treatments and outcomes were collected in detail. Patients readmitted into other institutions were asked to provide clinical records. Hospitalization costs for each patient, except that for prostheses, were recorded from our hospital information system.t test was used to compare continuous variables and Pearson chi‐square test was used to analyze categorical variables between the two groups. Multivariate logistic regression analysis was used to determine independent risk factors for prolonged LOS in variables which showed P < 0.1 in t test and Pearson chi‐square test. The level of significance was defined as P < 0.05 and all statistical analysis was performed with SPSS v22.0 .Descriptive and univariate analyses were initially conducted to examine the relationship between LOS and variables. Continuous variables, including age, BMI, HB, albumin, estimated blood loss, HHS, and hospital costs, were presented as the mean ± standard deviation. Categorical variables, including gender, living situation, operation history, diagnosis, catheter use, drain use, blood transfusion, comorbidities, CCI score, ASA score, and complications, were presented as numbers with percentages. Independent Of the 311 enrolled patients, 196 patients (63.02%) discharged on post‐operation day 1–3 (LOS ≤ 3 group) and 115 patients (36.98%) discharged on post‐operation day 4 or later (LOS > 3 group). The mean postoperative LOS was 3.69 ± 1.96 days.2  of all 311 patients. No significant differences were observed in age and BMI between the two groups . LOS > 3 group had significantly higher proportion of patients who lived alone than LOS ≤ 3 group . Diagnosis showed significant difference between two groups  and the average BMI was 23.32 ± 3.68 kg/mvs 10.4%, P = 0.007). No significant differences were observed in catheter use, estimated blood loss, and blood transfusion between two groups. Variables with P < 0.1, including gender, living situation, diagnosis, preoperative HB, postoperative HB, drain use, and blood transfusion, were then examined by multivariate logistic regression analysis to determine independent risk factors for LOS > 3.In regard to surgical factors, drains were more often used in LOS > 3 group than in LOS ≤ 3 group . Diabetes, respiratory disease, osteoporosis, number of comorbidities, and CCI score, showing P < 0.1 in univariate analysis, were then examined by multivariate logistic analysis to determine independent risk factors for LOS > 3.Patients with comorbidities accounted for 44.7% of the cohort, with 24.4% presenting one comorbidity, 15.4% presenting two comorbidities, and 4.8% presenting three or more comorbidities , living alone , and primary osteoarthritis of hip  were identified as independent risk factors for LOS > 3. Primary osteoarthritis of hip showed significantly higher risk for prolonged LOS when compared with ONFH, while other primary diagnoses didn't show significant influence on LOS when compared with ONFH. Preoperative HB, postoperative HB, drain use, blood transfusion, diabetes, respiratory disease, osteoporosis, number of comorbidities, and CCI score were not identified as independent risk factors for prolonged LOS in this multivariate model after adjusting for other factors, and were determined to be confounding variables.In multivariate logistic analysis model, female gender , respectively (Table The mean HHS at 90‐day follow‐up was 94.6 ± 4.5 and 93.8 ± 5.5 in LOS ≤ 3 and LOS > 3 group (P = 0.079). In LOS ≤ 3 group, four cases of postoperative dislocation occurred and were all successfully treated with closed or open reduction, and one of them was followed with abduction bracing for 3 months. One periprosthetic femoral fracture occurred with major trauma and was revised to a cementless long stem. In LOS > 3 group, the most common complication was dislocation (four cases), followed by pneumonia (one case), fasciitis of thigh (one case), scrotal hematoma (one case), and poor nutrition (one case). Dislocations were all successfully managed by non‐operative treatment in LOS > 3 group. Scrotal hematoma occurred secondary to adductor tenotomy in a patient with severe restricted abduction of the hip and was successfully treated by open debridement.The 90‐day readmission rates were 2.6% (5/196) in LOS ≤ 3 group and 7.0% (8/115) in LOS > 3 group, with no significant difference between two groups (P < 0.001), suggesting that longer hospital LOS was associated with higher costs . We speculated that muscle weakness and decreased soft‐tissue tension which were common in female patients may lead to slower postoperative rehabilitation and further result in prolonged LOS.We found that female gender was 2.62 times more likely to have LOS > 3, which is in accordance with previous findings showing that females had a higher chance of increased hospital stayRecent studies have identified living alone as a predictor for delayed dischargeet al. reported the mean age of 419 Chinese patients underwent primary THA was 57.6 ± 16.6 yearsAge was not found to be an independent factor to predict LOS in this study, possibly because the mean age in this study was much lower than previously reported. The mean age of this cohort was 54.8 years, in contrast to previously reported 64.7–71.0 years in western countrieset al. from Mayo Clinic demonstrated a J‐shaped relationship between BMI and LOS. Patients with BMI of 25–35 had lowest LOS and BMI over 30 was associated with longer LOSWith regard to the influence of BMI on LOS, there was conflicting evidence in the literature. Some studies reported a positive correlation between BMI and LOSet al. found different diagnoses, including ONFH, primary osteoarthritis, and rheumatoid arthritis, had no significant effects on LOS in an Asian populationHigh prevalence of ONFH and DDH in contrast to very low prevalence of primary hip osteoarthritis have been observed in Chinese populationWe combined number of comorbidities, ASA score, and CCI score to evaluate the presence and severity of comorbidities. All of these tools have been proven to be valid and reliable for measuring comorbidities in patients undergoing THAThe safety and efficiency of the ERAS program with reduced LOS for unselected patients undergoing THA were confirmed in this studyThere are some limitations in this study. First, the number of patients included in this study was relatively small. However, 311 consecutive, unselected patients in a single medical team treated by the same experienced surgeon gave our conclusion considerable power. Unlike data from several institutions or national registers, the ERAS protocols and surgical techniques in our study were consistent. Second, LOS > 3 was regarded as delayed discharge in this study. Several recent studies in the United States demonstrated the efficiency of discharge on post‐operation day one or on the day of surgeryFemale gender, living alone, and primary osteoarthritis of hip were identified as independent risk factors for LOS > 3. Comorbidities, number of comorbidities, and CCI score showed no significant influence on LOS after adjusting for other risk factors in multivariate regression model. Despite younger age and smaller proportion of patients with comorbidities in our cohort, the experience from our institution suggested aggressive management of comorbidities in the ERAS program can minimize the influence of comorbidities on LOS. It is safe for THA patients with LOS less than 3 days to go home in a Chinese population. The cost‐saving benefits of the ERAS program with reduced LOS for THA were confirmed in this study.


Critically ill patients frequently require red blood cell (RBC) transfusions. The aim of giving a RBC transfusion is to increase oxygen delivery to tissues in anemic patients. The oxygen delivering capacity depends not only on the hemoglobin (Hb) level and oxygen saturation, but also on tissue perfusion. In current clinical practice, transfusion decisions are based on the Hb level only. However, baseline Hb level does not correlate with a positive effect of a RBC transfusion on tissue perfusion . The effp values of the correlations are corrected for multiple testing with Holm-Bonferroni correction. A p value of less than 0.05 was considered statistically significant. Statistical analyses were performed using SPSS .We performed sublingual Sidestream DarkField (SDF) imaging  within 1 h before and after transfusion of 1 leucodepleted RBC unit in 18 anemic non-bleeding critically ill patients on a tertiary intensive care. The study was ethically approved by the medical ethical committee of the Amsterdam University Medical Centre . Written informed consent was obtained from all participants or their legal representatives. Software AVA 3.2, MicroVision Medical, Amsterdam, The Netherlands, was used to analyze the videos and to calculate the “De Backer” score  and perfused vessel density (PVD)) and the Microvascular Flow Index (MFI) [p = 0.567, PVD: rho = − 0.445, p = 0.192, MFI: rho = − 0.276, p = 0.534). In line with previous findings, the effect of a transfusion depended on the baseline microcirculatory flow, with patients with impaired baseline values showing an improvement and patients with normal baseline values showing a deterioration .Patient characteristics are shown in Table p = 0.288; PVD: rho = − 0.089, p = 0.726; MFI: rho = − 0.404, p = 0.288) indicating that the severity of illness does not correspond with the flow in the microcirculation before transfusion. However, there was a positive correlation between SOFA score and the change in PPV and MFI values after transfusion, in which the microcirculation improved in the patients with a SOFA score > 8 but deteriorated in those with lower SOFA scores. PVD did not correlate with the SOFA score (Fig. No correlation was found between baseline SDF values and the SOFA score (PPV: rho = − 0.382, ore Fig. .Fig. 1SIn conclusion, these results suggest that patients with high SOFA scores have improvement of their microcirculation after a RBC transfusion, while patients with a low SOFA score show a decrease in flow and perfusion following a transfusion. This suggests that we should take the severity of the illness of the patient into account when deciding whom to transfuse, when microcirculatory flow analysis is not available.


For each interaction they reported the social context  and their affective state, including homesickness. Homesickness in the past weeks and momentary homesickness were both higher in international students than in Dutch students. Feeling homesick was highest at participants' current residency, when interacting with parents, or when using video‐chat. When participants felt more homesick, they reported less pleasant and more unpleasant affect. In conclusion, EMA provided insight in cross‐situational variations in homesickness.Homesickness is common among university students and associated with mental health problems. Most previous studies assessed homesickness as a summary of the past weeks. However, there may be significant fluctuations across situations. At the current residence, homesickness may especially be triggered during (phone) interactions with attachment figures. Dutch and international 1st‐year students ( Homesickness has been defined as “a negative emotional state primarily due to separation from home and attachment persons, characterized by longing for and preoccupation with home, and often with difficulties adjusting to a new place”  of social interactions enables this, as it involves intensive repeated measures in daily life  and 45 questionnaires (SD = 19).Participants received detailed EMA instructions and were asked to complete as many questionnaires as possible for 14 days. Some participants voluntarily continued data recording until the second meeting, which took place within a week after the EMA period and involved completing several more questionnaires (not considered here). Participants completed a mean number of 15 EMA days . The degrees of freedom for F tests were determined according to the method by Kenward and Roger . The remaining EMA data included 3365 events. For H1, momentary homesickness levels were averaged across interactions for each person separately and compared across groups using a nd Roger . All modβ = .27, F = 26.59, p < .0001. This effect remained after adding nationality  as a moderator, with no significant UHS‐8 by nationality interaction, F = 2.79, p = .09. Thus, students with higher proneness homesickness reported more momentary homesickness.Standardised UHS‐8 scores positively predicted momentary homesickness, UHS‐8 scores and averaged momentary homesickness levels were both higher among international students , overall mean momentary homesickness (grand‐mean centred) and their interaction as predictors. The contextual factors examined when testing H2 were included as covariates.As these findings may have been confounded by some combinations being more common than others (e.g. interactions with parents were least likely to take place in person), a model including all four contextual variables was also run. Group interactions were by necessity excluded, leaving 2338 events in the model. Nonetheless, the main effects for Location, Role and Contact Mode remained significant: participants felt most homesick in their current residence, regardless of whom they were interacting with and how; during interactions with parents, regardless of where they were and what the mode of interaction was; and when chatting by video, regardless of where and with whom they chatted. Homesickness was higher away from home and during interactions with parents, which supports our hypothesis.Pleasant affect. There was a negative effect for momentary homesickness, β = −.09, F = 8.51, p = .004. The momentary homesickness by overall mean momentary homesickness interaction was not significant, F = 1.19, p > .27.Unpleasant affect. There was a positive effect for momentary homesickness, b = .22, F = 117.06, p < .0001. In addition, the momentary homesickness by overall mean momentary homesickness was significant, F = 5.68, p = .02. The slope of the effect of momentary homesickness on unpleasant affect was significant for participants with lower overall mean momentary homesickness, b = 0.28, t(3285) = 7.00, p < .0001 and for participants with higher overall mean momentary homesickness, b = 0.17, t(3286) = 9.16, p < .0001. The difference between the slopes was significant, indicating that when participants with lower overall mean momentary homesickness were homesick, they experienced more unpleasant affect than when participants with higher overall mean momentary homesickness were homesick.We examined homesickness in 1st‐year university students. In line with H1, international students reported more proneness to homesickness and more momentary homesickness than Dutch students. Both homesickness measures were moderately correlated, indicating that students who rated themselves as being more homesick over the past 4 weeks continued to experience more homesickness momentarily. This corresponds with earlier findings among children at camp , while homesick securely attached individuals may experience pleasant affect during such interactions (thus enabling them to cope better with distress). Attachment measures could be included in future studies.Future studies could also examine the antecedents and consequences of momentary homesickness, to find out when homesickness might elicit social interaction or result from it. Also, signal‐contingent recording of affective states could be employed. Compared to event‐contingent recording data, signal‐contingent recording data are better suited to time‐series analysis, which allows for examining both concurrent and lagged associations between homesickness and affect. Signal‐contingent recording would also allow for assessing homesickness in non‐social contexts .In conclusion, our study provides preliminary data supporting the merits of studying momentary homesickness. Identifying high‐risk homesickness situations may aid the development of (preventive) interventions for people at risk of homesickness‐related health problems.


To observe the effect of pretreatment with ketorolac tromethamine on sufentanil-induced cough in general anesthesia patients.2) were recorded at T0 (immediately before pretreatment), T1 (5 min after pretreatment), T2 (before intubation), T3 (1 min after intubation) and T4 (5 min after intubation). The incidence of adverse reactions, including nausea and vomiting, dizziness, drowsiness, delay of recovery, restlessness in the recovery period, respiratory depression and postoperative incision pain, was analyzed.A total of 102 patients were screened, and 90 patients were scheduled for elective surgery under general anesthesia. The 90 patients were randomly divided into two groups: the control group (C group) and the observation group (KT group). Five minutes before anesthesia induction, the observation group was given ketorolac tromethamine 0.5 mg/kg intravenously within 3 s, while the control group was given the same amount of normal saline intravenously. All patients were given a sufentanil bolus of 0.5 μg/kg (within 3 s) intravenously. One minute later, propofol 2.5 mg/kg and vecuronium 0.15 mg/kg were injected intravenously, and endotracheal intubation was guided by laryngoscopy. The number of coughs that occurred within 1 min after sufentanil injection was recorded. The mean arterial pressure (MAP), heart rate (HR) and pulse oxygen saturation (SpOP <  0.05). At T0, T1, T2, T3 and T4, there were no significant differences in MAP, HR and SpO2 between the two groups (P >  0.05). There was no significant difference in the dosage of sufentanil, propofol, remifentanil and vecuronium, the incidence of nausea and vomiting, the delay of recovery, dizziness, drowsiness or respiratory depression between the two groups (P >  0.05). However, the incidence of restlessness and the number of patients with VAS scores > 3 in the KT group were significantly lower than those in the C group (P <  0.05).Within 1 min after sufentanil injection, the incidence and severity of cough in the KT group was significantly lower than that in the C group .Chinese Clinical Trial Registry (registration number#  Sufentanil, commonly used in general anesthesia for its strong analgesic properties, can produce an irritating cough during intravenous induction , 2. StudVarious agents, such as remifentanil, dexmedetomidine, magnesium sulfate, lidocaine, and dezocine, have been used to suppress cough during the induction of general anesthesia , 6. HoweAspirin is a common nonsteroidal anti-inflammatory and analgesic drug. Alexander T et al. reported that a moderate dose of aspirin (500 mg/day) could reduce angiotensin converting enzyme inhibitor-induced cough . KetorolThe purpose of this study was to investigate the effectiveness of ketorolac tromethamine for treating the sufentanil-induced cough response by intravenous injection prior to general anesthesia induction.This study was approved by the Institutional Research Ethics Committee of the Suqian People’s Hospital of Nanjing Drum-Tower Hospital Group, Suqian, Jiangsu, China. The trial was registered in the Chinese Clinical Trial Registry (No. Chi CTR2000030287). Written informed consent was obtained from each patient following the principles of the Helsinki Declaration. And This study is adhered to CONSORT guidelines.2, were enrolled in this study. The patients were scheduled for elective surgery under general anesthesia in Suqian People’s Hospital of Nanjing Drum-Tower Hospital Group from February 2020 to March 2020. The exclusion criteria were a history of asthma, chronic cough, and upper respiratory tract infection within 2 weeks. Patients with a history of peptic ulcer or bleeding, heart disease, aneurysm, liver disease, kidney disease, or participation in other clinical trials or who the researchers considered inappropriate to participate in this experiment were also excluded. Ninety patients were randomly divided into two groups via a computer-generated random number list: the control group  and the observation group .A total of 102 adult patients with ASA physical status I or II, aged 18–65 years, weighing 45 to 89 kg, with BMIs between 18.0 and 30.0 kg/m2), and electrocardiograms (ECGs) were routinely monitored. Patients were cannulated through the median cubital vein of the forearm with a 20G venous trocar needle. 5 min before general anesthesia induction, KT group patients were given ketorolac tromethamine 0.5 mg/kg  intravenously within 3 s, while those in the C group were given 5 ml of normal saline only. The ketorolac tromethamine or normal saline was prepared by a nurse anesthetist and administered by an experienced anesthesiologist who was blind to the procedure. All patients were given 100% oxygen via a face mask with an oxygen flow rate of 5 L/min for 3 min. General anesthesia was induced with a bolus of sufentanil 0.5 μg/kg administered within 3 s intravenously, and 1 min later, propofol 2.5 mg/kg and vecuronium 0.15 mg/kg were infused sequentially. Endotracheal intubation was performed using a Macintosh laryngoscope. The depth of general anesthesia was maintained under propofol 5 mg/kg/h, remifentanil 10 μg/kg/h and vecuronium 0.05 mg/kg/h and was adjusted based on the vital signs of the patients.No patient received premedication in this study. In the operating room, noninvasive blood pressure (NBP), pulse oxygen saturation .PO2 were recorded at the following time-points: T0, before pretreatment of ketorolac tromethamine or normal saline, i.e., the baseline value; T1, 5 min after pretreatment; T2, before intubation; T3, 1 min after intubation; and T4, 5 min after intubation.The mean arterial pressure (MAP), heart rate (HR) and SPO2 less than 90% for more than 15 s when patients without oxygen inhaled during the recovery period. The postoperative incision pain of the patients was evaluated by the VAS scoring method, with a score of 0–10. The number of patients with VAS scores > 3 was recorded.The incidence of adverse reactions, including nausea and vomiting, dizziness, drowsiness, delay of recovery, restlessness in the recovery period and respiratory depression, was analyzed. In brief, the adverse reactions of the two groups were evaluated by professional anesthesiologists according to the following unified criteria: because nausea and dizziness are subjective assessments, for the evaluation of nausea and dizziness, the patients (who had recovered from the anesthesia) were questioned by the anesthesiologist and were recorded as having nausea and/or dizziness if the answer was “Yes”. The vomiting judgment was performed according to the patient’s self-report and the anesthesiologist’s observation. Drowsiness was defined as sleeping again within 120 s of waking up without external interference. Recovery delay referred to the patient’s consciousness not being recovered and the patient being unable to make correct responses to external stimulation and language instruction 120 min after general anesthesia. Restlessness in the recovery period was defined as the patients mood being more excited in the recovery period, even crying and being restless, and the patients making strong movements that could not be comforted. Respiratory inhibition referred to respiratory arrest time greater than 15 s or SIn our preliminary study, the incidence of cough elicited by 0.5 μg/kg sufentanil infused within 3 s was 31.8% (7/22), which was reduced to 4.5% (1/22) when ketorolac tromethamine pretreatment was performed. To achieve 80% statistical power with α = 0.05, each group would require no less than 33 cases. Considering that there may be a dropout rate of 20%, we recruited 51 patients for each group to allow for missing data.P-value < 0.05 was considered significant.SPSS 22.0 software  was used for statistical analysis. The presented data were evaluated for normal distributions by the Kolmogorov–Smirnov test. Measurement data are presented as the mean ± standard deviation, and Student’s t test was used to assess the differences between two groups. The differences in ranked data were analyzed by the Mann–Whitney U test. The chi-square test or Fisher’s exact test was adopted to assess the difference in categorical data presented as absolute or relative effect sizes. A P >  0.05)  (Table The incidence and severity of cough within 1 min after sufentanil injection in the KT group was significantly lower than that in the C group (5) Table .Table 2PO2 between the two groups at T0, T1, T2, T3 and T4 (P >  0.05)   Table .Table 4P <  0.05). There were no significant differences in the incidences of nausea and vomiting, delay of recovery, dizziness, drowsiness or respiratory depression between the two groups (P >  0.05) . Motov S et al. found that intravenous infusion of 30 mg ketorolac tromethamine can significantly improve moderate to severe pain in emergency patients . StudiesTo evaluate the possible adverse reactions and safety of ketorolac tromethamine injection pretreatment, we compared the mean arterial pressure, heart rate and blood oxygen saturation values of the two groups of patients at different time points. The results suggest that pretreatment with ketorolac tromethamine injection does not have adverse effects on the vital signs of patients. Additionally, the results showed that the incidence of nausea, delayed recovery, dizziness, drowsiness and respiratory depression was not significantly increased when ketorolac tromethamine was used in advance, making it safe for patients. However, it is undeniable that one of the main risks of NSAIDs, such as ketorolac tromethamine, is that they may affect bleeding during and after the operation by inhibiting platelet function. However, the dosage of drugs used in this study was not large and was within the scope of reasonable use in the instructions. In addition, this study has limited the research subjects; for example, patients who had a history of peptic ulcer or bleeding, liver or kidney disease, or blood system diseases before operation were excluded. Under these premises, ketorolac tromethamine will not have a significant impact on the operation or postoperative bleeding.There are also some deficiencies in our research. First, due to the limitation of objective conditions, we have not studied the mechanism of ketorolac tromethamine in inhibition of the cough response and cannot give more reasonable inferences about the relevant mechanisms. We describe the relevant effects objectively because there is no relevant report about ketorolac tromethamine injection or other nonsteroidal drugs inhibiting sufentanil-induced cough. Second, the pretreatment dose of ketorolac tromethamine that was used (0.5 mg/kg) may not be the most appropriate dose for ketorolac tromethamine to inhibit the sufentanil-induced cough response, but it was given according to the early postoperative analgesic dose recommended in the drug instructions . Third, Pretreatment with intravenous ketorolac tromethamine 0.5 mg/kg can significantly reduce the incidence and severity of sufentanil-induced cough during induction of general anesthesia, which can also significantly and safely reduce postoperative incision pain and restlessness in the recovery period. To a certain extent, it provided a comfortable medical experience and humane care, which is worth popularizing.


Glucocorticoids (GC) are the foundation of the chemotherapy regimen in acute lymphoblastic leukemia (ALL). However, resistance to GC is observed more frequently than resistance to other chemotherapy agents in patients with ALL relapse. Moreover, the mechanism underlying the development of GC resistance in ALL has not yet been fully uncovered. In this study, we used bioinformatic analysis methods to integrate the candidate genes and pathways participating in GC resistance in ALL and subsequently verified the bioinformatics findings with in vitro cell experiments. Ninety‐nine significant common differentially expressed genes (DEGs) associated with GC resistance were determined by integrating two gene profile datasets, including GC‐sensitive and ‐resistant samples. Using Kyoto Encyclopedia of Genes and Genomes (KEGG) and REACTOME pathways analysis, the signaling pathways in which DEGs were significantly enriched were clustered. The GC resistance‐related biologically functional interactions were visualized as DEG‐associated Protein–Protein Interaction (PPI) network complexes, with 98 nodes and 127 edges. MYC, a node which displayed the highest connectivity in all edges, was highlighted as the core gene in the PPI network. Increased C‐MYC expression was observed in adriamycin‐resistant BALL‐1/ADR cells, which we demonstrated was also resistant to dexamethasone. These results outlined a panorama in which the solitary and scattered experimental results were integrated and expanded. The potential promising target of the candidate pathways and genes involved in GC resistance of ALL was concomitantly revealed. These results outlined a panorama in which the solitary and scattered experimental results were integrated and extended. The potential promising target of the candidate pathways and genes in GC resistant acute lymphoblastic leukemia was concomitantly revealed. Combination chemotherapy regimen based on vincristine and prednisolone plus other classical chemotherapeutics and/or novel targeting agents is regarded as the essential care for patients with ALL.GC agonists inhibit leukemogenesis by binding the GC receptor and subsequently activating or suppressing transcription of target genes, which are related to various cellular processes such as cell cycle arrest and apoptosis.Recently, high‐throughput sequencing and microarrays of human disease samples have generated massive bioinformatics data, which facilitated understanding the molecular mechanisms involved in the related biological process. In this study, we identified and integrated the common differentially expressed genes (DEGs) from two gene expression profiles of GC‐sensitive and ‐resistant ALL samples. Subsequently, we verified those bioinformatics findings with in vitro cell experiments. Our findings integrate individual experimental results from previous studies to illustrate the landscape of biological processes that lead to acquisition of GC resistance. Based on these results, novel treatment opportunities and therapeutic targets can be envisaged.22.1http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE5820 and http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE19143, both unique, were downloaded from the NCBI‐gene expression omnibus (NCBI‐GEO) (://www.ncbi.nlm.nih.gov/geo/), a public functional genomics data repository.http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE5820 was performed on GPL96 Affymetrix Human Genome U133 platform and included 13 GC‐sensitive and 16 GC‐resistant samples . Regarding the http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE19143 data, total RNA of 14 non‐infant GC‐sensitive and 13 non‐infant GC‐resistant samples were isolated and mRNA array was performed on GPL96 Affymetrix Human Genome U133A Array . GC‐resistant samples were those with poor response to prednisolone, defined as failure to show effective cytoreduction after 7 days of GC therapy.Microarray datasets of gene expression profiles with the accession numbers 2.22 transformation was performed, and the Log2‐fold change (Log2FC) was calculated in the preprocessed microarray data derived from Series Matrix File on GEO database for integrated analysis. P < .05 and |Log2FC| > 1 was considered as the cut‐off criterion for significantly DEG screening.Differentially expressed genes between GC‐sensitive and ‐resistant samples were identified by analyzing raw data with GEO2R on GEO database. A Log2.3://david.ncifcrf.gov/conversion.jsp), a web‐based platform for gene functional annotations and biological meaning elucidation. Pathway analysis allows to understand molecular interactions in the pathway maps. Pathways enrichment analysis was generated by the Kyoto Encyclopedia of Genes and Genomes (KEGG) and REACTOME, which were included in the DAVID website, with P < .05 as the threshold value.GO enrichment analysis was performed using the DAVID (2.4http://string-db.org/), an online protein–association network platform, was utilized to expand the DEG‐encoded proteins and protein‐protein interaction (PPI) network. Further, the PPI network was imported into Cytoscape software for analyzing protein interaction links and modules, and accessing the interactions of the candidate DEG‐encoding proteins associated with GC resistance of ALL. Hub genes were identified by cytoHubba analysis in Cytoscape.String JAVA platform (2.5://www.oncomine.org/resource/login.html). The genetic alterations of hub genes were investigated on the cBio Cancer Genomics Portal .The mRNA expression level of the hub genes was validated on the Oncomine database  and TargetScan (http://www.targetscan.org/vert_71/). The target genes authenticated by miRwalk and TargetScan were analyzed by intersection. Target genes‐miRNA interaction network was constructed using Cytoscape software.GC resistance‐related miRNAs were identified by searching for the terms “GC resistant AND miRNA” in PubMed. Based on the papers obtained by the search, hsa‐miR‐142‐3p and hsa‐miR‐17‐5p were selected as the miRNAs associated with GC resistance.2.7://cistrome.org/db/). The target genes‐TF interaction network was constructed using Cytoscape software.The genes which overlapped between GC‐resistant genes and human TFs (transcript factors) were considered the GC‐resistance TFs. The targeted genes were predicted on the Cistrome Data Browser  was added to BALL‐1 cell culture medium to maintain drug resistance. The medium was changed every other day. Cells in logarithmic growth phase were used in experiments. BALL‐1 cells were incubated in ADR‐free medium for 2 weeks for further experiments.Due to lack of dexamethasone‐sensitive and ‐resistant ALL cell lines, BALL‐1 and adriamycin (ADR)‐resistant cells BALL‐1/ADR were employed to evaluate dexamethasone sensitivity first and for subsequent experiments. Cells were preserved in our laboratory  and cultured in RPMI 1640 medium  supplemented with 10% heat‐inactivated fetal bovine serum  in a humidified incubator  maintained at 37°C with 5% CO2.9BALL‐1 and BALL‐1/ADR cells were incubated with serially diluted dexamethasone solution ranging from 0 to 200 μg/mL for 72 hours. The 3‐‐2,5 diphenyltetra‐zolium bromide  assay was performed to detect cell proliferation as previously described.2.10TM Reverse Transcription System kit according to the manufacturer's protocol . cDNA was amplified using SYBR Green PCR master mix . PCR was performed on ABI7500 Real Time PCR system . Results were analyzed using the ∆CT and 2−∆∆CT quantification method. The nucleotide sequences of the primers were as follows: 18s: sense: 5′‐GACACGGACAGGATTGACAGATTG‐3′, antisense: 5′‐TGCCAGAGTCTCGTTC.Total RNA was extracted using TRIzol reagent  and was subjected to reverse transcription with GoScriptGTTATCG‐3′; c‐myc: sense: 5′‐TCCTGGCAAAAGGTCAGAGT‐3′, anti‐sense: 5′‐TCTGACACTGTCCAACTTGAC‐3′.2.11Western blot analysis was performed as described in our previous study.2.12t test and one‐way analysis of variance (ANOVA) test were used to assess significant differences between groups according to data characteristics. Significance was set at a P < .05. All data were analyzed using SPSS statistics software 23.0 or GraphPad Prism Software 6.0.Experiments were performed in triplicate. Results of measurement data were expressed as means ± SEM Student's 33.1http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE5820 and http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE19143 were downloaded from NCBI‐GEO. From the two above GSE datasets, 363 and 611 DEGs were extracted, respectively, with P < .05 and |Log2FC| > 1 as threshold values. DEGs are listed in Table GC‐sensitive and ‐resistant ALL gene expression profiles 3.2P value methods, Figure To understand the functional changes leading to GC resistance in ALL, the 99 candidate common DEGs were mapped on the DAVID database for GO analysis. As shown in Table 3.3Pathway enrichment analysis was performed to determine the candidate pathways connected to GC resistance‐associated DEGs and analyze their alterations. Downregulated DEGs were mainly enriched in “Ribosome pathway” in KEGG_PATHWAY analysis, and “Antigen activates B Cell Receptor (BCR) leading to generation of second messengers” and “RAF/MAP kinase cascade” in REACTOME_PATHWAY analysis. Upregulated DEGs were predominantly enriched in “Legionellosis,” “Transcriptional misregulation in cancer” and “Pathways in cancer” in KEGG_PATHWAY analysis, and “Viral RNP Complexes in the Host Cell Nucleus”, “Chemokine receptors bind chemokines,” and “Binding of TCF/LEF:CTNNB1 to target gene promoters” in REACTOME_PATHWAY analysis Table .3.4P value of 9.84E‐13, indicating a reliable GC‐resistant PPI network  with PPI enrichment 3.5The 64 and 194 target genes of hsa‐miR‐142‐3p and hsa‐miR‐17‐5p, respectively, were verified using the two databases miRwalk and TargetScan Table . The genCREM, ATF3, ELF4, and FOSL2, the four genes overlapping between TFs and GC‐resistant DEGs, were subjected to target gene prediction. Table 3.6MYC, CXCL8, and ATF3 were considered the hub genes and queried on Oncomine database and cBio portal platform to investigate their gene expression and genetic alterations in lymphoblastic leukemia. The mRNA expression level of MYC, CXCL8 and ATF3 exhibited a 2.564, 4.446, 3.605‐fold change, respectively, between lymphoblastic leukemia and normal samples in the examined study3.7For confirmation, we first evaluated cytotoxicity of dexamethasone in BALL‐1 and BALL‐1/ADR cells. Using MTT assay, we observed markedly lower dexamethasone sensitivity in BALL‐1/ADR cells than in the parental cells BALL‐1. The IC50 of dexamethasone in BALL‐1 cells and BALL‐1/ADR cells was 5.57 ± 1.32 μg/mL and 32.40 ± 1.33 μg/mL, respectively.Based on the MTT results, we examined C‐MYC expression at the mRNA and protein level using qRT‐PCR and western blot Figure A,B. A siTaken together, using MTT, qRT‐PCR, and western blot assays, we validated the potential molecular mechanism of GC resistance in lymphoid tumor cells.4Despite the reassuring achievements in the treatment of patients with ALL, resistance to GC agonists has been a major obstacle in eliminating leukemia cells and maximizing cure.In this study, we generated an integrated, biologically functional landscape of GC resistance in ALL using bioinformatic analysis. First, a total of 99 common DEGs (52 upregulated and 47 downregulated) were identified between GC‐sensitive and ‐resistant samples by integrating two gene profile datasets from two different researches and analyzing the datasets with bioinformatic methods. Further, the 99 candidate DEGs were enriched and categorized into 3 groups: biological process, molecular functions, and cellular component terms using GO functional analysis. Finally, DEG‐related PPI network was expanded, and 98 nodes were identified with 127 edges, of which one node exhibited the highest connectivity in all edges and was regarded as the core gene in the PPI network.The upregulated DEGs were mainly enriched in the BP terms related to response to stimulus, positive regulation of biological process, and positive regulation of cellular process. The downregulated DEGs were instead mainly enriched in BP terms connected with negative regulation of transcription from RNA polymerase II promoter, defense response to bacterium, and innate immune response.://www.genome.jp/kegg/pathway.html) pathway was one of the top pathways identified, which derived from multiple TF alterations, including genes fusion, amplification, mutation, deletion, rearrangements and translocation, resulting in various oncogenic processes such as differentiation resistance, inhibition of apoptosis, and cellular invasion. Chromosomal translocations and rearrangements of mixed lineage leukemia (MLL) gene, which is located at 11q23, are frequently represented as t  , t   and t  , result in fusion proteins and subsequently lead to aberrant gene expression associated with leukemogenesis and chemotherapeutics resistance. Patients with ALL bearing MLL‐rearrangements show poor survival also due to cellular resistance to various chemotherapeutics, especially to GC, which is in accordance with the results of KEGG analysis.Transcriptional misregulation in cancer (map05202 on KEGG database: 3), t 11; (q23; p1MYC, which was identified as the core gene in GC resistance‐associated PPI network and is the node that showed the highest connectivity degrees therein, is also a modulator of numerous cell processes by transcriptional regulation of its target genes. We did not perform survival analysis due to lack of data on ALL survival in the two gene expression profiles, in the TCGA, and in Oncomine database. However, the role of MYC in lymphoid malignancy was elucidated. MYC upregulation, caused by deregulated activity of MYC transcriptional network, enhances cancer proliferation and cellular drug resistance according to recent researches. Schubbert S et al revealed that targeting MYC and PI3K pathway could eliminate leukemia‐initiating cells in T‐ALL.In this study, to validate the reliability and applicability of bioinformatics analysis, we investigated C‐MYC in BALL‐1 and BALL‐1/ADR cells, which displayed dexamethasone sensitivity and resistance, respectively. Increased expression of C‐MYC was observed in BALL‐1/ADR cells, which is consistent with bioinformatics analysis results.In summary, bioinformatics analysis was used to identify the biological networks and in vitro experiments were performed to verify the bioinformatics findings. Nevertheless, validation in a larger group of patients and in‐depth experiments in vivo and in vitro are needed to improve and examine the accuracy of the bioinformatics analysis.Taken together, the bioinformatic analysis employed here proved to be a convenient and valid tool that offered us a novel and systematic insight into the mechanism of GC resistance in ALL. Several pathways were identified which are potentially involved in GC resistance in ALL. Importantly, our data revealed a comprehensive interaction network which highlighted MYC as a hub gene among various candidate genes. Our findings integrate individual experimental results from previous studies to illustrate the landscape of biological processes that lead to acquisition of GC resistance. Based on these results, novel treatment opportunities and therapeutic targets can be envisaged.There are no conflict of interest to disclose.Jianda Hu, Yanxin Chen conceived and designed the experiment; Peifang Jiang, Jingjing Wen, Donghui Gan and Yingyu Chen operated the experiment, Jiazheng Li, Yuwen Chen, Ting Yang analyzed the data, Yanxin Chen, Liangyan Wang, Zhengjun Wu and Jianda Hu wrote the paper. Ting Yang, Minhui Lin and Jianda Hu reviewed the paper.This article does not contain any studies with human participants or animals performed by any of the authors. Click here for additional data file. Click here for additional data file.


Upper gastrointestinal bleeding (UGIB) has a high mortality rate and requires efficient and directed acute management. This project aimed to assess patient outcomes following changes to UGIB management protocols at Northern Hospital, Victoria, Australia. Changes involved streamlining management under a single inpatient unit, earlier endoscopy, blood transfusion thresholds, and risk stratification.This was a cohort study of 400 patients aged ≥18 years admitted to Northern Hospital who underwent endoscopy for acute UGIB. Data of preprotocol changes (Group 1) and prospectively postprotocol changes (Group 2) were collected retrospectively. Primary outcomes were inpatient mortality, rebleeding, radiologic or surgical intervention, and endoscopic reintervention. Secondary outcomes included length of stay (LOS) ≥4 days and blood units transfused. Univariate analyses were conducted comparing groups and associations between variables and outcomes, followed by multivariate analyses for each outcome.P = 0.95). Rebleeding reduced by 4% , LOS ≥4 days reduced by 15.1%  and median blood units transfused decreased with adjusted incidence rate ratio of 0.81 (P = 0.00). Early endoscopy (i.e. ≤12 h) for all patients increased by 15% (P < 0.00) and there were 12% more high‐risk patients (i.e. Glasgow–Blatchford score ≥ 12) in Group 2 (P = 0.01).There was no difference in mortality on multivariate analysis (Following changes to UGIB protocols at this Australian hospital, endoscopic times decreased with reductions in rebleeding, LOS ≥4 days, and blood transfusion rates. These findings demonstrate improved outcomes after the implementation of new treatment targets focusing on streamlined care of patients presenting with UGIB. The 2017 upgrade of management protocols for acute upper gastrointestinal bleeding at Northern Hospital focused on faster times to endoscopy, reduced blood transfusion thresholds and new risk stratification tools. A review of patient outcomes following these changes demonstrated significant improvements in re‐bleeding rates, length of stay and blood transfusion rates. While the prevalence of upper gastrointestinal bleeding (UGIB) has decreased over previous decades, significant mortality rates remain despite advances in diagnostic and management tools.This was a cohort study of 400 patients aged ≥18 years with acute UGIB admitted to the Northern Hospital who underwent endoscopy. Data from 200 patients in Group 1 were collected retrospectively prior to protocol changes between March 2016 and May 2017. Group 2 consisted of 200 patients whose data were collected retrospectively following protocol changes from May 2017 to March 2018. Multiple sources were used for data collection including the endoscopy reporting software at the Northern Hospital (Endobase), searches of hospital coding by Client Data Management, and from a prospectively collected UGIB audit initiated in the new protocols. Remaining data were collected from patient files accessed from the Central Processing Unit.Patients were categorized in subgroups of demographics, that is, age and gender, medication, comorbid illness, admission (i.e. from emergency department [ED] or inpatient), treating team, presentation , preendoscopic assessment and treatment including systolic blood pressure (SBP), hemoglobin (Hb) and need for blood transfusion. Endoscopic diagnoses were categorized as no abnormalities detected, nonvariceal bleeding, and variceal bleeding. Continuous variables were dichotomized, that is, age (≥65 and <65 years), Hb (≥70 and <70 g/L), and SBP (≥100 and <100 mmHg). Comorbidities recorded included organ failure or malignancy and combinations of diseases were categorically quantified. Medications were recorded for drug classes with increased UGIB risk, including antithrombotic, antidepressants, and nonsteroidal anti‐inflammatory drugs (NSAIDS) or steroids.Time to endoscopy was defined from initial referral by the treating team to the commencement of the procedure based on anesthetics records. Timeframes were measured as <6 h, 6–12 h, 12–24 h, and >24 h. They were further categorized as <12 h and <24 h for all patients, and <6 h for variceal UGIB patients. Specific timeframes analyzed were based on new protocols recommendations, including endoscopy within 24 h for nonvariceal UGIB patients with GBS ≥7, and early endoscopy (i.e. ≤12 h) for high‐risk nonvariceal patients i.e. GBS ≥12. Urgent endoscopy (i.e. <6 h) was indicated for active ongoing bleeding or variceal bleeding.The Glasgow–Blatchford score (GBS) was calculated for each patient with low risk defined as GBS <12, and high risk as GBS ≥12. Blood pressure values used to calculate the GBS were from the initial presentation, generally postresuscitation for ED admissions or on initial assessment by the treating team for inpatient admissions.The primary outcomes were inpatient mortality, inpatient rebleeding, need for surgical or radiological intervention, and endoscopic reintervention. Rebleeding was defined as melena, hematemesis or other clinical concerns of rebleeding after initial endoscopy. Endoscopic reintervention was defined as repeat endoscopy for the purpose of achieving hemostasis of rebleeding. Secondary outcomes included length of stay (LOS) ≥4 days, readmission within 30 days, and units of blood transfused. LOS ≥4 days was selected as it was the lowest median value between groups. Patients presenting with UGIB as inpatients were excluded when analyzing LOS as ongoing treatment was generally non‐UGIB related. Units of blood transfused were recorded as the total number of packed red blood cells received after suspected or confirmed UGIB. Readmission within 30 days included UGIB‐related cases only. Intensive care unit (ICU) admissions were excluded in this study.P value <0.050. Univariate analysis was then carried out comparing UGIB patients with nonvariceal versus variceal UGIB. Mann–Whitney U tests were used for continuous variables with binary factors and Kruskal–Wallis tests for multi‐factored continuous variables. Further univariate analysis identified significant associations between variables and each outcome. Multivariate analyses were conducted with generalized linear analyses using a forward stepwise selection process adjusting for variables found to significantly associated on univariate analysis, or those statistically different between groups. Only variables with a P value of <0.050 when adjusted for were included in the multivariate analysis. These variables included: admission (i.e. from ED or as inpatient), GBS, antiplatelet use, anticoagulant use, blood transfusion requirement, age, hemoglobin level and gender. The baseline adjusted odds ratios (AOR) and an adjusted incidence rate ratio (AIRR) of 1 was allocated to Group 1 for multivariate analyses. Univariate analysis was also used to compare patients with nonvariceal versus variceal UGIB for time to endoscopy and each outcome. The percentage of patients requiring endoscopic intervention based on GBS was calculated using the absolute values and percentages.Differences between groups were identified using Chi tests for discrete variables. Patient characteristics were summarized using absolute values and percentages for categorical variables, and with medians and interquartile ranges for continuous variables. Skewness was established by testing for normality with Shapiro–Wilk tests. Significance was defined as P = 0.006) (Table Four hundred patients were included in the cohort with 200 patients (50%) in Group 1 preprotocol changes and 200 patients (50%) in Group 2 postprotocol changes. There was no significant difference in patient demographics between groups in terms of age, gender, medication usage , presentation, or endoscopic diagnosis (Table P = 0.009). Regarding the association between GBS score and need for endoscopic intervention, a larger percentage of intervention was required in patients with higher GBS  the improvements in time to endoscopy for both the 24 and 12 h timeframes remained significant for the nonvariceal group (Table 3). The number of nonvariceal patients with GBS ≥7 receiving endoscopy within 24 h increased significantly by 13.2%, though the number of nonvariceal patients with GBS ≥12 receiving early endoscopy did not significantly improve with an 8.6% increase (Table 3). There were no improvements in time to endoscopy for the variceal group of patients with the number of patients receiving endoscopy within 24 h decreasing from 100.0 to 88.9%, and from 77.3 to 74.1% within 12 h (Table 3). Notably there was a significant drop for variceal patients receiving urgent endoscopy (i.e. within 6 h) from 72.7% in Group 1 to 44.4% in Group 2 (Table 3).The overall number of patients receiving endoscopy within 24 h increased from 73% in Group 1 to 86.5% in Group 2, while the number of patients receiving early endoscopy (i.e. ≤12 h) increased by 15% (Table P = 0.609) on multivariate analysis  0.34–2.77; P = 0.952) (Table P = 0.026) (Table P = 0.058) (Table P = 1.000) with no significant findings between groups (Table Seven patients died (3.5%) from Group 1 and nine (4.5%) from Group 2 . This discrepancy is noteworthy when considering how patient outcomes changed between groups as inpatient admissions are associated with worse outcomes for UGIB patients.P < 0.000)  Table . There wThe Glasgow–Blatchford score has demonstrated efficacy in predicting patient outcomes including need for endoscopic intervention, need for blood transfusion and mortality.P = 0.015). There was an increase of 8.7% of high risk (i.e. GBS ≥ 12) nonvariceal patients receiving endoscopy within 12 h though this was not significant (P = 0.415), and 30.8% did not reach the recommended target (Table P = 0.044). There was also a slight decrease for these patients within 12 h by 3.2%, and within 24 h from 100.0 to 88.9%  or multivariate analysis (P = 0.879), however data on readmission at other hospitals or mortality after discharge were not collected. LOS of ≥4 days was reduced by 15.1% (Table P < 0.000). Analysis of this timeframe within specific subgroups may provide added insight into changes in patient outcomes. Overall the median units of blood transfused decreased which took into account hemoglobin levels, GBS score and admissions (Table There was no significant difference in readmission rate within 30 days between groups on univariate (1% Table . This tiFollowing protocol changes at Northern hospital for UGIB management there was an increase in early endoscopy with improvements in rebleeding, LOS ≥4 days and units of blood transfused. While time to endoscopy decreased overall within 24 and 12 h room for improvement remains within the high‐risk subgroups. These findings demonstrate improved outcomes through the streamlining of patient care under a single, dedicated Gastroenterology unit which aided in the overall implementation of revised treatment targets in UGIB management at Northern Hospital. While the prevalence of UGIB continues to decrease, there is an ongoing need for specialized and expedient acute care of these high‐risk patients.


Fusarium species are the fungal pathogens most commonly responsible for the mycotic keratitis, which are resistant to the majority of currently available antifungal agents. The present study was designed to assess the efficacy of a combination of low doses chlorhexidine with two other commonly used drugs (voriconazole and natamycin) to treat Fusarium infections.Fusarium strains in vitro using a checkerboard-based microdilution strategy. In order to more fully understand the synergistic interactions between voriconazole and chlorhexidine, we utilized a Galleria mellonella model to confirm the combined antifungal efficacy of chlorhexidine and voriconazole in vivo. We found that for voriconazole, natamycin, and chlorhexidine as single agents, the minimum inhibitory concentration (MIC) ranges were 2–8, 4–16, and > 16 μg/ml, respectively. In contrast, the MIC values for voriconazole and chlorhexidine were reduced to 0.25–1 and 1–2 μg/ml, respectively, when these agents were administered in combination, with synergy being observed for 90% of tested Fusarium strains. Combined chlorhexidine and natamycin treatment, in contrast, exhibited synergistic activity for only 10% of tested Fusarium strains. We observed no evidence of antagonism. Our in vivo model results further confirmed the synergistic antifungal activity of chlorhexidine and voriconazole.We utilized combinations of chlorhexidine and natamycin or voriconazole against 20 clinical Fusarium spp., and these agents may thus offer value as a combination topical antifungal treatment strategy.Our results offer novel evidence that voriconazole and chlorhexidine exhibit synergistic activity when used to suppress the growth of  Fusarium species are the causative pathogens in between 36 and 67% of all traumatic keratitis cases, in which F. oxysporum was the most frequently isolated species followed by F. solani [Fusarium-related keratitis remains challenging to treat as these fungi are intrinsically resistant to most available antifungal agents. While advances in the standard treatment for keratitis have been developed in recent years, with natamycin (NAT) and voriconazole (VOR) being the current treatment agents of choice, further optimization of these therapeutic regimens is still warranted [Keratomycosis is a form of fungal infection that can be challenging to treat, and that can result in permanent and severe vision damage when not adequately treated . Fusariu. solani . FusariuFusarium infections, and 5% NAT is currently the first-line treatment for mycotic keratitis in certain nations, the poor penetration of this compound has been linked to failed treatment in some cases [While previous studies have shown that NAT can be effective for the treatment of me cases . More reme cases  while alme cases . Furtherme cases . The utiFusarium isolates. We employed a checkerboard microdilution strategy to reliably identify potentially useful combinations of these therapeutic agents in vitro. We then employed a G. mellonella model to validate our findings in vivo.The goal of the present study was to assess the impact of combinations of NAT or VOR with CHL on clinical Fusarium isolates, respectively. CHL did not exhibit antifungal activity, even at the highest tested concentration. When combined with VOR, the MIC values for CHL and VOR were reduced to 1–2 μg/ml and 0.25–1 μg/ml, respectively, with synergy being observed for 18 Fusarium strains (90%). In contrast, such synergistic interactions were only observed for 2 Fusarium strains (10%) treated with a combination of CHL and NAT  values of > 16 μg/ml, 2–8 μg/ml, and 4–16 μg/ml to the , we infected G. mellonella with F. solani Jsfs1 and then treated these larvae using CHL and/or VOR. The survival in groups treated with VOR, CHL, and VOR with CHL was 15%, 10% and 33.3%, respectively. VOR treatment slightly improved larval survival, whereas CHL alone failed to improve larval survival, compared with the conidia group. Treatments with VOR combined with CHL significantly (P < 0.05) prolonged the survival of larvae . The difference between our findings and these prior studies may be attributable to the fact that relatively few fungal isolates were tested and that lower concentrations of CHL were employed herein.Herein we evaluated the potential combination antifungal activity of antifungal agents against pathogenic contents . Most baolutions , while Colutions . There apatients . Xu et a strains . In the xysporum . In our F. solani has been successfully treated with a combination of 0.02% CHL and AMB (Amphotericin B), underscoring the potential of CHL as an approach to the clinical management of fungal keratitis [In two blinded randomized trials by the same investigators, they observed patients of fungal keratitis treated with natamycin compared to CHL gluconate at various concentrations. Their results indicated that 0.2% CHL yielded the best results , 14. Howeratitis . HoweverFusarium strains. We observed no evidence of antagonism. As G. mellonella exhibit immunological response similar to those of mammals and are easy to manipulate, can be maintained at low costs, and incur minimal ethical concerns [G. mellonella model to evaluate the in vivo synergistic activity of these treatments. We determined that combination VOR + CHL treatment of infected G. mellonella larvae was associated with significant increases in larval survival. What’s more, the concentration of CHL is about 0.00015%, which is very low and proved to be safe when used in ophthalmic [Fusarium cell membranes without affecting drug efflux pump activity [In this study, we evaluated therapeutic interactions between CHL and VOR or NAT via a checkerboard microdilution strategy. As a first-line drug used for the management of fungal keratitis, NAT exhibited poor synergy ability with CHL both in vitro and in vivo. In contrast, the combination of CHL and VOR treatment exhibited synergistic activity against 90% of tested concerns , they caconcerns . We therhthalmic . The mecactivity .G. mellonella larvae relative to control groups, suggesting that these two compounds exhibit excellent synergy in vitro and in vivo and are thus ideal for treating Fusarium keratitis.In order to expand upon these in vivo studies, we additionally conducted microscopic analyses of infected larvae Fig. , which cFusarium species in vitro and in vivo. These findings suggest that CHL and VOR may be a viable therapeutic combination treatment for Fusarium infections, although future clinical trials and studies will be needed to validate this finding and to explore the underlying molecular mechanisms.Our results demonstrate that CHL and VOR exhibit synergistic efficacy against Fusarium isolates (12 F. solani and 8 F. oxysporum strains) from clinical cultures , NAT (purity≥99%) and CHL (purity≥99%) were obtained as powders from Selleck Chemicals , and were dissolved with DMSO  to prepare 1600 μg/mL stock solutions.Fusarium strains were grown for 7 days at 30 °C on Sabouraud dextrose agar (SDA), after which they were isolated and resuspended in a 2 mL volume of sterile saline. Sterile gauze was utilized to filter conidia suspensions, after which a hemocytometer was used to quantify concentrations therein, which were adjusted to 1–5 × 106 cfu/mL.Fusarium isolates at 1–5 × 104 cfu/mL. Plates were incubated for 48 h at 35 °C, after which MIC values were determined by identifying the minimum antifungal agent dose necessary to achieve 100% inhibition of fungal growth relative to control untreated wells. We additionally included A. flavus strain ATCC 204304 as a quality control strain in the present analysis.We conducted antifungal susceptibility tests based upon the CLSI M38-A2 . BrieflyFusarium strains, with this approach having been adapted from the CLSI M38-A2 microdilution method. Briefly, we added 50 μl volumes of serially-diluted VOR or NAT horizontally across microdilution plates, while 50 μl CHL samples that had been serially diluted were added in a vertical direction, with 100 μl of a prepared inoculum suspension also being added to each well. Incubation times and MIC determinations for this assay were as above. Combination drug interactions were classified based upon the fractional inhibitory concentration index (FICI) [A checkerboard microdilution strategy was used to evaluate synergistic interactions between CHL and NAT or VOR against x (FICI)  which waGalleria mellonella caterpillars from the final instar larval developmental stage  were maintained under dark conditions and were utilized within 1 week of receipt. In total, 20 randomly selected larvae  were utilized per group. Two control groups were injected with 10 μL of saline or with no solution, respectively. Infected animals were injected with a 10 μl volume containing Fusarium Jzfs1 (1 × 107/mL) using a 25 μl Hamilton syringe. Injections were made into the hemocoel of each larva through the last left proleg, with this region having first been cleaned with an alcohol swab. Following the completion of this injection process, larvae were transferred to plastic containers at 37 °C, with survival being assessed each day over a 6-day period. All experiments were conducted in triplicate.Galleria mellonella killing assays were conducted at 37 °C, as above, with 1 × 107/ml cells/larva being used for initial inoculation. VOR and CHL were diluted in saline and then used to treat infected G. mellonella in the following combinations: VOR (3 μg/mL), CHL (1.5 μg/mL), and VOR + CHL . As controls, additional G. mellonella caterpillars were injected twice using saline. All drugs were injected through the last left proleg of each larva. The G. mellonella survival curves were analyzed by the Kaplan-Meier method, and differences were determined by using the log-rank (Mantel Cox) test. Differences were considered significant at P values of < 0.05.Fusarium presence within G. mellonella tissues was assessed via collecting larvae from each group on day 3 post-infection and treatment. These larvae were fixed with 10% neutral formalin, after which they were dehydrated with an ethanol gradient . Samples were then paraffin and xylene embedded, sliced to prepare 8 μm sections, and stained with hematoxylin and eosin (HE). Samples were then evaluated via an FSX100 fluorescence microscope  at 10× and 40×. As controls, saline-injected larvae were also collected.


The prognostic ability of cardiac troponin I (TnI) has been demonstrated in general populations and among cardiovascular disease patients, but it has not been evaluated in cancer patients.This study assumes to have the prognostic ability of cardiac troponin in cancer patients visiting the emergency department.Cancer patients visiting the emergency department were enrolled in this retrospective cohort study. Patients with previously known coronary artery disease or clinically indicated coronary angiography were not included. The maximal value from Siemens ADVIA Centaur troponin I Ultra assay within 24 hours was assessed. The primary endpoint was 180‐day all‐cause death, including cardiovascular and noncardiovascular death.P < .001, all). These findings were consistent within clinical subgroups including solid and hematologic cancers.A total of 9135 cancer patients  were enrolled. Lowest (0.006 ng/mL), assay‐specific <99th % (0.007‐0.039 ng/mL), below median ≥ 99th % (0.040‐0.129 ng/mL), and above median ≥ 99th % (≥0.130 ng/mL) TnI were found in 4487 (49.1%), 3158 (34.6%), 852 (9.3%), and 638 (7.0%) patients, respectively. There was 3192 (34.9%) all‐cause deaths including 137 (1.5%) cardiovascular and 3047 (33.4%) noncardiovascular deaths in the 180‐day follow‐up period. The risks of all‐cause, cardiovascular, and noncardiovascular death increased across higher TnI strata (hazard ratio [HR] = 1.3‐2.9; 2.1‐9.3; 1.3‐1.8; Cancer patients visiting the emergency department with elevated troponin I were at increased risk of 180‐day death. Cancer patients with elevated TnI may need additional evaluation or careful follow‐up even without cardiovascular disease diagnosis. We investigated the ability of cardiac troponin to predict mid‐term (180 days) death risk in cancer patients who visited the emergency department of a tertiary hospital.22.1We performed a retrospective single‐center cohort study of patients over 18 years old who visited the emergency department at Samsung Medical Center, a tertiary hospital located in Seoul, and who underwent a cardiac troponin I test within 24 hours of arrival between January 2007 and May 2016. Patients without a current or prior history of cancer were excluded. Patients with the following specific conditions that can accompany troponin elevation were also excluded: having a mechanical circulatory‐support device, ever underwent resuscitation, history of heart transplantation, coronary artery disease history, revascularization, or clinically indicated coronary angiography during hospital stay.The Samsung Medical Center Institutional Review Board approved and waived the requirement for informed consent because only anonymized data were involved and results were reported in aggregate. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines (supplementary document).2.2All data were retrieved from the Clinical Data Warehouse Center at Samsung Medical Center (Darwin‐C). In cases of mortality outside the hospital, the specific cause of death was retrieved from the government operated organization Statistics of Korea. The timing of all clinical events, arrival or discharge time, death, and laboratory tests were defined using the timestamp in patients' electrical medical records. The study index date was used as the visit time to the emergency department.The Siemens ADVIA Centaur XP analyzer  was used for cardiac troponin I measurement. It has a lowest cardiac troponin I (TnI) analytic sensitivity of 0.006 ng/mL, an upper refence limit at the 99th % of 0.040 ng/mL, and a coefficient of variation <10% at 0.030 ng/mL. The maximum level of TnI within 24 hours after emergency department visit was grouped into four categories using the lowest (0.006 ng/mL), <99th % (0.007‐0.039 ng/mL), less than median ≥ 99th % (0.040‐0.129 ng/mL), and median ≥ 99th % or higher (≥0.130 ng/mL). In instances of multiple TnI measurements, the highest value measured within 24 hours was selected. The first measured value was used for the other laboratory tests and vital sign measurements. All electrocardiography ST‐T changes were independently read and confirmed by experienced physicians (M.S. and J.C.).The primary endpoint was 180‐day all‐cause death. The major cause of death was determined by the death codes in the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD‐10) and it was used to classify cardiac and noncardiac deaths (supplementary document). No patient was lost to follow‐up with respect to death.2.3Clinical characteristics are shown according to TnI levels. Continuous data are described as means with standard deviations. Categorical data are presented as frequencies. Differences were assessed with the Kruskal‐Wallis or chi‐square test. Changing trends across TnI levels were assessed with the Jonckheere‐Terpstra test.Associations between TnI level and death were assessed with Cox regression models. For sensitivity analysis, three multivariate Cox regression models adjusted for the following clinical parameters were used: model 1 included basic demographics and visit year; model 2 included model‐1 parameters and clinical comorbidities and dyspnea symptoms, which were the most associated symptoms among TnI level and have been shown to have prognostic value in cancer patients visiting emergency departmentsP < .05.R version 3.6  was used for analyses. Hazard ratios (HR) for compared outcomes are reported with a 95% confidence interval (CI). Statistical significance was defined by two‐tailed 33.1A total of 37 747 patients who visited the emergency department and underwent TnI testing within 24 hours were screened for potential cardiovascular disease. Most TnI results were available within 2 hours . After excluding 28 344 patients without cancer and 268 patients who underwent cardiopulmonary resuscitation, received mechanical circulatory support, had a prior history of coronary artery disease diagnosis or revascularization, or heart transplantation, or underwent urgent coronary angiography within 48 hours of visiting the emergency department, a total of 9135 patients were enrolled in this study , 3158 (34.6%), 852 (9.3%), and 638 (7.0%), respectively. Age, male gender, and most clinical risk comorbidities increased with higher TnI levels. Typical angina‐like chest pain did not increase with TnI but dyspnea and other respiratory symptoms did  all‐cause deaths including 281 (3.1%) cardiac deaths and 2911 (31.9%) noncardiac deaths during the 180‐day follow‐up period. The proportion of cardiac deaths among all‐cause deaths increased across the higher TnI levels , but there was no further increase of risk when TnI was higher than median ≥ 99 % (≥0.130 ng/mL). The risk of cardiovascular death increased consistently across higher TnI levels  levelPanel A: Frequency of chief complaining symptom according to the level of TnI. The frequency of dyspneic symptom increased across strata of higher TnI.Panel B: Frequency of ECG ST‐T change according to the level of TnI, which increased across strata of higher TnI.Click here for additional data file.Supplementary Figure 2 The increase of all‐cause death risk across cardiac troponin I (TnI) strata is mostly driven by the increase of cardiovascular death.Click here for additional data file.Supplementary Table 1 Clinical outcome according to the cardiac troponin I (TnI) levelClick here for additional data file.