Primary cardiac sarcoma (PCS) has a poor prognosis compared to other sarcomas due to late presentation, challenging resection, incidence of metastases, and limited efficacy of systemic therapies.  A medical record search engine was queried to identify patients diagnosed with PCS from 1992 to 2017 at the University of Michigan. 0 resections. Patients received a median of 2 (1–6) systemic therapies. Median overall survival (OS) was 12.1 months (range 0–79). Median OS was 14.0 months and 8.2 months in patients who did or did not undergo resection, respectively (p=0.018). Brain metastases occurred in 12 (31%) patients, 9 (75%) of whom had left heart tumors, at a median of 8.5 months (range 0–75) from diagnosis. Median OS was 5.6 months (range 0–30) after the diagnosis of brain metastases.  Thirty-nine patients with PCS had a median age of 41 years (range 2–77). Common histologies were angiosarcoma , high-grade undifferentiated pleomorphic sarcoma , and leiomyosarcoma . Sites of origin were left atrium (18), right atrium (16), and pericardium (5). AS was the most common right-sided tumor; UPS was more common on the left. Eighteen patients presented with metastases involving lung (10), bone (7), liver (5), and brain (4). Twenty-five patients underwent resection, achieving 3 R PCS portends a poor prognosis, because of difficulty in obtaining complete resection of sarcoma, advanced stage at diagnosis, and high risk of brain metastases. Providers should be aware of the increased risk of brain metastases and consider brain imaging at diagnosis and follow-up. Primary cardiac tumors are rare, with an overall incidence of 0.001–0.02% [We present a case series of 39 patients with PCS in attempt to characterize and better understand disease presentation, location, treatment modalities, and overall survival of patients with PCS. We highlight patterns of metastatic disease, histologic subtypes, and the barriers to improvements in overall survival of PCS patients.The University of Michigan Electronic Medical Record Search Engine (EMERSE) was searched using the terms “cardiac sarcoma” and “heart” plus “sarcoma” to identify patients with a diagnosis of primary cardiac sarcoma treated at our institution between 1992 and 2017. Patients with sarcomas originating within the pulmonary vasculature or great vessels were not included in this analysis. Details regarding demographics, clinical presentation, pathologic features, treatment protocols, and outcome were extracted from clinical records. All research was approved by the University of Michigan Institutional Review Board (HUM00068553).p value <0.05. All analyses were conducted using SAS .Descriptive statistics, such as median and range, were calculated for continuous variables, and frequencies were presented for categorical variables. To compare two categorical variables, a frequency table was created and analyzed using the chi-squared test or Fisher's exact test. Overall survival (OS) was estimated by the Kaplan–Meier method and compared using the log-rank test. Statistical significance was defined as a two-sided Thirty-nine patients with PCS presenting to the University of Michigan between 1992 and 2017 were identified. Median age at diagnosis was 41 years. Patient demographics and brief outline of disease characteristics are summarized in n=29), chest pain (n=8), cough (n=3), bilateral lower extremity edema (n=3), and hemoptysis (n=3). Twenty patients had evidence of pericardial effusion at diagnosis, including all 5 patients with pericardial tumors and 11/16 patients with right-sided tumors. Twelve patients had evidence of tamponade at diagnosis, one of which had a left atrium (LA) tumor, 8 had right atrium (RA) tumors, and 3 had pericardial tumors. Eight patients had pulmonary hypertension at time of diagnosis. There were no clinically significant arrhythmias present at diagnosis.All patients were symptomatic at time of diagnosis, most frequently with dyspnea (n=11) and pericardium  compared to other histologies. UPS (n=8) and LMS (n=4) were the most commonly observed left-sided tumors (Angiosarcoma was the most common tumor histology and was more commonly located on the right side of the heart (d tumors .Metastatic disease was present in 18/39 (46%) of PCS patients at the time of diagnosis. The distribution of metastases at the time of disease diagnosis is listed in p=0.01) compared to right-sided and pericardial tumors. The most common histological variant was UPS (n=6). Other histological types included angiosarcoma (3), leiomyosarcoma (2), and fibrosarcoma (1). All patients with right-sided tumors and brain metastases at diagnosis (n=3) also had lung metastases. One patient had evidence of a right to left shunt on echocardiogram as detected by a bubble study.Twelve patients developed brain metastases, 4 of whom had brain metastases at initial diagnosis. All presented with neurologic symptoms. Median time from diagnosis of PCS to diagnosis of brain metastases was 8.5 months (range 0–75.8 months). Left-sided cardiac tumors were more commonly associated with brain metastases , all of whom had left atrial tumors. Nine patients had R1 resections, 11 patients had R2 resections, and the surgical margin in 2 patients was unknown. Five patients with solitary brain metastases underwent craniotomy as primary management of their metastatic disease.Twenty-five patients (64%) underwent surgical resection of their PCS. Eleven of the twenty-five  patients had evidence of metastatic disease at diagnosis. An RIn total, 11 patients (26%) received radiation therapy. Three patients had radiation to the primary cardiac tumor, one to alleviate superior vena cava syndrome and two to optimize clinical status prior to systemic chemotherapy. Eight patients received radiation therapy to brain metastases (5 whole brain and 3 stereotactic radiotherapy). Four patients received radiation therapy after resection of solitary brain metastases. Four patients received radiation therapy alone for multifocal brain metastases. Two of these patients received palliative radiation to symptomatic lesions in the bone and lung.0, and R1. Twenty-eight patients (72%) received chemotherapy, with a median of 2 regimens (range 1–6). Twenty-one patients (75%) who received chemotherapy had resection of their primary tumor. Two patients received neoadjuvant chemotherapy followed by resection, Rn=2) or second-line (n=8) therapy. Eight patients received 3 or more lines of therapy. Other chemotherapy regimens frequently used in any line included paclitaxel (n=5), dacarbazine (n=3), and ifosfamide (n=3).Most patients received systemic therapy with palliative intent. Seventeen patients (61%) received doxorubicin plus ifosfamide (AI) as first-line therapy with a mean of 5 cycles (range 0.5–9). Ten patients received gemcitabine and docetaxel (GT) as first (p=0.02) for patients who did not , compared to 8.2 months .We found brain metastases occurred quickly and frequently in our PCS patients. Thirty-one percent 12/39) of our PCS patients developed brain metastases, compared to 1–8% in noncardiac sarcomas /39 of ou. This isThe prevalence of brain metastases in sarcoma is increasing due to prolonged survival from multimodal therapies that have poor CNS penetration , 18. In The management of brain metastases is largely dependent on the number of lesions and patient performance status. Surgical intervention is considered with solitary metastases, while radiation therapy is preferred for multifocal disease or in patients with marginal performance status. Metastasectomy of brain metastases is reported to result in increased post-brain metastases survival to about 9 months, compared with 2.7 months for those who did not receive surgical intervention . In our Surgical resection is the preferred management for localized sarcomas. As compared to other sarcomas, PCS patients are more likely to have advanced stage or inoperable primary tumor at presentation. Barriers to complete resection include anatomic location and declining performance status due to tumor at presentation. Given the difficulty in achieving complete resection with cardiac tumors, autotransplantation has been explored to allow for complete resection and optimal reconstruction. Ramlawi et al. reported on their institutional experience with cardiac transplant in 34 patients with left-sided cardiac tumors . In theip=0.12, respectively), while surgical resection did (p=0.02), highlighting the importance of local disease control. This survival benefit of resection has been noted in other reports of PCS and is independent of the presence of metastatic disease [Nearly 50% of our patients had evidence of metastatic disease at time of presentation, which is higher than the reported 20–30% in several case series . In our  disease . This ma disease . Further0) resections without metastatic disease will relapse, highlighting the need for systemic therapy [0) versus R1 resection, 53.5 months and 9.5 months, and those who received neoadjuvant chemotherapy versus primary surgery, 20 versus 9.5 months, respectively. The authors conclude that neoadjuvant chemotherapy improves the ability to achieve complete resection and thus translates into improved survival. However, the ability to deliver neoadjuvant chemotherapy relies on accurate preresection diagnosis. Given the rarity of these tumors and clear benefits to multimodality therapies, it is imperative to employ a multidisciplinary team approach. The creation of a multispecialty, multi-institution cardiac tumor board in which our institution participates enhances the ability for cross-discipline discussions to optimally manage these challenging tumors.Surgery alone, however, is not enough to prevent primary tumor recurrence or distant metastases. Most patients who undergo complete  compared to those who did not receive chemotherapy. Given the retrospective nature of this study, it is important to note that patients who receive chemotherapy generally have better performance status and organ function, which likely impacted the survival advantage noted with chemotherapy. Local disease control, resulting in improved cardiac function, likely results in better performance status and ability to tolerate aggressive therapies.In our patient cohort, those who received chemotherapy alone and those who underwent surgical resection and received systemic chemotherapy had a survival advantage (Primary cardiac sarcomas are rare, confer increased risk of brain metastases, are associated with shorter survival duration, and have a higher disease-specific mortality compared to soft tissue sarcomas arising in extracardiac sites. Increased mortality may be due to the difficulty with complete resection and high disease and symptom burden at presentation, making aggressive multimodal therapy difficult. Multidisciplinary care incorporating surgery, radiation, and systemic therapy when appropriate constitutes ideal management. Based on our findings, we recommend brain imaging at the time of primary cardiac sarcoma diagnosis given the incidence of brain metastases. Furthermore, our results suggest a role for aggressive multimodal therapy including resection and systemic therapy, even in the metastatic setting, to improve outcomes.


The Japan Coma Scale (JCS) score has been widely used to assess patients’ consciousness level in Japan. JCS scores are divided into four main categories: alert (0) and one-, two-, and three-digit codes based on an eye response test, each of which has three subcategories. The purpose of this study was to investigate the utility of the JCS score on hospital arrival in predicting outcomes among adult trauma patients.Using the Japan Trauma Data Bank, we conducted a nationwide registry-based retrospective cohort study. Patients 16 years old or older directly transported from the trauma scene between January 2004 and December 2017 were included. Our primary outcome was in-hospital mortality. We examined outcome prediction accuracy based on area under the receiver operating characteristic curve (AUROC) and multiple logistic regression analysis with multiple imputation.n = 15,860). The 10-point scale JCS and the total sum of Glasgow Coma Scale (GCS) scores demonstrated similar performance, in which the AUROC (95% CIs) showed 0.874 (0.871–0.878) and 0.878 (0.874–0.881), respectively. Multiple logistic regression analysis revealed that the higher the JCS score, the higher the predictability of in-hospital death. When we focused on the simple four-point scale JCS score, the adjusted odds ratio  were 2.31 (2.12–2.45), 4.81 (4.42–5.24), and 27.88 (25.74–30.20) in the groups with one-digit, two-digit, and three-digit scores, respectively, with JCS of 0 as a reference category.A total of 222,540 subjects were included; their in-hospital mortality rate was 7.1% (JCS score on hospital arrival after trauma would be useful for predicting in-hospital mortality, similar to the GCS score. Prompt and accurate assessment of severely injured trauma patients is crucial to guide proper treatment in initial management. To date, the Glasgow Coma Scale (GCS) has been widely utilized to evaluate consciousness level in a variety of clinical settings, including trauma care –4. TriagIn Japan, the Japan Coma Scale (JCS) is the most extensively adopted scale for assessing patients’ consciousness level because of its simplicity and applicability , 11. TheWe hypothesized that consciousness level assessed using the JCS score would predict patient outcomes or identify severe traumatic brain injury (TBI) similar to or better than the GCS. A simple assessment tool using the JCS would be useful and pragmatic in the emergency department setting. The aim of this study was to examine the utility of the JCS recorded on hospital arrival in predicting in-hospital mortality in patients after trauma using a large national database, which will help raise worldwide awareness of the JCS score’s applicability.The Okayama University Hospital ethical committee approved the study (ID 1903–021). The requirement for informed consent was waived because patient data was extracted anonymously.The design of the present study was a nationwide retrospective cohort study using registry database. We used data from a national trauma registry called the Japan Trauma Data Bank (JTDB), which has been described in detail elsewhere , 11. BriAll patients with trauma who were 16 years old or older directly transported from the injury scene between January 2004 and December 2017 were included in this study. Patients with burn injuries, in cardiac arrest at the scene or on arrival, those with AIS scores of 6 in any region, or those undergoing interfacility transport were excluded.The JCS was first reported in 1974 . The scaThe primary outcome was in-hospital mortality from all causes. The secondary outcome was the presence of severe TBI, which was defined as head AIS scores of 4 or 5.P value of < 0.05 was considered statistically significant. All analyses were conducted using IBM SPSS Statistics 25 .Continuous variables are presented as median and interquartile range values, whereas categorical variables are shown as frequencies and percentages. To account for missing data, multiple imputation was performed to analyze incomplete data, replacing each missing value with a set of 20 substitute plausible values , 19. Covn = 15,860). Distribution of in-hospital mortality percentages based on JCS and GCS scores are shown in Fig. A total of 222,540 trauma patients meeting the inclusion criteria were identified and included in this study Fig. . Study pData presented in Table Table As for secondary outcome measures, the 10-point scale JCS score demonstrated the highest predictability for severe TBI, in which the AUROC (95% CIs) was 0.781 (0.778–0.783) with a suggested cut-off value of 2  and the Glasgow Coma Scale  on arrival among complete cases.


The effects of the macrostructure of long chain fatty acids on the lipid metabolism and biosynthesis of lipid droplets (LD) was studied in mammary epithelial cells (MEC). MEC were exposed to similar compositions and concentrations of fatty acids in the form of either triglycerides (Tg), as part of the very-low-density lipids (VLDL) isolated from lactating cow plasma, or as non-esterified- free fatty acids (FFA). Exposing MEC to FFA resulted in two distinct processes; each independently could increase LD size: an elevation in Tg production and alterations in phospholipid (PL) composition. In particular, the lower PC/PE ratio in the FFA treatment indicated membrane destabilization, which was concomitant with the biosynthesis of larger LD. In addition, 6 fold increase in the cellular concentration of the exogenously added linoleic acid (C18:2) was found in MEC treated with FFA, implying that long chain fatty acids administrated as FFA have higher availability to MEC, enabling greater PL synthesis, more material for the LD envelope, thereby enhancing LD formation. Availability of long chain fatty acids administrated as VLDL-Tg, is dependent on LPL which its activity can be inhibited by the hydrolysis products. Therefore, we used increasing concentrations of albumin, to reduce the allosteric inhibition on LPL by the hydrolysis products. Indeed, a combined treatment of VLDL and albumin, increased LD size and number, similar to the phenotype found in the FFA treatment. These results reveal the role played by the macrostructure of long chain fatty acids in the regulation of LD size in MEC which determine the size of the secreted MFG. Milk fat is secreted in a structure termed milk fat globules (MFG) which consists of a triglyceride (Tg) core covered with three layers of polar lipids (PL) and proteins derived from the mammary gland epithelial cellular membranes . MFG areDespite its direct effect on milk organoleptic properties and human health, MFG size regulation has scarcely been studied and therefore, the mechanisms regulating this unique feature of milk are still elusive. MFG size is determined by the size of its precursors, the intracellular lipid droplets (LD) synthesized in the mammary epithelial cells MEC; –19). The. The19])From their site of synthesis, the cytoplasmic LD migrates toward the apical pole of the cell, where they are apocrine-secreted into the alveolar lumen, enveloped by the apical cell membrane bilayer. Eventually, the secreted MFG consists of a Tg core covered with three layers of PL and proteins, derived from the cellular membranes, termed milk fat globule membrane (MFGM) .PL plays a central role in regulating LD size, by either controlling membrane stability and hence the susceptibility of LD to fusion, or by providing the coating material for the Tg core –25. MembIn lipogenic tissues, long chain fatty acids have a role in activating PPARs family of transcription factors and their co-activators PGC-1 α and β which together regulate the expression of mitochondrial enzymes and transport proteins, thus regulating mitochondrial activity . In MEC,Long chain fatty acids from VLDL are available to peripheral tissues, including the mammary gland, through either VLDL receptor endocytosis  or the lThis implies that fatty acids macro-structure (i.e. FFA or VLDL), is relevant in terms of bioavailability of preformed fatty acids to the cells and to PL synthesis, and thus may affect MFG size. Moreover, the source of the FFA either from VLDL hydrolysis or from non-esterified FFA induced different metabolic response in the cell as was shown by Ruby et al.  who demoThe hypothesis that the macrostructure of long chain fatty acids may affect LD size is supported by findings in hepatocytes, demonstrating that elevated levels of FFA are associated with large cytoplasmic LD and greater cellular content of Tg . More spTaken together, these results imply that FFA has a role in the mechanisms underlying the regulation of MFG size; however the mechanism is still unknown. In vivo, this association is difficult to study because milk yield and total milk fat concentration, as well as homeorasis signals are all strong confounders of the relationship between MFG size and FFA in plasma.Accordingly, the aim of the present study was to isolate the effects of the biochemical macrostructure of preformed, long chain fatty acids (in the form of FFA vs. VLDL) on the morphometric features of MFG precursors, the MEC intracellular LD.DMEM/F12, penicillin, streptomycin, amphotericin B, L-glutamine solution, trypsin–EDTA solution C and fetal bovine serum (FBS) were all obtained from Biological Industries . Bovine insulin, hydrocortisone, ovine prolactin, bovine serum albumin (BSA) solution, hyaluronidase and DNase I were purchased from Sigma Aldrich Israel Ltd. . Collagenase type II was purchased from Worthington Biochemical Corporation .g for 15 min at room temperature. Plasma was collected and ultracentrifuged in a salt solution (11.42 g NaCl/liter) in a density of 1.006 g/ml [Blood samples were collected from the coccygeal vein of Israeli Holstein lactating cow, using vacuum tubes containing lithium heparin . The experiment was conducted at the Volcani Center experimental farm in Bet Dagan, Israel. The tubes were immediately placed on ice and centrifuged at 3,000006 g/ml . Brieflyg for 5 min. The sediment was treated with trypsin–EDTA and 0.04% (w/v) DNase. The cells were then washed with growth medium supplemented with heparin and treated with DNase alone, filtered through a 100-μm cell strainer  and washed with the growth medium.MEC for primary culture were isolated from cow mammary gland according to a protocol established in our laboratory . Study pPrimary MEC Cells were plated at 150,000 cells per 60-mm plastic dish for cellular lipid extraction and RNA extraction, or at 50,000 cells per well in 6-well plates on glass coverslips for Nile red or Mitotracker staining. After overnight incubation, the medium was replaced with DMEM/F12 without serum, containing 0.15% (w/v) FFA-free BSA and insulin (1 μg/ml), hydrocortisone (0.5 μg/ml) and prolactin (1 μg/ml) for 48 h to induce milk lipid and protein synthesis. Then cells were treated with FFA or VLDL for 24 h in the presence of insulin (1 μg/ml), hydrocortisone (0.5 μg/ml) and prolactin (1 μg/ml).Four fatty acids were used for the FFA treatment, based on the VLDL composition: palmitic (19% w/v), stearic , oleic  and linoleic , diluted with DMEM/F12 medium supplemented with 0.5% FFA-free BSA to a final concentration of 100 μM, which based on our established protocol induced changes in metabolic status of the cells and was not toxic –28. For Cells grown on glass coverslips were rinsed with PBS, fixed with 4% paraformaldehyde in PBS and stained with Nile red . Coverslips were then rinsed 3 times with PBS and stained with DAPI (Sigma) for 5 min. The coverslips were rinsed again with PBS and mounted with fluorescent mounting medium .Cells were incubated in DMEM/F12 medium with 250 nM Mitotracker deep red FM stain  for 30 min at 37°C. The cells were then fixed in ice cold 100% methanol for 15 min at -20°C and rinsed three times with PBS. Cells were mounted with fluorescent mounting medium (Dako) and slides were visualized with an Olympus DP73 digital camera using CellSens Entry software version 1.7 (Olympus). Mitochondrial fluorescence in each cell was quantified by ImageJ software version 1.48  using the following formula: corrected total cell fluorescence = integrated density of selected cell—(area of selected cell x mean fluorescence of background readings).Slides were visualized with an Olympus BX40 fluorescence microscope equipped with an Olympus DP73 digital camera using CellSens Entry software, and with an Olympus IX81 confocal microscope using Fluoview 500 software. LD diameter was measured using ImageJ software version 1.48. LD were divided into two or three  size groups: <1 μm, between 1 and 2 μm, and >2 μm. LD larger than 1 μm were designated “large” and those smaller than 1 μm were designated “small”.3, purity 99%), PI , PS , PC  and SM . Conjugated linoleic acid  was used as a standard for FFA. For the GC analysis, methanol  was purchased from Bio-Lab, petroleum ether  was from Gadot Lab Supplies  and sulfuric acid was from Bet Dekel . Retention times were determined by injection of commercial standard mixes of PL and Tg.For lipid extraction, methanol and chloroform  were purchased from Bio-Lab Ltd. . For HPLC analysis, chloroform and ethanol  and methanol (HPLC grade) were purchased from Bio-Lab. The triglyceride triolein (>99% pure) was purchased from Supelco . The PL standards were supplied by Sigma Aldrich Ltd. Israel and consisted of: PE  and stored at -20°C for HPLC analysis. For GC analysis, FAME were generated by methyl esterification and dissolved in a final volume of 100 μl petroleum ether before injection for GC analysis.To determine VLDL fatty acids composition and cell composition after the treatments, lipid extraction and methylation were performed on VLDL isolated from cow blood and on the harvested cells. Chromatographic analysis was performed with a GC  equipped with a fused-silica capillary column  under the following conditions: the oven temperature was programmed from 130°C to 170°C at a rate of 27°C/min, from 170°C to 215°C at a rate of 2°C/min, held at 215°C for 8 min, from 215°C to 250°C at a rate of 40°C/min, held at 250°C for 5 min. Run time was 37.9 min. Helium was used as the carrier gas at 2.21 ml/min. Flame ionization detector temperature was 270°C, and injector temperature was 280°C. Air and hydrogen flows were adjusted to give maximal detector response. Peak identification was based on relative retention times of two external standards. For polyunsaturated fatty acids (PUFA), PUFA-2 , and a FAME C8:0 to C24:0 mix . The area of each fatty acid peak was recorded using ChemStation software (Agilent Technologies). Fatty acids were recorded as percentage of total fatty acids within each sample (mol%).6 live cells. Live cell number was determined after Trypan blue staining, using a hemocytometer. Membrane composition is presented as weight percentage of each PL out of the summed quantity of recognized PL in each sample [Separation of polar and neutral lipids was performed by HPLC  combined with an evaporative light-scattering detector . The separation protocol was conducted with a gradient of dichloromethane, 99% methanol and 1% ammonium, and double-distilled water according to a previously described protocol [Total RNA was isolated from primary culture MEC by Gene Elute Mammalian Total RNA Miniprep Kit (Sigma Aldrich) according to the manufacturer’s instructions. The concentration and 260/280 nm optical density ratio of the RNA was determined by Nanodrop spectrophotometer . RNA samples were kept at -80°C until further analysis. Total RNA (1 μg) was reverse-transcribed to produce cDNA using the qScript cDNA Synthesis Kit (Quanta Biosciences) according to the manufacturer’s instructions.http://www.ncbi.nlm.nih.gov/tools/primer-blast/index) based on cDNA sequences published in the National Center of Biotechnology Information database or taken from the literature, as indicated . All data are reported as means ± SEM. Treatment and experiment number were defined as fixed effects in the model. All dependent variables were checked for homogenic variance by unequal variances in JMP software and where variance was not homogenic, Welch’s ANOVA test was performed. Comparisons were made by ANOVA followed by Tukey–Kramer HSD test.P < 0.0001), the number of large ones increased 12-fold (P = 0.0009).Treatment with FFA increased the total number of LD in the cells  comparedP < 0.0001, DGAT mRNA expression was 2-fold higher in the FFA treatment  was determined. The results shows that the concentration of linoleic acid (C18:2) was 6 fold higher in cells treated with FFA compared to VLDL, however this difference was not significant due to large variability between repetitions P < 0.1, . Oleic aP = 0.04, P = 0.03) while that of PE tended to increase  in the regulation of LD morphometric features in MEC. These findings imply that the form of presentation of long chain fatty acids to MEC, is as an additional metabolic factor involved in the modulation of LD size, beyond the established role played by fatty acid composition and concentration in LD biosynthesis and MFG secretion.MEC treated with FFA had higher concentration of cellular linoleic acid compared with cells treated with similar concentration and composition of fatty acids, in VLDL structure. Since linoleic acid originate from external source and cannot be synthesized endogenously in the cell, its higher cellular concentration indicates greater availability of exogenous, long chain fatty acids in this treatment. In addition, cells treated with FFA had higher Tg content accompanied by higher DGAT gene expression. DGAT catalyzes the final step of the biosynthesis of Tg . TherefoIt should be noted that LD size is usually positively correlated with cellular Tg content and lipogenesis capacity –57. SimiMembrane stability, as determined by its PL composition, can modulate LD size in various cell types, including MEC –28. In tChanges in PL composition could be attributed to mitochondria function or number because of at least one of the conversion steps between PS to PE is executed by a mitochondria enzyme, PSD . Here, wIn the present study, upon exposure to VLDL or FFA, a reduction in LPL expression was recorded. This could be attributed to negative feedback of FFA, which were exogenously added to the culture medium or formed during VLDL hydrolysis. This assumption is in accordance with the findings of Kadegowda et al.  who founThe released products of VLDL hydrolysis can allosterically inhibit LPL activity . LPL actThis work shows for the first time that the macrostructure of long chain fatty acids available to MEC has a role in regulating LD phenotype in terms of number and diameter, as well as the lipid composition of the cells and its membranes. In addition, the results suggest that LD size is modulated by the availability of long chain FA from the extracellular fluid, and not exclusively by total fat concentration and milk and fat synthesis capacity of the cells, as often assumed in in vitro and in vivo models of mammary gland and other lipogenic tissues.S1 Fig(A) Lipoprotein lipase (LPL) mRNA expression (AU). (B) NADH dehydrogenase (ubiquinone) 1α subcomplex assembly factor 3 (NDUFAF3) mRNA expression (AU) (C) Peroxisome proliferator-activated receptor gamma (PPAR-γ) mRNA expression (AU).(TIF)Click here for additional data file.S2 FigFatty Acid Binding Protein (FABP) mRNA expression (AU).(TIF)Click here for additional data file.S1 Data(XLSX)Click here for additional data file.


Limited information exists regarding sleep disorders in gout. Our objective was to assess the burden of sleep disorders in people with gout.t test the continuous variables.A brief anonymized Internet survey of people with physician-diagnosed gout who visited a gout education website assessed the frequency of sleep problems, sleep quality over the past 24 h , daytime sleepiness on a typical day (0 = none and 10 = most sleepy during the day), sleep quantity (number of hours of sleep), and the frequency of snoring or gasping, and snorting or stopping breathing during the sleep, using validated questionnaires, including the NHANES 2016 sleep questionnaire. We used Chi-square test to compare the categorical and Of the 454 website visitors who clicked the survey, 320 survey respondents reported physician-diagnosed gout. Mean age was 57 years , 72% were male, 77% were White, and mean gout duration was 7.6 . Of the respondents, 23% reported doctor-diagnosed sleep disorder . A mean 6.7 h of sleep per night was reported . Eighty-six percent reported snoring during sleep and 45% reported having snorted, gasped, or stopped breathing while asleep. Two thirds of the patients reported feeling sleepy during the day, at least 3–4 times a month or more. Sleep quality was 5.5 , and daytime sleepiness was 3.5  on a 0–10 scale (higher = worse).People with physician-diagnosed gout reported frequent sleep disorders and daytime sleepiness in an Internet survey. More in-depth studies are needed to better understand the association of gout with sleep disorders. Sleep disorders constitute a major public health burden for the US adults with a prevalence of 6% according to the National Health and Nutrition Examination Survey (NHANES) 2005–2006 , obstrucBoth gout  and sleeSeveral biologic mechanisms potentially link OSA to a higher risk of gout and gout flares, including hypoxia associated with OSA leading to enhanced nucleotide turnover subsequently leading to hyperuricemia, and increased urinary urate to creatinine ratio –21 or poGout is the most common inflammatory arthritis that affects 4% Americans, is often symptomatic and 63% of gout patients have metabolic syndrome comorbidities , 28, rishttp://gouteducation.org) were invited to participate in a brief anonymized Internet survey from January to October 2017. People who reported physician-diagnosed gout were invited to respond to a survey that queried people about demographics  website (finition ), the dufinition . The numfinition , in addiThe frequency of sleep problems including sleep apnea was assessed. Sleep quality was assessed using a single-item validated patient-reported Sleep Quality Scale  that assp-value < 0.05 was considered statistically significant.As a QA/QI initiative, this anonymized Internet survey did not require an approval from the Institutional Review Board. No written informed consent was needed since the anonymized survey was offered for voluntary participation at the GUAES patient education website informing people that they could click out of the survey if not interested, this will not directly benefit them and they can stop participating at any time. Chi-square test were used for categorical and t-test for continuous variables. A Of the 454 website visitors who clicked the survey, 320 survey respondents reported physician-diagnosed gout. The mean respondent age was 57 years SD, 13.4), 72% (166/232) were male, and 77% (179/232) were White  reported doctor-diagnosed sleep disorder, which was sleep apnea (17%) or possible sleep apnea  in the majority and other sleep problems in 2% . Only 14% 26/179) respondents never snored during the night, i.e., 86% (153/179) reported snoring during sleep with 34% (60/179) reported snoring 5 or more nights in the last week; 45% (71/157) reported having snorted, gasped, or stopped breathing while asleep (Table 6/179 resp = 0.002), but more daytime sleepiness, 3.1 vs. 4.6 (p = 0.001); (2) compared to people ≥ 65 years with gout, younger people with gout reported more daytime sleepiness (p = 0.03) and more frequent snorting, gasping, or stopping breathing while asleep in the past 12 months (p = 0.01)  compared to males with gout, females with gout reported better sleep quality in the last 7 days, 6 vs. 4.9 ( = 0.01) .In an anonymized cross-sectional Internet gout survey of people visiting a gout education website, a quarter of respondents with gout reported sleep problems, with sleep apnea being the most commonly diagnosed sleep disorder. Nine out of 10 respondents reported snoring during sleep, and 5 out of 10 reported snorting, gasping, or stopping breathing while asleep. This high prevalence of snoring, snorting, gasping, or stopping breathing while asleep indicates that the actual prevalence of OSA may be even higher than the 17% physician-confirmed OSA diagnosis reported by people with gout. Even the 17% prevalence of sleep apnea in gout is much higher than the 4–7% reported in the US general population previously . Our recSleep quality in gout on the single-item was much lower than that reported from two trials of pregabalin in fibromyalgia, a condition where sleep abnormalities are very common and often presenting features of the disorder, 5.5 vs. 6.2–6.7 . DaytimeSo, what are the implications of these study findings for clinical practice? Knowing that both gout and OSA are common in the general population, an earlier recognition of undiagnosed OSA and sleep disorders in people with gout can improve the ability to diagnose and treat sleep disorders. Our study indicates that a clinic QI initiative of querying patients with gout about sleep disorders may be appropriate, low-cost, and practical way to improve the recognition of coexisting sleep disorders in patients with gout. Even in the absence of a subsequent sleep disorder diagnosis, recognizing the impact of gout and gout flares on sleep can lead to a patient-centered care approach. Appropriate referral of patients with severe symptoms and supporting examination findings to a sleep study for confirming/ruling out OSA and/or a sleep expert for diagnosis of OSA and other sleep disorders can fill two quality gaps of delayed/missed diagnosis and delayed treatment of OSA and other sleep disorders.n = 179) and some sleep questions such as snorting/gasping/stopping breathing (n = 163) compared to that noted for race/ethnicity/sex . Self-reported sleep parameters are not without limitations, since over-reporting of sleep duration by self-report has been described, and self-report had only moderate correlation with objective assessment of sleep duration [This study should be interpreted considering study limitations. Findings may only be generalizable to patients with gout who use the Internet, and not all gout patients. The Internet study design may have selected for a younger people, who might be more technologically oriented. However, the use of Internet is growing in all segments of the society, and 70% and 27% of our survey respondents were ≥ 50 and ≥ 65 years old, respectively. Response bias is an important study limitation, and missingness of responses was higher for certain variables/questions such as ULT use (missing, duration . The lacIn conclusion, Internet users with self-reported physician-diagnosed gout commonly reported physician-diagnosed sleep disorders. A large proportion of patients with gout also reported frequent snoring, snorting, gasping, or stopping breathing while asleep, indicating an additional cohort with subclinical or undiagnosed OSA. Given high prevalence of sleep disorders in people with gout, further studies are needed to examine the true rates and types of sleep disorders in gout. An early diagnosis and treatment of sleep disorders in gout may reduce its impact and morbidity and may improve quality of life.


In crop breeding programs, breeders use yield performance in both optimal and stressful environments as a key indicator for screening the most tolerant genotypes. During the past four decades, several yield‐based indices have been suggested for evaluating stress tolerance in crops. Despite the well‐established use of these indices in agronomy and plant breeding, a user‐friendly software that would provide access to these methods is still lacking.iPASTIC) is an online program based on JavaScript and R that calculates common stress tolerance and susceptibility indices for various crop traits including the tolerance index (TOL), relative stress index (RSI), mean productivity (MP), harmonic mean (HM), yield stability index (YSI), geometric mean productivity (GMP), stress susceptibility index (SSI), stress tolerance index (STI), and yield index (YI). Along with these indices, this easily accessible tool can also calculate their ranking patterns, estimate the relative frequency for each index, and create heat maps based on Pearsonʼs and Spearmanʼs rank‐order correlation analyses. In addition, it can also render three‐dimensional plots based on both yield performances and each index to separate entry genotypes into Fernandezʼs groups , and perform principal component analysis. The accuracy of the results calculated from our software was tested using two different data sets obtained from previous experiments testing the salinity and drought stress in wheat genotypes, respectively.The Plant Abiotic Stress Index Calculator (iPASTIC can be widely used in agronomy and plant breeding programs as a user‐friendly interface for agronomists and breeders dealing with large volumes of data. The software is available at https://mohsenyousefian.com/ipastic/. The climate crisis has increased the frequency and intensity of both abiotic and biotic stressors. In recent decades, the effects of these stressors on crop production have become increasingly important .The nine proposed indices were first used to screen for drought‐tolerant genotypes and are more commonly known as drought‐stress indices. Nonetheless, these indices can be used in other studies—including those of abiotic and biotic stressors—for screening tolerant and susceptible genotypes. During the past four decades, these indices have been developed and used independently in numerous breeding programs. However, a software package that amalgamates all of these indices into a single source has thus far not been developed. Therefore, we offer the first user‐friendly online software that meets this need, the Plant Abiotic Stress Index Calculator . Alternatively, users can access the source codes in R language . In addition to the web application, iPASTIC is available in R language for more advanced users. Figure iPASTIC calculates the nine indices and the percentage of relative change due to stress relative to the non‐stress environment for a set of genotypes. It also calculates the ranking patterns of the genotypes, based on each index. Using the WebGL and Three.js frameworks , which are displayed with the Canvas tool. The relative frequency of each index can also be estimated. Principal component analysis (PCA) is another tool available in this software, which enables users to visualize the associations between the tested genotypes and index vectors in a PCA‐based biplot.Table Cabello, , this soCabello, . Based oCabello, , iPASTICIndices, includes two separate sheets. The first sheet displays average yield (for each trait) under non‐stressful and stressful conditions, relative change due to stress, and actual values of the nine measured indices. The second sheet displays genotype rankings for each index, along with sum ranks, average sum of ranks (ASR), and standard deviation (SD), all of which are downloadable in Excel format.After following the instructions on the website, the results are displayed in five separate tabs. The first tab, Frequencies, provides the relative frequency of genotypes based on yield and each index. This tab enables users to obtain more information regarding the distribution of the genotypes into different classes. When one index is selected, the genotypes belonging to each class are displayed at the bottom of the frequency plot.The second tab, Correlation Plots, associations among different indices and yield are shown in two distinct heat maps. Pearsonʼs correlation analysis estimates the correlation coefficients of the correlation among the actual values of the indices; Spearmanʼs rank‐order correlation analysis shows the relationships among the ranks of the indices. The user has the option of displaying the results as one of three different heat maps .In the third tab, Three‐dimensional, renders a 3D plot for each index along with yield. The third dimension is adjustable, and users can select any of the indices from the menu bar at the bottom of the page to create a 3D plot. iPASTIC also has a tool to check the position of each genotype individually. Selecting one or more genotypes in the “Genotypes control panel” on the right side of the indexʼs menu bar will display the position of the selected genotypes. Clicking on the bars in the 3D plot will display the label for each genotype. The viewing angle of the plot can be changed by dragging the 3D plot. After selecting the best position and viewing angle, the final graph can be downloaded as an image file.The fourth tab, PCA, shows the results of the PCA analysis, which is mostly used as a multivariate approach in investigative data analysis and for predictive models. It can also be used to visualize distance and relatedness between entries. PCA can be done by eigenvalue decomposition of a data correlation (or covariance) matrix, or singular value decomposition of a data matrix, usually after a normalization step of the initial data. The results of PCA are downloaded in an Excel file. In the output file, the summary of descriptive statistics , correlation (or covariance) matrix, eigenvalues, eigenvectors, factor loading, contribution of variables in each component, and factor scores for each genotype are displayed in separate sheets. In this section, the biplot is initially rendered on the first two principal components, but iPASTIC provides a useful tool that enables users to render the biplot on any two arbitrary principal components.The fifth tab, −1, and genotypes G1, G3, G25, G20, and G30 had the highest mean performance. Under salinity stress, shoot dry weight (Ys) ranged from 25.43 to 84.38 mg·plant−1, and genotypes G3, G47, G2, G20, and G46 showed the highest values. The relative change due to salinity stress for each tested genotype revealed that the genotypes G55, G47, G69, G71, and G46 had the smallest changes, being 2.19%, 2.53%, 2.86%, 4.59%, and 5.46% lower than the controls. Using the TOL index, genotypes with lower values are more tolerant to stress. Accordingly, genotypes G55, G69, G47, G71, and G23 were the most tolerant to salinity, and genotypes G88, G25, G34, G59, and G4 were the most sensitive. Genotypes that perform well under non‐stress and stressful conditions will have high values for the STI, MP, GMP, and HM indices and will be identified as tolerant. In this case, genotypes G2, G3, G20, G46, G47, and G50 had the highest values for these indices. The SSI identifies only those genotypes with minimal reductions under stressful compared to non‐stressful conditions  and saline (Ys) conditions for each seedling plant is in Ahmadi et al. . Detaile−1, but under salinity stress the yield potential of most genotypes ranged from 34 to 62 mg·plant−1 , G46 , and G2  were the most salinity‐tolerant genotypes in severe salinity conditions Appendix . The relAppendix . The relAppendix . The higAppendix , chickpeAppendix , and canAppendix . AppendiAppendix .Triticumaestivum L., T. durum Desf., T. urartu Thumanjan ex Gandilyan, T. boeoticum Boiss., Aegilops tauschii Coss., Ae. neglecta Req. ex Bertol., Ae. triuncialis L., Ae. crassa Boiss., and Ae. caudata L. All genotypes were grown in a greenhouse maintained at an optimal photoperiod and growing temperature at the Department of Genetics and Plant Breeding, Imam Khomeini International University, Qazvin, Iran, during 2016–2017. The experiment was arranged as factorial using randomized complete block design with three replications. The plants were well watered every 1–2 days to maintain 90% ± 5% field capacity (FC). The water stress treatment (FC = 25 ± 5%) was initiated at the three‐leaf stage of growth. Details on the growing conditions, stress treatments, and data collection are available in Ahmadi et al. , T. aestivum (3.64), Ae. neglecta (4.18), and Ae. caudata (4.36)  of the total variation in yield performance and the measured indices. Eigenvector coefficients revealed that Yp and Ys along with the indices, except YSI and RSI, had a positive association with PC1, whereas SSI and TOL had a negative association with PC2. Hence, using the PC1 results, tolerant genotypes will be selected based on high‐ranking yield performance and tolerance indices such as MP, GMP, and STI. In this case, Appendix . RegardiAppendix .iPASTIC) to calculate several yield‐based stress tolerance and susceptibility indices that are important in the identification of tolerant crop genotypes. In addition to the useful and practical tools described above in the Methods and Results, iPASTIC also has the following advantages: (1) It can analyze large data sets in minimal time; (2) It is a cross‐platform software that does not require additional downloads or installation; (3) Unlike other codes based on SAS and R packages, which require additional user knowledge, iPASTIC has a web‐based user‐friendly interface; and (4) It is compatible with the major browsers . These advantages, combined with its user‐friendly interface and tools for better selection of entry genotypes, make iPASTIC valuable for use in agronomy and plant breeding programs by students, teachers, and researchers alike.We developed a novel online software  and saline (Ys) conditions along with the relative change (RC) due to stress and tolerance and susceptibility indices calculated using iPASTIC software for Data Set 1.Click here for additional data file.APPENDIX S3. Yield performance rankings of 90 wheat genotypes and accessions under control (Yp) and saline (Ys) conditions along with the calculated tolerance and susceptibility indices using iPASTIC software for Data Set 1.Click here for additional data file.APPENDIX S4. (A–B) Relative frequency of yield performances under (A) control conditions and (B) stress conditions in 90 wheat genotypes and accessions. (C–D) Relative frequency of (C) mean productivity (MP) indices and (D) geometric mean productivity (GMP) indices calculated by iPASTIC software for Data Set 1.Click here for additional data file.APPENDIX S5. Relative frequency of (A) relative stress index (RSI), (B) stress tolerance index (STI), (C) stress susceptability index (SSI), and (D) yield index (YI) indices calculated by iPASTIC software for Data Set 1.Click here for additional data file.APPENDIX S6. Relative frequency of (A) yield stability index (YSI), (B) harmonic mean (HM), and (C) tolerance index (TOL) indices calculated by iPASTIC software for Data Set 1.Click here for additional data file.APPENDIX S7. Rendered heat‐map plot based on Pearsonʼs correlation analysis for Data Set 1. See Table Click here for additional data file.APPENDIX S8. Rendered three‐dimensional plot based on the STI index and yield performance (Yp and Ys) of the 90 wheat genotypes and accessions in Data Set 1. Each plot shows a view angle of distribution of entry genotypes into Fernandezʼs groups (A–D).Click here for additional data file.APPENDIX S9. Rendered principal components analysis–based biplot based on the correlation matrix of Yp, Ys, and nine tolerance and susceptibility indices calculated using iPASTIC software for Data Set 1.Click here for additional data file.APPENDIX S10. Yield performance of nine wheat genotypes under control (Yp) and saline (Ys) conditions along with the relative change (RC) due to stress and tolerance and susceptibility indices calculated using iPASTIC software for Data Set 2.Click here for additional data file.APPENDIX S11. Yield performance rankings of nine wheat genotypes under control (Yp) and saline (Ys) conditions along with the calculated tolerance and susceptibility indices using iPASTIC software for Data Set 2.Click here for additional data file.APPENDIX S12. Rendered heat‐map plot based on Pearsonʼs correlation analysis for Data Set 2. See Table Click here for additional data file.APPENDIX 13. Rendered three‐dimensional plot based on the STI index and yield performance (Yp and Ys) of the 90 wheat genotypes and accessions in Data Set 2.Click here for additional data file.APPENDIX 14. Rendered principal components analysis–based biplot based on the correlation matrix of Yp, Ys, and nine tolerance and susceptibility indices calculated using iPASTIC software for Data Set 2.Click here for additional data file.


Staphylococcus aureus (S. aureus) is a common cause of bacteremia, which leads to significant morbidity and mortality. We investigated the relationship between time to positivity (TTP) and clinical outcomes in children with S.aureus bacteremia in the China.Staphylococcus aureus bacteremia inpatient was performed in Children’s Hospital of Chongqing Medical University in China between 29 January 2014 and 29 August 2017. TTP and clinical parameters were determined and analyzed. The receiver operating characteristic (ROC) curves were plotted for optimal cut-off selection, multivariate logistic regression tests were performed to evaluate the association between TTP and clinical outcomes.A retrospective study of P = 0.000). Septic shock occurred in 57.14% of patients with early TTP and in 18.57% of patients with late TTP (P = 0.002). Detailed multivariate and statistical analysis revealed that early TTP, need for vasoactive agent were independent risk factors of in-hospital mortality; early TTP, need for vasoactive agent and APACHE II score ≥ 15 were independent risk factors of septic shock incidence in S. aureus bacteremia children.Overall, 84 cases were enrolled. We stated that in-hospital mortality is significantly higher in the early TTP (≤17 h) than in the late TTP (> 17 h) group (57.14% vs 7.14%, S. aureus bacteremia children. These results have important implications in the assessments and management of pediatric S. aureus bacteremia in a clinical setting.Overall, TTP of ≤17 h appeared to correlate with the worse outcomes for Retrospectively registered. Staphylococcus aureus (S. aureus) is a common cause of bloodstream infections [S. aureus bacteremia (SAB) leads to significant morbidity and mortality, both in adults and children [H. influenza [, S. pneumonia [N. meningitides [fections  and S. achildren –4. The pchildren , 6. Prevchildren , 8, and children –12. TTP nfluenza  , S. pneneumonia , 14, andngitides . Severalngitides , 16, 17.S. aureus blood culture positive; (iv) with systemic inflammation reaction syndrome status. The exclusion criteria included any of the following: (i) patients who were lost to follow-up; (ii) patients with incomplete clinical information; (iii) patients without TTPs in medical records.This study was performed in Children’s Hospital of Chongqing Medical University, a 1500-bed tertiary level III teaching hospital in Chongqing, China. SAB children hospitalized in Children’s Hospital of Chongqing Medical University between 29 January 2014 and 29 August 2017 were enrolled retrospectively. The inclusions had the following characteristics: (i) inpatients (not include the emergency department); (ii) age < 18 years; (iii) with ≥1 Staphylococcus aureus bacteremia (SAB) was defined as at least 1 positive S. aureus blood culture with systemic inflammation reaction syndrome status (SIRS), SIRS was defined according to the criteria previous published on Pediatr Crit Care Med [9/L (infants), < 1.0 × 109/L (< 1 year old), and < 1.5 × 109/L (≥1 year old). The source of infection consisted of pneumonia, bone and joint, skin or soft tissue, endocarditis, CNS  infection, incisions, catheter related infection , and multiple sites. Nosocomial infection was defined as S. aureus infection that occurred > 48 h after hospital (not include the emergency department) admission or < 48 h after discharge. The length of hospitalization was defined as the time period between admission and discharge. The classification of septic shock was defined according to the criteria previously published in JAMA [Care Med . Time to in JAMA .2 production every 5 min by means of a fluorescent signal. Bottles with positive results were examined by Gram staining, and their contents were subcultured. Species identification and susceptibility tests were performed using Vitek identification and susceptibility cards (bioMe’rieux Vitek).Approximately 3 mL of blood was inoculated into BACTEC plus aerobic bottles, which were then transported to the laboratory and immediately incubated in an automated continuous monitoring system. The BD diagnostic system was used for blood culture, which monitors COThe collected data included TTP of blood culture, demographic characteristics , underlying conditions , hypoalbuminemia, APACHE  II scores, sources of infection as mentioned earlier, prior antibiotic exposure, appropriate antibiotic exposure, immunosuppressants use, nosocomial infection, methicillin-resistance, need for invasive mechanic ventilation, need for vasoactive agent, length of hospitalization, the incidence of septic shock and in-hospital mortality.The primary outcome was in-hospital mortality. Since previous studies suggested that septic shock meant worse outcomes in adult SAB patients , it was Χ2 test or Fisher’s exact test. The log-rank test for Kaplan-Meier time-to-positivity analysis was constructed. Receiver operating characteristic (ROC) curves were plotted for the rate of sensitivity and 1-specificity. Youden’s Index was used for optimal cut-off selection, and the area under the curve (AUC) was calculated. The non-parametric test was constructed for the comparison of two groups. Univariate and multivariate logistic regression tests were constructed, for exploring the independent risk factors of septic shock and in-hospital mortality. Univariate logistic regression test was constructed for all independent risk factor exploration of in-hospital mortality, septic shock. Multivariate logistic regression test was constructed for the variates that showed differences in Univariate logistic regression test. The odds ratio (OR) and their 95% confidence interval (CI) were calculated for the statistically significant variables. All the tests were performed using SPSS (Version 19.0.0 for Windows), and p-value < 0.05 was considered to be statistically significant.The continuous variables were presented as medians, and the first and third quartiles; the Student’s t test, Chi-square test, or the Mann-Whitney U test were used for analysis. The categorical variables were presented as rates and incidences, and assessed by means of the S. aureus blood culture positive and systemic inflammation reaction syndrome status were enrolled retrospectively. Of them, 4 cases were lost to follow-up, 3 cases had incomplete clinical information and 4 cases missed their TTPs in medical records. Therefore, 84 cases were finally included in the study  age of the enrolled SAB children was 56.00  months, median (IQR) weight was 15.00  kilogram, and 65.5% (55/84) of them were male. Less than half of the patients  had underlying conditions. Among the 35 patients (41.7%) with prior antibiotic exposure, only 13 cases (15.5%) reported appropriate. Immunosuppressants were used in 20 cases (23.8%). The most frequent infection source was multiple sites , followed by pneumonia (27.38%), and bone or joint infection (15.48%). Methicillin-resistance was detected in 29 cases (34.5%), and nosocomial infection in 14 cases (16.7%).P = 0.001) and septic shock incidence (P = 0.001)  of blood culture of the 84 SAB children was 21.80 h . The bar chart of TTP is shown in Fig. 01) Fig. . ReceiveP = 0.033). Vasoactive agent was needed in 50.0% cases (7/14) in early TTP group but only in 18.6% cases (13/70) in the late TTP group (P = 0.012). In-hospital mortality was 57.1% (8/14) in early TTP group but 7.1% (5/70) in late TTP patients (P = 0.000). Septic shock occurred in 8 patients  in early TTP group and in 13 patients  in late TTP patients (P = 0.002). Taken together, these results indicated critical clinical differences between the early and late TTP groups.A comparison between these two TTP groups was shown in Table Univariate logistic regression test demonstrated that in-hospital mortality was correlated with hematologic malignancy, immunosuppressants use, need for invasive mechanical ventilation and vasoactive agent, neutropenia, APACHE II score ≥ 15 and early TTP. Multivariable logistic regression test showed that early TTP, need for vasoactive agent were independent risk factors of in-hospital mortality Table .Table 2LThe univariate logistic regression test demonstrated that the incidence of septic shock was correlated with hematologic malignancy, immunosuppressants use, need for invasive mechanical ventilation and vasoactive agents, neutropenia, APACHE II score ≥ 15, and early TTP. As before, multivariable logistic regression showed that early TTP, need for vasoactive agent and APACHE II score ≥ 15 were independent risk factors of incidence of septic shock Table .Table 3LThe prognostic role of TTP in SAB children remained unclear, which prompted us to conduct the present study. We explored the correlation between TTP and clinical characteristics and clinical outcomes in SAB children. As noted above, the median TTP in this group of children was 21.80 h , and the optimal TTP cut-off was 16.955 h, which were longer than those of adult SAB patients having the optimal TTP cut-off of 12 or 14 h , 11, 16.To our knowledge, this is the first study to explore the relationship between TTP and clinical outcomes of SAB in children. Here, we have documented that early TTP group patients had 97-fold higher in-hospital mortality and 7-fold higher incidence of septic shock than those with late TTPs. Early TTP was an independent risk factor of in-hospital mortality and septic shock incidence, which indicated that early TTP is indeed associated with worse clinical outcomes in children with SAB. The concept of early TTP of blood cultures is directly related with a higher bacterial load in blood. This is in line with the previous studies in adults, in which early TTP was considered an indicator of poor clinical outcomes , 22, 23.2 supply. This may also indicate an association with severity and mortality. Not surprisingly, as Badia et al. [We also documented that patients needing vasoactive agents had a 40-fold higher in-hospital mortality and 27-fold higher incidence of septic shock. Need for vasoactive agent was in fact another independent risk factor of in-hospital mortality and septic shock. Sepsis has been described as a paradigm of acute whole body inflammation with systemic damage in the vascular endothelium , and it a et al.  showed tIn addition, patients with APACHE II scores≥15 also presented 10-fold incidence of septic shock, and a statistically significant difference in early TTP group. APACHE II score has been advocated as the gold standard for risk evaluation in critically ill patients , and couOur finding that prior antibiotic exposure and appropriate antibiotic exposure had little impact on TTPs and clinical outcomes is consistent with other studies , 17, 22,n = 84) may result in type II error and reduce the ability to determine the statistical significance of the variables. Third, as the data were collected from the medical records retrospectively, some information was unfortunately missed. Clearly, multi-center, prospective studies in the future, using a larger sample size, should strengthen the results of this study.Lastly, we would like to address the potential limitations of this study. First, as a single- center study, the data were collected from one academic teaching hospital in China, the results may not easily extrapolate to patients admitted to other hospitals or in other countries. Second, the relatively small sample size of our study (S. aureus bacteremia children. TTP of ≤17 h may correlate with the worse outcomes for these children.Early TTP, need for vasoactive agent were independent risk factors of in-hospital mortality; early TTP, need for vasoactive agent and APACHE II score ≥ 15 were independent risk factors of septic shock in


Surgical stress induces the release of neuroendocrine mediators and cytokines during perioperative period, which may have adverse effects on cancer patients. While the surgical stress responsse can be affected by anesthetic technique. Therefore, we designed this study to assess whether subcostal transversus abdominis plane (TAP) block can affect perioperative neuroendocrine stress response, postoperative analgesia and postoperative recovery in patients undergoing radical gastrectomy under general anesthesia.Sixty-five patients were recruited. Patients randomly received general anesthesia (control group), or general anesthesia combined with TAP block (40 mL of 0.375% ropivacaine) (TAP group). The primary outcome was neuroendocrine levels including norepinephrine (NE), epinephrine (E), cortisol (Cor), glucose (Glu), interleukin (IL)-6 and IL-10 during 48 h after surgery. Secondary outcomes included pain score, hemodynamic variables and recovery characteristics.Data from 61 of 65 patients were analyzed. The levels of NE, E, Cor, and Glu were blunt by TAP block during perioperative period. The levels of IL-6 and IL-10 were significantly lower in TAP group than in control group. TAP block efficiently relieved postoperative acute pain up to 12 h postoperatively with more stable perioperative hemodynamics compared with control group.Subcostal TAP block blunts perioperative stress response and provides efficient analgesia, with good hemodynamic stability and minimal adverse effects. Gastric cancer is one of the most commonly diagnosed cancers around the world. Surgical resection is currently the mainstay of curative treatment for this cancer, which is recommended to maximize the probability of complete tumor clearance, reduce loco-regional recurrence, and improve long-term survival . TransabTransversus abdominis plane (TAP) block, as an emerging regional anesthetic technique, can provide efficient analgesia by blocking the regulation of sensory nerve at the anterior abdominal wall , which cSubcostal, mid-axillary and lumbar triangle of Petit approaches are widely used in TAP block . The bi-clinicaltrials.gov .Our study was approved by the Ethics Committee of China-Japan Union Hospital of Jilin University (2016ks008) and was in accordance with good clinical practice and the guiding principles of the Helsinki Declaration. The written informed consents were obtained from all patients. The trial was registered prior to patient enrollment at Patients meeting the following inclusion criteria were enrolled: patients who were scheduled for open radical gastrectomy; patients who had no contraindication to local anesthetic, and patients whose American Society of Anesthesiologists’ (ASA) physical status I, II or III. Emergency patients and patients with preoperative infection, or patients with a history of immune disease, endocrine system disease, blood transfusion, or chemotherapy were excluded from this study.Patients were randomly divided into two groups by a computerized random-number generator with 1:1 ratio for TAP group and control group. The pre-anesthetic interview was carried out by a single investigator to assess the eligibility of participants and to record the baseline data. Another anesthesiologist (not involved in study) who took the corresponding opaque envelope in the operating room performed the block and anesthesia induction, so he was unblinded to group allocation. A resident anesthetist who was blinded to randomization was responsible for collection of intraoperative data and blood. Postoperative data and blood were collected by another investigator who visited the participants at 1, 6, 12, 24, 48 h after surgery. All patients underwent surgery from the same operative team. The patients allocated to respective groups were administered as follows: TAP group: general anesthesia and ultrasonography-guided TAP block with 40 ml of 0.375% ropivacaine; Control group: standard general anesthesia (no sham intervention for TAP block).No preoperative sedatives or analgesics were administered before the operation. Routine monitoring including electrocardiogram, invasive arterial blood pressure, pulse oximetry, and end-tidal carbon dioxide was established before anesthetic induction. All patients underwent standard general anesthesia induced by midazolam 0.02 mg/kg , propofol 2.0–2.5 mg/kg , sufentanil 0.3 μg/kg , and cis-Atracurium 0.15 mg/kg . In order to maintain general anesthesia, intravenous and inhaled volatile anaesthetics of nitrous oxide, sevoflurane , sufentanil, and cis-Atracurium were used. During the operation, the MAC value was maintained within 1.2–1.5% by regulating the inhalation concentration of nitrous oxide and sevoflurane. Tidal volume and rate were adjusted to maintain an end-tidal PCO2 of 30–40 mmHg. When hemodynamic values increased more than 15% above pre-induction baseline values, an appropriate dose (0–10 μg) of sufentanil was used to intervene. Heart rate (HR) < 40 beats/min (bradycardia) was intervened with 0.5 mg atropine, and mean arterial blood pressure (MAP) < 60 mmHg (hypotension) was treated with 5 mg ephedrine. The body temperature was maintained between 36 °C and 37 °C during the operation.TAP block was administered after anesthesia induction. In the TAP group, TAP block was performed bilaterally under ultrasound  guidance at 30 min before the surgical incision. The probe was placed in the midline of abdomen below the xiphoid and moved right laterally along the subcostal margin to the anterior axillary line. After the probe identified the plane between the rectus and transverse abdominal muscles, a 100-mm, 20-G Stimuplex block needle was guided within the plane to the point just inferior to the right costal margin such that the tip laid between the obliquus internus abdominis and transversus abdominis within the neurovascular fascial plane. After aspiration, to exclude vascular puncture, 1 mL test dose was injected to determine the flow resistance and confirm needle tip placement within the fascial plane. Then, 10 mL 0.375% ropivacaine was multi-point injected in this plane laterally along the subcostal margin. The probe was moved back to the anterior axillary line, and another 10 mL 0.375% ropivacaine was injected through the needle inferior to the costal margin within the TAP using an identical technique, making this two injected drug a continuous plane under the costal margin, from the medial margin of the rectus abdominis muscle to anterior axillary line. The left side of TAP block was conducted with the identical technique.After extubation, patients were transferred to the post-anesthesia care unit (PACU), and all of them received morphine patient-controlled analgesia (PCA) with a standard dosing regimen: 2 mL/h continuous infusion (a bolus of 1 mL with a lock-time of 15 min) by using the electronics pump .The primary outcome was neuroendocrine mediators and cytokines at different time points of 48 h after operation. Venous blood samples were collected before anesthesia (baseline), immediately after surgery, and at 6, 24, and 48 h after surgery, and stored in pre-chilled tubes on ice and then centrifuged within 90 min. The separated plasma was stored at − 80 °C. Glucose (Glu) level was measured immediately after venous blood was collected using glucometer . Plasma levels of norepinephrine (NE), epinephrine (E), C-reactive protein (CRP), cortisol (Cor), interleukin (IL)-6, and IL-10 were measured by micro enzyme-linked immunosorbent assays kits .The second outcomes included pain scores, hemodynamic variables and recovery characteristics during the first 2 postoperative days. Pain scores included VAS scores at rest and during movement (cough or rotating the body) in the first 2 postoperative days. The MAP and HR were continuously measured and recorded before anesthesia, during induction, tracheal intubation, incision, immediately after tracheal extubation, as well as at 6, 24, and 48 h postoperatively. The other recorded observations included additional sufentanil consumption, postoperative opioid requirement, and recovery profiles . Sedation was assessed by Ramsay score . Additionally, discontinuing PACU was determined by a standard score test (= 10: PACU should be discontinued). The study processes are shown in Additional file The minimum detectable difference of plasma cortisol concentration was estimated immediately after surgery between two groups. The mean and SD values of plasma cortisol were as follows: MTAP = 410 nmol/L, MControl = 521 nmol/L, STAP = 142 nmol/L, and SControl = 16.4 nmol/L. Based on sample size analysis performed using PASS 11.0 , with α = 0.05 and β = 0.2, a minimum sample of 25 cases in each group was required, respectively.2 or Fisher exact test. P value < 0.05 was considered significant.Statistical analyses were performed using SPSS 18.0 . The normal distribution of data was evaluated using Shapiro-Wilk test. Data were expressed as mean (± SD) or percentages of the total number of patients (%). Comparisons of NE, E, Cor, Glu, cytokines, hemodynamic data, and VAS scores between groups were performed by repeated-measures analysis of variance. The differences for opioid consumption, time to first flatus, and time in PACU were analyzed using Student’s t test followed by 2-tailed Dunnett test. Categorical data were analyzed by using χTotal 65 patients were enrolled from February 2017 to August 2017. According to the exclusion criteria, 4 patients were excluded, and data from 61 patients  were finally analyzed. Baseline characteristics showed no significant difference between two groups , 24 h  and 48 h postoperatively   , 24 h (P < 0.0001), and 48 h postoperatively (P < 0.001)  . In TAP group, HR and MAP showed no significant difference relative to baseline except for induction and intubation time point.Pain scores for different time points are presented in Table P < 0.001)  Table . In cont1) Table .Table 3In this prospective, randomized trial, we found that the levels of NE, E, Cor, and Glu were blunt by TAP block during the perioperative period. Additionally, the levels of IL-6 and IL-10 were lower in TAP group significantly. Moreover, TAP block could efficiently relieve postoperative acute pain up to 12 h postoperatively with more stable perioperative hemodynamics compared with control group. Thus, TAP block can be used as an adjunct to general anesthesia to suppress stress responses and control pain in open radical gastrectomy surgery.Perioperative stress response could be accurately indicated by changes of neuroendocrine mediators and cytokines via direct activation of the somatic and sympathetic nervous systems. It is well known that epidural block could block the sympathetic response and efficiently block the plasma levels of cortisol and relevant cytokines in patients –16. TAP Surgical trauma and perioperative pain initiate neuroendocrine response, and stimulate the release of cytokines. The pro- and anti-inflammatory cytokines are crucial for acute-phase immune response after surgery. Wind et al.  have shoEfficient analgesia of TAP block has been well documented in human studies. Recent Meta-analyses have suggested that TAP block improves postoperative pain at both rest and movement up to 24 h postoperatively independent of the surgery types , 31. In There were some limitations in our study. First, we only enrolled patients who underwent elective open radical gastrectomy and met the inclusion criteria, which limited the external generalizability of our results. Second, we used sufentanil for analgesia, known to affect the neuroimmunoendocrine network, which may influence our results. Third, patients in control group were not given subcostal TAP block with placebo, thus our study may be an open randomized controlled trial. Fourth, different anesthetic and antalgic medications may have complex effects on the prognosis of patient, in terms of postoperative recuperation, cancer migration, invasion, and interference with immune system, but we did not evaluate the long-term clinical effects on these individuals. Therefore, our findings are preliminary and a more comprehensive trial that assesses the long-term functional outcomes is necessary.In conclusion, subcostal TAP block could inhibit the undesirable stress response and provide efficient analgesia without increasing the adverse reactions for open radical gastrectomy. For patients with malignant tumor, the relationship between reduction in stress response and long-term clinical outcomes needs to be further studied.Additional file 1. Figure S1. The flow chart of this study.


Proximal humerus fractures comprise approximately 2% of all pediatric fractures. In general, upper extremity fractures have increased in children. However, recent trends of proximal humerus fractures are not analyzed yet. The aim was to study the incidence and treatment trends of proximal humerus fractures in children.All 300 children, aged < 16 years, who suffered from a proximal humerus fracture in the catchment area of Oulu University Hospital, Finland, between 2005 and 2015, were included. Radiographs were reviewed, and patients, injuries, treatments, and outcomes were comprehensively studied. Annual incidence was based on the child population at risk, which changed between 84.500 and 88.100 in the study time.P = 0.045). Bayonet displacement increased the risk of surgical fixation up to 16-fold  in a multivariate analysis when adjusted with other potential risk factors. Higher age was also associated with operative treatment (P = 0.002). The most usual recreational activities were horse riding, downhill skiing, snowboarding, and trampolining.The annual incidence of childhood proximal humerus fractures was mean 31.4/100,000 and no variation trend was found. The majority (92%) was treated nonoperatively, however, there was an increase of operative fixation from 0 to 16% during the study time (Difference 16, 95% CI 0.3 to 34.9%, Contrary to most upper extremity fractures in children, proximal humerus fractures did not increase during the long study period. However, their operative treatment increased compared to nonoperative treatment, but the evidence supporting that trend remains unclear. Proximal humerus fractures in children comprise approximately 2% of all pediatric fractures . They arThe proximal growth plate of the humerus is responsible for 80% of the bone’s longitudinal growth. Further, the periosteum is metabolically active in the immature skeleton , 12; thePediatric upper extremity fractures in general have increased since the beginning of the 2000s , but cloStatistics Finland. All cases who had been diagnosed with S42.2 in the International Classification of Diseases (ICD version 10) were included. The patients’ original hospital charts and radiographs were reviewed to confirm the diagnosis and get particulars regarding the type on fracture, treatment, and results. Type of injury, age, sex, the side of the injury, date, the day that the injury occurred, and clinical findings were studied. Patients with pathological fractures were excluded.This population-based study consisted of 300 children younger than 16 years old, who had a proximal humerus fracture in the Oulu University Hospital district between 2005 and 2015. The hospital was the only pediatric trauma center in the study area and the respective children population at risk was 84.500–88.100 during the study time, according to the official statistics by The proximal humerus fractures were classified by the AO-classification for epiphyseal 11-E/1 or 11-E/2, metaphyseal 11-M/3, and metaphysis-diaphysis junction groups . Growth Angular deformity, fracture displacement (gap), translational (ad latus) displacement, comminuted fractures, and potential shortening were analyzed in anterior-posterior, lateral, and Y-projections of the radiographs; glenohumeral joint congruency and luxation were recognized. The treatment was first classified as operative versus non-operative. Operatively treated cases were analyzed closer to determine the reduction type (closed/open) and osteosynthesis type. The type of anesthesia was recognized. Short-term outcomes and complications, as determined by the treating surgeon, were reviewed from hospital registries.The annual incidence of proximal humerus fractures in an unselected child population and its potential changing trend were the main outcomes of the study. Secondary outcomes included the operative treatment rate and its potential change, and its associated factors, as well as injury and patients’ characteristics.P < 0.05 (5%). Data were analyzed using IBM SPSS Statistics, version 24 and StatsDirect statistical software, version 2.08.The annual incidence was determined for 100,000 children at risk. Frequencies and proportions were reported. Year by year differences of proportions were evaluated by using the standardized normal deviate (SND) test for independent variables. Pearson’s chi-square test and Fisher’s exact test were used for categorical variables. Binary logistic and multivariate regression analysis were used to determine the risk with 95% confidence intervals (CIs) for operative proximal humeral fracture treatment according to the potential risk factors . The threshold of statistical difference was set at P = 0.777). The mean incidence was 38.20 in girls and 25.35 in boys  to 2015   in 2005 and 52% (N = 13/25) in 2015, respectively . Their mean age was 10.2 years at the time of fracture , while 39.9% involved the growth plate. The following fractures were found: 11 SH type-1 fractures, 107 SH type-2, and two SH type-3 fractures. There were 15 (5.0%) proximal humerus fractures located in the meta-diaphyseal transitional zone.There were 177 girls and 123 boys with a proximal humerus fracture. The proportion of boys was 39.1% (P = 0.045) . However, a wide majority of the patients were still treated nonoperatively, three of them by closed reduction under general anesthesia without surgical fixation, while only 24 (8%) were treated operatively with surgical fixation.There was an increasing trend of operative treatment, while the rate changed from 0 to 16% during the study time  Fig. . The treN = 14) were performed > 1 day after the injury, while 29.2% (N = 7) were operated on the next day and 12.5% (N = 3) were operated on the day of the injury.More than half of the operations , followed by downhill skiing and snowboarding . Trampolining  and traffic accidents  were other common injury causes. Six injuries were ice-hockey related (2.0%). The mechanism of injury was falling on the same level in 19.3% of the cases (N = 58) or falling from height > 1.5 m .The most usual fracture cause was riding a horse .Ten cases, who were primarily treated nonoperatively, had to be surgically fixed later because of redisplacement. Further, one patient was re-operated after primary surgical treatment  due to a symptomatic scar. One in five (20.2%) of the boys suffered from complications and 14.7% of the girls . Short-term symptoms in radial (N = 6), median (N = 5), axillary (N = 1), and musculocutaneous nerves (N = 1) were also found. Two patients (N = 2) showed wide plexus brachialis injuries. One of them recovered well during a further follow-up of 8 months. The rehabilitation included active physical therapy. Another plexus injury resulted in persistent morbidity.During the short-term follow-up of 6 months, 37 patients (12.3%) suffered from stiffness and limited range of movement, in particular, decreased shoulder rotation. Five patients suffered from persistent nerve damage, with the ulnar nerve being the most commonly injured (N = 7/8) of them Kirschner wires were left on the skin and in one (N = 1/8) the wires were left under the skin. There were in total nine patients whose Kirschner wires were left under the skin; majority of them (N = 8/9) recovered without any complication, while the rate of infection was 47% (N = 7/15) among the cases who had the wires on the skin. The percutaneous Kirschner wires which were left on top of the skin increased the risk of surgical site infection as compared with the wires left under the skin .Eight patients had a postoperative superficial fixation material infection; in seven (P = 0.002). Higher age was also associated with the operative treatment. One in five  children > 12 years of age were operated on compared to 1.1% (N = 1/87) of children < 9 years (P < 0.001). In the year 2005 13.0% (N = 3/23) of the patients were > 12 years old, and the respective number was 24.0% (N = 6/25) in 2015 .There was a gender difference in operative versus nonoperative treatment ; the association for surgical fixation was up to 16-fold  in the multivariate analysis when adjusted with other potential risk factors. In turn, the patients with a displacement less than half of the bone thickness were rarely surgically operated . Further, angular deformity > 40° was associated with the increased association of operative treatment, but was not significant  (Table N = 8/23) of the fractures were displaced > 50% of the bone thickness in year 2005. The respective rate was 48% in 2015 (N = 12/25) .The association for operative treatment increased with an increasing displacement. Patients with a fracture displacement more than a bone thickness  were exclusively treated surgically  usually decreases the abduction motion of the shoulder, thus justifying surgical fixation . In turnThe weakness of the study was that the injury mechanism and associated background factors were not always well explained in the hospital charts. Injury history and clinical findings were based on the hospital registries. As a limitation, the number of patients who were operatively treated was not high, despite the long study period and satisfactory population at risk. A great majority of proximal humerus fractures are traditionally treated by nonoperative means. Further, there was no long-term follow-up data available, and the facture patients’ final recovery could not be determined.The strength of this study was its inclusive population-based design: all patients in the geographic catchment area during the study period were included. There were no other pediatric trauma centers in the area and slight proximal humerus fractures were followed-up in the study center too, despite the potential first contact in primary health care. Treatment was the same for every patient despite their economic situation and possible insurance status. It is still possible that there were a few non-inhabitant patients who were treated outside the study center; however, their number must be infinitesimal.The incidence of proximal humerus fractures in children has been stable, but the rate of operative treatment, rather than nonoperative treatment, has increased during the last decade. A bayonet position associates with surgical treatment; however, the reason for increasing surgical fixation remains unclear.


The EuroQol Group Five-Dimensional (EQ-5D) instruments have been validated in China for measuring health-related quality of life (HRQoL) and are increasingly being used in health economic studies. However, there is paucity in the literature documenting long-term changes in the EQ-5D results in the Chinese populations. This study aims to identify such changes and their determinants using the EQ-5D-3 L instrument.Data were obtained from the National Health Services Surveys in China, which included the EQ-5D-3 L since 2008. We compared the differences between the 2008 and 2013 surveys in the percentage of reported problems, visual analogue scale (VAS) scores, and the EQ-5D-3 L utility index derived from the national value sets. Factors associated with population changes in these EQ-5D results were identified using logistic, linear and Tobit regression models, respectively.p < 0.05) in 2013. The regression models revealed a rise  in VAS scores, but a slight drop  in utility index in 2013 compared with 2008 after controlling for variations in demographic, behavioral, socioeconomic and residential variables. But the effect sizes of the changes over time (estimated by “average change divided by baseline standard deviation”) did not reach the threshold of clinical importance after adjustment for variations in other factors. Higher socioeconomic status  was associated with better EQ-5D-3 L results.Compared with 2008, reported problems in self-care (3.3% vs 3.1%), usual activities (4.8% vs 4.6%) and anxiety/depression (6.4% vs 5.3%) decreased, whereas reported problems in mobility (5.1% vs 5.9%) and pain/discomfort (9.3% vs 12.6%) increased significantly (The changing trend (decrease) of the utility index is contradictory to that (increase) of the VAS scores, although neither is deemed clinically important. It is evident that socioeconomic and regional disparities in HRQoL exist in China. Health-related quality of life (HRQoL) is a multi-dimensional concept that measures self-reported well-being in physical, mental, and social functioning. It captures the impacts of health problems and diseases on quality of life –4. HRQoLOver the past few decades, significant progress has been made in measuring HRQoL. The EuroQol Group Five-Dimensional (EQ-5D) series is perhaps one of the most simple and frequently used instruments since early 1990s . The EQ-The EQ-5D-3 L instrument has been validated in Chinese populations , 17 and This study aimed to identify changes in the EQ-5D-3 L results over time in China and their determinants. The study was undertaken using the EQ-5D-3 L instead of the EQ-5D-5 L for two reasons. First, two surveys five years apart (2008 and 2013) were available. Over this period of time, China experienced dramatic changes in social and economic development, including reforms of the health system. In this context, changes in HRQoL are likely to occur. Second, the EQ-5D-3 L generates a utility index based on the national value sets derived from public preferences, as well as a VAS indicating individual ratings on their own conditions –46. ThisData were obtained from the 2008 and 2013 National Health Services Surveys (NHSS), the largest national wide health surveys in China. The NHSS have been conducted every five years since 1993 with coordination from the Centre for Health Statistics and Information under the Ministry of Health . The EQ-A four-stage stratified cluster probability sampling strategy was adopted to select representative participants in the NHSS , 50. EacThe questionnaires were administered through face-to-face household interviews conducted by trained local medical workers. The interviewers were rigorously selected considering their qualifications, professional knowledge, sense of responsibility, attitudes, and communication skills. Pre-survey training workshops were offered to all of the interviewers following a standardised protocol. Eligible interviewers had to demonstrate their proper understanding about the purpose of the NHSS and ability to meet data collection standards developed by the Centre for Health Statistics and Information. They also needed to follow pre-defined instructions when problems arose during data collection –51.The face-to-face interviews occurred in the households of participants. Prior to the interviews, the interviewers explained the purpose and procedure of the survey and obtained oral informed consent from each participant. Family members were allowed to serve as a proxy respondent only when the selected participant was younger than 15 years, absent from home, or unable to communicate at the time of the survey. Overall, less than 18% of the returned questionnaire (17% in 2008 and 18% in 2013) were completed by a proxy respondent , 52.A quality assurance team was established in each participating sub-district/township. The returned questionnaires were checked by the quality assurance officers for completeness at the end of each day. Missing data, if any, were addressed through a second interview by the same interviewers. The sampled households were not allowed to be replaced unless three interview attempts failed or the sample size of the residential community/village did not reach 60 . The surThree indicators were calculated: percentage of reported problems, utility index and VAS scores.The descriptive system of EQ-5D comprises five dimensions: mobility (MO), self-care (SC), usual activities (UA), pain/discomfort (PD) and anxiety/depression (AD). This study used the EQ-5D-3 L, measuring problems at three levels: no problem, moderate problem, severe problem.U). The conversion was based on the value sets developed by Zhuo et al. [The combination of reported problems on the five dimensions for each individual was converted into a summarised utility index  technique: one developed by Liu et al. and another by Zhuo et al. , 43. BotThe EQ-5D-3 L also contains a VAS, asking respondents to rate their overall health on a scale ranging from ‘worst imaginable health state’ (0) to ‘best imaginable health state’ (100). VAS reflects individual ratings on their own health , 19.Changes in HRQoL are determined by a variety of factors at the individual, family, community and society levels –57. TherDemographic variables: Gender and age represent the basic biological feature of respondents.Behavioral variables: The NHSS collected data regarding the current status of smoking (past week), drinking (past 12 months), and physical exercise (past 6 months) of the respondents. Respondents were asked whether and how frequent they had engaged in the aforementioned behaviors at the time of the survey. Respondents were deemed to be physically active if they engaged in regular physical activities at least once a week over the past 6 months.Socioeconomic variables: Socioeconomic status was measured by educational attainment and household income. Respondents were asked to indicate the highest level of school education they had attained. Household income was estimated based on self-reported average income per capita and converted into quintiles (from the lowest 20% to the highest 20%).Residential variables: Respondents were divided into two groups, urban or rural, based on their geographical location in three regions: eastern, central and western. There exist great geographic disparities in socioeconomic development in China. Urban residents enjoy a higher level of entitlement than their rural counterparts. Overall, the eastern coastal region of China is highly developed, whereas the western region lags far behind, with the central region being somewhere in between.Time variable: China’s most recent health system reform started in 2009. The reform achieved great progress in a few years in terms of universal coverage of health insurance and improved access to medical care [cal care , 64. We χ2 tests. Logistic regression models were established to determine the changes over the two years after controlling for the influence of other independent variables. A p value of less than 0.01 was considered statistically significant in line with the Bonferroni adjustment method for multiple comparisons [We presented the percentages of reported problems on the five dimensions of EQ-5D-3 L. Reported “extreme problems” were rare, and thus were merged with the category of “moderate problems” , 47. Difparisons .t tests or analysis of variance (ANOVA). Linear regression models were established to determine changes in VAS scores over the two years after controlling for variations in other independent variables. Because the utility index is bounded to 1, Tobit regression models were established to determine changes in the utility index after controlling for variations in other independent variables [p value of 0.05 was considered statistically significant in the linear and Tobit regression analyses.Means of the utility index and VAS scores were calculated and compared using student ariables . A p valThe importance of changes in the utility index and VAS scores were also estimated using the indicator of effect size: average change divided by baseline standard deviation (SD), which was proposed by Cohen . The CohAll statistical analyses were performed using STATA 14.0 for Windows.p < 0.001), more likely to smoke (p < 0.05), drink (p < 0.001) and exercise (p < 0.001); they also reported higher levels of education (p < 0.001). There was a dramatic increase (p < 0.001) in the proportion of urban respondents: 49.84% in 2013 compared with 27.71% in 2008 . Elderly respondents accounted for less than 20% of respondents 16.45%). More than half of the respondents resided in rural areas (58.79%). Compared with 2008, the 2013 respondents were older (6.45%. MoPain/discomfort was the most frequently reported problem (11.3%), followed by anxiety/depression (5.7%) and mobility (5.6%). Problems in self-care were least reported (3.1%). Compared with 2008, reported problems increased in pain/discomfort (by 3.3 percentage points) and mobility (by 0.7 percentage points) in 2013. By contrast, reported problems in anxiety/depression, self-care and usual activities decreased by 1.2, 0.2 and 0.2 percentage points, respectively  in the utility index, but an increase (p < 0.001) in VAS scores in 2013, albert in very small effect sizes . However, some subgroups stratified by age and region defied the overall trends, showing an increase in both the utility index and VAS scores  and mobility (AOR = 1.07), but a decreased likelihood of reporting problems in self-care (AOR = 0.90), usual activity (AOR = 0.92), and anxiety/depression (AOR = 0.80) compared with 2008  utility index vs increased  VAS scores, after adjustment for variations in the other independent variables. But the effect sizes of those changes over time did not reach the threshold of minimal clinical importance  of the utility index is contradictory to that (increase) of the VAS in China over the period between 2008 and 2013, although neither is deemed clinically important. Such a change (or lack of) cannot be fully explained by the changing demographic and socioeconomic status in China. Further studies are warranted to explore the underlining reasons, in particular the role of health reforms . Meanwhi