The aim of the current study was to evaluate the influence of hydrofluoric (HF) acid concentration and conditioning time on the shear bond strength (SBS) of dual cure resin cement to pressed lithium disilicate ceramic compared to treatment with an Etch and Prime self-etching glass-ceramic primer (EP). A total of 100 samples of pressed lithium disilicate  were randomly divided into five groups (n = 20) according to surface treatment: two different concentrations of HF (5% or 9%), for different durations (20 or 90 s), or treatment with EP. Adhesion of light-cured resin cement to the treated surface was tested by the SBS test. The substrate surfaces of the specimen after failures were examined by SEM. Data were analyzed using Weibull distribution. The highest cumulative failure probability of 63.2% of the shear bond strength (η parameter) values was in the 9% HF −90 s group (17.71 MPa), while the lowest values were observed in the 5% HF −20 s group (7.94 MPa). SBS values were not affected significantly by the conditioning time (20 s or 90 s). However, compared to treatment with 5% HF, surface treatment with 9% HF showed a significantly higher η (MPa) as well as β (reliability parameter). Moreover, while compared to 9% HF for 20 s, EP treatment did not differ significantly in SBS values. Examination of the failure mode revealed a mixed mode of failure in all the groups. Within the limits of this study, it is possible to assume that IPS e.max Press surface treatment with 9% HF acid for only 20 s will provide a better bonding strength with resin cement than using 5% HF acid. Restoring teeth with full-coverage metal-ceramic crowns has been the gold standard for more than five decades, although compared to natural teeth; they often present a compromised aesthetic appearance . TherefoLithium disilicate can be conventionally or adhesively cemented to tooth structure. The choice of cementation, conventional or adhesive, should be in correspondence with the abutment dimension. Conventional cementation is associated with technique simplicity, whereas adhesive cementation is associated with a technique-sensitive multistep procedure that is problematic in cases of subgingival margins . The cliSurface treatment of lithium disilicate is attained by combined hydrofluoric (HF) acid and subsequent silane application. During the cementation procedure, chemical bonds and micromechanical interlocking are formed at the resin-ceramic interface. Micromechanical retention is provided by HF acid etching of the ceramic surface, while chemical coupling is provided by the application of a silane coupling agent ,10,11. TAccording to the manufacturer’s directions of use, etching the lithium disilicate surface is recommended with 5% HF acid for 20 s . HoweverSeveral years ago, an alternative product termed Monobond Etch and Prime , which is a self-etching ceramic primer (EP) containing the etching agent and silane components in the same vial, was launched for simultaneous etching and silanization. The product is free of HF acid, which has been replaced by a water/alcohol solution of tetrabutyl ammonium dihydrogen trifluoride (TADF) etchant. The performance of this self-etching primer was compared to the conventional surface treatment method combining prior HF acid application and subsequent silanization and reported to be similar ,25,26.Currently, there are inconclusive data among studies on the preferable method to treat lithium disilicate prior to cementation by resin cement, concerning a surface treatment with 5% compared to 9% HF, as well as the amount of conditioning time that is needed. Thus, the aim of the current study was to evaluate the influence of HF acid concentration (5% vs. 9%) and conditioning time (20 vs. 90 s) on the shear bond strength of dual cure resin cement to pressed lithium disilicate ceramic compared to treatment with a self-etching glass-ceramic primer (EP). Our null hypothesis was that different concentrations of HF acid or conditioning times as well as treatment with a self-etching glass-ceramic primer (EP) will not affect the bond strength values.A total of one hundred pressed lithium disilicate  ingots, 12 mm in diameter and 10 mm in thickness (A2 HT) one surface per ingot, comprised the study sample. The samples were randomly divided into 5 groups, 20 ingots each, according to the surface treatment, as shown in −2, Bluephase, Ivoclar Vivadent, Schaan, Liechtenstein). The other one-third of the mold will be subsequently filled with dual cure luting composite resin cement  prior to adhesion to the lithium disilicate ingots. Variolink DC was preferred over Variolink LC because the latter is restricted to restorations of low material thickness and sufficient translucency, whereas the former cover all indications.Polyethylene molds  were used to fabricate standardized resin cylinders. Two-thirds of the mold was initially filled with light cure resin cement  and light cured for 40 s with an LED-curing unit  for shear bond strength (SBS) testing via a knife-edge rod, according to ISO 29022:2013, at a crosshead speed of 0.5 mm/min of continuous loading until fracture or debonding occurred, and the load was recorded a,b. The Examination of the debonded surfaces of the samples was performed microscopically at ×10 and ×16 magnifications . Failure was classified as adhesive (between the resin cement and the lithium disilicate), cohesive (within the resin cement) or mixed mode (part between the cement and the ceramic and part within the cement).Two samples from each group were randomly selected and examined using scanning electron microscopy  . The acquisition conditions were as follows: 25 kv, 90 µA, at ×2000 magnification.The data for the shear bond strength (SBS) values were analyzed using a Weibull distribution, which gave the probabilities of failure occurrence; variables: η (characteristic life)—is the highest cumulative 63.2% failure probability of the shear bond strength (SBS) values. Β—the slope of the curve plot. The significant difference was calculated within a confidence interval of 95%.The results of the shear bond strength test according to the Weibull distribution (Weibull parameters) are presented in The treatment with the highest characteristic life (η parameter in MPa) was the 9% HF −90 s group (17.71 MPa), while the lowest values were observed in the 5% HF −20 s group (7.94 MPa). No statistically significant differences in the characteristic life were found using a 20 or 90 s conditioning time in either the 9% HF or 5% HF groups. SBS values thus were not affected significantly by the conditioning time.However, compared to treatment with 5% HF, surface treatment with 9% HF showed significantly higher SBS, as indicated by the η parameter, while, EP treatment did not differ significantly in comparison to 9% HF for 20 s .Similarly, the reliability (β parameter) of 9% HF was significantly higher than that of treatment with 5% HF.Examination of the failure mode after debonding of the samples revealed mixed mode failure in all the samples, meaning that part of the ceramic surface was always covered with the cement and part of the surface was denoted from the cement and revealed the lithium disilicate surface.Examples of SEM photomicrographs of the failure modes are given in The results of the present study have led to partial rejection of our null hypothesis; HF acid concentration did affect the bond strength values, while surface treatment with 9% HF showed significantly higher SBS than 5% HF treatment. This is reflected by both significantly higher η (MPa) values and better reliability (β parameter). However, the SBS values were not affected significantly by the conditioning time in either the 5 or 9% HF groups. Even if IPS e.max CAD and Press have initially similar material composition, the handling and process steps differ and by means the end result material properties differ, that includes as well other lithium silicate based glass ceramics. This is the reason that the results must be related to IPS e.max Press only.Lithium disilicate microstructure consists of small, interlocking, densely packed, needle-like lithium disilicate crystals that are randomly oriented, with the addition of much smaller secondary lithium orthophosphate crystals. HF etching produces a porous surface by dissolving and removing the glassy matrix containing silica and silicates. The secondary crystal phase provides greater micromechanical retention of the surface . 9% HF mSome of these findings are consistent with those previously reported. Fonzar et al. tested the influence of HF acid concentration and etching time on the micro-shear bond strength (µSBS) of lithium-silicate glass ceramics (zirconia-reinforced lithium-silicate) and IPS e.max CAD to resin cements . SimilarVeríssimo et al.  comparedThe current results, which show that conditioning time did not affect the bond strength values, are not in agreement with other previous reports. Sudré et al.  tested tWhen recommending a combination of acid concentration and exposure time, other factors that were not tested in the current study should also be evaluated, mainly the strength of the ceramic after acid etching and bonding and its optical properties. Prochnow et al.  evaluateApparently, different processing techniques (pressing vs. CAD/CAM) of the lithium disilicate ceramic material may influence their surface characteristics and fatigue performance. Schestatsky et al. demonstrated that pressed lithium disilicate monolithic crowns showed better fatigue performance than CAD/CAM milled crowns when adhesively cemented to a dentin-analog material .Based on the current results and the aforementioned studies, our recommended protocol is 5% HF for 20 s, since prolonged conditioning time (90 s) had no effect on the SBS values. Although the 90 s application yielded a higher β parameter and consequently better reliability, the differences were not statistically significant. Regarding the comparison of the SBS values in the current study, between surface treatments by EP versus HF acid + silane, significantly higher SBS was obtained compared to 5% HF and no significant difference compared to 9% HF for 20 s. These results are in agreement with previous studies, meaning that EP provides comparable bond strengths to lithium disilicate to those obtained by the traditional bonding protocol using HF acid etching followed by silane ,30,31,32The limitation of this study was that, similar to other in vitro studies, a laboratory study design cannot fully reproduce the clinical conditions. Moreover, the samples of the lithium disilicate used were discs and not full crowns. Additionally, only two conditioning times were tested, and the samples were not artificially aged. The current study intentionally aimed to test the specimens without aging to determine the possibility that the differences are attributed to the aging process; however, a combined regime of with and without aging would overcome that issue. Due to these limitations, further in vitro and in vivo research is required.Within the limitations of the current study, we can conclude that the highest shear bond strength (SBS) values between IPS e.max Press and dual cure resin cement were obtained with surface treatment with 9% HF. This gives significantly higher and reliable results. SBS values were not affected significantly by the conditioning time (20 s or 90 s). Therefore, it is possible to assume that IPS e.max Press surface treatment with 9% HF for only 20 s will provide a better bonding strength than using 5% HF acid for 20 s, as per the manufacturer recommendation. In addition, SBS values with EP treatment were comparable to those with 9% HF for 20 s.


Spatially fractionated radiation therapy is hypothesized to allow for safe, hypofractionated, dose- escalated radiation therapy for large tumors.,Tumor lysis syndrome (TLS) is comprised of a combination of metabolic abnormalities and acute kidney injury that usually occurs in patients with hematologic malignancies undergoing cytotoxic treatment.An 85-year-old woman with hypertension and chronic kidney disease (CKD) stage III (baseline creatinine approximately 1.70-1.80 mg/dL) presented to a hospital emergency department with 2 months of vaginal bleeding soaking 3 to 4 pads per day and dysuria. Hemoglobin was 9.4 g/dL and creatinine was 2.07 mg/dL on admission. Initial diagnostic computerized tomography (CT) of the abdomen and pelvis demonstrated marked endometrial thickening as well as bilateral mixed cystic and solid nodular masses inseparable from the uterus. In conglomerate the masses measured 13 × 9 × 9 cm A-C. The Physical examination revealed pale clear tumor masses circumferentially filling the vaginal vault and approaching within 3 cm of the introitus; the tumor had parametrial extension but no rectal involvement. Vaginal biopsy was obtained and demonstrated high-grade carcinoma. Immunohistochemistry was positive for PAX-8, napsin A, pancytokeratin, and CK7. Stains were negative for WT-1 and CK20 and supported a diagnosis of clear cell carcinoma. CT chest was obtained to complete staging and was negative for pulmonary metastases. Work-up yielded a diagnosis of International Federation of Gynecology and Obstetrics stage IVB clear cell carcinoma of the endometrium. The patient was deemed not to be a surgical candidate and so was referred to radiation oncology for palliative radiation therapy.Given her pain and bleeding, the patient was offered palliative radiation to the pelvis 20 Gy in 5 fractions or further dose escalation with lattice SBRT on a phase II clinical trial (NCT04553471). She consented to lattice SBRT and was simulated supine without intravenous contrast due to CKD. Iodinated KY jelly was placed intravaginally to help delineate the lower extent of the target volume. Planning target volume (PTV) 20 Gy  consisted of GTV_2000 with a 1-cm isotropic expansion, which was prescribed to 20 Gy in 5 fractions. PTV_6670 consisted of a geometric arrangement of spherical vertices, each with a diameter of 1.5 cm and a minimum of 4 cm of spacing from center-to-center, placed to achieve the desired rapid dose fall-off within GTV_2000. Each spherical vertex was prescribed to a dose of 66.7 Gy in 5 fractions as an SIB within GTV_2000. Specific care was taken to refrain from placing any high dose spheres within a vagina avoidance structure, which was designed by the treating radiation oncologist and located in the inferior third of the PTV_2000. A total of 7 high-dose spheres were placed within the superior two-thirds of GTV_2000, with appropriate separation from the surrounding organs-at-risk to ensure all clinical dosimetric planning guidelines were achieved. The volumetric-modulated arc therapy plan was delivered every other day. The patient tolerated treatment well with only grade 1 nausea, diarrhea, and fatigue, which were present before initiating lattice SBRT.She was seen in a scheduled follow-up visit 4 days after the completion of therapy. Her gynecologic oncologist remarked on his examination that the vaginal tumor was “markedly diminished in size after radiation therapy but not gone.” He recommended proceeding with platinum-based chemotherapy, but the patient decided against initiation of chemotherapy at that time. Thirteen days after completion of radiation therapy, the patient was found down and bradycardic at home by emergency medical services after the reporting of seizure-like activity by her family. Family members also reported progressive weakness and diminished urine output for several days before this event. In the emergency room, the patient was noted to be minimally responsive and bradycardic with heart rate in the 20s and mean arterial pressure in the 30s, which improved with transcutaneous pacing, norepinephrine, and epinephrine drips. Admission labs are shown in 3, down from 625 cm3 at time of simulation (28% volume reduction).Chest radiograph demonstrated dilatated pulmonary vasculature and bilateral lung opacities due to pulmonary edema. CT head was negative for acute intracranial pathology. CT abdomen and pelvis showed a smaller uterine tumor as well as extensive retroperitoneal, mesenteric, and pericardiophrenic lymphadenopathy and peritoneal metastases . There wThe patient was treated with calcium gluconate, insulin-dextrose, albuterol, and sodium zirconium cyclosilicate for hyperkalemia and rasburicase for hyperuricemia. High-rate fluids titrated to a urine output of 100 cc/hr were administered to help with blood pressure, augment renal clearance, and prevent intrarenal crystallization during TLS. Renal dysfunction and metabolic derangements were progressive despite medical management, and the patient declined escalation of care with dialysis. The patient was discharged to home hospice 2 days after admission. She passed away at home.,23TLS is a severe complication of cytotoxic therapy, which can lead to seizure, cardiac dysrhythmia, and death. TLS is rare in patients with solid tumors.Six cases of radiation-induced TLS in solid tumor malignancies have previously been described.32,,Patients due to receive therapy for malignancy should be risk stratified for TLS. Predictive factors include type and burden of malignancy, anticipated response to cytoreductive therapy, CKD, and pretreatment uric acid and lactate dehydrogenase.,,ARID1A gene expression in roughly 50% of patients, leading to deficient DNA repair after radiation therapy.40Retrospective analysis of clinically available imaging from patients enrolled in the phase I trial of lattice SBRT demonstrated clinically significant shrinkage (median 24.4% by volume) by their first posttreatment imaging a median of 81 days after lattice SBRT.Although the trial is still ongoing, we felt it was important to report this event to reduce the risk that it occurs in the future. Spatially fractionated radiation therapy has a long history, but there is renewed interest in this technique, and it continues to be used outside of prospective studies and without independent safety monitoring. Similar to this event, the literature suggests that TLS could occur greater than 1 week after completion of radiation therapy. Radiation oncologists would not typically consider patients receiving radiation therapy to be at risk for TLS, so it may not be observed with routine clinical follow-up.Ultimately, the phase II trial protocol was amended to require monitoring of complete blood counts and comprehensive metabolic panels at baseline as well as days 0, 2 to 3, and 7 after completion of treatment for all patients. The details of this protocol amendment are presented in


The incidence of FI was 64·14 %. Multivariate logistic regression analysis showed factors independently associated with poor prognosis after CPB included FI , age , New York Heart Association (NYHA) class III/IV cardiac function , macrovascular surgery  and initial sequential organ failure assessment score . Thus, the incidence of FI within 7 d of EN after CPB was high, which was associated with a poor prognosis.We conducted a prospective, observational study to determine the incidence of feeding intolerance (FI) within 7 d of initiating enteral nutrition (EN) in patients undergoing cardiopulmonary bypass (CPB) and to evaluate the association between FI and a poor prognosis. Patients who underwent CPB surgery at Fujian Medical University Union Hospital between March 2020 and June 2020 were enrolled. According to the presence or absence of FI within 7 d after EN, patients were divided into FI and non-FI groups. According to the occurrence of a poor prognosis  and prolonged mechanical ventilation (> 48 h)), patients were divided into poor prognosis and good prognosis groups. The mean age of the 237 CPB patients, including 139 men and ninety-eight women, was 53·80 ( However, feeding intolerance (FI) during EN, especially after cardiopulmonary bypass (CPB), can impact nutritional support programmes significantly.The 2019 guidelines on enteral nutrition (EN) by the European Society for Clinical Nutrition and Metabolism (ESPEN) state that patients who can fully adapt to EN and have strong recovery ability should receive EN,4.During CPB, redistribution of blood flow to critical body organs, such as the brain, results in earlier reduction in blood flow to abdominal organs. Moreover, other factors, such as haemodilution, cause the gastrointestinal tract to be in a state of low perfusion and hypoxia, which leads to functional gastrointestinal injury,6. According to the literature, the incidence of FI in critically ill patients during EN is between 30·5 and 65·7 %, which causes critically ill patients to fail to meet their nutritional goals, prolongs the duration of mechanical ventilation and increases the length of stay at the intensive care unit (ICU),7. A case–control retrospective study reported that FI within 3 d of admission to the neurological ICU was an independent predictor of poor prognosis in patients with severe neurological diseases. The contribution of malnutrition to a poor prognosis has increasingly attracted the attention of medical practitioners. The present research has, however, focused mainly on FI in critically ill patients after non-cardiac surgery and pre-mature infants, with relatively fewer reports on the incidence of FI and whether FI affects the prognosis in CPB patients. Therefore, we aimed to determine the incidence of FI and to investigate whether FI is associated with a poor prognosis in CPB patients.FI is the most common clinical manifestation of functional gastrointestinal injury; a higher incidence of gastrointestinal functional injury is associated with a higher incidence of FI, patients were divided into FI and non-FI groups. Patients with an ICU duration of stay of < 24 h, gastrointestinal tumours, chronic diarrhoea, total intestinal obstructions, gastrointestinal resections on admission, and in whom the initial EN time was longer than 48 h after operation and patients with serious mental illnesses were excluded from the study.In this prospective, observational study, CPB patients aged >18 years admitted to the Fujian Medical University Union Hospital from March 2020 to June 2020 were included. According to the definition of FI, whereby one or more of the following features are present: large gastric residual volume, abdominal distension, vomiting, diarrhoea or constipationAll patients received appropriate fluid resuscitation and ventilation therapy. Routine conditions for EN include a semi-decubitus position between 30° and 45°. Patients were assigned to receive either a nasogastric tube EN or an oral EN. Oral intake was performed based on the patient having removed the endotracheal tube and no swallowing disturbance, the gastric tube was indwelling at the bedside, and the position of the gastric tube was determined by the sound of air and water and PH. Gastrointestinal motility drugs were added when the gastric residual amount was more than 200 ml or when abdominal distension occurred. When the patient was constipated, laxative treatment was administered; when the patient had diarrhoea, antidiarrhoeal treatment was administered. According to our ICU mechanical ventilation guidelines, all patients receive the same care. When the extubation standard was reached, mechanical ventilation of the patient ceased.The present study was conducted according to the guidelines laid down in the Declaration of Helsinki, and all procedures involving human subjects/patients were approved by the ethics committee of the Fujian Medical University Union Hospital (ethics number: 2020KY014). Written informed consent was obtained from all participants.A data collection table was designed by the researchers. Partial data were prospectively collected by a stationary researcher using the hospital clinical electronic database. Data collected included demographic characteristics , education level, marital status, lifestyle  and past medical history ). The clinical data included preoperative data (New York Heart Association (NYHA) cardiac functional classification), intraoperative data , postoperative data  score on the first day after surgery, the highest vasoactive-inotropic score (VIS) within 24 h after surgery, the highest lactic acid score within 24 h after surgery, the MAP within 24 h after surgery, duration of mechanical ventilation, length of ICU and hospital stay), relevant data on FI  and EN-related data .The main outcome indicators were death during hospitalisation, postoperative complications, including gastrointestinal haemorrhage, acute kidney injury, liver insufficiency, neurological events  and long-term mechanical ventilation.. Vomiting was defined as the reflux of any visible gastrointestinal content regardless of the amount of vomit . Diarrhoea was defined as an increase in faecal moisture and stool frequency; frequency of defecation > 3 times/d or faecal volume > 200 g/d. A large gastric residual volume was defined as a single gastric residue withdrawal of > 200 ml. Abdominal distension was defined as abdominal distension or fullness discomfort, which could be subjective. Liver insufficiency was defined as a peak serum total bilirubin level of > 7 mg/dl after surgery. Prolonged mechanical ventilation was defined as ventilation for ≥ 48 h. According to The Kidney Disease: Improving Global Outcomes (KDIGO) criteria, AKI was defined as any of the following: an increase in serum creatinine by ≥ 0·3 mg/dl (≥ 26·5 µmol/l) within 48 h; or increase in serum creatinine to ≥ 1·5 times baseline level within 7 d after surgery; or urine volume < 0·5 ml/kg per h for 6 h. Poor prognosis was defined as the occurrence of gastrointestinal haemorrhage, acute kidney injury, liver insufficiency, neurological events  or prolonged mechanical ventilation.FI within 7 d after EN: the patient had one or more of the following symptoms within 7 d after receiving EN, including vomiting, diarrhoea, abdominal distension, constipation or large gastric residues formula for the determination of the VIS value was used: VIS = dopamine (μg/kg per min) + dobutamine (μg/kg per min) + 10 × milrinone (μg/kg per min) + 100 × adrenaline (μg/kg per min) + 100 × norepinephrine (μg/kg per min) + 10 000 × pituitrin (U/kg per min). All vasoactive drugs were continuously pumped through a micropump.The SOFA score used the worst value of each parameter within 24 h of the operation. The VIS score and lactic acid value were the highest values within 24 h after surgery. For the calculation of the vascular active drug usage peak 24 h after surgery reports, the Gaiest test was used for comparison between groups. Non-normally distributed data are represented by medians and interquartile ranges , and the rank sum test was used for comparison between the groups. The count data are described by frequencies and percentages; the χ2 test or Fisher’s exact test was used for comparison between groups. Univariate logistic regression analysis was used to identify risk factors associated with poor prognosis, and multivariate logistic regression analysis was conducted to determine significant risk factors. P values < 0·05 were considered statistically significant.All data were analysed using SPSS 25.0 statistical software (SPSS Inc.). Normally distributed data are described as means and standard deviations, and the group The inclusion of participants in the study is summarised in sd 12·25) years. The mean SOFA score of the study participants was 11·82 (sd 1·914). Compared with the non-FI group, the FI group had a significantly longer operation time , CPB time , aortic clamping time  and length of hospital stay .As shown in P = 0·034), age , NYHA functional class III/IV , macrovascular surgery , and SOFA score  retained statistical significance, indicating that these variables were predictors of poor prognosis after CPB.The baseline clinical characteristics of patients with a poor prognosis are shown in The present study is the first prospective, observational study to evaluate the correlation between FI and poor prognosis in patients undergoing CPB surgery. The results showed that: (1) the incidence of FI after CPB was 64·14 %; (2) FI was significantly associated with prolonged mechanical ventilation (> 48 h), acute kidney injury and neurological events in patients after CPB; and (3) FI, SOFA score, age, NYHA functional class III/IV and macrovascular surgery were independent predictors of poor prognosis after CPB. Therefore, for patients with EN after CPB, assessing FI can help identify patients at risk of poor prognosis.et al. showed that the incidence of FI was 30·5–65·7 % in critically ill patients and was higher (50·0–88·9 %) in mechanically ventilated patients. In this present study, the incidence of FI within 7 d of EN in CPB patients was 64·14 %; the incidence of constipation was high  and the incidence of abdominal distension was low . During CPB, the redistribution of blood flow to critical body organs, such as the brain, results in an earlier reduction in blood flow to abdominal organs. Moreover, other factors, such as haemodilution, cause the gastrointestinal tract to be in a state of low perfusion and hypoxia, which leads to functional gastrointestinal injury. Furthermore, in this present study, all the patients underwent mechanical ventilation after CPB. A study has shown that mechanical ventilation can cause bile reflux and gas to enter the stomach, with increased intra-abdominal pressure leading to gastrointestinal dysfunction. Therefore, FI, as the most common clinical manifestation of functional gastrointestinal injury, is easy to occur during the implementation of EN after CPB.The systematic review by Blaser  on severe neurological diseases found that FI within 3 d of ICU admission was independently associated with poor prognosis in patients with severe neurological diseases. Gungabissoon et al. reported that EN FI in critically ill patients was associated with failed nutritional goals, prolonged duration of mechanical ventilation, increased number of hospitalisation days and 60-d mortality. This present study found that FI was significantly related to a poor prognosis of patients after CPB . According to recent research, > 45 % of nurses immediately stopped EN when FI was present, resulting in reduced energy and protein intake of 1780·23 kcal (7448·48 kJ) and 100·58 g, respectively. Thus, it can be seen that the frequency of EN in patients with FI decreases, or even interrupts feeding, thus leading to nutritional deficiency, which impacts patient prognosis. Poor nutritional status can significantly affect intestinal epithelial cell renewal  and intestinal barrier function, which may lead to impaired digestion and absorption of nutrients, as well as atrophy of lymphoid tissue, decline of immune system function, and an aggravation of intestinal bacterial translocation,20. Because of impaired intestinal barrier function and bacterial translocation, the intestinal epithelium and lung epithelium are exposed to high concentrations of foreign antigens, forming the centre for the initiation and maintenance of an inflammatory response, which may lead to or aggravate multiple organ damage or failure.Another significant finding in the present study was the association of FI with poor prognosis in CPB patients. A case–control study2/FiO2 ratio, platelet count, bilirubin level, cardiovascular hypotension, nervous system status and renal function. A prospective study of 857 cardiac ICU patients found that the SOFA score was an independent predictor of mortality and hospital stay in patients undergoing cardiac surgery. Moreover, in the early assessment after adult cardiac surgery, the SOFA score was related to morbidity and mortality; the SOFA score on the first day after surgery can predict the 30-d mortality rate. In the present study, the multifactor analysis showed that the SOFA score was an independent risk factor for a poor postoperative prognosis of CPB patients , which was consistent with the results of previous studies. The incidence of prolonged mechanical ventilation in our study population (> 48 h) was 15·2 %, acute kidney injury 22·4 %, neurological events 5·9 % and death 3·0 %. Compared with data from the Adult Cardiac Surgery Database of the National Association of Thoracic and Cardiac Surgeons in the USA, the mortality and prolonged mechanical ventilation (> 48 h) rate in the present study is comparable, but the incidence of acute neurological damage is higher, which may be related to the study population that included patients who had macrovascular surgery. Therefore, in clinical work, patients with high SOFA scores should be closely observed for the function of each organ, and corresponding measures should be taken to reduce the incidence of poor prognosis.SOFA score is significantly associated with a poor prognosis in patients undergoing CPB. The SOFA score is a scoring system used to evaluate multiple organ dysfunction or failure in ICU patients and is based on the PaOet al. studied 38 830 patients who underwent coronary artery bypass surgery alone and found that with the increase in operation age, the burden of co-morbidities increases, and age is the main predictor of 30-d mortality after surgery. An international study found that the mortality rate of type A aortic dissection after surgery increased significantly with age, and age over 70 years was an independent predictor of postoperative mortality. At the same time, age is also an influential factor of FI. A previous study has shown that age is also an influential factor for FI in EN patients. Our study also found that the age in the FI group was significantly higher than that in non-FI group (54·26 (sd 11·907) v. 52·98 (sd 12·863) years). In addition, a study of 638 patients over 80 years of age after aortic valve replacement found that NYHA functional class III/IV was an independent predictor of hospital mortality. In the present study, the multivariate analysis showed that age  and NYHA functional class III/IV  were independent risk factors for poor prognosis in patients with CPB, which was consistent with previous studies. Studies have shown that with age, the cardiovascular system presents progressive structural and functional changes, especially with regard to the decrease in the number of myocardial cells and the increase in interstitial collagen fibres, resulting in impaired left ventricular diastolic function and decreased cardiac function. At the same time, the burden of co-morbidities increases due to the decline in the functional reserve of various organs in elderly patients. In addition, with the increase in age, jejunal villi become sparse and thick, and the mucosa gradually shrinks, resulting in an increase in the incidence of FI after EN. Therefore, we should pay close attention to the occurrence of FI in elderly patients with NYHA functional class III/IV in clinical work and take corresponding measures in time to reduce the incidence of adverse prognosis.Age and NYHA functional class III/IV were significantly associated with poor prognosis in patients undergoing CPB. Thorsteinsson The results of this present study should be interpreted considering the following limitations. First, this project was a single-centre prospective study with a small sample size. A multicentre prospective cohort study with a large sample size is recommended to further verify the predictive value of FI on poor prognosis in CPB patients. Second, we only analysed the results of hospitalised patients and did not follow up patients after discharge. Therefore, we were unable to determine the long-term effect of FI on poor prognosis indicators in patients who had CPB.In the present study, FI within 7 d of initiating EN was associated with a poor prognosis  and prolonged mechanical ventilation (> 48 h)) in CPB patients. These results highlight the need for clinicians to focus more on early FI after CPB. However, these results need to be verified in larger prospective studies.


The soil carbon (C) stock, comprising soil organic C (SOC) and soil inorganic C (SIC) and being the largest reservoir of the terrestrial biosphere, is a critical part of the global C cycle. Soil has been a source of greenhouse gases (GHGs) since the dawn of settled agriculture about 10 millenia ago. Soils of agricultural ecosystems are depleted of their SOC stocks and the magnitude of depletion is greater in those prone to accelerated erosion by water and wind and other degradation processes. Adoption of judicious land use and science-based management practices can lead to re-carbonization of depleted soils and make them a sink for atmospheric C. Soils in humid climates have potential to increase storage of SOC and those in arid and semiarid climates have potential to store both SOC and SIC. Payments to land managers for sequestration of C in soil, based on credible measurement of changes in soil C stocks at farm or landscape levels, are also important for promoting adoption of recommended land use and management practices. In conjunction with a rapid and aggressive reduction in GHG emissions across all sectors of the economy, sequestration of C in soil (and vegetation) can be an important negative emissions method for limiting global warming to 1.5 or 2°CThis article is part of the theme issue ‘The role of soils in delivering Nature's Contributions to People’. Since soils contribute positively and negatively to each of these processes, evidence for each will briefly be summarized in §1 below, before examining in §2 how soils could be managed more effectively to maximize their contribution to this vital NCP, exploring what needs to be done to put this in to practice in §3, and providing some conclusions in §4. (a)Soils of the world constitute the largest reservoir of terrestrial carbon (C) stocks. They comprise both soil organic carbon (SOC) and soil inorganic carbon (SIC), and are an important component of the global C cycle . Estimat (i)Current estimates of the global SOC stock range from 1500 to 2400 PgC . However2 ever since the dawn of settled agriculture. Ruddiman [Soils of agroecosystems have been a major source of CORuddiman  estimate−1, while boreal and arctic forests and woodlands average nearly 600 Mg SOC ha−1. Arctic and boreal forests and woodlands cover approximately 30 million km2, which in combination with their large SOC density makes them the dominant component of the global forest SOC stock. Collectively, these soils represent more than 62% of global forest and woodland SOC on less than 37% of the global forest and woodland area. Although vastly distributed across regions with low human population densities, these ecosystems and their soils are not removed from vulnerability. Climate change and attendant increases in wildfire are significant sources of SOC vulnerability in the boreal zone [−1 [2), these wet biomes comprise 56 Pg SOC, or approximately 14% of global forest and woodland SOC stocks. Key climate and SOC management issues in these biomes also include increased wildfire, as well as land use pressures such as forest conversion to agricultural uses or plantations [Forests and woodlands store a disproportionate share of the global SOC stock: they represent slightly less than 40% of global land area, but at approximately 400 Pg SOC, they store more than 45% of the SOC stock to 1 m –14. Otheeal zone –20. Forentations –25.2, or more than 72% of global land area. Nonetheless, forests and woodlands occupy approximately 13% of these lands. The limited areal extent and low SOC density of forests and woodlands in these dry biomes equate to only 12 Pg SOC . However, wooded ecosystems are often disproportionately important providers of climate regulation and other ecosystem services in these dry biomes. In these biomes, especially in subtropical to tropical climates, subsistence uses long in equilibrium with forest and woodland dynamics have become increasingly challenged by climate change and demand for food, fibre and fuel resources [Forests and woodlands in biomes where they are not the dominant vegetation type are also important to the global SOC stock. Deserts, steppes and shrublands are the dominant vegetation types on over 58 million kmesources –29. (ii)ca 1526 PgC), SIC is the second largest pool of terrestrial C (ca 940 PgC), thus exceeding atmospheric C (ca 880 PgC) and land plants (549–615 PgC) [−1 as After SOC (615 PgC) –32. Glob615 PgC) , 930 PgC615 PgC) , 695–748615 PgC)  and 940 615 PgC) . Because1404 PgC  with a gof years –40.a), SIC is mainly restricted to soils of arid and semiarid regions (b). Although SIC (as carbonates) can represent a substantial fraction in shrubland and grassland soils, forest soils are typically acidic and have little to no SIC [SOC and SIC often occur in the same soil. Unlike SOC, however, which exists in humid, semiarid and arid soils a, SIC is regions b. Althouo no SIC ,42.Figu3), of the carbonic acid system that also includes gaseous carbon dioxide (CO2), bicarbonate . In humid regions SOC is higher than SIC, while in arid regions SIC is higher. Arid regions contain roughly 78% of the global SIC, semiarid 14% and humid regions less than 1% [3 amounts than deserts bordering steppes with greater rainfall (ca 250 mm), such as the Chihuahuan Desert [2+ in rain can give rise to SIC regardless of parent material [2+, such as limestone, give rise to soils with about twice the amount of soil CaCO3 than neighbouring parent materials low in Ca2+ [Globally, carbon stocks of SOC and SIC are inversely related a,b. In h than 1% . The amo than 1% . In casen Desert ,46. Althmaterial , in gene in Ca2+ .2+ [Soil age within arid regions has important implications for carbon sequestration since progressively older soils contain progressively more SIC . Althoug2+ ,51. Thusb) do not differentiate between SIC precipitated in the soil profile (pedogenic) versus SIC existing as detrital particles of limestone (lithogenic) because routine laboratory methods, such as acid dissolution or dry combustion, cannot distinguish between the two types. In the field, however, pedogenic carbonate can be identified when carbonate crystals are organized into discrete bodies, such as filaments, nodules, pendants, subsoil horizons running parallel to the land surface and as petrocalcic horizons with laminar and plugged horizons [Inventories of global stocks of SIC e.g. b do not horizons . At the horizons . Lithogehorizons . (b)4) and nitrous oxide (N2O), both of which are potent GHGs with 100-year global warming potentials of around 28 and 265, respectively [2O is generated mainly by the microbial transformation of nitrogen (N) under low oxygen conditions, and is dependent on the speciation of N, which varies mainly with pH [4) can be produced when organic materials decompose under low oxygen conditions in arable soils [4 [4 sink, followed by grasslands, with the sink strength weakest in cultivated soils and those receiving N fertilizer [4 sink strength of soils globally will have declined [Soils of agricultural and other managed ecosystems are also an important source of GHGs , includiectively . In soil with pH . This is with pH . Methanele soils  with sigle soils . Cultivasoils [4 . Mineralrtilizer –61; as sdeclined . An obje (c)2, CH4 and N2O, soils can exert other physical effects on climate through alteration of albedo and their influence on regional water cycles. The extent to which soils affect albedo is largely determined by how they influence the darkness of land surface, and whether they affect snow cover. Some soil amendments, such as biochar, darken the surface of soil and have been shown to reduce albedo [Soils are not a significant source of biogenic volatile organic compounds or aerosols, but they are involved in biophysical climate feedbacks. In addition to their impacts on the global C cycle, and as a source or sink for COe albedo –64, whice albedo , therebye albedo  and snowSoils are also important in regional water cycles , which m. 2 (a)2 into plant biomass-C, (ii) transfer of biomass-C into soil and its conversion into soil organic matter (SOM) and (iii) stabilization of SOM leading to increase in its mean residence time (MRT). Photosynthesis is often limited by deficiency of essential plant nutrients , and of plant available water (green water) supply in the root zone. The amount of biomass-C returned to soil of resource-poor small landholders is affected by the competing uses of crop residues for other purposes  [Soils can act as negative emission technologies (NETs) ,72, alsobiofuel) . Conversbiofuel) .The MRT of SOC depends on a wide range of factors , some of2 sinks.Thus, soil and crop management practices important to creating a positive soil/ecosystem C budget include a system-based conservation agriculture or CA , and lib−1 yr−1) than that in agroecosystems of dryland regions (0.1–0.2 MgC ha−1 yr−1) . The technical potential of SOC sequestration has been assessed since the 1990s, and many of the available updates are cited in this article. In general, the potential of SOC sequestration is relatively more in cool and humid climates (0.5–1.0 MgC ha1 yr−1) 2+ source. If Ca is directly from silicate minerals (i.e. ‘first generation’) and if SIC is pedogenic, then CO2 has been pulled from the atmosphere via the Ebelmen–Urey reaction. This unidirectional reaction not only represents long-term continental-scale weathering of silicates, it also represents short-term soil profile weathering and accumulation of pedogenic carbonates in ‘non-flushing’ soils of arid and semiarid climates. In its expanded form, the Ebelmen–Urey reaction can be used to track C sequestration in both soil and groundwater (2 react with one mole of Ca silicate (represented as CaSiO3), resulting in one mole of C sequestered as pedogenic CaCO3 and one mole of C released as CO2.Identifying whether SIC is pedogenic or lithogenic is less important for understanding C sequestration by SIC than identifying the Caundwater . Two mol2+ and two moles of 2+ and precipitates as either (i) pedogenic CaCO3 if groundwater is pumped to the surface for irrigation or (ii) marine limestone if groundwater migrates into rivers and then oceans  and produces Ca2+ and 3 ). In addition, plants exert controls on pH via carbonic acid as well as the formation of many other types of organic acids. Plants also exert strong controls on soil moisture and on Ca2+ availability, both of which effect the stoichiometry of the extended Ebelman–Urey reaction 2 absorption from the atmosphere over geological timescales , (i) the grinding of these rocks to increase the surface area and (iii) the spreading of these crushed rocks on soils where they absorb atmospheric CO2 [Another soil-related NET is enhanced weathering of silicate rocks . Enhanced weathering involves (i) the mining of rocks containing minerals that naturally lead to COeric CO2 ,86. Conset al. [2 yr−1, is reported for the spreading of crushed rock over a very large surface area in the tropics [et al. [2 yr−1 for dunite and 4.9 PgCO2 yr−1 for basalt. Slightly lower potentials were estimated by Lenton [2 yr–1 by 2100, but with mean annual removal an order of magnitude less at 0.2 PgCO2-eq yr–1 [In a systematic review of the costs and potentials of enhanced weathering, Fuss et al.  reported tropics . The pot [et al.  to be 95y Lenton , where t-eq yr–1 . Renfort-eq yr–1  [this is (d)3 of water for an irrigated crop site in Egypt produces an average of 690 Mg CO2 per year. So, any reduction in requirement for irrigation by prudent soil management would deliver climate benefits.When soils are managed well to maximize SOC storage, they have a higher water holding capacity , and are2O release from fertilization is 1 kg of N2O–N for every 100 kg N fertilizer applied, with additional indirect losses. Over a 100-year time horizon, one kg of N2O is around 265 times more potent than one kg of CO2 [2-eq kg−1 fertilizer [2, CH4, N2O), but it also contributes to adaptation to climate change by reducing its negative impacts Judicious management of the global C cycle has strong policy implications, especially with regards to managing soils of agricultural and forestry ecosystems . Policy 2 in soil (SOC and SIC) and in biomass (forest C-stock) would be a step in the right direction. Policies must be pro-farmer and pro-nature and specifically designed to enhance the land-based C sink (−1 (3.30 PgC yr−1) and that in the forest biomass at 2.0–4.6 PgC yr−1 (3.30 PgC yr−1) [−1 [Payments to land managers for sequestration of atmospheric COd C sink . The land C sink  or aboutr−1) [−1 , restorir−1) [−1  and manar−1) [−1 . Policy r−1) [−1 , and thrr−1) [−1 . Biodiver−1) [−1 . Policy r−1) [−1 . In addi (b)Education is needed to fully realize the beneficial roles that soils can play in the regulation of climate, and ecosystem services more broadly. The arenas of this education are fourfold: (i) soil science education and training for students and professionals; (ii) public outreach and education about the critical nature of soils to supporting life on Earth; (iii) education for all people in the ways that soils are connected with issues of equity and environmental justice; and (iv) education of policy makers to identify and implement appropriate policies to harness the land-based sinks.The first of these educational spheres is the longstanding strength of the soil science discipline, and in many ways this is the easiest to sustain. Current understanding of the role of soils in climate regulation is the product of more than a century of academic and applied research, education and training in institutions of western scientific learning ,104. ExpEducation for the public, in order that all people are encouraged to examine and embrace our collective dependence on soils, is at least as important as the education of scientific and technical professionals. This need becomes all the more important as Earth's population continues to grow and urbanize, leading to ever larger numbers of people who lack direct connection to soils and their role in climate regulation, food production, water quality protection and the many other ecosystem services that they provide. However, the myriad ways in which humanity depends upon soils creates diverse opportunities to connect people to soils in individualized ways. The diversity of ways in which talented educators of our time are engaging in this work is impressive. From ‘Soil Kitchen’ events that provide real-time soil testing in urban communities , to joinTo provide solutions to the climate crisis, soils education must address issues of equity and environmental justice. Indeed, soils, the climate crisis, and equity and environmental justice issues share a common theme: each is a nexus, a convergence of multiple interacting factors . In the  (c)2+ from silicates is essential for direct CO2 capture and storage as both pedogenic carbonate and enhanced weathering. Currently, ground basalt is the common source Ca2+. To remove one Pg of CO2 through enhanced weathering (reaction 1), approximately 3 Pg of basalt would have to be mined, crushed, and transported [2+, such as silicate-derived Ca2+ in gypsum or in calcium hydroxide, would be feasible.Research is needed to develop better measurements, monitoring, standardization, upscaling from pedons to continents, identifying ecologically sensitive regions, understanding the biogeochemistry of terrestrial C, including black C, hydrophobicity and MRT in the context of land use and management . For SICnsported . ResearcSequestration needs to be tailored to the environment where it will be implemented. Research is, therefore, needed to identify optimal areas using continental-scale ‘Land Resource Regions' or ‘Major Land Resource Areas . Enhance3 in global Mollisols, for example, from 8.25 to 9.25%, could sequester 14 Pg of C [3.Research is also needed to determine the unintended consequences of geoengineering. This is especially relevant to manipulating the SIC system. An increase of 1% CaCO Pg of C  over the. 42 and other GHGs (CH4 and N2O) and attendant global warming, severe loss of biodiversity [The onset of agriculture circa 10 000 years ago  and thativersity , as welliversity . Thus, tiversity . Sequestiversity , while p


Clostridioides Difficile Infection (CDI) are of major concern in spinal cord injury (SCI) rehabilitation.Antibiotic Associated Diarrhoea (AAD) and 9 live Lactobacillus casei Shirota (LcS) in preventing AAD and CDI and in patients with SCI and to determine whether proton pump inhibitors (PPI) and under nutrition-risk are risk factors for AAD/CDI. LcS or placebo was given once daily for the duration of an antibiotic course and continued for 7 days thereafter. Follow up was set at 7 and 30 days after the antibiotic course finished. The primary outcome was occurrence of AAD up to 30 days after finishing LcS/placebo. This trial is completed and registered (ISRCTN:13119162).A multi-centre, randomized, double-blind, placebo-controlled (the ECLISP) trial, was conducted in three tertiary spinal cord injury centre in the UK to assess the efficacy of consuming a probiotic beverage containing at least 6.5 × 10n = 181) or placebo (n = 178). Overall, no statistical difference was seen in occurrence of the primary outcomes of AAD at 30 days follow up . In the secondary analyses LcS was associated with a lower risk of AAD at 7  and 30 days follow up  in the participants who took PPI regularly. Under nutrition-risk was associated with an increased risk of AAD at 7  and 30 days follow up . No intervention-related adverse events were reported during the study.Between November 2014, and November 2019, 359 consenting adult SCI patients , from 3 SCI centres responsible for providing approximate 45–50% of UK SCI service, with a requirement for antibiotics due to infection were randomly allocated to receive LcS (The present study indicates that LcS could not prevent AAD/CDI in unselected SCI patients. LcS might have the potential to prevent AAD in the higher risk group of patients on regular PPI. Confirmatory studies are needed to allow translation of this apparent therapeutic success into improved clinical outcomes.Yakult Honsha Co., Ltd. Clostridioides difficile infection (CDI) in patients with spinal cord injury (PWSCI) patients are reported in range of 14.9 to 30.3%. Probiotics, have been proposed to prevent AAD / CDI by maintain a healthy gut microbiota in hospitalised patients on antibiotic therapy.The prevalence of antibiotic associated diarrhoea (AAD) and of Lactobacillus casei Shirota (LcS) supplement could not prevent AAD in PWSCI  but was associated with a lower risk of AAD at 7  and 30 days follow up  in participants who took PPI regularly.Our study identified that the use of a single strain The present study found that LcS could not prevent AAD in PWSCI but has the potential to prevent AAD in the higher risk group of PWSCI on PPI and at risk of under nutrition. Confirmatory studies are needed to allow translation of this apparent therapeutic success into improved clinical outcomes.Alt-text: Unlabelled box1Antibiotic associated diarrhoea (AAD), described as unexplained diarrhoea that occurs in association with antibiotic administration, is a common complication of antibiotic treatment. It is reported that about 30.3% of patients will develop AAD upon administration of antibiotics Clostridioides Difficile (CDI) occurs most often as a consequence of disruption of the gut microbiota following the use of broad spectrum antibiotics, and is therefore considered the specific cause in a subgroup of AAD. C. difficile is a spore-forming, Gram-positive anaerobe. It is a particularly virulent pathogen because it produces an enterotoxin and a cytotoxin, both of which cause mucosal injury and damage to the colon. When antibiotic therapy disrupts this natural defence, C. difficile multiplies and produces toxins, causing diarrhoea. In some cases, severe inflammation (C. difficile associated colitis) can develop Infection with the recently renamed live microorganisms which, when administered in adequate amounts, confer a health benefit on the host’, have been proposed to prevent AAD/CDI by restoring or maintaining a healthy gut microbiome in hospitalized patients on antibiotic therapy, particularly those on broad-spectrum antibiotics Probiotics, defined as ‘People with SCI (PWSCI) may be particularly vulnerable to diarrhoea and its consequences because of their long hospital stays for acute care and rehabilitation Lactobacillus casei Shirota: LcS) for the prevention of AAD and CDI in adults with SCI. The objectives of the study were: (1) to test the efficacy of daily consumption of a probiotic drink containing at least 6.5 x 109 live LcS in preventing AAD and CDI in SCI patients, and (2) to determine whether  under nutrition risk and PPI use are a risk factor for AAD/CDI.Diarrhoea can moreover delay rehabilitation, increase the risk of developing pressure ulcers/delay wound healing and reduce quality of life (QOL). There is growing interest in probiotics to reduce the risk of AAD / CDI. An early study identified the use of PPIs and malnutrition or under nutrition risk 22.1This study was a prospective, multi-centre, randomized, double-blind, placebo-controlled study. Patients who had been prescribed antibiotics were identified and approached for consent. After obtaining written informed consent, study data were collected at the time of prescribing antibiotics (baseline) and at follow up, set at 7 days and 30 days after the end of the antibiotic course . The study was conducted within the National Health Service in the UK. The three centres involved in this study are responsible for about 45–50% of all specialist SCI service in the UK.2.2The inclusion criteria were: patients aged ≥ 18 years, who had sustained a SCI, had been admitted to one of the three investigatory centres, were due to receive antibiotics for an infection, and who were able to take the study drinks within 48 h of the first dose of antibiotic. Patients were excluded from the study for the following reasons: previous recruitment to the study (a patient could not be recruited more than once) and were excluded if they had antibiotic use in the 30 days prior to recruitment – although a single dose of prophylactic antibiotic given 14 to 30 days before recruitment was permitted. Also, patients with diarrhoea within the seven days prior to recruitment, with known gastrointestinal disease that could result in diarrhoea and several other conditions and comorbidities were also excluded. (Supplement 9 colony-forming units (CFU) LcS/bottle, or placebo daily for the duration of the antibiotic course and for 7 days thereafter. The study drink was given at the drug round by nurses. Consumption was monitored on a daily basis by the study team. Minor non-compliance was defined as: two consecutive days of not drinking the study intervention; major non-compliance: three or more consecutive days missed. If participants missed the intervention for more than three days, they were withdrawn from the study.Between November 2014 to November 2018, 359 consenting SCI patients, who were within 48 h of commencing antibiotics, were randomly allocated to receive a fermented milk drink (Yakult®: 65 ml) containing a minimum of 6.5 x 10The participants’ demographics, baseline clinical and nutritional information were collected. These included age, sex, level of SCI and completeness of injury using the International Standards for Neurological Classification of Spinal Cord Injury The perceived risks of the various antibiotics were used to categorise patients into three groups: “low-risk” antibiotics , “medium risk” antibiotics  and “high risk” antibiotics  as described in previous studies ,8,16 and2.3To estimate the size of the sample, we used data from our previous study 2.4A random allocation was carried out by the statistical advisor (SPH) using randomization.com to generate random permutated blocks of 30 for each study site and for previous single dose prophylactic antibiotic use (15 to group 1 and 15 to group 2 per block with no stratification or minimization), until sample size criteria were met. The randomization sequence was concealed from the study team. The study team allocated study drink as per the randomization list and the team was blinded to patient allocation. Emergency unblinding codes were available at individual sites, but these were not used. The randomization list was forwarded to the product supplier (Yakult Europe B.V.) by the study data analyst. The product supplier arranged delivery of product packs to study sites, each with a sticker/code specific for each participant. The placebo was an acidified milk without LcS with nutritional values and organoleptic characteristics  equivalent to those in the probiotic product. The probiotic drink and the placebo were presented in identical packaging to prevent unblinding by site's staff. 2.5The primary outcome was defined as the occurrence of AAD during and up to 30 days after the antibiotic course finished. The bowel movements were monitored routinely by the nursing staff on the ward using the Bristol stool scale 2.6C. difficile toxin. In the present study, CDI was defined by the hospital microbiology laboratory on confirmation of the presence of C. difficile toxin, but the method of C. difficile toxin detection varied between the laboratories: i.e., screening for glutamate dehydrogenase (GDH) antigen followed by toxin A and B detection, enzyme immunoassays for C. difficile toxin A and toxin B, or toxin-producing C. difficile gene detection by polymerase chain reaction testing, or a combination of these Whenever diarrhoea was reported, a stool sample was collected and sent to the hospital laboratory for the detection of 2.7The primary statistical analysis was carried out on the basis of intention-to-treat, with all participants being analyzed according to their allocated treatment group irrespective of what treatment they actually received.2 test were used to compare rates of diarrhoea, as well as rates of AAD and CDI across categorical variables. Relative risks with 95% confidence intervals, were used to describe the treatment effects of LcS.Fisher's exact test and χA series of screening univariate analyses were undertaken. Logistic regressions were used to establish which factors individually influenced the occurrence of diarrhoea, its duration (and CDI at Abx+7d and Abx+30d follow up). Linear regression was used for continuous outcome measures for duration of diarrhoea and episodes of diarrhoea. Thereafter, statistically significant univariate predictors were used in, multiple binary logistic regression and multiple regression analysis to determine statistically significant predictors for AAD, CDI and other secondary outcomes, after accounting for their relationship to other pertinent variables. Sub-group analyses were performed within treatment arms to analyze the following for association with AAD/CDI occurrence: (i) risk of under nutrition and (ii) use of PPIs. No allowance for multiplicity was made for the secondary outcomes.To reduce the bias implicit in utilizing only complete cases, multiple imputation procedures for the data was used using the SPSS  multiple imputation function with fully conditional specification (maximum iterations of 500) using a Predictive Mean Modeling method to produce 10 imputed datasets. The imputation model included all variables  involved in the analyses, with PMM imputed variable limits set for imputed values to be within the range of available data. Main outcome variables (i.e. AAD and CDI) were not imputed. These 10 imputed datasets were then individually analyzed as normal; thereafter standard multiple imputation procedures were used to combine the multiple scalar and multivariate estimates quantities 2 and β coefficients with t-test significance are reported. For all tests, a p-value of 0.05 or less, or when the 95% CI for OR did not cross 1.0 were considered as statistically significant. Statistical analysis was performed using the Minitab statistical software  and SPSS .For logistic regression odds ratio (OR), Nagelkerke's R and correctly classified cases are reported. For linear regression, adjusted R2.8The present study, conducted according to the guidelines laid down in the Declaration of Helsinki, received ethical approval from the National Research Ethics (REC) Committee (reference no. 14/SC/1101) and approval from the local research and development department at each participating site. After the study had been explained by a research coordinator and all questions had been answered, each participant signed an informed consent form prior to trial initiation.The original study protocol was registered at ISRCTN (IRCTN13119162). The study steering group was set up in July 2014 and the study commenced its recruitment in November 2014. Changes were recommended to the original, approved protocol to improve recruitment specifically in relation to the inclusion and exclusion criteria of patients’ enrolment. The new version of the protocol was developed in accordance with the consolidated standards of reporting trials 2010 guideline and subsequently approved by the sponsor and funder and the REC. [Supplementary File 1]A register was kept of all patients who withdrew from the study. The reason for consent withdrawal was documented, if provided by the participants, along with the following core patient characteristics: age, gender and level and severity of SCI. To monitor the progress and conduct of the study, all investigators attended meetings before the study and met for communal bi-annual updates and end of study meeting in Jan 2019.The study was additionally monitored by an external Clinical Research Associate (PHARMExcel) according to applicable provisions of the sponsor's subcontractors monitoring procedures, in conformance with ICH-GCP FDA guidelines, ISO 14,155 and UK-specific laws/regulations.2.9Participants were considered at risk of under nutrition on the basis of the Spinal Nutrition Screening Tool (SNST) 3This study was funded by Yakult Honsha Co. Ltd. The funder did not have any role in the design of the study, the collection, analysis, or interpretation of the data, the writing of this manuscript, or the decision to submit this manuscript for publication. Dr Samford Wong as chief investigator and corresponding author had full access to the final dataset and made final decision to submit for publication.4Over the 72 months of the study period, 459 patients were approached by the study team; 48 (10.5%) patients refused to participate in the study, 44 (9.6%) potentially eligible patients were missed because of the tight recruitment timeframe, and eight (1.7%) were excluded as insufficient study drinks were available at the time. Of the 359 patients who met the inclusion criteria and agreed to participate in the study, 41 (11.4%) participants withdrew during the study. The participant flow is summarized in n = 246, 68.9%) and non-traumatic in 111 case (31.1%). The median onset of SCI was 157 days (IQ range: 2661 days).The baseline characteristics of the 359 patients , and the outcomes summary are summarized in n = 123) at the time of recruitment and 63 (17.7%) were malnourished on dietitian assessment. We compared participants’ nutrient intake in a small group of selected patients using the food record chart. No difference was observed between the LcS (n = 6) and placebo (n = 6) groups with regards to the estimated daily intake of energy, protein and dietary fibre. 132 (37.9%) of 348 participants were prescribed PPI , respiratory tract infections , post-operative infections , sepsis , pressure ulcers , wound infections , cellulitis , abscess , toe/finger infection , osteomyelitis , tooth infections  and others . The number of participants on high-risk antibiotics were closely comparable between the LcS and placebo groups (51.9% in LcS group and 59.6% in placebo group).Most participants (64.9%) received one antibiotic as their entry criterion to the study, but 23.4% received two, 7.5% received three and 4.2% received four or more antibiotics. A total of 25 different antibiotics were recorded in the present study: the oral route was used in 46.6% and the intravenous route was used in 53.4% of participants. The median length of antibiotic course was 8 days ; no statistically significant differences with regard to nature or duration of antibiotic intake were observed between the LcS and the placebo groups. The indications for antibiotic treatment, in descending order, were as follows: urinary tract infections  stay; laxative use; PPI use, body mass index (BMI), percentage of nil-by-mouth status and use of enteral feeding tubes .n = 4, 2.2% v Placebo: n = 6, 3.4%). (Ten (2.8%) severe adverse events were reported in this study. They were not apparently related to the use of investigational product and occurred almost equally in the two groups . 55.1p = 0.639). . Table 3Ab6p = 0.858) and duration of AAD  or the number of episodes of AAD . . 6.12: 0.823, p = 0.36) and AAD at Abx+30d . However, in the group of patients who were on regular PPI, LcS use was associated with a lower risk of AAD at 7  and 30 days follow up  when compared with placebo  and at 30 days follow up  Participants who were allocated to LcS or placebo and at risk of malnutrition were found to have a statistically significantly increased prevalence of AAD at Abx+7d and at Abx+30d  and at 30 days follow up   Risk factors for antibiotic associated diarrhoea / Clostridioides difficile infectionThe multivariate logistic/regression analysis revealed independent risk factors for AAD at Abx+7d: age older than 65 years, use of high-risk antibiotics, study site and number of drugs.  The risk factors for AAD at Abx+30d were mechanical ventilation, study site and number of laxatives. The risk factors for frequent diarrhoea were age 65 or above, study site, being GDH positive and number of drugs. The risk factors for increased duration of diarrhoea were being nil by mouth, malnutrition as assessed by dietitian, number of drugs and study site. The risk factors for CDI at Abx+7d were being GDH positive and having a history of weight loss, whereas those for CDI at Abx+30d were being GDH positive and having a long duration of antibiotic treatment. Supplement Table 4 provides a summary of the univariate and multivariate results.8This is the first randomised placebo-controlled trial with an adequate sample size in a group of patients with SCI, which has evaluated the efficacy of LcS for the prevention of AAD and CDI. Although this specific probiotic drink could not prevent AAD in all SCI patients, finding suggests that taking LcS is associated with a lower risk of AAD in people with SCI who are on regular PPI therapy.The present study's conclusion is different from our earlier open-labelled study `The inclusion of patients treated in different SCI centres could be considered a strength, but can also be regarded as a weakness. Infection control policies, AAD/CDI definition and antibiotic management were different in the participating SCI centres, thus the influence of these factors on the study results could not be excluded.p < 0.01). These results are in agreement with results of a similar published study The present study suggests malnutrition risk could increase the incidence of AAD in 30 days follow up  is similar to some previous studies in patients with SCI 14.9–36%) % 6,7,8],87,8] an,87,8] an9 CFU LcS was selected based on the previous trial's data acidophilus CUL60, CUL21, B. bifidum CUL20, B. lactis CUL34 in 6 x 109 CFU /day), Helps et al. 9 CFU /day), and Rajkumar et al. casei immunitas DN-114,001 in 10 x 109 CFU /day) as did Selinger et al9 CFU /day).Current evidence remains unclear in whether probiotics could reduce the incidence of AAD/CDI in general hospitalised populations ,6,7. TheThe compliance with LcS therapy in the present study was good (92.4%), with no known severe adverse events directly related to LcS. It is possible that a higher dose might have yielded a greater benefit. However, the effect of increasing dosage of probiotics should be monitored carefully as unexpected adverse events may also occur.Another important criterion for any probiotic is that the strains used survive the passage through the stomach and arrive in a viable state in the small intestine and colon. LcS has been shown to survive and be well tolerated in the upper gastrointestinal tract and reach the large intestine in a viable state The present study does not provide support for a general use of LcS to prevent AAD in SCI patients but suggests that LcS may help to prevent AAD in SCI patients taking PPI regularly. Confirmatory studies are now needed to allow translation of this apparent therapeutic success into improved clinical outcomes. Further research should define the most appropriate target populations. Study designs using standardized definitions of AAD and CDI will help to evaluate the effect of probiotics in preventing AAD/CDI as well as in providing more homogeneous evidence for future systematic review and meta-analysis.SW- study chief investigator, protocol development, data collection, data analysis, manuscript preparationSPH- protocol development, data evaluation, statistical support / analyst, manuscript revisionAF – protocol development, data evaluation, gastroenterology adviser, manuscript revisionNK – site principal investigator, protocol development, manuscript revisionRH – site principal investigator, data evaluation, gastroenterology adviser, manuscript revisionJOD – protocol development, clinical supervision, validation and guardian of laboratory data, manuscript revisionAV- data collection, data evaluation, manuscript revisionGH- protocol development, validation and guardian of laboratory data, manuscript revisionRS – protocol development, data evaluation, manuscript revisionAJ – protocol development, clinical supervision, data evaluation, manuscript revisionDr Samford Wong (Chief Investigator) has received funding support from Yakult Honsha Co Ltd. Yakult Europe B.V. provided free LcS/Placebo and the necessary equipment to maintain the cold chain. Prof Alastair Forbes receives honoraria form Fresenius Kabi, Takeda and Dr Falk Pharma. All the other authors have no conflicts to declare.


Simulations and experimental achievements carried out during more than two years of investigations are reported here, detailing the technical expedients that were necessary to increase the single layer CVD graphene absorption first to 39% and then up to 84%. Graphene absorption increased when an asymmetric Fabry–Perot filter was applied rather than a symmetric one, and a further absorption increase was obtained when graphene was embedded in a reflective rather than a transmissive Fabry–Perot filter. Moreover, the effect of the incident angle of the electromagnetic radiation and of the polarization of the light was investigated in the case of the optimized reflective Fabry–Perot filter. Experimental challenges and precautions to avoid evaporation or sputtering induced damage on the graphene layers are described as well, disclosing some experimental procedures that may help other researchers to embed graphene inside PVD grown materials with minimal alterations.Graphene is emerging as a promising material for the integration in the most common Si platform, capable to convey some of its unique properties to fabricate novel photonic and optoelectronic devices. For many real functions and devices however, graphene absorption is too low and must be enhanced. Among strategies, the use of an optical resonant cavity was recently proposed, and graphene absorption enhancement was demonstrated, both, by theoretical and experimental studies. This paper summarizes our recent progress in graphene absorption enhancement by means of Si/SiO Graphene-based absorbers are receiving a considerable interest due to their potential applications in photovoltaics ,2,3, as In the THz and IR regions, however, high quality graphene may show strong interaction with light thanks to generation of surface plasmon polaritons (SPPs), making graphene a promising alternative to typical plasmonic materials ,23,24,25In addition, tunable graphene electromagnetic response may be achieved by chemical and/or electrical doping or by using a magnetic field ,31,32.In the Vis and NIR regions, on the contrary, absence of SSPs makes it necessary to couple graphene with resonant structures such as metamaterials, photonic crystals and plasmonic materials ,37,38,39Many examples of perfect graphene-based absorbers have been reported in the literature basing on the critical coupling concept ,41,42.Thongrattanasiri et al. have simulated 100% absorption in doped graphene nanodisks by exploiting the critical coupling conditions .Piper et al.  have demLiu et al.  have demXiao et al.  have repJin et al.  have revAnother strategy to enhance graphene absorption is to exploit the electric field enhancement by resonant cavities ,49,50. TNulli et al. reported theoretically that the optical absorption of single-layer graphene can be enhanced up to 50% by increasing the electric field on the surface of undoped graphene by placing graphene inside symmetric Fabry–Perot structures .Ferreira et al. have calculated the same absorption result for single layer graphene by utilizing one Fabry–Perot cavity and they have simulated also that graphene optical absorption can increase up to 100% using two symmetric Fabry–Perot cavities .Zand et al. have used a genetic optimization algorithm coupled to a transfer matrix code to design one-dimensional aperiodic multilayer microstructure embedding single layer graphene, where near-total absorptions at selected wavelengths is obtained by existence of critical coupling . They siFurchi et al.  have dem2/Vs, which is generally much higher than the real one , leading sometimes to too overoptimistic predictions [Many of the theoretical studies found in the literature simulating perfect graphene absorption consider for single layer graphene a very high mobility µ of about 10,000 cmdictions ,65.Apart from the work from Furchi et al., the enhancement of graphene absorption by using an optical resonant cavity has been rarely explored experimentally due to the many experimental challenges related to embedding graphene inside metals or dielectric stacks ,66.The graphene absorption enhancement inside an optical resonant cavity is generally narrowband and is, therefore, more suitable for application in photodetectors, sensors, or absorption filters ,66,67.In the present work, we summarize our recent studies ,68,69 onIn the optimized structure, a high absorption of 84% at 3150 nm was measured  in case 2 (L) layers, for use in the near to mid IR. Three different Fabry–Perot filters were simulated: (i) a symmetric FP filter with identical top and bottom mirrors (FP1), (ii) an asymmetric FP filter where the bottom mirror had a higher reflectance due to a larger number of layers with respect to the top mirror (FP2), and (iii) an asymmetric reflective FP filter obtained by further increasing the bottom mirror layers (FP3). FP1 and FP2 filters worked in transmissive mode, while FP3 worked in reflective mode, due to the high reflectance of the bottom mirror (99.7%). The structure of FP1, FP2, and FP3 filters was the following: (i) air/HLH LL HLH/sub, (ii) air/HLHL HH LHLHLH/sub, and (iii) air/HLH LL HLHLHLHLH/sub, respectively. For FP1 and FP3 the cavity was (LL), i.e., constituted by a half wavelength thick SiO2 layer, for FP2 the cavity (HH) was made by a half wavelength thick Si layer. This last FP structure, a bit different from the other two, was chosen because of its particular distribution of the electric field characterized by two maxima. A single layer graphene (SLG) was embedded inside the FP structure and located at the position where the electric field was maximum to enhance its absorption. SLG was covered by a 30 nm thick MgF2 layer, meant to protect graphene during the later sputtering deposition. A Fabry–Perot optical filter consists of a cavity separated by two flat and parallel high reflecting mirrors where light experiences multiple reflections. Simulation of FP filters was carried out by using the Wave Optics Module of Comsol Multiphysics software. Our Fabry–Perot filters consisted of a sequence of alternate quarter wave thick high refractive index Si (H) and low refractive index SiOG) where SLG is positioned. The central wavelength of the Fabry–Perot filters is different for the three cases because it results from different experiments, however, central wavelength position in the considered wavelength range, only causes small variations of T, R, and A due to the wavelength dependence of Si and SiO2 optical constants. As we can observe from 2 with optical thickness equal to a quarter wavelength . Si and SiO2 layers were fabricated by radio frequency sputtering in MRC  systems, starting from 99.999% purity Si and/or SiO2 targets, as described elsewhere [2 layer covering graphene, a radiofrequency sputtering of 200 W and a sputtering pressure of 1 Pa were used. For the first 30 nm of SiO2 layer deposited onto graphene, a milder sputtering condition was used: i.e., sputtering power of 50 W and sputtering pressure of 3 Pa. For FP3 filter, grown in a different system, the same sputtering conditions (sputtering power of 200 W and sputtering pressure of 0.53 Pa) were used for Si and all the SiO2 layers, due to the fact that such system geometry allowed a milder sputtering process.The Fabry–Perot filters consisted of alternate layers of Si and SiOlsewhere ,68,69. F2 layer was carefully evaporated in a Balzer BAE 250 evaporation system, and the evaporation rate was controlled by a quartz crystal microbalance.MgF2. After the growth, graphene was removed from the back of the Cu substrate by means of an oxygen plasma cleaner . For graphene transfer, a procedure reported elsewhere was applied [Single layer graphene was grown by CVD on Cu foils previously submitted to a pre-oxidation treatment at 250 °C for 90 min. CVD growth conditions were the following: substrate temperature 1070 °C, 10 mbar pressure by using 0.025 SCCM ethanol vapor with 20 SCCM Ar and 10 SCCM H2 layers which separate the top and bottom mirrors. In the asymmetric FP2 filter, two maxima of electric field occurred, and graphene was positioned onto the upper Si layer of the cavity (HH). In the asymmetric reflective FP3 filter, graphene was positioned in the middle of the cavity (LL), i.e., sandwiched between the two SiO2 layers.2 protective layer. After the evaporation of the MgF2 layer, the two samples were transferred back into the sputtering chamber for the deposition of the top multilayer structure.The fabrication procedure of the multilayer structure was the following. First, the bottom multilayer structure and two CVD graphene layers were fabricated separately in the sputtering and CVD chambers, respectively. For each sputtering deposition run, two substrates (quartz or Si) were loaded in the chamber, one for the reference and the other for the graphene-based FP filter. Similarly, two graphene layers were prepared in the same run, one for insertion into the FP filter and the other for characterizations. Then, the graphene layer was transferred on the top of the bottom multilayer by the mild transfer process described above. The multilayer structure topped by graphene and the reference multilayer (without graphene) were transferred into the evaporation chamber for the growth of 30 nm MgF−1 in the latter case. For FTIR measurements, a Fixed-Angle Specular Reflectance Accessory from Perkin Elmer was used.Transmittance and reflectance measurements in the NIR were carried out with a PerkinElmer 900 spectrophotometer, while MIR measurements were performed with a high resolution FTIR Perkin Elmer instrument. The reflectance measurements were obtained by using calibrated standards, i.e., an Ocean Optics Al mirror certified in the range 250–2500 nm in the first case and an Al infrared reflectance standard with a SiO overcoat certified by the National Physics Laboratory (NPL) in the wavenumber range of 4000–200 cmThe Raman measurements were carried with a Renishaw inVia Reflex Raman spectrometer using a 514.5 nm excitation source.tG (0.35 nm) [σ(ω) the intrinsic contribution to the graphene relative permittivity, the thickness of single layer graphene and the graphene optical conductivity, respectively.ω)=εg(ω) ,74, wherω)=εg(ω) ,76,77:εg εb(2.5) ,79, tG (0.35 nm) ,81, and The graphene optical conductivity was considered as the sum of interband transitions and Drude-like intraband conductivity ,83,84,85= (e24ℏ) ,86, Ef tlsewhere .Single layer graphene permittivity was simulated also as a function of the wavelength and Fermi level, as shown in 2 evaporation, after SiO2 sputtering on MgF2/graphene layers and after the whole filter fabrication process.The quality of graphene was checked after each experimental step, i.e., after MgF2 layer directly onto SLG, a mild sputtering condition was applied by increasing the sputtering pressure and decreasing the radiofrequency power. Notwithstanding, graphene damage could not be avoided, as demonstrated by Raman analysis (not shown here), and a further graphene protection was necessary. Therefore, to avoid the sputtering of the SiO2 layer directly onto graphene, a thin protective MgF2 layer was evaporated prior to the sputtering of SiO2. We have chosen MgF2 due to its refractive index and extinction coefficient values, very close to those of SiO2. This is necessary since MgF2 becomes part of L (the low index layer) of the multilayer stack. Other fluoride materials could have served the purpose. Furthermore, the evaporation of the MgF2 layer required some care since we observed that if evaporation occurred at a high rate, graphene defects band D increased. 2 at high (2 Å/s) and low (0.1 Å/s) evaporation rates. Only the latter case left graphene unchanged. The effect of deposition rate of SiO2 was preliminarily evaluated in experiments with ML graphene with unoptimized MgF2 deposition (curve of 2 deposition on SL graphene can be seen in the red and blue curves of 2), suggests that some extent of the modifications of the D and 2D bands by SiO2 is not due to lattice damage but to optical and electronic “proximity” influences on graphene by the stack.Initially, for the growth of the first 30 nm of SiOcurve of b. The ef2 and SiO2 deposition  evaporation of the thin MgF2 layer should occur with a very low rate, (iii) the presence of the thin MgF2 layer is not by itself sufficient to avoid the damage if the sputtering process is too energetic, (iv) the combination of evaporated MgF2 and mild SiO2 sputtering increases the graphene D band but preserves the optical and electrical properties of pristine graphene, finally (v) we cannot certainly assign the measured D band increase to an effective graphene “damage” while inside the stack due to possible proximity effects by the embedding layers on the Raman spectrum itself.The results obtained after several attempts to not damage graphene can be summarized as following: (i) a thin MgFR is the reflectance of the top and bottom mirrors, while on the right-hand is the finesse of the asymmetric filters (FP2 and FP3). In our FP filters, the finesse increased from 21 to 31.5 when passing from the symmetric structure of Above, the left-hand side formula represents the finesse of the symmetric FP filter (FP1), where Absorption of unpatterned and undoped single layer graphene up to 84% has been never reported experimentally in a Fabry–Perot filter. Comparable or even higher absorption values have instead been obtained by other authors by using graphene coupled to non-planar resonant plasmonic structures ,91,92.Enhancing the light-matter interaction in single-layer graphene by the use of optical microcavity requires no stringent constrains on the graphene electrical properties, such as the sheet resistance, and may find application in a variety of graphene-based devices, such as optical absorption modulators, light emitters, and optical attenuators, and provides new routes to graphene photonics for applications in spectroscopy, communications, sensing, and security.Results, validated here at NIR and MIR wavelengths, may be applied in principle at different wavelengths ranging from Vis to THz by properly choosing the materials of the layers and of the substrate. Moreover, as obtained by our previous simulations, modification of the filter amplitude and bandwidth may be achieved by: (i) using multilayer graphene instead of single layer graphene , (ii) usResults are in accordance with what has been reported by other authors. In , Xiao etGraphene absorption discussed so far was obtained in the case of a TE polarization. For the optimized FP structure, i.e., the FP3 filter, the simulation was carried out, also, in case of TM polarization. 2 layers. Results demonstrated that graphene absorption greatly increases when graphene is embedded inside an asymmetric Fabry–Perot structure, reaching its maximum in case of a reflective Fabry–Perot filter. SLG properties were preserved during the sputtering process by applying a thin, slowly evaporated MgF2 layer, allowing the effective embedding of graphene inside thick monolithic structures fabricated by conventional PVD techniques. Such a high graphene absorption discloses exciting potentiality for exploitation of 2D materials in new optoelectronic devices for application in the NIR-MIR spectral range.This work summarizes our recent findings on single layer graphene absorption when embedded in dielectric multilayer stacks. The increase of single layer graphene absorption obtained by exploiting the electric field enhancement inside a resonant optical cavity was modeled and experimentally demonstrated in three different Fabry–Perot filters with central wavelengths varying in the NIR-MIR spectral ranges. The Fabry–Perot filters were fabricated by radiofrequency sputtering, and consisted of alternate quarter wave thick Si and SiO


BIRC5 was higher than that in normal samples, and the expression of BIRC1 and BIRC5 significantly varied in different stages. Moreover, the BIRC1–3 and BIRC5 mRNA levels were associated with overall survival (OS), and the BIRC1–2 and BIRC5–6 mRNA levels were associated with progression-free survival (PFS). Among patients with lung squamous cell carcinoma (LUSC), the expression level of BIRC1 was lower and that of BIRC5 was higher than those in normal tissues, and BIRC5 expression significantly varied in different stages. BIRC1 expression was associated with OS, whereas BIRC2 and BIRC6 expression was associated with PFS. Enrichment analysis showed that most IAPs are associated with ubiquitin- and apoptosis-related pathways. Collectively, this study suggests BIRC5 as a potential diagnostic and staging marker, BIRC1 as a potential marker of OS, and BIRC2 and BIRC6 as potential PFS markers for patients with NSCLC. These highlight new targets for the early detection, treatment, and management of NSCLC.Inhibitors of apoptosis proteins (IAPs) have been associated with tumor development and progression by affecting apoptosis through cell death signaling pathways. To date, eight IAPs (BIRC1–8) have been identified in mammalian cells. However, the role of IAPs in non–small cell lung cancer (NSCLC) development and progression has not been explored in depth. In this study, we used public datasets and bioinformatics tools to compare the expression, prognostic significance, and function of IAPs in NSCLC and its subtypes. Expression of IAPs in cancer and normal tissues and at different stages of NSCLC was compared with gene expression profiling interactive analysis, and their prognostic significance was analyzed with the Kaplan–Meier Plotter database. The correlations among IAPs were analyzed with the STRING database and SPSS19.0. Functional annotation of IAPs was analyzed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment on the basis of the DAVID tool. Among patients with lung adenocarcinoma (LUAD), the expression level of  Non–small cell lung cancer (NSCLC) has one of the highest mortality rates among malignant tumors globally, which accounts for approximately 80% of all lung cancers . The twoInhibitors of apoptosis proteins (IAPs) are among the most extensively studied molecular and therapeutic targets in treating cancers, and their dysregulated expression has been reported in NSCLC . IAPs plBIRC2 expression indirectly induces NSCLC cell apoptosis by preventing the formation of the caspase-8–activating platform . The “expression analysis” mode was selected, with each IAP  added as input. LUAD and LUSC were selected as cancer types. Differentially expressed genes were selected according to a log2 fold change cutoff of 2 and q-value < 0.05. All other options were set to the default values.The differential mRNA expression of IAPs between NSCLC and normal samples was evaluated separately for LUAD and LUSC with gene expression profiling interactive analysis ; data on BIRC8 mRNA expression and survival of patients with LUAD and LUSC are lacking from the database. Patient samples were split into two groups according to the median expression level (high versus low expression). The Kaplan–Meier curve, hazard ratio with 95% confidence interval, and log-rank p-value were used to evaluate the relationship between the expression of each IAP and the overall survival (OS) or progression-free survival (PFS) of patients with NSCLC (LUAD and LUSC).To further explore whether IAPs can be potential prognostic biomarkers in NSCLC, we evaluated the prognostic value of https://string-db.org/), which includes data compiled from several sources. “BIRC1, BIRC2, BIRC3, BIRC4, BIRC5, BIRC6, BIRC7, and BIRC8” were input to the “multiple proteins” box with “Homo sapiens” selected as the organism. Other options were left as default options. Cytoscape 3.7.1 software was used for construction of the PPI network and further visualization for analysis.The PPI network was constructed from the STRING database (https://www.ncbi.nlm.nih.gov/geoprofiles/?term=) were used to determine the correlations among expression levels of IAPs in NSCLC, using the keywords “BIRCX NSCLC” (where X refers to 1–8 for the eight IAPs), and each profile was obtained (https://www.ncbi.nlm.nih.gov/geoprofiles/62790008). Scatter plots were constructed and pairwise correlations between all IAPs were analyzed according to the Pearson correlation coefficient using SPSS 19.0 software; p < 0.05 was considered statistically significant.Gene Expression Omnibus profiles (https://david.ncifcrf.gov/). GO annotation enrichment analysis was conducted to identify the unique biological properties of IAPs, including biological processes, cellular components, and molecular functions. The top five terms were selected according to the p value. KEGG pathway enrichment analysis was performed to explore the key pathways of IAPs; p < 0.05 was considered statistically significant.The biological functions of IAPs were analyzed using Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways on the basis of the DAVID tool , followed by small cell lung cancer, toxoplasmosis, pathways in cancer, NOD-like receptor signaling pathway, NF-κB signaling pathway, focal adhesion, and apoptosis. More than half of the IAP members are mainly involved in the top four pathways  are enriched in ubiquitin-mediated proteolysis. The ubiquitin–proteasome system has become a key system of pathogenesis in several cancers . Thevebipoptosis . In addipoptosis . Overexppoptosis . SKP2 prpoptosis . In addipoptosis . Thus, wBIRC1 and BIRC5 are potential diagnostic markers for both LUAD and LUAC. BIRC1, BIRC2, and BIRC5 are potential prognostic markers for LUAD, whereas BIRC2 and BIRC6 are prognostic markers for patients with NSCLC. From GO and KEGG enrichment analysis, we found that most IAP members are associated with ubiquitin and apoptosis. These highlight new targets for the early detection, treatment, and management of NSCLC.In this study, we systematically analyzed the expression and prognostic value of IAPs in different subtypes of NSCLC, which can help to provide a more thorough understanding of the molecular biological properties of this cancer. Our results indicate that