The predictive potential of the neutrophil‐to‐lymphocyte ratio (NLR) and plasma lactate was investigated in regard to the prognosis of patients with sepsis.Sixty‐three nonsurgical and nontrauma adult patients with sepsis admitted to the intensive care unit (ICU) from September 2016 to October 2018 were consecutively included in the study. In addition, healthy subjects were assigned to a control group. Neutrophil and lymphocyte counts were evaluated via a complete blood count. Plasma lactate, procalcitonin (PCT), and C‐reactive protein (CRP) levels were measured. The main outcome was 28‐day mortality.P = 0.049; and 3.7 (3‐6.6) vs 2.72 (2.13‐4.3) ng/mL, P = 0.008, respectively. There were no statistical differences in the concentrations of PCT and CRP between nonsurvivors and survivors: 6.1 (3.43‐33.59) vs 9.43 (4.24‐37.68) ng/mL, P = 0.44; and 108 (77.8‐153) vs 114.5 (71.43‐162) ng/mL, P = 0.672, respectively. With an optimal cutoff of 14.08, the sensitivity and specificity of NLR for prediction of 28‐day mortality were 78.3% and 50%, respectively. And the sensitivity and specificity of plasma lactate level to predict 28‐day mortality, at an optimal cutoff value of 2.99 mmol/L, were 82.6% and 55%, respectively.Neutrophil‐to‐lymphocyte ratio and plasma lactate levels of the patients were significantly higher than those of control subjects: 19.44 (14.3‐34.53) vs 14.09 (8.17‐28.99), Neutrophil‐to‐lymphocyte ratio and plasma lactate were associated with poor outcomes in patients with sepsis and predicted mortality. It is also one of the leading causes of intensive care unit (ICU) mortality, despite early administration of antibiotics and hemodynamic management.Therefore, finding tools that may assist physicians in early identification of patients with sepsis, especially those at high risk, may improve outcomes in patients with sepsis. Plasma biomarkers may have diagnostic, prognostic, and theranostic values, all of which are important factors influencing outcomes in patients with sepsis.Systemic inflammation is related to alterations in circulating blood cell composition as a response of the immune system to stress or sepsis.The primary purpose of this study was to determine the capability of NLR and plasma lactate to predict mortality during hospitalization and later (in 28 days) in patients with sepsis from the Department of Critical Care Medicine, compared to established sepsis‐related biomarkers (PCT and CRP).22.1We conducted a prospective, observational study at the Changhai Hospital, China, a 2000‐bed tertiary care hospital involving patients with sepsis. Sixty‐three nonsurgical and nontrauma adult patients with sepsis admitted to the Department of Critical Care Medicine from September 2016 to October 2018 were consecutively included in the study. Enrollment within 24 hours after onset of sepsis was chosen to eliminate confounding factors, such as variable onset time, and to improve group homogeneity. In the present study, sepsis and septic shock were defined in accordance with the Third International Consensus Definitions (infection + increment of SOFA ≥ 2).The protocol and procedure for obtaining informed consent were approved by the Institutional Ethical Committees, and consent forms were provided by first‐degree relatives or patients.2.2Baseline characteristics of the patients including demographics (age and gender), comorbidities , and primary diagnosis were recorded. Blood samples were collected within 24 hours after diagnosis. Routine blood tests, blood gas analysis, and PCT concentrations were conducted in the hospital's central laboratory. Routine blood tests, including neutrophil count and lymphocyte count , CRP , and plasma PCT concentrations were measured in duplicates as recommended by the manufacturer using a time‐resolved amplified cryptate emission technology assay . Plasma lactate was evaluated on an ABL800 Flex . All samples were encrypted and analyzed by trained laboratory technicians blinded to the patients' diagnoses.2.3P < 0.05. Box plots were used to present results. The chi‐square test was used to compare the two sets of data, and the Mann‐Whitney U test was used to compare the two sets of measurement data. Receiver operating characteristic (ROC) curves were constructed to compare prognostic performance and to determine the optimal cutoff points for the biomarkers. Spearman's rank correlation coefficient (rs) was used to determine correlation between conventional inflammation‐related biomarkers.All analyses were performed using SPSS 21.0 software, and statistical significance was set at 33.1Sixty‐three consecutive patients meeting the criteria of sepsis were enrolled, with 40 (63.5%) patients in the survivor group and 23 (36.5%) patients in the nonsurvivor group. Patients who underwent a rapid fatal outcome (within 24 hours after ICU admission) were excluded from the analysis. Baseline clinical characteristics of the 63 patients included in the present study are listed in Table 3.2P = 0.049; and 3.7 (3‐6.6) vs 2.72 (2.13‐4.3) ng/mL, P = 0.008, respectively. There were no statistical differences in the concentrations of PCT and CRP between nonsurvivors and survivors: 6.1 (3.43‐33.59) vs 9.43 (4.24‐37.68) ng/mL, P = 0.44; and 108 (77.8‐153) vs 114.5 (71.43‐162) ng/mL, P = 0.672, respectively  values were 19.44 (14.33‐4.53) vs 14.09 (8.17‐28.99), 5‐IQR75 v3.3P = 0.049) for the ability of NLR to predict 28‐day mortality, with a sensitivity of 78.3% and specificity of 50%. The optimal cutoff was 14.08. The area under the ROC curve was 0.701 (P = 0.008) for the ability of plasma lactate level to predict 28‐day mortality, and the sensitivity and specificity, at an optimal cutoff value of 2.99 mmol/L, were 82.6% and 55%, respectively  compared to NLR (AUC = 0.634) and plasma lactate (AUC = 0.701) alone , between lactate and CRP , and PCT . However, there was no significant correlation between NLR and CRP  and PCT .Spearman's rank correlation coefficient (rs) was conducted to assess the correlations among NLR and lactate levels and biomarkers of inflammation (PCT and CRP). There was significant correlation between NLR and lactate . The association between increased mortality and raised NLR was also consistent with that in prior studies; Shahidi reported that the NLR was a simple, cheap, rapidly accessible, and independent indicator of short‐ and long‐term mortalities in critically ill patients.Results of the current study indicated that NLR was significantly elevated in the nonsurvivors compared to that in the survivors. NLR may simply reflect an appropriate tissue perfusion response that is adaptive. There was significant correlation between NLR and lactate (rs = 0.412, Results of the present study suggested lactate as the single best‐performing biomarker for identifying nonsurvivors and survivors of sepsis. Under normal physiological conditions, the half‐life of lactate is approximately 20 minutes. Therefore, a persistently high lactate level reflected its continuous production or lack of elimination.In conclusion, raised NLR and lactate levels showed significant association with increased mortality in patients with sepsis. NLR and lactate may be important prognostic biomarkers to optimize treatment and manage patients. Larger, multicenter trials may be needed to further verify these findings.


Salmonella cocktail  when contamination was introduced through inoculated flour. The bread and pastry flour mix (3:1) was inoculated with the Salmonella cocktail, and subsequently dried back to original preinoculation moisture content, achieving a Salmonella population of 7.6 log CFU/g. Inoculated flour was used to prepare a typical commercial donut batter, which was fried using 375°F (190.6°C) oil temperature. No viable Salmonella was detected using an enrichment plating protocol in the donuts after 2 min of frying, resulting in >7-log reduction in Salmonella population. The internal donut temperature increased from ∼30°C to ∼119°C at the end of 2 min of frying. The water activities of the donut crumb and crust after 2 min of frying, followed by 30 min of ambient air cooling, were 0.944 and 0.852, respectively. The donut pH after ambient-air cooling was 5.51. The D- and z-values of the Salmonella cocktail in donut dough were determined using thermal-death-time disks and temperature-controlled water baths. The D-values of the cocktail were 8.6, 2.9, and 2.1 min at 55°C, 58°C, and 61°C, respectively, whereas the z-value was 10°C. This study validated that >7-log reduction could be achieved if donuts are fried for at least 2 min in the oil at 190.6°C, and calculated D- and z-values present the heat resistance of Salmonella in donut dough at the start of the frying processes. However, results from this study should not be extrapolated when donut composition and frying parameters are changed significantly.This study validated a typical commercial donut frying process as an effective kill-step against a 7-serovar  In addition, the aw, pH, and proximate composition of donuts were also determined.The main purpose of this study was to validate a frying process simulating commercial donut manufacturing to control Salmonella cocktail in donuts during frying using 375°F (190.6°C) oil temperature for 2 min; (2) determination of the internal temperature profile, pH and aw of donuts during frying; and (3) determination of D- and z-values of the 7-serovar Salmonella cocktail in proofed donut dough.This research was divided into the following three studies: (1) validation of frying as a kill-step to inactivate a 7-serovar Salmonella cocktail) bread and pastry flour mix. The donuts were fried in soybean oil at 190.6°C for 2 min followed by 30 min of ambient air cooling (F+C), with product sampling at 1 and 2 min of frying and at F + C to enumerate the surviving Salmonella population. This study utilized a randomized complete block experimental design with three replications as blocks and six sampling times as treatments . For the temperature profiling, pH and aw determination study, noninoculated flour mix was used to prepare donut dough. This study was also designed as randomized complete block (three replications) with four sampling times as treatments . Microbial, pH and aw data were statistically analyzed by analysis of variance at p ≤ 0.05 using SAS version 9.3 . An additional donut frying study was conducted using noninoculated flour mix to provide samples after frying and F + C for proximate analyses.For the frying validation study, donut dough was prepared using an inoculated  for each replication separately. This study utilized a randomized complete block design with three replications and microbial plating was done in duplicate.The mean D- and Salmonella were obtained from the American Type Culture Collection , and Salmonella Tennessee and three dry pet food isolates were obtained from Richter International, Inc. . These Salmonella serovars were selected because of their relatively high heat resistance, association with foodborne illness outbreaks, and/or isolation from low moisture food environment. The working cultures were propagated individually following the method described by Channaiah et al.  and pastry (100 g) flours were weighed into a sanitized sealable plastic tub , mixed, and spread into a uniform layer. Flour mix was then mist-inoculated inside the biosafety cabinet as described by Channaiah et al. .®, KitchenAid®, St. Joseph, MI) and mixed with a sanitized spatula. Yeast, shortening, and water were then added to the dry ingredients, the mixing bowl and paddle were attached to the mixer, and the ingredients were mixed for 1 min at speed-1, followed by 5 min of mixing at speed-2. The dough was rounded into a ball, placed into a greased bowl, covered with aluminum foil, and rested at room temperature (∼25°C) for 45 min. The dough was then rolled into a ½-inch (12.7 mm) sheet, and rested for 10 min at room temperature. The dough was resheeted, cut into shape using a donut cutter [3 inch (76.2 mm) diameter with 1 inch (25.4 mm) inner hole diameter], placed onto a frying screen (four donuts per frying batch), and placed inside a proofing cabinet preset at 100°F (37.8°C) and 60–70% relative humidity for 30 min.All ingredients and the dough formula used for the donut preparation were provided by AIB International, Inc., Manhattan, KS . Flour mThe donut frying parameters (oil temperature and frying time) were determined after a series of frying trials mimicking the end-product quality of commercially prepared donuts. The oil and internal donut temperatures during frying were monitored and recorded using fine-gauge thermocouples [Type-T Thermocouples ] connected to an eight-channel data logging system . During temperature monitoring, the data logger recorded temperatures every second. For monitoring internal donut temperatures during frying and ambient-air cooling, the thermocouples were inserted from the side into the center of two randomly selected donuts. The proofed donuts on the frying screen with attached thermocouples were transferred into the hot soybean oil at 375°F (190.6°C) and fried for 1 min on each side, followed by 30 min of ambient air-cooling on a sanitized wire rack.Salmonella population.For frying validation, donuts (prepared from inoculated flour mix) were randomly sampled at 1 and 2 min of frying, and at F+C. At each sampling point, donuts were quickly removed from the hot oil and transferred into stomacher bags containing 100 mL of chilled (∼4°C) 0.1% peptone solution, hand massaged for 1 min to arrest additional thermal microbial destruction, and analyzed to determine the surviving w measurements, samples were taken at pre- and postproofing, after 2 min of frying, and F+C. Donut samples after 2 min of frying and F + C were immediately separated into crust  and crumb  components, and analyzed. The sample pH and aw were measured as described by Channaiah et al.  agar] and selective media [XLD agar], whereas for the D- and z-values study, only injury-recovery media was used to enumerate Salmonella populations. The Salmonella enumeration and enrichment were conducted according to Channaiah et al., For the frying validation study, et al., et al., et al., et al., et al., et al., et al., et al., Salmonella destruction.Although, frying is an ancient and popular food preparation process, only a handful of researchers have explored the science behind validating a frying process in French fries . The aw of the donut crumb after frying and F + C  remained similar to that of the dough; whereas, the aw of the donut crust decreased to 0.830 ± 0.009 and 0.852 ± 0.007 after frying and F+C, respectively.The pH and aThe proximate analyses of donut dough and fried donuts are presented in Salmonella cocktail contained 11.1 ± 0.10 log CFU/mL, and inoculated flour contained 7.6 ± 0.32 log CFU/g (as enumerated on injury-recovery media). As flour was inoculated at such high levels, the presence of Salmonella in other ingredients was not tested because Salmonella population enumerated in the current study would be directly due to the artificial inoculation. The Salmonella populations in the postproof dough  were similar to that in the inoculated flour  in meatballs. In this study, deep-frying fresh meatballs (40 g each) in canola oil at 176.7°C for 5.5 min resulted in 5-log reduction, and cooking of fresh meatballs at 176.7°C for 12.5 min also resulted in 5-log reduction.The 7-serovar ed flour . After 1ve media . Howevert et al.  evaluateet al.  may be the most effective form of validation, food processors are often reluctant to introduce any kind of microbial cultures into their processing facilities, and selection of an appropriate surrogate is often a challenge. Therefore, the food industry tends to rely upon published laboratory- and/or pilot-scale studies that utilize pathogens of interest and/or their surrogates. The current study, along with similar validation studies conducted for various bakery products, can be used by the bakery industry to assess the pathogen control capabilities of their manufacturing processes. In similar validation studies, Channaiah et al. , 2017 vaz-values are presented in z-values of 7-serovar Salmonella cocktail in proofed donut dough are presented in R2 values for all regression lines were >0.9. The D-values of Salmonella cocktail were determined at much lower temperatures (55–61°C) compared with the maximum internal donut temperature (∼119°C) reached during frying because during preliminary D-values studies, the time required to achieve high target temperatures resulted in significantly lower Salmonella populations that were inadequate to calculate D-values. Although extrapolating Salmonella thermal destruction at 119°C from the data determined at 55–61°C could cause some linearity problems, these D-values were determined to estimate the Salmonella heat resistance in donut dough at the start of the frying process. The D-values of Salmonella cocktail in dough were 8.6, 2.9, and 2.1 min at 55°C, 58°C, and 61°C, respectively, with a z-value of 10°C. In similar studies, Channaiah et al.  in proofed hamburger bun dough and plain muffin batter had D-values of 28.6 and 62.2, 7.6, and 40.1, and 3.1 and 16.5 min at 55°C, 58°C, and 61°C, respectively, and z-values of 6.6°C and 10.4°C, respectively. The differences in the D- and z-values in the current study (proofed donut dough) and those generated by Channaiah et al.  and muffin batter  in Channaiah et al. (Salmonella cocktail in proofed donut dough compared to that in muffin batter (Channaiah et al., Salmonella in donut dough. Channaiah et al. (Enterococcus faecium in hamburger bun dough at 55°C, 58°C, and 61°C were approximately four to seven times greater than the 3-serovar Salmonella cocktail, and hence E. faecium can be used as a conservative surrogate strain for Salmonella to validate various thermal processes for bakery products if in-plant studies are desired.The linear regression graphs used to calculate D- and h et al. , 2017 deh et al. , 2017 foh et al. , 2017 sth et al.  also demet al., E. coli O157:H7, Salmonella and Listeria monocytogenes in ready-to-eat chicken-fried beef patties. Osaili et al. (E. coli O157:H7, 67.68 to 0.22 min for Salmonella, and 81.37 to 0.31 min for L. monocytogenes at temperatures 55–70°C. The lower D-values for Salmonella cocktail reported in our study can be attributed to differences in food matrices used and fat content in chicken-fried beef patties. In addition to differences in food matrices and intrinsic factors, variation in the thermal resistance of the bacterial strains used to prepare the inoculum and experimental methodologies could account for differences in D-values.An earlier study (Osaili i et al.  reportedSalmonella population. This study can be used by commercial donut manufacturers utilizing similar operational parameters to fulfill the FSMA requirements to scientifically validate frying a critical processing step in donut manufacturing. The D- and z-values determined in this study can also give a clear understanding of Salmonella heat resistance in proofed donut dough, and can be used for optimizing donut frying processes. It should be noted that individual donut frying processes should be validated when donut proximate composition and frying parameters are different than those studied in the current research.The current study demonstrated that frying donuts at >190°C oil temperature for at least 2 min will result in >7-log reduction in


N) were rapidly prepared by a microwave irradiation procedure and were characterized by electron microscopy (EM), laser scattering, infrared spectroscopy (IR), and by their fluorescence spectrum. It was found that the CDN had a strong catalytic effect on the fluorescence reaction of 3,3′,5,5′-tetramethylbenzidine hydroxide ((TMB)–H2O2) which produced the oxidation product of TMB (TMBOX) with strong fluorescence at 406 nm. The aptamer (Apt) was adsorbed on the CDN surfaces which weakened the fluorescence intensity due to the inhibition of catalytic activity. When the target molecule isocarbophos (IPS) was added, it reacted with the Apt to form a stable conjugate and free CDN which restored the catalytic activity to enhance the fluorescence. Using TMBOX as a fluorescent probe, a highly sensitive nanocatalytic method for determination of 0.025–1.5 μg/L IPS was established with a detection limit of 0.015 μg/L. Coupling the CDN fluorescent probe with the Apt–IPS reaction, a new CD fluorescence method was established for the simple and rapid determination of 0.25–1.5 μg/L IPS with a detection limit of 0.11 μg/L.The strongly fluorescent and highly catalytic N-doped carbon dots (CD At present, the most important applications of carbon dots are clinical therapy, bioimaging, and fluorescence sensing [2S. Ahmed et al. [3O4 nanoparticles to detect 0.25–50 ng/mL β-lactoglobulin with a detection limit of 37 pg/mL. However, there are no reports on a non-labeled Apt-mediated CD fluorescent probe or a catalytic 3,3′,5,5′-tetramethylbenzidine hydroxide oxidation product (TMBOX) probe for IPS.Nucleic acid aptamers (Apt) can specifically bind to target molecules and have been applied in genomics, food safety, medical diagnosis, biomedicine, and biological analysis . Using A sensing ,24,25. I sensing  inventedd et al.  reportedd et al.  used a fd et al. . Shi et d et al.  used car2 nanosheet–TMB colorimetric system. Shi et al. [2O2 and 0.0010–0.50 mM glucose by spectrophotometry. Ju et al. [OX probe, two new, rapid, and sensitive methods for the detection of IPS were established.3,3′,5,5′-Tetramethylbenzidine hydroxide (TMB) is a non-carcinogenic and non-mutagenic chromogenic agent . At presi et al.  used caru et al.  designedu et al. , and IPSu et al. ,37,38,39A model of Hitachi F-7000 fluorescence spectrophotometer  and a model of TU-1901 double beam UV-visible spectrophotometer  were used to record the fluorescence and absorption spectra. The reaction was carried out in an HH-S2 electric hot water bath . The characterization of nanoparticles was carried out on an S-4800 field emission scanning electron microscope . The laser scattering was carried out on a Zeta Sizer Nano nanometer and particle size and zeta potential analyzer . The sub-boiling water was obtained from a SYZ-550 quartz sub-boiling distiller . The carbon dots were synthesized on a WX-6000 microwave digestion instrument . 3 solution, 0.1 mol/L sodium citrate solution, 30% H2O2 solution, 0.1 mol/L NaBH4 solution, and 3,3′,5,5′-tetramethylbenzidine  were purchased from Shanghai Maclean Biochemical Technology Co., Ltd. . A 0.2 mol/L pH 3.6 HAc–NaAc buffer solution, 0.2 mol/L NaH2PO4–Na2HPO4 buffer solution, 1.0 mol/L HCl solution, 0.25 mol/L NaOH solution, and 30 mg/L IPS standard solution were prepared. All reagents were of analytical reagent grade. All the solutions were prepared with ultrapure water.Nucleic acid aptamers (Apt) with the sequence: 5′-3′ AGC TTG CTG CAG CGA TTC TTG ATC GCC ACA GAG CT were purchased from Shanghai Sangon Biotech Co., Ltd. . Isocarbophos 061673) was purchased from Beijing Century Aoke Biotechnology Co., Ltd. . Profenofos, citric acid (AR), and urea (AR) were purchased from the National Pharmaceutical Group Chemical Reagents Company . Glyphosate was purchased from the Beijing Bailingwei Technology Co., Ltd. . A 10 mmol/L AgNOg: Under ultrasonic irradiation, 1g glucose and 0.8 g urea were dissolved in 30 mL of water to form a transparent solution, which was then transferred to a digestion tank, sealed, and placed in a microwave digestion apparatus. The temperature was set at 140 °C, with a pressure of 4.5 atm, holding time of 10 min, and the irradiation time of 10 min. After completion of the operation, the mixture was cooled to room temperature to obtain a brownish yellow solution. It was dialyzed against a dialysis bag with a cut off molecular weight of 3500 Da for 12 h, and the C concentration, calculated as total amount of carbon, was 17 mg/mL CDg.CDN: One gram of citric acid and 0.8 g of urea were sonicated in 30 mL of water to form a transparent solution, which was then transferred to a digestion tank, sealed, and placed in a microwave digestion apparatus at a temperature of 140 °C and a pressure of 4.5 atm, and irradiated for 10 min. Then, it was cooled to room temperature to obtain a pale yellow solution, for which the total amount of carbon was calculated to determine a concentration of 17 mg/mL CDN solution.CDS: One gram of trisodium citrate and 0.8 g of urea were sonicated in 30 mL of water to form a transparent solution, which was then transferred to a digestion tank, sealed, and placed in a microwave digestion apparatus at a temperature of 140 °C and a pressure of 5.0 atm. The holding time was 10 min and the irradiation time was 10 min. After completion of the reaction, it was cooled to room temperature to obtain a pale yellow clear solution, for which the total amount of carbon was calculated to determine a 13 mg/mL CDS solution.CD2PO4–Na2HPO4 buffer solution, 200 μL of 1.55 μmol/L Apt solution, and 100 μL of 0.1 mg/L carbon dot solution were combined and diluted to 1.5 mL with water. The fluorescence spectrum was measured at a specific excitation wavelength of each CDS, and the ΔF was calculated by the subtraction of blank F0 without isocarbophos (IPS) from F.CD probe: in a 5 mL test tube, 15 μg/L isocarbophos standard solution, 200 μL of 0.2 mol/L pH 7.4 NaHOX probe: in a 5 mL test tube, 1.5 μg/L IPS standard solution, 30 μL of a 1.55 μmol/L Apt, 100 μL of 1 mmol/L pH 3.6 HAc–NaAc buffer solution, 50 μL of 0.1 mg/L carbon dot solution, 40 μL of 2 mmol/L (0.006%) H2O2 solution, 50 μL of 0.5 mmol/L TMB solution, and 200 μL of 1 mmol/L pH 3.6 HAc–NaAc solutions were combined and diluted to 1.5 mL. The tube was heated in a 50 °C water bath for 15 min, the reaction stopped with ice water. Under the excitation wavelength of 285 nm, the voltage of 350 V, and the slit of 5 nm, the fluorescence spectrum was recorded. The fluorescence intensity at 406 nm was measured to be F406 nm. The blank (F406 nm)0 without analyte was recorded. ΔF406 nm = F406 nm − (F406 nm)0 was calculated. TMB2O2/TMB to form TMBOX oxidation products. When a certain concentration of the Apt was present, it adsorbed on the surface of the carbon dot, resulting in the CD catalytic action weakening. After the target molecule, IPS, was added it specifically bound to the Apt, and the CDs released to cause restoration of the catalytic action due to the affinity of Apt–IPS being larger than that of Apt–CD. With the increase of the concentration of IPS, the higher the desorption of CDs, the faster the catalytic reaction of H2O2/TMB, the greater the concentration of TMBOX formed, and the fluorescent signal gradually increased. Using TMBOX as a fluorescent probe and the catalytic effect of CD to amplify the signal, a new and highly sensitive fluorescence method for determination of IPS was established  of 0.015 μg/L IPS, which was defined as 3 times the standard deviation (3 σ) that was obtained from 5 replicates of the parallel blank. So the catalytic fluorescence system was selected to determine the concentration of IPS in the sample. This method was simpler and more sensitive than the reported spectral method for determining IPS (g/CDN/CDS, the slope of the ΔF working curve of the Apt–IPS–CDN system was the largest, so the CDN system was the most sensitive and could be used for fluorescence detection of 0.25–1.5 μg/L IPS, with a detection limit of 0.11 μg/L IPS. In addition, the microwave preparation of CDN was simple and rapid (Under optimal conditions, the relationship between the IPS concentration and its corresponding ΔF was obtained . In the ning IPS . Among tnd rapid .2O2–TMB nanocatalytic analytical fluorescence system, the interference of coexisting ions on the fluorescence measurement of 0.1 μg/L IPS was investigated experimentally. Results showed that concentrations of 1000 times Zn2+, Ca2+, Ni2+, Co2+, Ba2+, Mg2+, K+, glyphosate, tributylphosphine, and profenofos, 500 times Mn2+, CO32−, HCO3−, NO2−, and Al3+, 250 times NH4Cl, Fe3+, Bi3+, Cu2+, and Pb2+, and 100 times Cr6+, Fe2+, and Hg2+ had no interference on the determination of IPS (N fluorescence system, influences of coexisting ions on the fluorescence measurement of 0.5 μg/L IPS were also examined experimentally. Results showed that concentrations of 1000 times Zn2+, Ca2+, Ni2+, Ba2+, Mg2+, K+, and glyphosate, 500 times Mn2+, NH4Cl, CO32−, HCO3−, NO2−, tributylphosphine, and profenofos had no interference on the determination of IPS (N system, especially for other organic phosphoruses such as tributylphosphine and profenofos.For the Hn of IPS . For then of IPS . The speN–H2O2–TMB fluorescence method, the water samples were analyzed five times in parallel. The results (Domestic sewage, farmland water, and pond water were collected in 50 mL samples, filtered to remove suspended particles, and stored at 5 °C. The original pH of the sample was 5.6 and was measured by pH meter, and was adjusted to pH 7 with 0.1 mol/L NaOH solution. Using the Apt–IPS–CD results  show thaN with high fluorescence were synthesized by the microwave digestion procedure. Based on the catalytic action of CDN on the H2O2/TMB fluorescence reaction and the specific binding of IPS to Apt, two new fluoresce methods were established for analysis of IPS at the μg/L level. These methods have the advantages of simple operation, high sensitivity, and good selectivity.In this paper, CD


The suicide risk was higher in kidney cancer patients than in the general population. The purpose of this study was to characterize the suicide rates among kidney cancer patients and to identify the potential risk factors associated with suicide from the Surveillance, Epidemiology, and End Results (SEER) database.Kidney cancer patients were identified from the SEER database during 1973‐2015. Suicide rates and standardized mortality ratios (SMRs) of this population were calculated, and the US general population during 1981‐2015 was chosen as a reference. Univariable and multivariable Cox regression were performed to find out potential risk factors of suicide.P = 0.048; 1983‐1992 vs 2003‐2015, HR: 1.99, 95% CI: 1.18‐3.35, P = 0.010), male sex , unmarried status , non‐black race , higher histologic grade  and cancer‐directed surgery not performed  were independent risk factors of suicide among kidney cancer patients.There were 207 suicides identified among 171 819 individuals with kidney cancer observed for 948 272 person‐years. The suicide rate was 21.83 per 100 000 person‐years, and SMR was 1.83 (95% CI: 1.59‐2.10). On Cox regression, diagnosis in early years (1973‐1982 vs 2003‐2015, HR: 2.03, 95% CI: 1.01‐4.11, Diagnosis in early years, male sex, unmarried status, non‐black race, higher histologic grade, and cancer‐directed surgery not performed were significantly associated with suicide among kidney cancer patients. In order to prevent suicidal death, clinicians should pay more attention to patients with high‐risk factors of suicide. The SEER database reported cancer‐specific outcomes from specific geographic areas covering 28% of the US population. The data in the SEER program were considered to be representative of the entire US population.2.2Patients were identified using the primary site codes (C64.9 and C65.9) for kidney and morphology codes  based on International Classification of Diseases for Oncology codes (3rd edition) for kidney cancer.2.3Demographic and clinical variables of interest were collected through the software of SEER*Stat, including year of diagnosis , age at diagnosis , gender , marital status , race , SEER histologic stage , histologic grade , histologic subtype , survival time, vital status, surgery , and radiotherapy . Based on marital status, the patients were classified as married and unmarried, and the unmarried status included single, widowed, divorced/separated, and unmarried or domestic partner. The exclusion criteria included patients with unknown age, unknown follow‐up, and all autopsy or death certificate cases. The steps of patient selection were exhibited in Figure 2.4The primary outcome of this study was suicidal death, which was ascertained by cause of death code (suicide and self‐inflicted injury) in the software of SEER*Stat.2.5P‐value was used for multiple comparisons. SMR was calculated using the ratio of actual mortality with expected mortality. Because of the lack of suicide rates during 1973‐1980 in the Centers for Disease Control and Prevention's Web‐based Injury Statistics Query and Reporting System, the US general population between 1981 and 2015 was chosen as a reference, and a sensitive analysis with the kidney cancer patients diagnosed in 1981‐2015 was performed to validate the robustness of SMRs. Ninety‐five percent of CI of SMR was obtained through the method of Byar's approximation.http://www.r-project.org/). All tests were two‐sided, and the significance level was set at P < 0.05.The suicide rates between groups were compared with the chi‐square test, and the Bonferroni‐corrected 33.1Overall, 171 819 patients with kidney cancer were identified from the SEER database in 1973‐2015, including 109 810 male patients and 62 009 female patients. Of these, 207 patients (0.1%) died of suicide, 69 182 patients (40.3%) died of other causes, and 102 430 patients (59.6%) were alive. Among all patients, 107 623 (62.6%) of them were married, while 56 515 (32.9%) of them were unmarried. Caucasian was the predominant race. A total of 154 139 (89.7%) patients underwent cancer‐directed surgery and 167 176 (97.3%) patients did not receive radiotherapy. For the patients committed suicide, 179 (86.5%) of them were males, and 28 (13.5%) of them were females. Concerning marital status, 110 (53.1%) of them were married, whereas 92 (44.4%) of them were unmarried. Similarly, Caucasian was also the predominant race. 189 (91.3%) patients received cancer‐directed surgery, and only 4 (1.9%) patients received radiotherapy. Patient demographics and clinical characteristics were summarized in Table 3.2P < 0.001). The results showed that higher suicide rates in patients with kidney cancer were associated with male sex , unmarried status , white race , and cancer‐directed surgery not performed . The result of the chi‐square test for linear trend showed that suicide rates among kidney cancer patients increased with histologic grade (P < 0.001) and disease stage (P < 0.001). Meanwhile, no statistical differences in suicide rates were found with respect to year of diagnosis, age at diagnosis, histologic type, radiotherapy, and time from diagnosis. SMRs were used to compare suicide mortality in the study population to that in the general population. A SMR of 1.83 (95% CI: 1.59‐2.10) was noted between kidney cancer patients and the US general population, with 1.57 (95% CI: 1.35‐1.82) for males, 1.60 (95% CI: 1.06‐2.31) for females, 1.85 (95% CI: 1.60‐2.13) for the white race, 1.14 (95% CI: 0.46‐2.35) for the black race, and 2.19 (95% CI: 0.94‐4.31) for other races. A general decline of suicide rates over time after diagnosis was observed, though a statistical trend was not found (P = 0.064). Significantly increased suicide rates among kidney cancer patients with general population were found in the initial 9 years after cancer diagnosis . The suicide rates and SMRs of kidney cancer patients diagnosed in 1973‐2015 and 1981‐2015 were presented in Table From 1973 to 2015, there were 207 suicides among 171 819 patients with kidney cancer observed for 948 272 person‐years, yielding a suicide rate of 21.83 per 100 000 person‐years. The suicide rate of US general population reported by the Centers for Disease Control and Prevention was 11.93 per 100 000 person‐years between 1981 and 2015,3.3P < 0.001), male sex , older age at diagnosis , unmarried status , white race , higher histologic grade , later disease stage , and cancer‐directed surgery not performed . On multivariable Cox regression, the results showed that diagnosis in early years  and male sex  were predictive of suicide. Meanwhile, unmarried status  was a significant risk factor of suicide. In addition, the factors associated with high risks of suicide included non‐black race , higher histologic grade , and cancer‐directed surgery not performed . Conversely, apparent associations of suicide with age at diagnosis, SEER disease stage, histologic subtype, and radiotherapy were not found. Table The result of univariable analysis presented that significant associations with high risks of suicide were obtained with respect to diagnosis in 1983‐1992  were at significantly higher risk of suicide compared with those in recent years (2004‐2010).Regarding specific clinical variables of kidney cancer, several findings should be noteworthy. It was well known that low histologic grade meant well differentiated of cancer cells, predicting good prognosis and improved health‐related quality of life.Increased suicide risks were commonly associated with cancer types of poor prognosis.As shown in Table Suicidal behavior in patients with cancer is affected by various factors. Compared with other causes of death such as accident, suicide is preventable.There were some limitations in our study. Besides pathological factors, suicide was affected by psychological and social factors which could not be provided by the SEER database. Moreover, there was also a lack of sufficient medical information in the SEER database, such as pharmacotherapy and genetic factors. Additionally, our study was based on the SEER database, which only collected the corresponding data of cancer patients in the US. Therefore, further study coving more countries should be conducted. Finally, data of failed suicide could not be obtained and exhibited, which might result in an under evaluation to suicide risk.5In summary, our study identified the independent risk factors of suicide for patients with kidney cancer. Diagnosis in early years (1973‐1992), male sex, unmarried status, non‐black race, higher histologic grade, and cancer‐directed surgery not performed were significantly associated with high risks of suicide. Whereas, age at diagnosis. SEER disease stage and radiotherapy did not relate to suicide. Thus, based on our study, clinicians could better screen and perform interventions to those with high risks of suicide, especially at vulnerable stages throughout diagnosis, treatment, and follow‐up. Further investigations are still needed.The authors declare that they have no conflict of interest. Click here for additional data file.


To evaluate the basal/total ratio of daily insulin dose (b/T) in outpatients with diabetes type 1 (DM1) and type 2 (DM2) on basal-bolus regimen, by investigating whether there is a relationship with HbA1c and episodes of hypoglycemia.n = 476) and DM2 (n = 541) outpatients, with eGFR >30 mL/min/1.73 m2, on a basal-bolus regimen for at least six months, were recruited from 31 Italian Diabetes services between March and September 2016. Clinicaltrials.govID: NCT03489031.Multicentric, observational, cross-sectional study in Italy. Adult DM1 (p = 0.0011). The b/T was significantly higher in the patients taking metformin in both groups, and significantly different according to the type of basal insulin . The b/T ratio was not correlated in either group to HbA1c or incidence of hypoglycemia . In the multivariate analysis, metformin use and age were independent predictors of the b/T ratio in both DM1 and DM2 patients, while the type of basal insulin was an independent predictor only in DM1.Total daily insulin dose was significantly higher in DM2 patients (52.3 ± 22.5 vs. 46 ± 20.9 U/day), but this difference disappeared when insulin doses were normalized for body weight. The b/T ratio was lower than 0.50 in both groups: 0.46 ± 0.14 in DM1 and 0.43 ± 0.15 in DM2 patients (The b/T ratio was independent of glycemic control and incidence of hypoglycemia.The online version of this article (10.1007/s40200-018-0358-2) contains supplementary material, which is available to authorized users. Insulin is the most effective drug for the treatment of diabetes . Basal-bCurrent guidelines , 3 proviOur multicentric, observational, cross-sectional study aimed to evaluate the basal/total ratio of daily insulin dose (b/T) in a large series of DM1 and DM2 patients by looking for a possible relationship with the glycemic control  and the occurrence of hypoglycemia.From March 2016 to September 2016, we performed an observational, cross-sectional, multicenter study in outpatients with DM1 and DM2 diabetes. The study was commissioned by the Italian Association of Clinical Endocrinologists (Associazione Medici Endocrinologi - AME) and approved by the Ethical Committee of Cuneo Hospital (BASAL Study— OSS 001/2016 – rif ENDO 30). The Clinicaltrials.gov ID is NCT03489031. The research was open to all specialists taking care of patients with diabetes in Italy.The primary endpoint was glycemic control, evaluated by HbA1c levels, according to b/T.Secondary endpoints were occurrence of major hypoglycemic episodes according to b/T; differences between patients with DM1 and DM2.An ad hoc form was developed and used to record all medical findings. The form was emailed to all participating centers that then emailed or faxed it back to our data manager. Data were checked for accuracy.The following data were required: age, gender, body weight and height, country of origin, type of diabetes and its duration, units of basal and total  daily insulin, type of basal insulin , use and dosage of metformin, and number of major hypoglycemic episodes (<40 mg/dL or requiring caregivers intervention) in the last three months. Serum creatinine and HbA1c levels obtained within the previous two months were also required.Each participating center recruited between 20 and 40 outpatients with diabetes. Inclusion criteria were as follows: adult outpatients (≥20 and ≤ 80 years) with DM1 or DM2, on basal-bolus insulin regimen  for at least six months, usually assuming three daily meals, and capable of informed consent.2), use of OADs ; hospitalization for any cause, glucocorticoid or oncologic treatment, or patients who had performed Ramadan in the last six months.Exclusion criteria: pregnancy or breast-feeding, severe liver or renal failure  was calculated as the body weight in kilograms divided by the square of the body height in meters.2 or Fisher’s test, as appropriate.Variables were preliminarily tested for normal distribution with the Shapiro-Wilks W test. Data were expressed as mean ± SD, or median and interquartile range (IQR) as appropriate. Continuous variables with non-normal and normal distribution were analyzed by ANOVA for repeated measures followed by the Tukey test, completely randomized ANOVA followed by the Games-Howell test, Mann-Whitney U test and t test for unpaired samples, respectively, as appropriate. Differences in categorical variables were analyzed by χSetting b/T as the dependent variable, two separate sets of linear regressions were performed. The first set was univariate; the second included all the variables whose β-coefficient was significant in the univariate analysis. In the case of multiple independent variables, a multicollinearity test was performed. Variables were rejected from the analysis if there was a variance inflation factor greater than 2.p ≤ 0.05 with the Bonferroni correction.The level of statistical significance was set at Calculations were performed using SPSS (IBM SPSS Statistics – version 21).The study was performed in 31 Italian centers, equally distributed among northern, central and southern Italy. We enrolled 1017 patients (aged 56.9 ± 17.7 years), male 57% and female 43%, nearly evenly subdivided between DM1 and DM2, namely 47 and 53%, respectively. Table p = 0.00001). Total daily insulin dose was significantly higher in DM2 patients, but this difference disappeared if insulin doses were normalized for body weight.Metformin was used in a greater proportion of DM2 patients than in DM1 patients (40% vs. 13.9%), at higher dosages  and in DM2 patients .The total insulin daily dose was significantly higher in patients with eGFR >60 mL/min/1.73 mp = 0.011). The b/T was significantly higher in patients taking metformin, in both groups: DM1, 0.52 ± 0.11 vs. 0.45 ± 0.11 (p = 0.00001) and DM2, 0.45 ± 0.11 vs. 0.41 ± 0.11 (p = 0.00001).The b/T ratio was lower than 0.50 in both groups, and significantly different between DM1 and DM2 patients  and in DM2 (p = 0.021) patients. It was higher with Degludec (0.48 in DM1 and 0.44 in DM2), intermediate with Glargine (0.44 in DM1 and 0.43 in DM2), and lower with Detemir (0.45 in DM1 and 0.39 in DM2).In the univariate analysis, the b/T ratio was not related to HbA1c or to the incidence of hypoglycemia, in both DM1 and DM2 patients. In both groups, the b/T ratio was significantly directly correlated to metformin use and inversely correlated to age Tables . The b/Tp = 0.007; ß = 0.135, p = 0.003; ß = 0.232, p < 0.0001; respectively); only age and use of metformin maintained a statistical relationship with b/T in DM2 patients .In the multivariate regression, age, type of insulin and use of metformin were significantly associated with b/T in DM1  . HoweverWe found a direct correlation between the b/T ratio and the use of metformin both in DM1 and DM2 patients. Metformin acts primarily by decreasing the endogenous glucose production, in particular the hepatic gluconeogenesis after a meal , 21. It The daily percentage of basal insulin decreases in patients suffering from renal impairment. It is well known that the kidney plays a pivotal role in insulin metabolism and excretion. Insulin is filtered at the glomerulus and almost completely reabsorbed and degraded by cells lining the proximal convoluted tubules. This mechanism accounts for 50–60% of the renal uptake of insulin, while the remaining 40–50% is removed from the post-glomerular peritubular capillaries . In patiWe found an inverse correlation between age and the b/T ratio. It is known that ageing promotes insulin resistance in DM1  and in DThe strengths of this study are inherent in its design, reflecting the current therapeutic approach to diabetes mellitus in real life practice.As for the limitations, this study focused on a homogeneous population, in terms of ethnicity and lifestyle, from all regions in Italy. These findings cannot therefore be generalized to patients with diabetes from other countries and ethnic groups. We acknowledge that information on carbohydrate consumption, carbohydrate counting education and physical activity are lacking. Moreover, the residual β cell function was not evaluated. This could play a role, in particular in DM2 patients, in influencing insulin requirements and the distribution between prandial and basal insulin. Moreover, it is to take into account that in real world, DM2 obese patients are rarely managed with basal bolus insulin regimen and metformin alone.Finally, the putative relationship between the b/T ratio and the analyzed outcomes must be interpreted with caution, because the design of the study was cross-sectional and not longitudinal.In conclusion, in a large series of Italian outpatients with diabetes treated with an insulin basal-bolus regimen, the b/T ratio was lower than 50% and significantly higher in DM1 than in DM2 patients. The b/T ratio was independent of glycemic control and the incidence of hypoglycemia, while it was correlated to metformin use and age in both DM1 and DM2 patients. Further longitudinal studies are necessary in order to define a causal association between the b/T ratio and the efficacy and safety of insulin treatment.ESM 1(DOC 26 kb)