To maintain adequate oxygenation is of utmost importance in intraoperative care. However, clinical evidence supporting specific oxygen levels in distinct surgical settings is lacking. This study aimed to compare the effects of 30% and 80% oxygen in off-pump coronary artery bypass grafting (OPCAB).This multicenter trial was conducted in three tertiary hospitals from August 2019 to August 2021. Patients undergoing OPCAB were cluster-randomized to receive either 30% or 80% oxygen intraoperatively, based on the month when the surgery was performed. The primary endpoint was the length of hospital stay. Intraoperative hemodynamic data were also compared.P = 0.808). The incidence of postoperative acute kidney injury was significantly higher in the 30% oxygen group than in the 80% oxygen group . Intraoperative time-weighted average mixed venous oxygen saturation was significantly higher in the 80% oxygen group . The 80% oxygen group also had a significantly greater intraoperative time-weighted average cerebral regional oxygen saturation than the 30% oxygen group .A total of 414 patients were cluster-randomized. Length of hospital stay was not different in the 30% oxygen group compared to the 80% oxygen group .The online version contains supplementary material available at 10.1186/s13054-023-04558-8. Sustained hypoxia that did not improve with rescue therapy was not reported in either group. Intraoperative mechanical ventilatory profiles are shown in Additional file Treatment separation was well achieved between the study groups during OPCAB: the mean time-weighted average PaOP = 0.808) and per-protocol analyses  hospital LOS after OPCAB was 7.0 (6.5–7.5) days for the 30% oxygen group and 7.0 (6.6–7.4) days for the 80% oxygen group. There was no significant difference in hospital LOS between the two groups, in both intention-to-treat . Only one patient in the 80% oxygen group required postoperative renal replacement therapy. Two patients in the 30% oxygen group died in hospital because of aspiration, and no additional mortality was reported within 30 days after surgery. There were two cases (one case in each group) of postoperative stroke. Similar results were found in per-protocol analyses , serum cardiac troponin T levels were measured. The maximum values and areas under the curve of troponin T levels within 72 h after surgery were significantly higher in the 30% oxygen group than in the 80% oxygen group. In the other two hospitals , serum cardiac troponin I levels were measured, but the two groups were not significantly different. Likewise, no difference was found in creatine kinase MB levels among the two study groups  tended to be higher in the 30% oxygen group than in the 80% oxygen group .While the first postoperative serum lactate concentration was also comparable between the two groups  and PaO2  than the 80% oxygen group  during surgery. The 30% oxygen group also had a lower increased intraoperative cerebral regional oxygen saturation (51.7% [14.5]) compared to the 80% oxygen group . The per-protocol analyses are summarized in Additional file While time-weighted average intraoperative hemoglobin concentration and CO were similar for both groups, arterial oxygen saturation  and primary outcomes  ml/min/m2 vs 303 [60] ml/min/m2). The authors looked further into the data, stratifying patients by whether intraoperative time-weighted average indexed DO2 was lower than 270 ml/min/m2 . On the other hand, within the ‘low DO2’ stratum, the incidence of AKI in the 30% and 80% oxygen groups was 34.6% and 20.9%, respectively, while the time-weighted average CO was 3.1 l/min and 3.0 l/min. First, the difference in DO2 between the DO2 strata appeared to be mainly due to the difference in CO. We infer that patients with relatively high CO did not benefit from 80% oxygen because DO2 was already sufficient, whereas those with lower CO did. Taken together, it may be helpful to raise DO2 by increasing FiO2 in patients with low CO for the prevention of postoperative AKI. Based on these findings and hypothesis, the authors expect that the effects of a high FiO2 may be advantageous in specific hemodynamic environments such as OPCAB where low CO and hypotension are frequent [Although some cohort studies showed that increased oxygen exposure was associated with a higher risk of acute kidney injury after major surgery , there hpatients . Likewistionship . In our ed blood , which ied blood . Indeed,ed blood , 36. Thuc injury . In our l/min/m2 , 39, morfrequent , althoug2 has been acknowledged in critically ill patients [2 significantly increased mortality in critically ill patients [2 was associated with a composite of postoperative respiratory complications  in a dose-dependent manner [2 with respiratory insufficiency after surgery [2/FiO2 ratio after OPCAB between the 30% and 80% oxygen groups. Interestingly, MV time was shorter and the incidence of prolonged MV was lower in the 80% oxygen group  [There have been concerns about hyperoxia-related myocardial injury after noncardiac surgery (MINS) , and evel injury , 51, 53.l injury , 53. On 2 levels were randomized in this study instead of specific PaO2 targets. Even at the same FiO2, arterial blood oxygenation may vary substantially depending on the individual lung condition. Although PaO2 was not measured at prespecified time points during surgery, it is very likely that treatment separation was well achieved considering the mean difference in time-weighted average PaO2 among the two groups (124 mmHg vs 316 mmHg; see Table 2 rather than PaO2 targets could be more pragmatic during clinical practice. Second, although the primary endpoint of this study was the hospital LOS, criteria for hospital discharge were not protocolized. This may have contributed to the failure to detect the difference in hospital LOS between the study groups. However, we expected that this aspect made the present study pragmatic and better reflect the real-world clinical situation. Third, the exploratory secondary clinical outcomes including postoperative AKI were not prespecified in a clinical trial registry, thereby having an exploratory nature despite the significant difference in the incidence of AKI. Fourth, we regulated intraoperative FiO2 level in the study protocol, but not postoperative supplemental oxygen therapy. Considering the importance of postoperative management, the benefits from high FiO2 might have been more evident, or even an opposite conclusion could have been reached, had the postoperative FiO2 level been also regulated. Further studies are warranted for this topic.We recognize several limitations of this study. First, intraoperative FiO2 of 0.8 provided tissue oxygenation with superior hemodynamics without any worse outcome related to hyperoxia.In conclusion, intraoperative administration of 80% oxygen or 30% oxygen did not affect hospital LOS after OPCAB. However, 80% oxygen during OPCAB may decrease the incidence of postoperative AKI and serum NGAL concentration. Furthermore, global oxygen supply and cerebral regional oxygen saturation were also superior in the 80% oxygen group to the 30% oxygen group. Although it failed to reduce hospital LOS, an intraoperative FiOAdditional file 1. Supplementary materials for the CARROT study.


Some articles suggest that using HbA1c alone for diabetes diagnosis is inappropriate. It requires considerable researches to explore the efficacy of HbA1c for diagnosing hyperglycemia in patients with pancreatic disease.This study analyzed 732 patients, comprising of 331 without pancreatic disease and 401 patients diagnosed with pancreatic diseases. All participants underwent the HbA1c assay and oral glucose tolerance test. Kappa coefficients were calculated to assess agreement between the HbA1c and glucose criteria. The receiver operating characteristic curve (ROC) was used to calculate the optimal HbA1c value. DeLong test was analyzed to compared the aera under curves (AUCs).There were 203 (61.3%) patients with NGT, 78 (23.6%) with prediabetes, and 50 (15.1%) with diabetes in patients without pancreatic diseases. In patients with pancreatic disease, 106 participants were diagnosed with NGT (36.4%), 125 with prediabetes (31.2%), and 130 with diabetes (32.4%). Patients with pancreatic disease exhibited elevated levels of bilirubin, transaminase enzymes, aspartate transaminase, high density lipoprotein cholesterol and total bile acid. The sensitivity and specificity of the HbA1c (6.5%) for diagnosing pancreatic diabetes were 60.8%  and 92.6% . In prediabetes, the sensitivity and specificity of HbA1c (5.7%) is 53.2%  and 59.6 . The optimal HbA1c value for diagnosing diabetes was 6.0% , with the sensitivity of 83.8% and the specificity of 76.8%. The optimal HbA1c value for the diagnosis of prediabetes was 5.8% , with the corresponding sensitivity and specificity of 48.0% and 72.6% respectively. The combined tests  presented the sensitivity of 85.7% and the specificity of 92.6%  in pancreatic diabetes.From our results, the recommended HbA1c by ADA criterion may not be sufficiently sensitive to diagnose hyperglycemia in pancreatic disease. The optimal value of 5.8% and 6.0% improved the accuracy for diagnosing prediabetes and diabetes and should be considered to be applied. Besides, we advocate the combination of HbA1c and FPG test for the diagnosis of diabetes in patients with pancreatic diseases. Due to its convenience and stability, HbA1c has evolved into an alternate tool to OGTT . The ADA22.1This was a cross-sectional study conducted at the Department of Pancreatic Surgery, West China Hospital. During the research, all procedures abided by the guidelines of the ethical standards of the institutional research committees of the West China Hospital and the Helsinki Declaration of 1964 and its later amendments or comparable ethical standards. Patients in West China Hospital of Sichuan University, between June 2017 and December 2019 were enrolled in our study. They were divided into two groups: patients without pancreatic diseases and patients with pancreatic disease including chronic pancreatitis, pancreatic ductal adenocarcinoma and pancreatic benign and low-grade tumor. The inclusion criteria were as follows (1): patients aged 18 or older; (2) current lifestyle measures, including medicine and physical activity, that did not influence the results of tests ; and (3) patients provided informed consent. The exclusion criteria were as follows: (1) patients with known diabetes(n=23); (2) patients with gastrointestinal bleeding (n = 2), history of gastrointestinal surgery (n = 1), blood transfusion (n = 1), moderate to severe anemia (n = 2), and severe liver, heart, or kidney disease (n = 12); (3) patients suffering from acute pancreatitis (n=23); (4) patients with data missing (n=4) Figure 12.2Our primary outcome was the differential performance of HbA1c for detecting prediabetes or new-onset diabetes compared to ADA’s glucose criteria. HbA1c was tested by high-performance liquid chromatography  HLC-723G7, TOSOH Japan) at admission according to the method certified by the National Glycohemoglobin Standardization Program (NGSP). After at least an 8-hour overnight fast, the FPG and OGTT was performed. All patients underwent the glucose test with a 3-day diet containing 150 g carbohydrate per day to avoid hunger diabetes. FPG levels were tested using the glucose oxidase method . In addition, on the same day as the OGTT, 5ml of venous blood was drawn for testing liver function , creatinine, and lipid metabolism .2.3According to glucose criteria by the ADA, patients with FPG ≥ 7.0 mmol/L or/and 2h OGTT ≥ 11.1 mmol/l were diagnosed with diabetes mellitus. Prediabetes was defined as FPG of 5.6 to 6.9 mmol/L and 2h OGTT of 7.8 to 11.0 mmol/L. FPG < 5.6 mmol/L, and 2h OGTT < 7.8 was considered as normal glucose tolerance (NGT).2.4Data are presented as the frequencies for categorical variables and the means ± standard deviation (SD) for continuous variables. All data were analyzed by SPSS version 24.0 . Categorical data were analyzed using Pearson’s chi-square test or Fisher test. Continuous data were analyzed using samples t test or Kruskal–Wallis H nonparametric test. Kappa coefficients were calculated to assess agreement between glucose test results obtained from the HbA1c and glucose criteria criteria. The negative predictive value (NPV) and positive predictive value (PPV) were calculated as described previously . The rec33.1We conducted an analysis on a total of 732 patients, comprising of 331 individuals without pancreatic disease and 401 patients diagnosed with pancreatic diseases. In the pancreatic disease group, there were 176 (43.9%) patients with pancreatic ductal adenocarcinoma (PDAC), 103 (25.7%) patients with chronic pancreatitis (CP) and 122 (30.4%) patients with pancreatic benign and low-grade tumor (PBLT) including 37 non-function pancreatic neuroendocrine tumor, 38 intraductal papillary mucous neoplasm, 37 solid pseudopapilloma, and 20 cystadenoma. 3.23.3Receiver operator characteristic (ROC) curves were generated to determine optimal cutoff points detecting diabetes or prediabetes Table 4.3.4In our study, patients with pancreatic disease exhibited elevated levels of bilirubin, transaminase enzymes, aspartate transaminase, high density lipoprotein cholesterol and total bile acid Table 1.In our study, glycated hemoglobin or FPG alone was not sufficient enough to diagnose diabetes correctly. We try to explore the performance of the combined tests (FPG>7.0 mmol/L or HbA1c >6.0%) for diagnosing diabetes in our patients. 4To assess the performance of HbA1c in detecting prediabetes or diabetes among patients with pancreatic disease, we analyzed the performance of HbA1c (6.5%) as recommended by the ADA criteria. The overall sensitivity and specificity of the HbA1c threshold (6.5%) for the diagnosis of diabetes in patients with pancreatic disease were 60.8%  and 92.62% , indicating that nearly 40% of diabetes cases went undiagnosed by HbA1c in our study. In prediabetes, similarly, HbA1c (5.7%) is not also a good predictor with low sensitivity and specificity of 53.2%  and 59.6% . Therefore, careful consideration is necessary when deciding whether to apply the ADA’s HbA1c criteria in this specific population.In our study, the recommended glycated hemoglobin level by ADA is not sufficient for the diagnosis of diabetes or prediabetes in patients with pancreatic diseases. Thus, we analyzed the optimal threshold for prediabetes and diabetes through ROC curve. According to our data, the optimal cutoff value for diagnosing prediabetes was 5.8%, with the sensitivity and specificity of 48.0%  and 72.6%  respectively. The optimal cutoff value of 6.0% showed a higher sensitivity (83.8% vs 60.8%) and could detected more diabetes compared with the recommended value. In different pancreatic diseases, we obtained the optimal cutoff value respectively. These new cutoff values also showed a higher sensitivity with a subsequent improved detection rate.The HbA1c threshold level of 6.5% for diagnosing T2DM has been widely discussed . PreviouIncreasing data have shown that underlying factors, such as age, ethnics, diet, nutrition status, and specific disease, may affect the accuracy of HbA1c for diagnosing diabetes , 29–31. In our study, we found that it is not satisfactory to diagnose diabetes secondary to pancreatic disease when using either the conventional FPG criterion or HbA1c levels alone. Compared with HbA1c or FPG alone, the simultaneous measurement of HbA1c and FPG (HbA1c: 6.0% and FPG: 7.0 mmol/L) might be a tentative tool for identifying diabetes in patients with pancreatic diseases. Many studies have shown that, using a combination of an FPG of 7.0 mmol/L or higher and the HbA1c criterion improved diagnostic precision . In our There were some limitations in our study. First, this was a cross sectional study, and we could not present evidence of a causal association between HbA1c levels and pancreatic diseases. Second, there was limited patients in our study, and a multicenter clinical trial evaluating the change in this specific population is essential. In addition, the diagnosis criteria for pancreatic diabetes is under controversial, and stringent standards need further be researched.5Based on the results of our study, we conclude that the recommended HbA1c of 5.7% and 6.5% by ADA criterion may not be sufficiently sensitive to diagnose prediabetes and diabetes secondary to pancreatic disease. The cutoff value of 5.8% and 6.0% improved the accuracy and should be considered to be applied. Besides, we advocate the combination of HbA1c (6.0%) and FPG (7.0 mmol/L) test for diagnosing diabetes secondary to pancreatic diseases.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Medical Ethics Committee of West China Hospital at Sichuan University. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.Study conception and design, acquisition of data, analysis and interpretation of data, writing the manuscript: GC, RZ, LY and YC and/or revision of the manuscript: All authors. All authors contributed to the article and approved the submitted version.


DCF demonstrated the highest emulsifying capacity at pH 11 (82.13%), but the highest stability was shown at pH 5 (82.05%). Furthermore, CPI-12.0 at pH 11 shows the highest foaming capacity (83.16%) and stability (83.10%). Despite that, the CPI-10.0 manifested the highest antioxidant capacity , as well as ACE-I (35.67%). Overall, the extraction pH had significant effects in producing chia protein isolates (CPI) with improved nutritional and functional qualities.This study aims to determine the effects of various alkaline pHs on the nutritional and functional properties of protein isolated from defatted chia flour (DCF). The DCF isolated using alkali extraction method at pH 8.5, 10.0, and 12.0 were coded as CPI-8.5, CPI-10.0, and CPI-12.0, respectively. The highest extraction yield and protein recovery yield was demonstrated by CPI-12.0 , with a total protein content of 74.53%, and glutelin showed the highest portion (79.95%). The CPI-12.0 also demonstrated the most elevated essential (36.87%), hydrophobic (33.81%), and aromatic (15.54%) amino acid content among other samples. The DCF exhibited the highest water (23.90 gg The role of protein in a healthy diet is becoming more generally acknowledged as a consequence of growing food demand induced by population expansion, as well as a need for sustainable food alternatives generated by socioeconomic changes. The search for natural protein sources, including bioactive substances, to create functional foods and nutraceuticals with high nutritional effects and concurrent health benefits is intensifying . DietarySalvia hispanica L.) are an ancient pseudo-cereal that has evolved into the golden and super seeds of the twenty-first century due to their superior nutritional content and techno-functional qualities  protein equivalent, pH 2–11) using an Ultra-Turrax homogenizer  at 950.3× g for 1 min. Volumes were recorded before and after homogenization, and the foam capacity/stability was calculated using Equation (6):V2 is the volume of suspension plus the foam (mL) and V1 is the initial volume of protein suspension (mL). The foam stability was determined by measuring the total volume after 5 to 120 min of the foam formation.The foaming capacity (FC) and stability (FS) were studied according to the method of Sha et al.  with sliDPPH radical scavenging assayThe DPPH scavenging activity of samples was measured using the method described by Shao et al.  with a sABTS radical scavenging assay2S2O4 were reacted in the dark for 12 h at 25 °C before diluting with phosphate buffer (0.7 ± 0.02 at absorbance 734 nm). A 50 μL sample and 150 μL of ABTS+ were mixed and stood for 5 min, and the absorbance was determined by a microplate reader  at 734 nm. The ABTS radical scavenging activity was calculated using Equation (8), and the result was expressed in % of the ABTS radical scavenging activities.The ABTS radical stock solution was prepared according to the method described by Zielinska et al.  with sliFerric reducing antioxidant power (FRAP) assay−1 TPTZ solution in 40 mmolL−1 HCl, 2.5 mL of 20 mmolL−1 FeCl3, and 25 mL of 0.3 molL−1 acetate buffer (pH 3.6). An aliquot of 40 μL of the sample was mixed with 0.2 mL distilled water and 1.8 mL FRAP reagent. The absorbance of the reaction mixture was spectrophotometrically measured at 593 nm after incubation at 37 °C for 10 min using a microplate reader . Results were expressed in absorbance value.The procedure described by Wootton-Beard et al.  was foll1) was pre-incubated at 37 °C for 10 min, followed by incubation with 150 μL of the substrate (8.3 mM HHL in 50 mM sodium borate buffer containing 0.5 M NaCl at pH 8.3) at 37 °C for 30 min. Distilled water was used as the blank and control, while Captopril (1 mgmL−1) was used as positive control. The reaction was stopped by the addition of 250 μL 1 M HCl, and the resulting hippuric acid was extracted by the addition of 500 μL of ethyl acetate. After centrifugation  , a 200 μL of the upper layer was transferred into a glass tube and dried for 15 min at 90 °C. The hippuric acid was re-dissolved in 1 mL of distilled water, and the absorbance was measured at 228 nm using a fluorescence microplate reader . The ACE-I activity was calculated using Equation (9), and the result was expressed in % of ACE-I inhibition.The ACE inhibitory (ACE-i) activity was determined using the method of Luo et al. . Brieflyp < 0.05, determining the significant differences between data.All experiments were carried out in triplicates. The Shapiro–Wilk test was employed to determine the normality of the experimental data. The data obtained from all the analysis were normally distributed and were subjected to a one-way analysis of variance (ANOVA). The differences among means were assessed using the Duncan multiple range test. The data were analyzed using SAS version 9.4  and were expressed as the mean ± standard deviation with The total extraction, protein recovery, and proximate composition of DCF and CPIs extracted at different alkaline pH were presented in According to The fractionation of protein based on solubility discovered that the most dominant protein fraction in DCF and CPIs was glutelin (44.79% to 79.95%), consistent with the previous studies by Segura-Compos  that repThe amino acid composition has a potential role in the bioactivities of protein isolates. p < 0.05) from 34.76% (DCF) to 34.88% (CPI-8.5), 35.69% (CPI-10.0), and 36.87% (CPI-12.0). These data indicated that the extraction pH significantly affected the amino acids compositions following a previous study by Olivos-Lugo et al. [According to o et al. , which ro et al. . Moreoveo et al. ,45. TherSolubility is a prerequisite techno-functional quality of proteins and a key determinant of its applications since many of their functional properties are dependent on the capacity to hydrate and solubilize in water/buffer . The proIt is well established that the denaturation of protein during alkaline and acid treatments leads to the formation of protein aggregates. Protein extracted at high alkaline pH may have resulted in a higher degree of protein denaturation, producing low molecular weight protein fractions, thus increasing the exposure of more hydrophobic groups and decreasing the surface polarity . TherefoA. trifoliata var. australis seed [The solubility of DCF and CPIs was investigated in an aqueous solution over a pH range of 2 to 11 to imitate the pH environment of the actual food matrix. The protein solubility values of all CPIs samples were observed ranging from 6.2 to 72.31%, with an inverse bell-shaped curve. The lowest protein solubility values for all samples were observed to occur consistently at pH 4 and 5 A, which lis seed  showed a−1) compared to the CPI from a previous study by Mohammed Osama et al. [−1) and was comparable to Coelho and Salas-Mellado [−1). The high WAC of DCF could be attributed to the high presence of fiber (20.17%) (−1). This outcome could be attributable to the low fiber content (−1), cowpea protein isolates (1.38 gg−1), mung bean protein isolate (1.55 gg−1), and quinoa protein isolates (1.7–1.9 gg−1) [A protein’s water absorption capacity (WAC) is a measurement of its ability to associate gravity with water. It is likely related to the products’ texture, mouthfeel, and viscosity . In conta et al.  (8.5 gg−-Mellado  (~22 gg−(20.17%) , as this content  and pola content  in CPIs solate 1. gg−1, an.9 gg−1) . −1, significantly higher than all the CPI samples. CPI-12.0 revealed the highest OAC value for CPIs (7.55 gg−1), followed by CPI-10.0 (6.52 gg−1) and CPI-8.5 (5.24 gg−1). The OAC is closely related to the lipid–protein interaction via the binding of the non-polar side chains of amino acids to the aliphatic lipid chains [−1 and were slightly higher than the CPI described by [−1. Compared to other plant protein sources, the CPIs in this study were also higher than quinoa isolates [According to CPI-10.0 .52 gg−1 d chains . In contd chains , factorsd chains , which rribed by , with a isolates , soy pror CPIs 7. gg−1, foisolates , sour chisolates , and chiisolates .Emulsion capacity (EC) is the ability of an emulsifying agent to generate a water-in-oil dispersion, whereas emulsion stability (ES) is the rate at which it degrades over time. The EC and ES of DCF and CPIs at different pH over a period of 120 min were demonstrated in As demonstrated in The ES of all samples at all pH levels was monitored for 120 min to determine the ability of the emulsion to resist physicochemical changes over time. Results are demonstrated in Foaming capacity (FC) is the percentage increase in volume after suspension mixing and represents the interaction between a liquid solution and the air, whereas foam stability (FS) is defined as the length of time the foam maintains its volume after being formed ,48. TherThe FS of all samples at all pH levels was monitored over 120 min to determine the range of feasible bubble persistence. Generally, a protein with an excellent surface-active characteristic and sufficient intermolecular interaction has good foaming ability . A signiThe antioxidant activities of the chia protein isolates were determined via DPPH and ABTS radical scavenging assays and FRAP reducing power assays are depicted in On the other hand, aromatic amino acids such as Tyr, His, Trp, and Phe are also proven to have a positive correlation with the antioxidant potential ,69. This−1 captopril (99.02%), as illustrated in The antihypertensive activity of CPIs ranged from 25.68% to 35.67%, which was lower than 1 mgmLThe protein isolation of DCF via alkaline extraction at different pH significantly affects the nutritional and functional properties of the CPIs. Extraction of DCF at pH 12.0 have successfully achieved the highest extraction yield (19.10%), protein recovery yield (59.63%), and total protein content (74.53%), as well as improved the proportion of essential (36.87%), hydrophobic (33.81%), and aromatic amino acids (15.54%). The alkaline extraction process does not aid in the water-absorption capacity and oil-absorption capacity of the CPIs. Still, it improves the protein solubility, foaming capacity, and foam stability in various pH environments. Even though alkaline extraction does not enhance the emulsifying capacity and emulsion stability, the protein extraction at pH 10.0 successfully produced CPIs with the highest antioxidant  and antihypertensive (35.67%) capacities. The CPIs developed from the underutilized DCF have a high potential to be employed as a new natural antioxidant and antihypertensive ingredients for functional food and nutraceutical application. In addition, the finding of this study may maximize the exploitation of the DCF as well as lessen industrial waste. With enhanced nutritional and functional values, more research investigations, including in vivo experiments, are clearly needed to establish this health-promoting impact of protein isolates from chia on humans.


ObjectiveThis study investigates the prevalence and risk of thyroid disturbances in pregnant women with pre-existing diabetes mellitus (DM) or gestational diabetes mellitus (GDM) in a tertiary hospital setting in Riyadh, SA. This research's findings may help identify potential risk factors associated with thyroid disturbances during pregnancy and facilitate early diagnosis for at-risk pregnant women.Subjects and methodsA retrospective cross-sectional study was conducted at an endocrinology clinic between October 2018 and December 2021 to evaluate the electronic records of pregnant women with DM or GDM who had documented normal thyroid function before pregnancy.ResultsThree hundred ninety-six files that met the selection criteria were deeply investigated and analyzed. The analysis showed that 378 (95.5%) patients were of Saudi nationality, and the mean age in years ± SD for the selected patients was 34.23 ± 5.468. The prevalence of obesity was 63.7%, with a mean body mass index (BMI) of 32.78 ± 6.78 kg/m2.The patients in this study were categorized into three groups based on their type of DM: 57 were diagnosed with type 1 DM (14.4%), 120 with type 2 DM (30.3%), and 219 with GDM (55.3%). The study identified 43 patients (10.85%) with subclinical hypothyroidism and 74 (18.69%) with hypothyroidism. Among the remaining patients, thyroid function was within the normal range for 264 (66.67%). The study also identified eight patients (2.02%) with subclinical hyperthyroidism and seven (1.77%) with hyperthyroidism. The prevalence of thyroid dysfunction was reported at 33.4%, with most of the dysfunction observed in the GDM group (20.7%). By comparison, the type 1 DM and type 2 DM groups presented a lower prevalence of thyroid dysfunction, accounting for only 4.1% and 8.6%, respectively.ConclusionsHypothyroidism, both clinical and subclinical, is more prevalent among patients with GDM than individuals with type 1 and type 2 DM. Research suggests a greater risk of developing hypothyroidism in patients with an increased BMI and among those older during pregnancy. The thyroid is one of the organs of the endocrine systems in the human body and can be impacted by sustained high blood sugar levels and the body's constant attempts to eliminate this carbohydrate imbalance. Diabetes and thyroid dysfunction have been found to coexist in studies, with thyroid disease affecting glucose metabolism and untreated thyroid dysfunction impacting the management of diabetes. Many studies have highlighted an association between several types of diabetes and hypothyroidism; however, the evidence supporting this association is inconsistent ,2. HowevIn Saudi Arabia, the prevalence of hypothyroidism among pregnant women is as high as 9.3% -a seriouA study in India concluded that women with GDM and hypothyroidism require intense surveillance and screening for other comorbidities, as they face an increased risk of perinatal complications . In addiA retrospective cross-sectional study was conducted in the endocrinology clinic at King Saud University Medical City (KSUMC), Riyadh, SA. Files of pregnant females who visited the clinic between October 2018 and December 2021 were accessed through the electronic records after approval from the Institutional Review Board of the research unit at King Saud University Medical City (project no. E-21-6025). A total of 1233 files were evaluated, of which 596 files (48.3%) correspond to patients with DM or GDM.GDM was diagnosed per ADA recommendations using a one-step strategy of a 75-g OGTT. The diagnosis was made at 24-28 weeks of gestation when the plasma glucose measurement was equal to or exceeded 92 mg/dL (5.1 mmol/L) after fasting for at least eight hours; plasma glucose measurement was equal to or exceeded 180 mg/dL (10.0 mmol/L) at one hour; or equal to or exceeded 153 mg/dL (8.5 mmol) two hours postprandially. In between the 596 files of patients with DM or GDM, 396 files (32.1%) were related to patients with known normal thyroid functions. The other 200 files (16.2%) belong to patients with hypothyroidism (14.9%), hyperthyroidism (0.32%), subclinical hypothyroidism (0.81%), and patients who have undergone thyroidectomy (0.16%). Thyroid profiles were evaluated according to the guidelines of the American Thyroid Association (ATA) with trimester-dependent reference ranges: first trimester, 0.1-2.5 IU/mL; second trimester, 0.2-3.0 IU/mL; and third trimester, 0.3-3.0 IU/ mL". Subjects were excluded if they had any history of endocrine disorders before pregnancy, including thyroid dysfunction and Cushing disease, as it may influence fasting plasma glucose (FPG) levels. The main goal of the current study was to evaluate the risk of thyroid disturbances in pregnant patients with DM or GDM and known normal thyroid functions before pregnancy. All the collected data was kept confidential and used only for research purposes according to the principles of the Declaration of Helsinki for medical research.Statistical analysisThe collected data were computerized, summarized, and statistically analyzed using IBM Corp. Released 2015. IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp. Qualitative parameters such as the family history of thyroid disorders, time of testing thyroid functions, type of thyroid disorder, Tg Ab, TPO Ab, body mass index (BMI), family history of DM, type of DM, history of comorbidities, neonatal complications, maternal complications, and history of other problems were displayed as frequencies out of the total. Moreover, quantitative parameters such as age, weight, height, number of children, gestational age, TSH, and T4 levels were presented as mean ± SD in different categories of thyroid disorders. ANOVA and Tukey’s post hoc tests were used to compare different types of thyroid disorders regarding all other parameters. Nonparametric Pearson’s correlation and linear regression between different items were calculated. The significance of the p-value was considered significant if it was less than 0.05.The files of 396 women who met the selection criteria were analyzed. Among these women, 378 (95.5%) were of Saudi nationality, and 18 (4.5%) were non-Saudi. They had a mean age of 34.23 years (SD 5.468), a mean weight of 81.52 kg (SD 16.308), a mean height of 157.75 cm (SD 5.966), and a mean of 2.88 children (SD 1.993). Based on BMI, 252 of the women (63.6%) were obese, and 112 (28.3%) were overweight. Furthermore, 31 patients (7.8%) had normal BMIs, and one patient (0.3%) was underweight. Patients were classified into three groups: 57 patients with type 1 DM (14.4%), 120 with type 2 DM (30.3%), and 219 with GDM (55.3%). Three hundred and sixty-one patients (91.2%) reported no other associated health morbidities. However, 35 patients (8.8%) suffered from different health problems such as ulcerative colitis, colon cancer, Crohn’s disease, thrombophilia, bronchial asthma, and hypertension. Additionally, 268 out of 396 patients (67.7%) reported no history of maternal or fetal complications; 92 (23.2%) reported a history of maternal or fetal problems such as pre-eclampsia, placental abruption, and macrosomia that necessitated emergent delivery through cesarean section; and the remaining 36 patients (9.1%) reported a history of some fetal problems such as microsomia and intrauterine growth retardation (IUGR) and were managed by normal delivery. The records also revealed that the timing of thyroid function testing varied among pregnant patients. Thyroid functions were estimated in 48 patients (12.2%) during the first trimester, in 98 patients (24.7%) during the second trimester, and in 250 patients (63.1%) during the third trimester. All the measured frequencies, family history of DM or thyroid disorders, and simultaneous maternal or fetal complications are presented in Figure In Figure The distribution of frequencies regarding different parameters among groups, classified according to thyroid functions, is presented in Table A non-parametric Spearman’s correlation was conducted to determine the relationship between the variables. In doing this, it was found that a family history of DM has a significant, moderately positive correlation with a family history of thyroid disorders (p <0.001 and r = 0.568). The significant correlations between different variables are highlighted in the correlation matrix in Table Linear regression was performed to confirm the association between different parameters. The identified relations showed considerable diversity; multiple relations detected by Spearman’s correlation were emphasized by linear regression. A significant negative relationship between the type of DM and the level of T4 (p = 0.043 and β = −0.023) was observed. Moreover, a highly significant positive relationship between a family history of DM and a family history of thyroid disorders was affirmed (p < 0.001 and β = 0.461). In addition, a strong association between Tg Ab and TPO Ab was confirmed by regression (p < 0.001 and β = 0.81 3). By contrast, more than 20 relations were identified by correlation and then denied by regression as a significant, weak correlation between the type of DM and the time of testing thyroid functions (p = 0.006 and r = 0.1 38). Also, many significant relations between different parameters were elaborated after linear regression, such as the relevance between the time of testing thyroid functions and a family history of DM (p = 0.049 and β = 0.042). Significant regressions were extracted and shown in Table In the present study, the mean age of participants was 34.23 years, similar to a local study  and highDue to the study’s retrospective design, BMI was entered at the first obstetric check-up, as pre-pregnancy BMI information was unavailable. Following the trend of increasing BMI reported by the World Health Organization  of the GDM group was found in a study carried out by Konar et al. . In contA retrospective study conducted by Izzo et al.  examinedLimitations and strengths: Given this study’s design, it is essential to note that a detailed history of participants and some lab results were not obtained. Unfortunately, due to the lack of TgAb and TPOAb, we could not investigate the autoimmunity factor associated with the relationship between DM and TD. Additionally, we did not have a control group with which to compare the prevalence of TD in healthy pregnant women to our population, limiting the broader applicability of our findings.Despite these limitations, our study’s total participation was higher than in other studies on the same topic. This comparatively high participation rate reflects the reliability and accuracy of our results. Finally, it is relevant to note that we did not only investigate GDM but also included pre-GDM and further classified them into type 1 and type 2 DM, allowing for diversity in our results and enabling us to compare the effect of TD on each group. Clinical and subclinical hypothyroidism are each more frequently observed in GDM patients than in those with type 1 and 2 DM. Further studies have indicated that pregnant patients with a higher BMI and advanced age are at greater risk of developing hypothyroidism during pregnancy. While there was no substantial discrepancy in TD between the GDM and pre-GDM groups, evaluating thyroid function in the high-risk group is highly advised because early prevention and management of TD can help to avoid fetal and maternal complications and enhance perinatal outcomes.


Azelastine hydrochloride (AZE) is a selective, non-sedating H1 antagonist with anti-inflammatory and mast cell stabilizing properties, which can be used as an alternative to intranasal corticosteroids. The objective of this study was to evaluate the efficacy of the new formulation of 0.15% AZE compared to that of the placebo at a dosage of two sprays per nostril twice daily for 4 weeks in patients with perennial allergic rhinitis (PAR).A total of 581 subjects were randomized in this double-blind (DB) placebo-controlled trial (NCT00712920) that compared 0.10%  and 0.15% AZE  to the placebo in PAR patients. The study consisted of a 7-day single-blind placebo lead-in period and a 28-day DB treatment period. The primary endpoint was the change from baseline in the 12-h reflective total nasal symptom score (rTNSS) for the entire 28-day study period of 0.15% AZE, two sprays per nostril BID compared to the placebo. The efficacy and safety of 0.15% AZE were compared to the placebo.p = 0.04) compared to the placebo group. LS mean improvement from baseline in the AM and PM combined rTNSS was 4.10 (4.26) units for 0.15% AZE and 3.81 (3.99) for 0.10% AZE. For individual symptoms, there was a statistically significant change in the LS mean (p = 0.04) improvement from baseline on the 12-h reflective assessment for the 0.15% AZE group for runny nose. Further numerical improvements were shown for itchy nose, nasal congestion, runny nose, and sneezing compared to the placebo. No deaths or serious adverse events related to the study medication were reported.Least square (LS) mean improvement from baseline in the morning (AM) and evening (PM) combined rTNSS was statistically significant for the 0.15% AZE group (The present formulation of 0.15% AZE is safe and effective in relieving PAR symptoms. It effectively relieves nasal and non-nasal symptoms.ClinicalTrials.gov, identifier: NCT00712920. Existing monotherapies such as oral and intranasal antihistamines, intranasal corticosteroids (INCS), oral and intranasal decongestants, and oral and intranasal anticholinergics are not sufficient to control AR in most patients. Patients are hesitant to use INCS due to concerns about the potential systemic effects of corticosteroids . Improvi1 antagonist with anti-inflammatory and mast cell-stabilizing properties (Azelastine hydrochloride (AZE) is a selective, non-sedating Hoperties . AZE is operties  but a faoperties . AZE is operties . A well-operties . Studiesoperties –10. The This study aimed to evaluate the efficacy of the new formulation of 0.15% AZE compared to that of the placebo at a dosage of two sprays per nostril twice daily for 4 weeks in patients with PAR. The efficacy and safety of 0.15% AZE was also compared to those of 0.10% AZE solution and placebo.2.2.1.This was a randomized, double-blind, placebo-controlled trial (DB-PC-RCT) that compared 0.10% AZE  and 0.15% AZE  to a placebo in PAR patients . The all2.2.In total, 43 investigational sites in the U.S. were selected from February to October 2007, prior to the onset of the pollen season to avoid interference with symptoms of seasonal allergic rhinitis (SAR) due to pollen.2.3.Patients aged over 12 years of age with a diagnosis of allergic rhinitis, a history of symptoms for more than 2 years, and a positive skin prick test to one or more of the allergens such as dust mites, cockroach, mold, and cat or dog dander during the previous year were eligible for randomization. IgE-mediated hypersensitivity to dust mites, cockroaches, mold, and cat or dog dander was confirmed by a positive response to a skin prick test within the previous year. A positive response was defined as a wheal diameter at least 3 mm greater than the negative control in the skin prick test. Patients receiving immunotherapy injections (antigen desensitization) had to be on a stable maintenance regimen for at least 30 prior to the first study visit. Concomitant medications that could confound study results were discontinued before enrollment, and their use was prohibited during the study period. The following washout periods are generally sufficient as per FDA guidelines: (i) intranasal or systemic corticosteroids (1 month); (ii) leukotriene modifiers (1 month); (iii) intranasal cromolyn (2 weeks); (iv) intranasal or systemic decongestants (3 days); (v) cetirizine, fexofenadine, loratadine, desloratadine, hydroxyzine (5–10 days); (vi) intranasal antihistamines (3 days); and (vii) other systemic antihistamines (3 days).The patients had to have moderate/severe PAR symptoms. At screening, subjects with a 12-h rTNSS [morning (AM) or evening (PM)] of at least 6/12 and a congestion score of 2–3/3 were eligible for inclusion. At inclusion, subjects were randomized if they had a 12-h rTNSS (AM or PM) of at least six on three separate symptom assessments (one of which was within 2 days of randomization) and a 12-h rTNSS of 2–3/3 separate symptom assessments (one of which was within 2 days of day 1).Key exclusion criteria included (i) the presence of nasal ulceration or nasal septal perforation, (ii) nasal surgery/sinus surgery within the previous year, (iii) pulmonary disease like asthma, (iv) the presence of clinically significant nasal polyposis /nasal structural abnormalities, (v) pregnant or nursing women, and (vi) hypersensitivity to drugs similar to azelastine and either sorbitol or sucralose.2.4.The study was reviewed and approved by institutional review boards (IRBs) at the participating sites. The Ethics Board was the Sterling Institutional Review Board, with approval numbers 2397-001 through 2397-043 (for 43 study sites). Patients provided written informed consent/pediatric assent. If the patient was a minor, written informed consent was obtained from a parent or legal guardian. The study followed all the applicable laws and guidelines of the International Conference on Harmonization (ICH)/Good Clinical Practices (GCP), following the principles of the Declaration of Helsinki, and the U.S. Code of Federal Regulations (CFR).2.5.During the treatment period, patients recorded the four nasal symptoms  in a diary prior to the AM and PM doses of the study medication on each study day. The severity of the symptoms was scored on a four-point scale (0–3), where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms, and 3 = severe symptoms. The rTNSS is the sum of the scores for each of the nasal symptoms (from 0 to 12) assessed twice daily (0–24). The 12-h reflective secondary symptom complex score (SSCS), comprising intensity scores for postnasal drip, itchy eyes, cough, and headache, was also measured.2.6.Once a potential study subject was identified and informed consent was signed, the subject was enrolled into the study and assigned a unique identification number consisting of two parts, the study site number and the subject number. Subject identification numbers were assigned sequentially in ascending order within each study site by the investigator. The subject identification number was used on all case report form, diaries, study medication supplies, and drug assignment records. Once issued, subject identification numbers were not reused and remained with the subject throughout the study. Randomization codes were provided by i3 Statprobe using a validated system that assigns random permutations of treatments to consecutive groups of six subjects. Randomization data were kept confidential.On day 1, subjects received blinded study medication according to the randomization schedule. The study blinding was preserved at the study sites until all subjects had completed the trial and the database had been locked, except for individual subject data in the context of a serious safety concern. Codebreaker labels were detached from the study medication kits and affixed to the drug assignment record. A codebreaker label was to be opened by the investigator only in case of a medical emergency  when it was judged necessary to know a subject's treatment assignment).2.7.Based on a previous study with 0.10% AZE in patients with SAR and considering a reduction of 1.5 units in AM and PM combined TNSS with a standard deviation (SD) of 4.8, it was determined that a sample size of approximately 180 patients per treatment group was required to demonstrate efficacy with two sprays per nostril twice daily compared to the placebo in the 0.10% AZE group and to demonstrate an observable dose–response difference between 0.10% AZE and 0.15% AZE. Since the effect size with two sprays per nostril twice daily of 0.15% AZE was greater than that of 0.10% AZE, the sample size of 180 patients per group was adequate to fulfill the primary objective of showing a statistically significant reduction in the overall change from baseline in the 12-h rTNSS at the 0.05 level of significance with 80% power.A gatekeeping strategy was employed to adjust for multiplicity. The 0.15% AZE–placebo comparison was first tested at the 0.05 significance level. If significant, the 0.10% AZE–placebo comparison was also performed at the 0.05 level. If the 0.15% AZE–placebo comparison was not significant at the 0.05 level, no comparison of the low dose of AZE to the placebo was made. The multiplicity strategy was limited to the primary analysis, and from a formal perspective, a secondary analysis was regarded as exploratory.3.n), mean, standard deviation, median, minimum, and maximum. Categorical data were expressed as frequencies and percentages. A repeated-measures analysis was performed on the primary efficacy variable, change from baseline in the 12-h rTNSS, for the entire 28-day study period, compared to the placebo, which included all changes in the rTNSS on each day from day 1 PM to day 28 AM as repeated measures in an analysis of covariance (ANCOVA) model for the intent-to-treat (ITT) population, defined as all randomized subjects who had at least one postbaseline efficacy observation. The model contained study day as a within-subject effect, treatment group, and site as the between-subject effects, and baseline as a covariate.For continuous variables like TNSS, descriptive statistics included the number of patients reflected in the calculation  method was used for dropouts and missing data. If a postbaseline TNSS score was missing, the last non-missing postbaseline TNSS score prior to the missing value was used for analysis. The same methodology was applied to the SSCS assessments. The LOCF method was also applied for summaries of individual nasal symptom scores and individual secondary symptom scores.4.4.1.A total of 581 subjects were randomized into the study, of which 535 (92.1%) completed the study . Completp = 0.017). The compliance to the study drug ranged from 90.1% (placebo) to 92.9% (AZE-0.15).The three treatment groups were comparable with regard to demographics . The bas4.2.p = 0.04) compared to the placebo group (p = 0.15). In placebo-treated patients, rTNSS scores decreased by 3.33 (4.35) units at 4 weeks.Least square (LS) mean improvement from baseline in the AM and PM combined rTNSS was statistically significant for 0.15% AZE (bo group . LS mean4.3.p = 0.04) and the LS mean percentage (p = 0.04) from baseline on the 12-h reflective assessment for the 0.15% AZE group for runny nose. Further numerical improvements were shown for itchy nose, nasal congestion, runny nose, and sneezing compared to the placebo . This was however not confirmed for 0.10% AZE (p > 0.05) (p < 0.001), cough (p = 0.028), and headache (p = 0.008) demonstrated statistically significant improvements for the 0.15% AZE group compared to the placebo. The difference was also greater for the 0.10% AZE group compared to the placebo (p < 0.053).The LS mean change from baseline in the overall reflective secondary symptom complex scores (rSSCSs) showed a statistically significant improvement for the 0.15% AZE group (−2.92) compared to the placebo group (−1.79) after 4 weeks of treatment ( > 0.05) . The LS 4.4.The mean duration of exposure was 27.4 days for patients in the 0.15% AZE group, 27.9 days for patients in the 0.10% AZE group, and 27.5 days for patients in the placebo group. The mean number of doses taken by the three groups was similar: 53.4 doses in the 0.15% AZE group, 53.8 doses in the 0.10% AZE group, and 52.8 doses in the placebo group. The most commonly reported AEs  in the 0n = 11 patients) and in the 0.10% AZE (n = 9 patients) groups. No subject had moderate or severe epistaxis or grade 2, 3, or 4 nasal irritation. The findings of direct visual nasal examination with 0.15% AZE and 0.10% AZE were similar to those seen with the placebo. No deaths or SAEs related to the study medication were reported.The frequency of dysgeusia was similar in the 0.15% AZE (5.This study in PAR compared two doses of AZE (0.15% and 0.10%) with a placebo. The higher dose of AZE (0.15%) was tolerated similarly to the lower dose (0.10%) but it was the only dose that showed a statistically significant clinical improvement over the placebo. This study was only powered for comparison to the placebo, and therefore no significance vs. 0.10% AZE was expected in this study.5.1.It is difficult to show efficacy in PAR compared to the SAR study; for example, peak symptoms are less common in PAR than in SAR, and many patients have a rapid disappearance of symptoms when they suffer from intermittent rhinitis, making the differences between placebo and active treatment less marked. Symptoms in PAR patients such as nasal congestion, sneezing, blocked nose, and rhinorrhea tend to peak during the night and in the early morning . Hence, In this study, patients receiving immunotherapy injections (antigen desensitization) had to be on a stable maintenance regimen for at least 30 days before the first study visit (adjustments to the regimen following a brief period of missed injections did not preclude participation). Patients receiving sublingual immunotherapy (SLIT) were excluded. A 6-month washout period was required after the last dose of sublingual immunotherapy. A total of five (2.6%), 11 (5.6%), and four (2.1%) subjects in the 0.15% AZE, 0.10% AZE, and placebo groups, respectively, received a stable maintenance regimen of immunotherapy injections during the study. Because these subjects received a stable maintenance regimen for years and the number of subjects receiving immunotherapy in the 0.15% AZE group was comparable to that in the placebo group and lower than that in the 0.10% AZE group, the inclusion of these subjects in the statistical analyses did not have a relevant impact on the demonstrated superiority of 0.15% AZE.Guidelines recommend a longer treatment duration for PAR studies than for SAR studies . It is e5.2.Despite these difficulties, the primary objective was successfully met. The dosage of 0.15% AZE was statistically significant and superior to the placebo in relieving PAR symptoms. Studies have shown that AR patients use medications as needed, rapidly switch medications, resulting in poor control, and stop medications when symptoms are controlled , it was AZE has a distinctive bitter taste. Experiencing the bitter taste immediately after the use of the spray may be an indication of the wrong administration technique, causing unintended deposition of the formulation in the throat instead of the nasal cavities. Since such bitter taste sensations may interfere with the subject's adherence to the prescribed therapy, an improvement in the formulation is likely to improve patient compliance and, subsequently, treatment success. The present formulation (0.15% AZE) contains sucralose/sorbitol to mask the bitter taste of AZE. Adverse events reported by study subjects and documented by the investigator such as “bitter,” “sweet,” “strange,” “unpleasant,” and “metallic” were all coded as dysgeusia. Thus, studies using a parallel group design cannot show the effectiveness of taste masking.The AEs occurring in the 0.10% AZE and 0.15% AZE groups were comparable, indicating that there was no dose-dependent increase in adverse effects. Somnolence and fatigue are two of the most common side effects associated with antihistamine usage. The present formulation of 0.15% AZE caused somnolence and fatigue in only 1.0% of the patients in the present study. The 0.15% AZE dosage effectively relieves not only nasal but also non-nasal symptoms . Nasal o5.3.The latest ARIA guidelines emphasize the onset of action as an important parameter for patients’ preferences for choosing the medication . Previou6.The present formulation of 0.15% AZE is safe and effective in relieving symptoms of PAR. It provides significant relief of both nasal and non-nasal symptoms. The maximum dose (two sprays per nostril twice daily) of 0.15% AZE did not reveal any safety concerns and was similar to that of 0.10% azelastine nasal spray.


Childbirth is a period of transition for women, which can have several physiological and psychological repercussions on their lives.To estimate the prevalence of postpartum post-traumatic stress disorder in a sample group of Tunisian women.This is a longitudinal prospective descriptive study carried out among women who were hospitalized for childbirth in the obstetrics gynecology department and those who consulted the outpatient perinatal consultation of the Tahar Sfar Mahdia hospital during a period of 7 months from March 15, 2020 to September 15, 2020. Data collection was based on a pre-established questionnaire determining the different socio-demographic and clinical characteristics.The women’s psychometric assessment was conducted using a PCLS psychiatric scale for screening for post-traumatic stress disorder.We collected 120 women with an average age of 28.3 ±5.3 years. Among our sample, two women had a history of depression (1.6%) and three participants had a history of an anxiety disorder (2.5%).Thirty-five patients (29.1%) had a pathological obstetric history. However, fifteen patients (12.5%) were hospitalized during their pregnancies. Eighty-seven patients (72.5%) expressed their anticipated fear of childbirth and one hundred two patients (85%) had a good marital relationship with good social support. 48.3% of deliveries were vaginal and 27.5% were by emergency cesarean section. Level three pain was expressed in 73.3% of deliveries. Psychometric assessment revealed a prevalence of PTSD at 5.8% with PTSD symptomatology in 18.4% of women.Postpartum post-traumatic stress disorder is a major public health problem that affects the healthy development of the newborn and the mental and physical recovery.None Declared


Allergen immunotherapy (AIT) is a safe, effective and disease-modifying treatment for allergic rhinitis. It is indicated for children with moderate to severe disease whose symptoms persist despite conventional therapy. There is a high prevalence of allergic rhinitis amongst Irish children; however, levels of AIT prescribing in Ireland are lower than neighbouring countries.The aims of this study are to describe current patterns of AIT prescribing and referrals amongst Irish paediatricians and to identify barriers to accessing AIT in Ireland.An electronic questionnaire was distributed to all paediatricians and paediatric trainees caring for children with allergic rhinitis.A lack of knowledge of AIT clinical criteria was the most frequently reported barrier with 50.5% (50/99) of general paediatricians unaware of the indications for referral compared to 27.3% (3/11) of respiratory physicians and 0% (0/8) of allergists. Accessibility is the next most cited barrier with 31.4% (37/118) of respondents unsure where to refer and 19.5% (23/118) reporting a lack of local services. Cost was reported to be a barrier by 12.7% (15/118). Paediatricians with an allergy or respiratory subspecialisation reported seeing significantly higher numbers of children with allergic rhinitis and were more likely to prescribe or refer a child for AIT.This study demonstrated positive attitudes towards AIT amongst all grades and specialities of paediatricians in Ireland. The main barriers to more widespread use are difficulties with the identification of suitable candidates by general paediatricians and a lack of local AIT services and referral pathways. Allergen immunotherapy (AIT) was first described in 1911 .AIT has been shown to be effective with a reduction in allergic rhinitis (AR) symptoms and medication usage during treatment . This imAIT is generally well tolerated though severe reactions including anaphylaxis have been described. Numerous international guidelines exist, including those by EAACI, BSACI and AAAAI , 6, 7. PAsthma and AR frequently co-exist. AIT has been shown to reduce usage of conventional medications for AR in addition to inhaled corticosteroid use in patients with co-existing asthma , 10. TheIrish children have a high prevalence of AR. A study of Irish schoolchildren demonstrated a prevalence of 23.5% for asthma and 10.6% for AR in children aged 6–9 years . In chilAccording to the Primary Care Reimbursement Scheme annual report 2019, a total of 3201 prescriptions representing a total of 266 patients were prescribed AIT in 2019. This number includes both children and adults entitled to free medications under national means-tested schemes and excludes patients treated in the private sector. Despite the limitations of this data, it suggests a very low rate of AIT prescribing in Ireland. Applying this number to the ISAAC study results and most recent Irish census data from 2016 suggests that even if all of the reported prescriptions were for children it still only represents 0.003% of children with AR and 0.01% of those with severe disease .AIT is safe and effective and is the only disease-modifying treatment for AR. It should be considered where symptoms are uncontrolled despite conventional therapies. Rates of AIT prescribing in Ireland are significantly lower than neighbouring countries and this study aims to identify barriers to accessing AIT.p < 0.05 was considered statistically significant. General paediatricians with a special interest in allergy or respiratory were included with dedicated allergists and respiratory physicians for analysis.A questionnaire was designed based on similar studies and international guidelines , 23. TheA total of 120 responses were received. One response was excluded as it had been completed by a subspecialist with no contact with patients with AR. Another was excluded as it was returned after the predefined data collection period. The remaining 118 responses represent 41.4% of the estimated population of interest and exceed the target of 100 responses. Respondent demographic data is described in Table The majority of respondents  were aware of AIT as a treatment option for AR in children. Despite this, only 60% (15/25) of general paediatric consultants were aware of local services compared to 90% (9/10) of respiratory consultants and all allergists (6/6).p < 0.001). EAACI was the most well-known (59%) followed by BSACI (43.6%), ARIA (35.9%) and AAAAI (15.4%).Only 33.1% (39/118) of respondents were aware of AR guidelines. This varied significantly between specialities with all allergists, 54.4% (6/11) of respiratory physicians and just 25.3% (25/99) of general paediatricians aware of guidelines (p < 0.001). Just 4% (4/99) of general paediatricians report seeing > 100 children with AR per year compared to 45.5% (5/11) respiratory physicians and 62.5% (5/8) allergists (p < 0.001). Furthermore, there was an association between number of children with asthma and/or AR seen and both knowledge of guidelines and experience with prescribing or referring for AIT . Respondents who were aware of AR guidelines were more likely to have referred for and prescribed AIT (p < 0.001 and p = 0.005).Allergists and respiratory physicians reported seeing more children with asthma and AR than general paediatricians. 9.1% (9/99) of general paediatricians reported seeing > 100 children with asthma per year compared to 63.6% (7/11) of respiratory physicians and 62.5% (5/8) allergists (p = 0.002). The relatively low rate of referral amongst allergists may reflect the fact that 75% (6/8) of them currently work in teams providing AIT and are therefore unlikely to refer patients outside their own service.In this study, 30.5% (36/118) of respondents have referred a child for AIT. Allergy or respiratory subspecialisation was associated with referral for AIT with just 24.2% (24/99) of general paediatricians having referred a child, compared to 72.7% (8/11) of respiratory physicians and 50% (4/8) of allergists (p < 0.001). Of those who have prescribed AIT, there is an association between specialty and the number of AIT prescriptions written. 87.5% (7/8) of those with an interest/subspecialty in allergy have written > 10 prescriptions and 37.5% (3/8) have prescribed AIT > 50 times. This compares to 45.5% (5/11) of those with a respiratory background and just 12.1% (12/99) of general paediatricians having prescribed AIT > 10 times (p = 0.005). 15/118 respondents currently work in a team prescribing AIT. Of these, 11 are consultants and 6/11 are allergists with the remaining 5/11 having a respiratory interest.AIT has been prescribed by 26.3% (31/118) of respondents. All allergists (8/8) have prescribed AIT along with 63.6% (7/11) of respiratory physicians and 16.2% (16/99) of general paediatricians (77.1% (91/118) of respondents consider SLIT to be effective while 1.7% (2/118) consider it to be ineffective and 21.2% (25/118) were unsure. A large proportion of general paediatricians  are unsure if SLIT is effective. This compares to 100% of allergists and respiratory physicians.SLIT is considered safe by 83.1% (98/118) of respondents with 0.8% (1/118) considering it unsafe. The remaining 16.1% (19/118) were unsure. Similarly, 61% (72/118) of respondents consider SCIT to be safe with 2.5% (3/118) considering it unsafe and 36.5% (43/118) were unsure. When those who are unsure are excluded, 99% (98/99) and 96% (72/75) of respondents consider SLIT and SCIT respectively to be safe.p = 0.002).53.4% (63/118) consider SLIT to be cost-effective with 8.5% (10/118) disagreeing. 38.1% (45/118) had no opinion. When these are excluded, 86.3% (63/73) of respondents consider SLIT to be cost-effective. There was an association between current/previous work as part of an AIT team and a negative view of SLIT cost-effectiveness. 17.1% (7/41) of those with AIT team experience consider SLIT not to be cost-effective compared to 3.9% (3/77) of those with no experience . This lack of knowledge was recognised by respondents as 115/118 (97.5%), including all general paediatricians, stated that they would like to know more about AIT.A lack of knowledge of AIT clinical criteria was frequently reported with 50.5% (50/99) of general paediatricians unaware of the indications for referral compared to 27.3% (3/11) of respiratory physicians and 0% (0/8) of allergists (p = 0.003).Accessibility is the next most cited barrier with 31.4% (37/118) of respondents unsure where to refer and 19.5% (23/118) reporting a lack of local services. This barrier affects general paediatricians only, with 37.4% (37/99) reporting this while all allergists and respiratory physicians are aware of referral pathways  reporting this. This is despite a study from 2012 which reported AIT being available in 14 centres across the country . This diThis study demonstrated differences between the opinions of Irish respiratory specialists and those in Europe. While they demonstrated a good level of knowledge and favourable attitudes towards AIT, just 45.5% of respiratory specialists that responded currently prescribe AIT and an additional 27.3% have previous experience doing so. This is significantly less than the 78% of Italian chest physicians prescribing AIT reported by Lombardi . Just 30This study has identified a group of paediatricians with a special interest or sub-specialisation in paediatric allergy or respiratory who see large numbers of children with asthma and allergic rhinitis. These doctors typically have experience of current or previous work with an AIT team and are aware of international guidelines. They are aware of the local services available and prescribe or refer many children for AIT. In contrast, many general paediatricians are unaware of what patients are suitable for AIT and where to access this treatment.This study demonstrated positive attitudes towards AIT amongst all grades and specialities of paediatricians in Ireland despite low rates of AIT prescribing. The main barriers to use are difficulties with the identification of suitable candidates by general paediatricians and an actual or perceived lack of local AIT services and referral pathways. This study highlights the need for educational sessions for general paediatricians and paediatric trainees to ensure that this treatment is considered for suitable patients. Further work should focus on quantifying the current availability of AIT services nationally to investigate the change in availability since the previous survey in 2012 and to ensure local referral pathways are put in place. This study is the first to evaluate the knowledge and attitudes of paediatricians in Ireland towards AIT and will be useful in the planning and delivery of AIT services nationally.


Following induction of remission with rituximab in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) relapse rates are high, especially in patients with history of relapse. Relapses are associated with increased exposure to immunosuppressive medications, the accrual of damage and increased morbidity and mortality. The RITAZAREM trial compared the efficacy of repeat-dose rituximab to daily oral azathioprine for prevention of relapse in patients with relapsing AAV in whom remission was reinduced with rituximab.RITAZAREM was an international randomised controlled, open-label, superiority trial that recruited 188 patients at the time of an AAV relapse from 29 centres in seven countries between April 2013 and November 2016. All patients received rituximab and glucocorticoids to reinduce remission. Patients achieving remission by 4 months were randomised to receive rituximab intravenously  (85 patients) or azathioprine  (85 patients) and followed for a minimum of 36 months. The primary outcome was time to disease relapse (either major or minor relapse).Rituximab was superior to azathioprine in preventing relapse: HR 0.41; 95% CI 0.27 to 0.61, p<0.001. 19/85 (22%) patients in the rituximab group and 31/85 (36%) in the azathioprine group experienced at least one serious adverse event during the treatment period. There were no differences in rates of hypogammaglobulinaemia or infection between groups.Following induction of remission with rituximab, fixed-interval, repeat-dose rituximab was superior to azathioprine for preventing disease relapse in patients with AAV with a prior history of relapse.NCT01697267; ClinicalTrials.gov identifier Rituximab is superior to azathioprine for the prevention of major relapse following cyclophosphamide induction therapy in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV).These data confirm the place of rituximab as the standard of care for maintenance therapy. But, despite a higher dose rituximab regimen, relapses still occurred during treatment, and there was an increased risk of relapse after stopping rituximab.The ongoing relapse risk together with associated safety concerns of extended rituximab therapy illustrate the need for newer therapeutic agents in AAV.Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are the major subgroups of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).Fixed-interval, repeat dose rituximab was superior to azathioprine as a maintenance strategy in a largely newly diagnosed AAV after induction with cyclophosphamide and glucocorticoid in the MAINRITSAN 1 trial.RITAZAREM was an international, randomised, controlled trial designed to assess whether fixed-interval rituximab was superior to azathioprine for the maintenance of remission following induction of remission with rituximab and glucocorticoids in patients with relapsing AAV. Furthermore, it was hypothesised that increased doses of rituximab would reduce the risk of relapse beyond the maintenance treatment period.The RITAZAREM trial had three phases. The protocol design and results of the induction phase have been reported.Induction phase (enrolment through month 4): induction therapy comprised of rituximab (four doses of 375 mg/m2/week) and oral prednisone/prednisolone commencing at either 1.0 mg/kg/day (high dose) or 0.5 mg/kg/day (low dose), both reducing to 10 mg/day or less, selected at physician discretion. Intravenous methylprednisolone up to a cumulative dose of 3000 mg was permitted in the 2 weeks before or 1 week after enrolment.Maintenance phase: (4–24 months from enrolment). Patients who had achieved remission, defined as a Birmingham Vasculitis Activity Score for Wegener’s granulomatosis (BVAS/WG) ≤1 and prednisone/prednisolone dose ≤10 mg/day, were randomised to receive rituximab or azathioprine.Follow-up phase: this off-treatment phase commenced after completion of the maintenance phase at month 24 and lasted for a further 12–24 months (36–48 months from enrolment).This paper reports the results of the maintenance and follow-up phases of the trial.Patients were aged over 15 years and had a diagnosis of GPA or MPA according to the Chapel Hill Consensus Conference 2012 definitions, and a current or prior positive test for proteinase 3 (PR3)-ANCA or myeloperoxidase (MPO)-ANCA.Patients were recruited from 29 centres in seven countries between April 2013 and November 2016. The last patient visit was in November 2019.RITAZAREM was an open-label, unblinded study. Patients who achieved disease remission by month 4 were randomised into the maintenance phase using a web-based system in a 1:1 ratio, to receive rituximab or azathioprine. They were stratified at randomisation according to:ANCA type: PR3-ANCA or MPO-ANCA.Relapse type: severe or non-severe. A severe relapse was defined as the development of a new or recurrent item of major disease activity on BVAS/WG.Oral glucocorticoid induction regimen: high or low dose.Intravenous rituximab 1000 mg repeated every 4 months for five doses . This dose was based on prior observational studies and the interval was designed to minimise the risk of relapse.Oral azathioprine 2 mg/kg/day for 24 months, then reduced by 50% and withdrawn at month 27. Patients intolerant to azathioprine received either methotrexate , 25 mg/week, if their estimated glomerular filtration rate (eGFR) was >50 mL/min, or mycophenolate mofetil 2 g/day, if their eGFR was ≤50 mL/min.A prednisone/prednisolone dose of 10 mg/day or less was a requirement for randomisation at month 4. This dose was reduced to 5 mg/day by month 6 through to month 16 then reduced to 2.5 mg/day and withdrawn at month 20 . Patient10.1136/ard-2022-223559.supp5Supplementary datapneumocystis (carinii) jiroveci infection and/or to prevent osteoporosis were prescribed according to local practice.Medications to prevent Evaluations, including clinical, laboratory and patient-reported outcomes, were performed at months 4, 8, 12, 16, 20, 24, 27, 30, 36, 42 and 48. The common closeout date for those patients remaining in the trial was when the final patient reached month 36.The primary outcome was time from randomisation to disease relapse, defined as the return or first appearance of at least one item on BVAS/WG. Major relapse required at least one major BVAS/WG item. Relapses were reviewed by a blinded adjudication committee. Secondary outcomes included the proportions who maintained remission at the end of the maintenance phase, or end of the follow-up phase; time to major relapse; cumulative accrual of damage measured by the Combined Disease Assessment instrumentCompliance for the rituximab group was defined as receipt of five doses of rituximab (unless withheld for IgG <3 g/L) and no oral immunosuppressive agents administered. Compliance in the azathioprine group was defined as ongoing receipt of azathioprine, methotrexate or mycophenolate mofetil between months 4 and 24.Enrolment continued until at least 160 patients were randomised. This sample size was calculated based on a goal of achieving 90% power under the alternative hypothesis of a HR of 0.42 at the 5% significance level with 58 observed relapses. This assumed a drop-out rate of 5% at 24 months and a relapse-free rate of 75% and 50% at 48 months in the rituximab and azathioprine arms, respectively.Results are reported for the 170 randomised patients, except for safety parameters for which data on all 188 enrolled patients are presented. The primary intention-to-treat analysis was based on a Cox proportional hazard model, adjusted for the stratification factors  for the difference in the distribution of relapse-free survival between the rituximab and azathioprine groups with a closed testing procedure. First, the null hypothesis was tested for a HR of 1 at all time points. If this was rejected at a 5% level, then two further subhypotheses were prespecified using time-varying covariates; up to 24 months and after 24 months. Hazard ratios and 95% CIs were reported. A p value less than 5% was considered statistically significant.Kaplan-Meier estimates for relapse-free survival at 24 and 48 months and median relapse-free survival with the corresponding 95% CIs by treatment allocation are also presented. Multivariable analysis was performed on risk factors for the development of hypogammaglobulinaemia. Data were analysed using R V.3.6.1.One hundred and eighty-eight patients were enrolled and received induction therapy with rituximab and glucocorticoids.Over the combined maintenance and follow-up phases, rituximab was superior to azathioprine for the prevention of major or minor disease relapse: HR 0.41, 95% CI 0.27 to 0.61, p<0.001 . The HR Thirty-eight of 85 (45%) patients in the rituximab group experienced 52 relapses, 11 major and 41 minor. Sixty of 85 (71%) patients in the azathioprine group experienced 89 relapses, 28 major and 61 minor. The overall HR for major relapse was 0.36, 95% CI 0.18 to 0.73, p=0.004. During the maintenance phase, 13/85 (15%) in the rituximab group relapsed compared with 32/85 (38%) in the azathioprine group. At month 24, the relapse-free survival rate was 0.85, 95% CI 0.78 to 0.93, for the rituximab compared with 0.61, 95% CI 0.51 to 0.73, for the azathioprine groups. During the follow-up phase, there were 33 relapses in 25 from the rituximab compared with 49 relapses in 28 in the azathioprine groups. Five patients in the rituximab group experienced a major relapse during the follow-up period compared with 11 in the azathioprine group. At month 48, the rate for continued remission was 0.50, 95% CI 0.40 to 0.63, for the rituximab and 0.22, 95% CI 0.14 to 0.35, for the azathioprine groups.In a multiple regression model, neither the glucocorticoid induction regimen (high or low dose) nor ANCA subtype (PR3-ANCA or MPO-ANCA) influenced relapse risk: HR 1.29, 95% CI 0.82 to 2.04, p=0.277 and HR 1.23, 95% CI 0.76 to 1.98, p=0.402, respectively . Individ10.1136/ard-2022-223559.supp1Supplementary data81/85 (95%) patients in the rituximab group were compliant and 78/85 (92%) in the azathioprine group. During the follow-up phase, 10/85 (12%) patients in the rituximab and 15/85 (18%) patient in the azathioprine groups continued immunosuppression. When the 11 patients non-compliant during the treatment period with the protocol-defined immunosuppressive therapy were excluded in the analysis, the HR for relapse was 0.38, 95% CI 0.25 to 0.58, p<0.001. When the 25 patients non-complaint during either the treatment or the follow-up phase were excluded in the analysis, the HR for relapse was 0.36, 95% CI 0.23 to 0.57, p<0.001.The median cumulative prednisolone dose during the maintenance phase was identical in both groups , deviations from the protocol were common, 44 (52%) in the rituximab and 57 (67%) in the azathioprine groups reported at least one deviation during the trial. At month 24, by which time the protocol-required cessation of glucocorticoids, 22/77 (29%) in the rituximab and 35/76 (46%) in the azathioprine groups were still receiving glucocorticoids, mean daily doses=2.28 mg (SD=5.45) for the rituximab and 2.8 mg (SD 5.5) for the azathioprine groups.There was no difference in the accrual of damage between groups. The modified Combined Damage Assessment score increased by a mean of 0.571 (SD 0.909) and 1.09 (SD 1.18) in the rituximab group compared with 0.533 (SD 0.777) and 1.38 (SD 1.65) in the azathioprine group during the maintenance phase and whole trial, respectively.No differences were observed between study groups in any domains of the SF-36 score. In the rituximab and azathioprine groups, median physical component scores at randomisation were reduced at 37.25 (range 2.8–61.6) and 36.5 (1.5–58.1) and median mental component scores were 54.55 (19.6–67.7) and 53.8 (16.7–72.6). Scores remained stable across the trial, both during the maintenance and follow-up phases .9 /L (0–3) in the rituximab group and 0×109 /L (0–5) in the azathioprine group. The median percentage of CD19 cells remained zero (0–5) in the rituximab group but increased to 0.1% (0–29) at month 12 and 0.3% (0–35.1) at month 24 in the azathioprine group. During the follow-up phase, the median CD19 cell counts were lower in the azathioprine group, this was confounded by the use of rituximab to treat relapses in this group  patients in the rituximab and 105 in 48 (56%) in the azathioprine groups . There w10.1136/ard-2022-223559.supp4Supplementary dataThis international, randomised, controlled trial demonstrated that rituximab was superior to azathioprine for prevention of disease relapse in patients with AAV with a prior history of relapse, following reinduction of remission with rituximab and glucocorticoids, and there was lower average glucocorticoid exposure in the rituximab group.The MAINRITSAN 1 trial demonstrated the superiority of rituximab over azathioprine for the prevention of relapse following induction of remission with cyclophosphamide in a study population with predominantly newly diagnosed AAV patients. The higher relapse rate found in this trial compared with the MAINRITSAN 1 trial reflects differences in patient populations and trial design.SAEs and infections were common, consistent with previous studies in AAV, and there were no new safety signals for these medications in this population. Hypogammaglobulinaemia, secondary immunodeficiency and impaired vaccine responses, is a concern with use of repeated doses of rituximab. Although median plasma IgG levels were stable in both the rituximab and azathioprine groups across the trial, 42% of patients in the rituximab group and 31% in the azathioprine group developed a plasma IgG level <5 g/L; however, it should be noted that all patients had received rituximab induction at trial entry. In RITAZAREM, higher glucocorticoid exposure and lower baseline plasma IgG levels were associated with the development of hypogammaglobulinaemia, a finding consistent with a prior reports.The strengths of this study include this being the largest cohort of patients with relapsing AAV recruited into a clinical trial, centralised randomisation and recruitment from 29 centres across four continents, minimising centre or regional bias. The study had low rates of treatment crossover and a long period of follow-up after trial medications were discontinued, a design aimed at detecting the prolonged effects or safety issues of the interventions.The study was limited by use of open-label trial medication, but potential impact on trial end-points was counterbalanced by a blinded adjudication end-point committee. Extended use of glucocorticoids was employed due to their known impact on relapse risk and the inclusion of a population at high risk of relapse, but their value could not be assessed and there remains a need to minimise glucocorticoids among patients with relapsing disease who have already accrued considerable exposure to glucocorticoids.In conclusion, the results of the RITAZAREM trial show that repeat-dose rituximab is more effective than azathioprine for prevention of relapse for patients with AAV with relapsing disease induced with rituximab and glucocorticoids. These data extend previous reports on the efficacy of rituximab for induction of remission for relapsing disease and confirms the place of rituximab as the standard of care for maintenance therapy. The results should also prompt further reductions in glucocorticoid exposure for AAV.10.1136/ard-2022-223559.supp2Supplementary data


Background: Patients with advanced lung cancer tend to experience dyspnea. Pulmonary rehabilitation has been reported as a method for relieving dyspnea. However, exercise therapy imposes a high burden on patients, and it is difficult to sustain in many cases. Inspiratory muscle training (IMT) imposes a relatively low burden on patients with advanced lung cancer; however, its benefits have not been demonstrated. Methods: We retrospectively analyzed 71 patients who were hospitalized for medical treatment. The participants were divided into an exercise therapy group and an IMT load + exercise therapy group. Changes in maximal inspiratory pressure (MIP) and dyspnea were examined using a two-way repeated measures analysis of variance. Results: MIP variations significantly increase in the IMT load group, with significant differences between baseline and week 1, between week 1 and week 2, and between baseline and week 2. The analysis also showed that the variations in dyspnea decreased in the IMT load + exercise therapy group with significant differences between baseline and week 1 and between baseline and week 2. Conclusions: The results show that IMT is useful and has a high persistence rate in patients with advanced lung cancer who present dyspnea and cannot perform high-intensity exercise therapy. Common symptoms of lung cancer include dyspnea, cough, weight loss, and chest pain . ResearcThe American Society of Clinical Oncology (ASCO) guidelines recommend a hierarchical approach to dyspnea, with reversible causes first, followed by non-pharmacological and pharmacological interventions as the last addition to the treatment plan and from those with fewer side effects and higher efficacy than those with a higher potential for side effects . PulmonaIn 2015, a study reported the efficacy of IMT loading for patients with advanced lung cancer without indication for surgery, and it was shown to be effective in improving dyspnea and QOL . HoweverThis retrospective cohort study included patients with advanced stage III–IV lung cancer who were hospitalized for medical treatment and underwent rehabilitation between April 2015 and March 2019 . The excPatient age, sex, body mass index, cancer type and stage, performance status, Barthel index, mBS rating as the degree of dyspnea at rest and on exertion , type of chemotherapy, line of therapy, use of oxygen therapy, spirometry, and maximal inspiratory pressure (MIP) were retrospectively analyzed. The percentage of vital capacity (%VC) forced expiratory volume in 1 s and forced vital capacity (FVC) were measured using an Autospiro AS-407 spirometer  based on a previous study . RelevanThe mBS rating and MIP were indicators of dyspnea. Therefore, the mBS rating and MIP were collected at three time points: baseline, 1 week later, and 2 weeks later. The mBS is a subjective rating scale that measures the degree or intensity of dyspnea at rest and on exertion. Dyspnea on exertion was assessed when it was felt most strongly during the day’s activities. The mBS is a 12-point scale ranging from 0 (none) to 10 (maximum) plus 0.5 and is also called the Clinical Rating Scale for Dyspnea (CR-10). Its score ranges from 0 to 10 (maximum). The mBS scale was adopted because it is considered appropriate for assessing relative changes in dyspnea.MIP was measured as previously described  using thAll rehabilitative strategies were carried out in daily sessions during their hospital stay (Monday through Friday). Daily sessions lasted 20–40 min for each rehabilitative intervention. Owing to the characteristics of this university hospital, the hospital stay is approximately 2 weeks, so the rehabilitation program is also set at 2 weeks. A pressure threshold device, commercially available as POWERbreathe Medic Plus KH2 , was used to provide IMT. It includes a mouthpiece and a calibrated spring-loaded valve that controls a constant inspiratory pressure training load that is maintained unless the patient drastically changes his breathing pattern. Exercise therapy did not include whole-body endurance exercises, such as riding an ergometer or treadmill running, because this study was designed for patients with severe respiratory symptoms. Exercise therapy consisted mainly of activities of daily living training, including respiratory muscle stretching, upper and lower limb resistance training, basic movements, and walking, under the guidance of physical therapists. The initial training workload was chosen to start at 0 and gradually increase until the patient-rated dyspnea and/or leg fatigue as 4 or 5 on an mBS. All patients received the same exercise therapy.IMT is believed to improve tolerance not only in the early phase of training but also in patient satisfaction and adherence by not inducing significant dyspnea. The IMT load + exercise therapy group performed IMT as previously described ,21,22 upχ2 test and Student’s t-test. Variations in MIP and MBS ratings were examined using a two-way repeated-measures analysis of variance (ANOVA) to investigate the effects of IMT. Mauchly’s test of sphericity was used to test the assumption of sphericity; when it yielded statistically significant results, the Greenhouse–Geisser ε correction was used to adjust violations of sphericity. In addition, Bonferroni’s method was used for multiple comparisons. Statistical analysis was performed using EZR software   vs. 40.3 [±8.4]), between weeks 1 and 2 (40.3 [±8.4] vs. 42.2 [±8.4]), and between baseline and week 2 (33.2 [±7.2] vs. 42.2 [±8.4]) . In contrast, the MIP variations in the exercise therapy group did not show significant changes between baseline and week 1 (39.9 [±11.2] vs. 41.7 [±9.4]), between weeks 1 and 2 (41.7 [±9.4] vs. 42.2 [±8.9]), and between baseline and week 2 (39.9 [±11.2] vs. 42.2 [±8.9]) . The multiple comparisons test showed that the variations in dyspnea at rest in the IMT load + exercise therapy group decreased, with significant differences between baseline and week 1 (2.3 [±0.9] vs. 1.4 [±0.9]) and between baseline and week 2 (2.3 [±0.9] vs. 1.3 [±1.0]) (p < 0.01 for both). In contrast, the variations in dyspnea at rest in the exercise therapy group did not show significant changes between baseline and week 1 (2.0 [±1.0] vs. 1.9 [±1.2]), between weeks 1 and 2 (1.9 [±1.2] vs. 1.8 [±1.9]), or between baseline and week 2 (2.0 [±1.0] vs. 1.8 [±1.9]) (p < 0.01 for both). In contrast, the variations in dyspnea on exertion in the exercise therapy group did not show significant changes between baseline and week 1 (3.9 [±1.0] vs. 3.6 [±1.3]), between weeks 1 and 2 (3.6 [±1.3] vs. 3.6 [±1.3]), or between baseline and week 2 (3.9 [±1.0] vs. 3.6 [±1.3])  . The var [±1.9]) . Moreove [±1.3]) .2O) [Notably, a few randomized controlled trials (RCTs) on dyspnea in patients with advanced lung cancer are adequately powered. Currently, no previous studies have limited their inclusion criteria to patients with advanced lung cancer or focused on short-term effects. In this present study, the results showed that IMT load significantly improved MIP and dyspnea at rest and on exertion in the participants. In addition, IMT is extremely beneficial and has a high persistence rate in patients with advanced lung cancer. Notably, IMT load improved MIP and dyspnea relatively early. Therefore, this study is extremely rare, as the results suggest that IMT loading may be useful as a non-pharmacological treatment for dyspnea in patients with advanced lung cancer who have received only medical treatment alone. We assume that this study referred to a situation in which the load intensity and time of IMT use were somewhat less than those in RCTs of patients with thoracic malignancies  because 2O) . In addi2O) . These d2O) , the impThe duration of IMT loading in this study is also noteworthy. Many previous studies have set a relatively long intervention period  ,25,26. TA previous study defined the minimally clinically important difference in rest and exertion mBS scores, which are indicators of dyspnea, as 1 in clinical practice . CurrentAs this was a retrospective cohort study, the sample was small, the results were limited to changes in MIP and dyspnea, and the effects of other indicators were not investigated. In addition, baseline %VC, FVC, and MIP ratings were statistically lower in the IMT + exercise group, which may better reflect the effects of IMT. The MIP after 2 weeks was nearly the same, and more load or more weeks may have been needed to improve MIP in the IMT load + exercise therapy group. The long-term effects of IMT are also unclear. More studies are needed to further investigate and confirm the effects of IMT on QOL and respiratory complications. In addition, dyspnea includes not only measures of inspiratory muscle strength but also the effects of malaise and mental function; however, these latter factors were not assessed in this study. Therefore, studies with rating scales for malaise, dyspnea, and mental functions are desirable.This study revealed that IMT load significantly improved MIP and dyspnea at rest and during exertion in patients with advanced lung cancer. Moreover, the effects of IMT load were observed relatively early. These results suggest that IMT is useful and has a high persistence rate in patients who have advanced lung cancer and dyspnea and are unable to undergo high-intensity exercise therapy.