Cerebral small vessel disease (CSVD) is a common cause of stroke and senile vascular cognitive impairment, imposing a heavy burden on public health care systems worldwide. Hypertension and 24-hour blood pressure variability (BPV), known to be significant risk factors for cognitive dysfunction, have been found to be associated with cognitive function in CSVD patients in previous studies. However, as a derived part of BPV, there are few studies on the relationship between circadian rhythm of blood pressure and cognitive dysfunction in CSVD patients, and the relationship between them is still unclear. Thus, this study aimed to investigate whether the disturbance of circadian rhythm of blood pressure can affect the cognitive function of patients with CSVD.n = 224) and the normal group (n = 159). Finally, a binary logistic regression model was used to assess the relationship between circadian rhythm of blood pressure and cognitive dysfunction in patients with CSVD.A total of 383 CSVD patients hospitalized in the Geriatrics Department of the Lianyungang Second People’s Hospital between May 2018 and June 2022 were enrolled in this study. The clinical information and parameters of 24-hour ambulatory blood pressure monitoring were compared between the cognitive dysfunction group (P < 0.05). (2) More patients in the cognitive dysfunction group had circadian rhythm abnormalities in blood pressure, especially the non-dipper and reverse-dipper types (P < 0.001). (3) In the elderly, there was a statistical difference in the circadian rhythm of blood pressure between the cognitive dysfunction group and the normal group, but this phenomenon did not exist in the middle-aged. (4) Binary logistic regression analysis showed that after adjusting for confounding factors, the risk of cognitive dysfunction in CSVD patients with non-dipper type was 4.052 times higher than that of dipper type , and reverse-dipper type was 8.002 times higher than those with dipper type .(1) Patients in the cognitive dysfunction group were older, had lower blood pressure on admission, and had a greater number of previous cardiovascular and cerebrovascular diseases (The disturbance of circadian rhythm of blood pressure may affect the cognitive function of patients with CSVD, and the risk of cognitive dysfunction in non-dipper and reverse-dipper types are higher. Circadian rhythms originated from the evolutionary needs to maximize the fitness of daily organisms on a 24-h timescale by enabling organisms to produce anticipatory and adaptive responses to recurrent light-dark cycles and associated environmental changes . Among tCerebral small vessel disease (CSVD) is a disorder of the micro-vessels in the brain, which shows various lesions in pathological examination or brain imaging with MRI or CT. Although the underlying pathogenesis remains unclear, CSVD is a common cause of stroke and senile vascular cognitive impairment, which contributes to 45% of dementia cases [Dementia is the leading cause of disability in people over 65 years of age worldwide, including in China, and leads to a heavy burden on public healthcare systems worldwide .In addition, as a subtype of cerebrovascular disease, the management of cerebrovascular risk factors also plays an important role in the treatment of CSVD, especially in the management of blood pressure. Furthermore, higher 24-hour blood pressure variability (BPV) was found to be associated with CSVD burden . Li XF eAlthough many previous studies have examined the effects of hypertension and ambulatory blood pressure changes on cognitive function in CSVD –11, therA total of 428 patients with CSVD treated at the Geriatrics Department of the Lianyungang Second People’s Hospital between May 2018 and June 2022 were selected. Eligible participants were recruited based on the following inclusion criteria: age ≥ 35 years old and the diagnosis of CSVD refers to the Chinese consensus on diagnosis and therapy of cerebral small vessel disease 2021 , brain Mn = 224) and the normal group (n = 159) according to whether or not the patients had cognitive impairment, for statistical analysis. In addition, if participants in this study were illiterate, written informed consent from the patients’ legal guardians must be obtained.Among the 428 patients, 13 met the exclusion criteria, 32 had incomplete or missing data, and 383 eligible patients were finally selected for the study, as shown in Fig. All supporting data in this study are available from the corresponding author on reasonable request. Ethical approval for this study was obtained from the ethics committee of Lianyungang Second People’s Hospital (No. 2020021).Baseline clinical information for all enrolled patients was collected from the database, including age, sex, educational level, MMSE score, SBP, DBP, glucose, history of hypertension, diabetes mellitus, prior stroke or TIA, cardiac disease, current smoking (any usage of cigarette per day in the past 30 days) and drinking  per day on average and drinking for more than 1 year; abstaining from drinking for more than 1 year is not). Laboratory findings included alanine aminotransferase, aspartate transaminase, urea nitrogen, creatinine, uric acid, albumin, total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, Lipoprotein a and C-reactive protein. In addition, we added carotid intima-media thickness based on carotid artery ultrasonography.The cognitive function of enrolled patients was assessed by MMSE within 48 h after the diagnosis of CSVD, and each patient was evaluated face-to-face by an experienced neurologist. A MMSE score of < 27 was used as the cut-off value of cognitive dysfunction.All patients underwent 24-h ambulatory blood pressure monitoring (ABPM)  within 48 h after diagnosis of CSVD, which were performed by trained nurses in accordance with the requirements of the 2020 Chinese Hypertension League Guidelines on Ambulatory Blood Pressure Monitoring. In the devices used, 7:00–21:00 was set as day-time and 21:00–7:00 was set as night-time. BP was measured every half hour during day-time and every hour during night-time. Patients were asked to get adequate rest or sleep during the night-time and maintain normal activities during the day-time. Daily activities and sleep and wake times were needed to be recorded in a diary. Patients were allowed to take part in daily activities during blood pressure monitoring. The criteria of effective blood pressure were: 40–255 mmHg for SBP, 10–195 mmHg for DBP, 40–240 bpm for heart rate. After wearing the device for at least 24 h, the patients removed it and the data from it was downloaded for analysis. Then relevant blood pressure parameters were collected, such as 24-h mean systolic blood pressure, 24-h mean diastolic blood pressure, 24-h mean standard deviation of systolic blood pressure, 24-h mean standard deviation of diastolic blood pressure, daytime mean systolic blood pressure (dmSBP), daytime mean diastolic blood pressure (dmDBP), nighttime mean systolic blood pressure (nmSBP), nighttime mean diastolic blood pressure (nmDBP). And then we calculated the ratios of night systolic and diastolic blood pressure reduction separately: the ratios of night systolic blood pressure reduction = (dmSBP-nmSBP)÷dmSBP× 100%, the ratios of night diastolic blood pressure reduction = (dmDBP-nmDBP)÷dmDBP× 100%. We defined the ratios of night systolic blood pressure reduction as the ratios of night blood pressure reduction (ΔMBP) when the blood pressure circadian rhythm shown by the ratios of night systolic and diastolic blood pressure reduction was inconsistent. Next, the circadian rhythms of blood pressure were classified according to ΔMBP: 0–10% was non-dipper type, 10–20% was dipper type, more than 20% was extreme-dipper type and less than 0% was reverse-dipper type.P value< 0.05 was considered significant.Data were analyzed using the SPSS software  and graphics were drawn using GraphPad Software . Baseline information included clinical parameters, medical history, biochemical variable and ambulatory blood pressure parameters. Kolmogorov-Smirnov test were used to assess the normality of numerical variables. Mann-Whitney U test were used for analysis in the case of non-normal distribution, described by median and interquartile range (IQR). The continuous variables of normal distribution were analyzed by independent sample T-test and expressed as mean ± standard deviation (SD), and chi-squared test or Fisher exact test for categorical variables. In addition, we used binary logistic regression models to assess the association between circadian blood pressure and cognitive dysfunction in patients with cerebral small vessel disease. A 2-tailed n = 224) and the normal group (n = 159) by MMSE score. Next, Table From May 2018 to June 2022, 383 eligible CSVD patients  were finally selected for this study. All patients were divided into the cognitive dysfunction group (P > 0.05).Compared to the normal group, patients in the cognitive dysfunction group were older, had lower MMSE score, baseline SBP and DBP. In terms of past medical history, not surprisingly, patients with cognitive impairment were more likely to have had cardiovascular or cerebrovascular diseases than those with normal cognitive function. As for biochemical variables, patients with cognitive dysfunction had higher urea nitrogen, creatinine, and lower alanine aminotransferase and albumin. There was no difference in gender, education level, glucose, other medical history and Laboratory indicators between the two groups , as shown in Fig. Next, we also stratified the two groups according to whether or not they were older than 60 years old. Table We then used circadian rhythm of blood pressure as a categorical variable to investigate the relationship between circadian rhythm of blood pressure and cognitive dysfunction in patients.In general, as shown in Table P<0.001), which still existed after we adjusted for confounding factors in Model 2 and Model 3. We can see from Model 3 that the risk of cognitive dysfunction in CSVD patients with non-dipper type was 4.052 times higher than that of dipper type , and reverse-dipper type was 8.002 times higher than those with dipper type .Univariate analysis showed that the influence of circadian rhythm classification of blood pressure on cognitive dysfunction was statistically significant in Model 1 (According to the statement by the Lancet Commission on dementia prevention, intervention and care, approximately 50 million people were living with dementia in 2020, and this number is expected to rise to 152 million by 2050 . AdjusteCSVD represents a group of diseases with heterogeneous etiology and pathological mechanisms that affect the small arteries, arterioles, venules, and capillaries of the brain . The effOnce cognitive dysfunction is allowed to progress to the dementia stage, much of the damage is irreversible. Therefore, early detection and intervention of cognitive dysfunction is particularly important. It is well known that dementia and cognitive impairment share similar risk factors, among which vascular factors are easily detected by screening. Therefore, effective control of vascular factors such as hypertension and dyslipidemia can delay the decline of cognitive function and reduce the occurrence of dementia , 14. In Although abnormal circadian rhythms of blood pressure have been recommended as an important cardiovascular risk factor by some national guidelines for hypertension management , few stuA retrospective cohort study found that nocturnal blood pressure rise was associated with reduced cognitive performance and could reduce MMSE by 2.9%, which can be used as a predictor of cognitive impairment among the elderly . TakahirIn this study, we found that the number of patients with abnormal circadian rhythm of blood pressure in the cognitive dysfunction group was higher than that in the normal group, especially among the elderly patients. Next, we included all enrolled patients in bivariate logistic regression models and found that the non-dipper and reverse-dipper types were at greater risk of cognitive dysfunction, which was consistent with their findings. Furthermore, we also found in Table In summary, abnormal circadian rhythm of blood pressure is a predictor of cardiovascular and cerebrovascular diseases independent of blood pressure level and has important clinical significance. However, different types of abnormal circadian rhythm of blood pressure may lead to significant differences in the risk of cognitive dysfunction in CSVD patients. This reminds us that medical professionals should actively restore and maintain the normal circadian rhythm of blood pressure in patients with CSVD while reducing blood pressure steadily in the early stage, which is critical for preventing target organ damage and improving the prognosis of patients. In addition, since each patient has a different type of blood pressure circadian rhythm, we suggest that anti-hypertensive regimens should be individually selected, and attention should be paid to the influence of the time of taking anti-hypertensive drugs on the different types of circadian rhythms of blood pressure.Nevertheless, this study had some limitations. First, as a single-center retrospective study, some selection bias might exist in the process of data collection and analysis. In addition, since this was a cross-sectional study, the causal relationship could not be determined, so further large-scale studies are needed. Second, the current study population was Asian Chinese, but CSVD may be influenced by genetic factors, thus the results of this study may not be applicable to other ethnic groups. Third, about 80% of the patients in this study had a history of hypertension, so the influence of different types of antihypertensive drugs on the circadian rhythm of blood pressure cannot be ruled out. Finally, due to database limitations, we were unable to collect the Montreal Assessment of Cognitive Function for each patient and were unable to classify patients with mild cognitive impairment.The disturbance of circadian rhythm of blood pressure may affect the cognitive function of patients with CSVD, and the risk of cognitive dysfunction in non-dipper and reverse-dipper types are higher.


The allergic phenotype is responsible for more than 50% of severe asthma cases. In a stepwise approach, add-on treatments such as anti-IgE are used for severe allergic asthma (SAA). This study was aimed to describe the real-world effectiveness of omalizumab in adult and pediatric patients with SAA in Colombia.This was an observational, non-interventional, retrospective study. Data from patients with SAA that received at least one month of treatment with omalizumab was obtained from medical records at eight sites in Colombia. Time-zero (t − 0) was defined as the date of initiation of omalizumab, and data was gathered for a 12-month period before t − 0 and a 12-month period after t − 0. Clinical outcomes, including exacerbations, were assessed at 6 and 12 months. Effectiveness of omalizumab was evaluated in terms of the reduction of the risk of exacerbations .p < 0,001).We included 143 patients with SAA. There was a decrease of 72.4% of the annualized rate of clinically significant asthma exacerbations during the year after omalizumab (from 1.74 before to 0.48 after) with a substantial reduction of the risk of exacerbations by 56.7% (RR [95% CI] 0.43 [0.30–0.63] The use of omalizumab in Colombia as a treatment for SAA notably reduced the risk of clinically significant exacerbations. This study is the first to evaluate omalizumab real-life effectiveness in pediatric and adult patients in the country. Asthma is a frequent and potentially serious chronic disease that causes major negative impact on individual and public health , 2. In CSevere asthma (SA) is defined as that which requires high doses of inhaled corticosteroids combined with at least any other controller drug, usually a long-acting beta agonist, corresponding to step 5 of the Global Initiative for Asthma (GINA), or which requires systemic corticosteroids (SC) use for > 50% of the previous year to prevent it from becoming ‘‘uncontrolled’’ or which remains uncontrolled despite this therapy . SA counThe immunoglobulin E (IgE) is the central actor of the allergic pathophysiological pathway , 12, andSeveral real-world studies have corroborated the benefits of omalizumab found in clinical trials –25. In CAlthough it has been described that allergies and allergic diseases could be different in the tropics , one repThis is an observational, non-interventional, multi-center, retrospective, real-world study aimed to evaluate the effectiveness of omalizumab in 143 patients diagnosed with SAA, who had received omalizumab in Colombia. We used secondary data obtained from medical records at participating sites. For this purpose, a before-and-after design was used defining time-zero (t-0) as initiation of add-on therapy with omalizumab. Data was gathered for a 12-month period before t − 0 and a 12-month period after t − 0. Clinical outcomes and asthma treatment were reassessed at 6 and 12 months after t − 0, which were defined as t − 1 and t − 2, respectively. In accordance with this design, the year prior to initiation of omalizumab was used as a non-intervened control group. In this study each patient represented his own control.We included patients over 6 years of age who had diagnosis of SAA, had received treatment for at least one month with omalizumab and had documented outcomes for a 24-month period .. SA was defined according to current American Thoracic Society (ATS) and European Respiratory Society (ERS) (ATS/ERS)  and GINAExclusion criteria were defined as having other respiratory diseases different from asthma, polyposis or rhinitis, patients who had received any other biologic therapy for asthma or any investigational biologic therapy for asthma in the 24-month period or had received omalizumab as an off-label indication.Considering previous analysis regarding real-world efficacy of omalizumab which reported reductions for asthma exacerbations and hospitalizations with Cohen’s d of 0.71 and 0.36, respectively, and selecting a size effect index > 0.25 and standard statistical thresholds of α = 0.05 and power = 0.8, a sample size of 143 subjects was calculated.The study was carried out in eight sites from six cities in Colombia, as presented in Table 1], forced vital capacity [FVC] and FEV1/FVC ratio), pharmacologic treatment for asthma .Data were obtained from the clinical records one year before and one year after the initiation of omalizumab. In addition to demographic data, we collected the following information: clinically significant exacerbations (defined as a worsening of asthma required a short cycle (three days or more) of oral corticosteroids (OCS) or, for patients who require regular long-term OCS administration, needed an increase in the OCS dose regimen ; and/or hospitalization ; and/or emergency room visit ), blood eosinophils count (EOS), serum IgE level, asthma control , spirometry variables . Allergic phenotype was defined by an IgE ≥ 30 UI/mL and a positive prick test . Current ACT, ACQ and GINA control asthma tool was used and evaluated according to the accepted cutoff.. The description of baseline characteristics, emergency room visits, asthma-phenotype associated variables , asthma-control variables , FEV1 and adverse events occurrence were evaluated as secondary endpoints. The correlation between the EOS (< 300 cells/μl or > 300 cells/μl) and clinical outcomes  was assessed as exploratory endpoint. For a simple comparison between responder and non-responder to omalizumab patients, we used a reduction of at least 50% of the number of exacerbations after one year of the use of the biologic as criteria of responder.The change of the annualized rate of clinically significant exacerbations after starting omalizumab (t − 1 and t − 2) in comparison with the previous year (t − 0) was defined as the primary endpointp < 0.05, the analysis was carried out with the statistical software Stata14®.Qualitative variables were expressed as absolute and relative frequencies, and quantitative variables as measurements of central tendency and dispersion, according to the Shapiro Wilk’s normality test. The annualized rate of clinically significant exacerbations was calculated for each period. To evaluate effectiveness of omalizumab, we analyzed the change of the risk of exacerbations in terms of the reduction of the annualized rate of clinically significant exacerbations. Data from patients before omalizumab initiation time (t − 0) were taken as control period (without exposure) and data after t − 1 and t − 2 were considered as intervention period (with exposure). To compare data between periods we used an analysis of variance (ANOVA) analysis. Data were analyzed for the whole group of participants and for the age groups < 18 and ≥ 18 years old. To evaluate the effectiveness of omalizumab, a multivariate analysis approach for comparing multivariate sample means was done using a multivariate analysis of variance (MANOVA) technique and taking three times (12 months before (t − 0), 6 and 12 months after starting omalizumab (t − 1 and t − 2). The number of clinically significant exacerbations was adjusted according to age, gender, and GINA classification. We performed a logistic regression analysis using improvement of control  as dependent variable. For the bivariate and multivariate analysis, we used age, sex, rhinitis, nasal polyposis, gastroesophageal reflux, blood eosinophils count, IgE level, SPT and asthma severity as independent variables. Statistical significance was set at A total of 143 patients with SAA were included in this study, with 113 (79%) of them being ≥ 18 years. Table p < 0.001). The annualized rate of hospitalizations in pre-omalizumab period was 0.46 compared with 0.15 in post-omalizumab period, with a reduction of 67.4%. The annualized rate of emergency visits was 1.11 in pre-omalizumab period and 0.34 in post-omalizumab period, with a reduction of 69.4%.The annualized rate of clinically significant asthma exacerbations was 1.74 in pre-omalizumab period and 0.48 in post-omalizumab period, with a reduction of 72.4%   after starting omalizumab. The percentage of uncontrolled patients decreased considerably with 46% less patients being classified as uncontrolled at t − 1 and remained similar until t − 2. On the contrary, the percentage of patients classified as well controlled increased from 8% (t − 0) to 44% (t − 2). The change in the percentage of patients initially classified as partly controlled increased with almost 14% more patients at t − 2. Fig. . Not all1 at t − 0. Of these, 38 (43.7%) and 28 (32.2%) had a follow-up evaluation at t − 1 and t − 2 respectively. The proportion of patients with a pre-bronchodilator FEV1 ≥ 80% significantly increased from 31.5% at t − 0 to 43.5% and to 60.7% at t − 1 and t − 2, respectively  of the patients had the evaluation of the pre- and post-bronchodilator FEVhese, 38 3.7% and As per protocol inclusion criteria, at starting omalizumab (t − 0) almost all patients (96.4%) used high or medium doses of ICS combined with a long-acting beta-agonist (LABA) and 11.5% used OCS. At t − 0 some of these SAA patients also used a leukotriene modifier (80.5%) and/or a long-acting anticholinergic bronchodilator (LAMA) (32.5%). At t − 2, only 3.5% of the patients who were receiving omalizumab continued using OCS, corresponding to a reduction of 69.5% of patients requiring OCS after one year. No other significant changes in the use of other medications for asthma was observed.p = 0.093). Similarly, we did not find any independent variable associated with improvement of asthma control in the multivariate analysis.As exploratory objective, we found a trend towards a higher decrease in the number of clinically significant exacerbations at both t − 1 and t − 2 in patients with EOS ≥ 300 cells/µl. However, there was no statistically significant difference, possibly because of the small sample size (n = 143 patients). We did not find significant differences between responder and non-responder to omalizumab patients, although the responder subjects tended to be younger  patients from the study population, in 6 cases (4.2%) due to adverse events as depicted in Table p < 0,001). Therapy with omalizumab was also associated with a significant reduction of hospitalizations and emergency room visits. Analyzed by age, these findings were similar in children and adolescents (< 18 years) and adults (≥ 18 years), although the effect size was higher in the pediatric population as it could be expected due to the greater relevance of allergy in this age group. Despite of the missing data, usual in real-world conditions, our study also showed a consistent improvement of asthma control and pulmonary function (FEV1), and a reduction of the proportion of patients requiring OCS.Our study consistently showed that in a real-world setting of patients with SAA older than 6 years in Colombia, add-on therapy with omalizumab was associated with a significant decrease of the annualized rate of clinically significant asthma exacerbations (72.4%) and a substantial reduction of the risk of exacerbations by 56.7%  in the clinical practice. In Colombia, omalizumab is available for most of the general population because its cost is covered by the National Insurance Health System. So, the starting and adherence to omalizumab are not influenced by the cost, and the subjects included in our study are representative of patients with severe allergic asthma using omalizumab in the country. We have important limitations related to the significant number of missing data and the variable quality of data acquisition which are recorded during the medical practice routine and depend on the attending physician or the medical history format (paper or electronic). Results from this study should be applied carefully to the general population in Colombia due to missing data for some of the executed analysis.In a real-life setting in Colombia, the use of omalizumab as a treatment for severe allergic asthma significantly reduces the frequency of asthma exacerbations, hospitalizations and emergency room visits due to respiratory causes, and improves the asthma control in both adult and pediatric patients. Our results support that reduction or withdrawal of OCS could be considered after omalizumab initiation. This study revealed the effectiveness of omalizumab in patients with different phenotypical characteristics with a positive response to treatment. Future research is needed in Colombia to further explore a possible relationship between phenotypic characteristics of severe allergic asthma and cost-effectiveness of omalizumab for our healthcare system.


Cancer is one of the main causes of death worldwide. Although immunotherapy brings hope for cancer treatment, it is also accompanied by immune checkpoint inhibitor-related adverse events (irAEs). Immune checkpoint inhibitor pneumonia (CIP) is a potentially fatal adverse event, but there is still a lack of effective markers and prediction models to identify patients at increased risk of CIP.A total of 369 cancer patients treated between 2017 and 2022 with immune checkpoint inhibitors at Shengjing Hospital of China Medical University and Liaoning People's Hospital were recruited for this study. Independent variables were selected by differences and binary logistic regression analysis, and a risk assessment nomogram was constructed for CIP risk. The accuracy and discriminative abilities of the nomogram were evaluated by calibration plots, receiver operating characteristic curves (ROCs) and decision curve analyses (DCAs).Binary logistic regression analysis showed that smoking history, acute phase proteins [interleukin (IL-6) and C-reactive protein (CRP)], CD8 + T lymphocyte count and serum alveolar protein [surface protein-A (SP-A) and Krebs Von den Lungen-6 (KL-6)] were significantly associated with CIP risk. A nomogram consisting of these variables was established and validated by different analyses.We developed an effective risk nomogram for CIP prediction in immune-checkpoint inhibitor administrated cancer patients, which will further assist early detection of immunotherapy-related adverse events. Cancer is a serious threat to human health and life and is the second most important cause of death after heart disease. In 2022, nearly five million new cancer cases and three million cancer deaths are projected to occur in China . Immune Immune checkpoint inhibitor pneumonia (CIP) is a kind of irAE that occurs in the lungs, and the main lesion is interstitial pneumonia originating in the lower lobes of both lungs. CIP has been reported to have a morbidity rate of 3–5% and a mortality rate of 10–17% and it may be higher in patients with lung cancers . GlucocoHasegawa et al. reported that SP-D inhibited the proliferation and motility of NSCLC by binding to epidermal growth factor receptor (EGFR) directly [Pulmonary surfactant is an important lipoprotein complex that is mainly produced by alveolar epithelial cells (AECs). Pulmonary surfactant plays an important role in alveolar air exchange and participates in pulmonary immune regulation and antiviral infection. Surfactant protein A (SP-A) and surfactant protein D (SP-D) are large, soluble, hydrophilic proteins that are important components of the pulmonary surfactant. The production of pulmonary surfactant may increase after alveolar epithelial cell injury. However, the markers of alveolar epithelial cell lesions lack specificity and are changed in many diseases, such as systemic sclerosis-associated interstitial lung disease  and idiodirectly , so serudirectly .Krebs von den Lungen-6 (KL-6), which is classified as one of the human Mucin 1 antigens, is a high molecular weight glycoprotein expressed predominantly by AECs, bronchial glandular epithelial cells and bronchial gland cells . KL-6 waAs an irAE with high mortality, CIP still lacks effective markers and prediction models. In this study, we aimed to identify risk factors and construct nomograms for evaluating the individual risk of CIP. We enrolled a total of 369 PD-1/PD-L1 monoclonal antibody-treated cancer patients as the training cohort and validation cohort. In the training cohort, variables associated with CIP risk in the differential analysis were included in the binary logistic regression analysis to identify independent risk factors, and a nomogram was established based on the variables. Then, we used a calibration curve , receiveA total of 245 immunotherapy-treated cancer patients from Shengjing Hospital (as a training cohort) and 124 patients from Liaoning People's Hospital  were enrolled in this study between January 1, 2017, and December 31, 2021, and were followed up until February 28, 2022. All of these patients had a definite pathological diagnosis of cancer and were treated with PD1/PD-L1 monoclonal antibodies. The patients with rheumatologic disease, radiation pneumonitis, drug-induced pneumonia and other pre-existing lung abnormalities were excluded from the study. At the same time, other information from these patients, including demographic characteristics , smoking history), the primary and secondary sites of the tumour and prior oncologic therapy, were also collected.High Resolution Computed Tomography (HRCT), which was obtained with 1.0–1.5 mm at 10-mm intervals at end inspiration from the lung apex to the base, was performed before and every three months during the PD-1/PD-L1 monoclonal antibody administration and reviewed by two independent radiologists (Liu Yang and Li Hongyi) blinded to the diagnosis and clinical course of the patients. Each radiologist described the phenotypic appearance and severity of CIP according to the CT findings: ground-glass attenuation (GGA), consolidation, traction bronchiectasis or honeycombing , 21. At Before administration of treatment, blood samples were collected and immediately frozen at − 80 °C until used to obtain a series of laboratory values, including acute phase proteins (IL-6 and CRP), T lymphocyte count and serum alveolar epithelial proteins .Taking KL-6 as an example, the serum was centrifuged to obtain the supernatant and diluted at 1: 100 in bovine serum albumin (BSA) to prepare the testing sample. A commercial enzyme-linked immunosorbent assay (ELISA) kit  was used, and the detailed protocol was as described previously , 23. BriP < 0.1 in the difference analysis were included in the binary logistic regression analysis. In addition, variance inflation factor (VIF) values were calculated to measure the degree of multicollinearity among the variables; that is, a VIF of > 5 indicates a high correlation of the variables [Continuous variables are expressed as the mean ± SD and were compared by Student's t-test, while categorical variables are presented as counts and percentages and were compared using the chi-square test or Fisher’s exact test. Cut-off values of the continuous variables were determined via ROC analysis using MedCalc software. Difference analysis and binary logistic regression analyses were used to analyse the risk factors, and the risk factors with ariables , and at P < 0.05 was considered to indicate statistical significance.All statistically significant risk factors in the multivariate analysis were used to construct the nomogram using R statistical software. We used calibration curves to measure the agreement between the predicted and actual outcomes. The predictive ability of the nomogram was assessed according to the area under the curve (AUC) of the ROC curve with an AUC closer to 1.0 indicating better results . The oveDuring the study period, 245 patients from Shengjing Hospital and 124 patients from Liaoning People's Hospital were recruited for this study. The follow-up time in both groups was less than 2 years, which was slightly longer in the training cohort, and 8.40% of all patients suffered from CIP, most of whom were grades 2–3 and received glucocorticoid therapy. One patient died of interstitial pneumonia complicated by severe pulmonary fungal infection, while the other patients were cured. The basic information of the recruited patients is shown in Table P < 0.1). Therefore, we included these variables in the logistic regression analyses.As shown in Table All VIF values of the variables were close to 1, indicating no collinearity among the independent variables, and the normality test indicated that the variables were normally distributed, but Box–Tidwell analysis indicated that the relationships between the variables and CIP were nonlinear; therefore, we classified these continuous variables for logistic analysis. A ROC curve and the Youden index (sensitivity + specificity-1) were used to determine the optimal cut-off values of the variables due to the lack of a reference value for cancer patients in the recent literature. When CIP was defined as an endpoint, the optional cut-off values were listed Table , and sigP < 0.01), IL-6 , CRP , CD8 + T lymphocyte count , SP-A  and KL-6  were independent influence factors of CIP.Binary logistic regression analysis was performed for CIP risk based on clinicopathological features. The results showed that smoking history , chemokines and cytokines  and MMPs and tissue inhibitors of MMPs. In our study, we found that serum alveolar epithelial proteins before treatment could predict CIP risk, but unfortunately, we were not able to study other serum proteins in predicting CIP. A previous study showed that changes in KL-6 levels are correlated with interstitial pneumonia caused by CTD . TherefoMany factors can damage AECs, such as preexisting pulmonary diseases, including chronic obstructive pulmonary disease (COPD), asthma and pleural effusion , and somThere are also many shortcomings of this study. First, this study is a dual-centre study from northeastern China, and there may be inclusion bias in the process of recruiting patients. Second, patients with CIP failed to undergo bronchoalveolar lavage or lung biopsy, which helps to clarify the specific lesions of CIP, especially the infiltration of immune cells. Finally, the sample size of this study was small, and no CTLA-4 inhibitors were used by the included patients. We look forward to a large-scale, multicentre prospective study to explore additional irAEs, especially CIP-related markers.Smoking history, acute phase proteins (IL-6 and CRP), CD8 + T lymphocyte count and serum alveolar epithelial proteins (SP-A and KL-6) are the risk factors of CIP. By combining risk factors, nomograms were constructed for CIP. The models provide an early prediction method for CIP before ICI administration, which facilitates early diagnosis and rational treatment.


Hypertension, often known as increased blood pressure, is a worldwide public health concern. Globally, ~1 billion people have hypertension and 7.1 million die from this disease. It is disproportionately more prevalent in resource-poor nations, with inadequate health systems like Ethiopia. Moreover, information on the burden of disease from hypertension in the specific area, especially in the newly organized Wolkait Tegedie zone, is essential to develop effective prevention and control strategies. Therefore, this study aimed to assess the prevalence of hypertension and associated factors among adult patients evaluated at the outpatient department of the two district hospitals in the Wolkait Tegedie zone, Northwest Ethiopia.p-value < 0.05 from the multivariable analysis were considered to have a significant association with the outcome.An institution-based cross-sectional study was conducted from September to October 2021. A systematic random sampling technique was used to select a total of 449 participants. The data were collected and then entered using EPI-INFO version 7 and exported to STATA 14 for analysis. Bivariable and multivariable binary logistic regression analyses were performed. Adjusted odds ratio (AOR) with a 95% confidence interval (CI) was used as a measure of association. Variables having a The prevalence of hypertension among adult patients in this study was 44.91% , of which 63.92% were new diagnoses. Being >60 years , having poor physical exercise , consuming cruddy oil , having a family history of hypertension , and having a history of diabetes mellitus (DM)  had a statistically significant association with having hypertension.There is a relatively high prevalence of hypertension among adult patients in the outpatient department of the two primary hospitals, Northwest Ethiopia. Factors such as being of older age, having poor physical exercise behavior, cruddy oil consumption, and family history of DM and hypertension had a positive significant statistical association with being hypertensive. Community-based screening programs for hypertension should be designed and implemented to prevent this silent killer disease. Health education and promotion that focus on healthy nutrition and physical exercise should be delivered. Globally, non-communicable diseases (NCDs) account for approximately three-fourths of all deaths , 2. HypeIn low socioeconomic countries, in addition to the big challenge of curing communicable diseases such as malaria and HIV, the increasing problem of hypertension in this region makes a double burden and a serious consequence . In resoIncreased blood pressure is one of the principal risks of life-threatening complications on vital organs such as the heart, blood vessels, kidneys, and brain, which leads to premature disability and mortality . GloballStudies showed that too much salt and fat consumption , 6, alcoTreating the complications of hypertension such as cardiac bypass surgery, stroke management, and dialysis is a costly intervention that drains individual and government budget . SignifiAn institution-based cross-sectional study was conducted from 1 September to 30 October, 2021, among patients who come to the OPD at the two primary hospitals in the Wolkait Tegedie zone. The Wolkait Tegedie zone is a newly emerging and newly organized zone in the Amhara region formed in 2021. Currently, it has 5 primary hospitals and 19 health centers. From these, ~13,000 and 8,000 patients are expected to visit adult OPD per year in the Kiraker and Nigus Ketema primary hospitals, respectively.The source population for this study was all the adult patients who come to the OPD of the two primary hospitals. Those patients who were available at the time of data collection were considered as the study population. However, adult patients who were unable to communicate and those with severe psychiatric problems were excluded from the study.The sample size for studying the prevalence of hypertension and associated factors was determined using both the precision approach and the power approach. The precision approach was calculated using a single-population proportion formula by considering a prevalence of 28.3% from the study done in the nearest setting , 95% conn = 449).Therefore, from the above alternatives, the highest sample size means the sample derived based on the power approach Kelsey method for variable underweight was used . Then, using systematic random sampling and this kth interval, each hospital sample was selected. Finally, a total sample of 432 patients (96.1%) responded and were included in this study  were selected using a simple random sampling lottery method from the total of five primary hospitals found in the Wolkait Tegedie zone. The 2 months' (data collection period) expected case fellow status in the OPD of each hospital was 2,166 cases/2 months for the Nigus Ketema primary hospital and 1,334 case/2 months for the Kiraker primary hospital. Therefore, by using the proportional allocation method to select the representative samples from each hospital, 278 from Nigus Ketema primary hospital and 171 from Kiraker primary hospital were selected as the final candidate samples. Then, we calculated the interval for selecting the sample, is study .The dependent variable of this study was having hypertension. It is defined as when the patient has reported regular use of antihypertensive medication (s) or persistently high blood pressure (systolic blood pressure (SBP) ≥ 130 or diastolic blood pressure (DBP) ≥ 80 mmHg) . In contDefined as when the patient has reported regular use of antihypertensive medication (s) or having an average of two times measurement of high blood pressure (SBP ≥ 130 or DBP ≥ 85 mmHg) .Calculated as weight in kilograms divided by height in square meters and interpreted as underweight (BMI < 18.5), normal (18.5–24.9), overweight (25.0–29.9), and obese (≥ 30.0) .Data were collected using pretested and structured interviewer-administered questionnaire and from a chart review. The data were collected by nurses who have a BSc degree and working in the OPD and supervised by the principal investigator. The interview questionnaire was structured into three sections, namely, sociodemographic characteristics, behavioral factors and medical-related questions, and measurements.The participants' weight and height were measured and recorded by the interviewers after the interview by following the standard steps. Blood pressure was measured using a standard mercury sphygmomanometer BP cuff with the appropriate cuff size. It was measured two times in a sitting position after reassuring the participant no smoking or caffeine 30 min before measurement and rested for at least 5 min. The second measurement was taken 10 min after the first measurement. Finally, the average of two BP measurements was calculated to determine the BP status of the participant.The quality of the data was ensured through training of data collectors and supervisors, close supervision, and prompt feedback. The training consisted of instruction on interview techniques as per the prepared tool. We used standard instruments. The accuracy of the measurement instrument was checked before the beginning of each data collection session by the principal investigator and/or data collectors. The data were checked for any inconsistencies, coding errors, out of range, completeness, accuracy, clarity, missing values, and appropriate corrections were made by the principal investigator and the supervisor consistently on a daily basis.p-value of < 0.2 in the bivariable analysis were entered into the multivariable analysis. Both the crude odds ratio (COR) and adjusted odds ratio (AOR) with 95% CIs were estimated to show the strength of associations. Finally, a p-value of < 0.05 in the multivariable logistic regression analysis was used. For this study, the Hosmer and Lemeshow goodness-of-fit test was used to assess whether the necessary assumptions for the application of multiple logistic regression were fulfilled and whether it was non-significant.The survey data were entered into the EPI-INFO version 7 and analyzed using STATA 14 software. Descriptive statistics are presented using texts, graphs, and tables. A binary logistic regression model was used to identify the factors affecting the prevalence of hypertension. Both bivariable and multivariable logistic regression models were carried out. Variables with a Ethical approval was obtained from the University of Gondar Institutional Ethical Review Board Committee. A support letter was obtained from the University of Gondar Research and Community Service for the respective hospitals, and permission was obtained from two executive directors of the hospitals. Participants were informed about the purpose, objectives, and their right to participate and not to participate in the study. Privacy and confidentiality of the study participants were ensured by not using a personal identifier, and data were collected in private conditions individually. Written informed consent was obtained from the study participants.2. One-tenth (10.19%) of the participants were overweight. Approximately 55 (12.76%) of patients had preexisting hypertension . About a quarter (25.23%) of study subjects were found to be aged > 60 years, with a median age of 46  years. More than three-fourths (78.24%) of the patients were from rural residences, and 304 (70.37%) patients had a low monthly income. The mean BMI of respondents was 20.63 (± 3.13 SD) kg/mrtension .The prevalence of hypertension among patients evaluated at the OPD in Kiraker and Nigus Ketema primary hospitals in northwest Ethiopia was 44.91% . Of the total of 194 patients with hypertension found in the two hospitals, 124 (63.92%) were newly diagnosed, whereas the remaining 79 (36.08%) were having preexisting hypertension.The prevalence of hypertension was more prevalent among old-age patients (age > 60) (57.8%), patients who consumed crude oil (60.09%), and patients who were doing poor physical exercise (53.95%) but did not have a significant difference between sex .p-value of ≤ 0.2 in the simple logistics regression analysis were considered for multiple logistics regression analysis. But variables such as the marital status of the patient with a p-value > 0.2 were excluded from multivariable analyses. Moreover, out of those variables considered for multivariate analysis, age of the patient, physical exercise behavior of the patient, types of dietary oil consumption, having a history of DM, and having a family history of hypertension were statistically significantly associated with having hypertension.All variables were analyzed using simple (bivariable) logistic regression analysis to assess the association between each variable having hypertension. Then, variables having a Patients >60 years old were likely to have nearly two times higher chance of hypertension compared to patients 18–40 years old . The odds of having hypertension among patients who were doing poor physical exercise were 1.74 times higher than in patients who were doing their physical exercise rigorously . Patients who consumed cruddy oil were 15.22 times higher to have hypertension compared to those patients who did not consume oil for dietary consumption .Patients with a family history of hypertension were 13 times more likely to be hypertensive compared to patients without a family history of hypertension . Moreover, patients with a history of DM were eight times more likely to have hypertension compared to those without a DM history  .Globally, hypertension is among the leading causes of mortality . It is tIn our study, patients aged >60 years were found to be with nearly two times higher chance of having hypertension compared to patients who were aged 18–40 years. This is supported by a systematic review and meta-analysis , a commuThe chance of having hypertension among patients doing poor physical exercise was higher than in patients doing physical exercise rigorously. This is supported by a community-based study in Gondar, Ethiopia . StudiesPatients who consumed cruddy oil were considered to have hypertension compared to those patients who did not consume oil for dietary consumption. This is because crude oil ingestion causes abnormality in lipid profile and the risk of incidence of hypertension . Crude oPatients with a family history of hypertension were more likely to be hypertensive compared to patients without a family history of hypertension. This is supported by a study in Gimbi, Ethiopia , southweMoreover, patients with a history of DM are more likely to have hypertension compared to those without a DM history. This is supported by a systematic review and meta-analysis , a commuThe strengths of this study come from the use of a relatively large sample size and two district hospitals compared to the previous study conducted in Ethiopia, which makes it representative of populations of study settings. Therefore, it can be generalized to all patients in the Wolkait Tegedie zone during the study period.This study has some limitations. Since it is a cross-sectional study, causality with explanatory variables cannot be ascertained. We did not include biochemical measurements such as serum glucose level and a 24 h urine sodium concentration.There is a relatively high prevalence of hypertension among adult patients in the Kiraker and Nigus Ketema primary hospitals, northwest Ethiopia. Factors such as being older age, having poor physical exercise behavior, having cruddy oil consumption, having diabetes mellitus, and having a family history of hypertension had a positive significant statistical association with being hypertensive. Community-based screening programs for hypertension should be designed and implemented to prevent this silent killer disease. Health education and promotion that focus on healthy nutrition and physical exercise should be delivered. Trained health coaches are necessary per household of each patient with hypertension in the prevention and continued risk for stroke.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 University of Gondar CMHS ERB. The patients/participants provided their written informed consent to participate in this study.Conceptualization, formal analysis, methodology, and supervision: AK, DB, HF, MM, and HA. Data curator and investigation: AK, DA, EM, and DB. Resources: AK, DA, EM, HF, MM, and HA. Software: AK, DB, HF, MM, HA, and EM. Validation: AK, DB, GT, EG, and EM. Visualization and writing original draft: AK, HF, MM, HA, GT, EG, and DB. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Mechanistic studies suggested that excess sympathetic activity promotes arterial hypertension while worsening insulin sensitivity. Older patients with type 2 diabetes are at particularly high cardiovascular and metabolic risk. However, data on sympathetic activity in this population is scarce.2, and had to be treated with stable doses of metformin only. We recorded ECG, finger and brachial blood pressure, and muscle sympathetic nerve activity (MSNA).We studied 61 patients with type 2 diabetes mellitus . They had to have diabetes for at least 2 years, a hemoglobin A1c of 6.5–10%, a body-mass-index of 20–40 kg/mp = 0.55). MSNA expressed as burst incidence was 52.7 ± 2.0 bursts/100 beats in women and 59.2 ± 3.1 bursts/100 beats in men (p = 0.21). Five out of 39 men (12.8%) and two out of 22 women (9.1%) exhibited resting MSNA measurements above the 95th percentile for sex and age. In the pooled analysis, MSNA was not significantly correlated with systolic blood pressure, diastolic blood pressure, body mass index, waist circumference, body composition, or HbA1c .MSNA was 37.5 ± 2.5 bursts/min in women and 39.0 ± 2.0 bursts/min in men (We conclude that relatively few older patients with type 2 diabetes mellitus exhibit increased MSNA. The large interindividual variability in MSNA cannot be explained by gender, blood pressure, body mass index, or glycemic control. The sympathetic nervous system could provide a mechanistic link between cardiovascular disease, particularly arterial hypertension, and type 2 diabetes mellitus. Increased sympathetic neural traffic, determined as muscle sympathetic nerve activity (MSNA), predisposes to arterial hypertension , and relclinicaltrials.gov registration NCT01276288 and NCT03254849). Patients had to have hemoglobin A1c values between 6.5 and 10.0% and a BMI of 20–40 kg/m2. Key exclusion criteria comprised uncontrolled arterial hypertension with systolic blood pressure ≥160 mm Hg, heart failure NYHA II–IV, estimated glomerular filtration rate <60 ml/min/1.73 m2, myocardial infarction, stroke, or vascular interventions in the previous 12 months, or significant liver disease. Patients with a history or findings during clinical examination consistent with diabetic neuropathy were excluded. We also excluded pregnant or lactating women. The study was conducted in accordance with the Declaration of Helsinki. We obtained written informed consent from all participants before screening. The study protocol was approved by the North Rhine Medical Association (Ärztekammer Nordrhein).We studied patients with type 2 diabetes on stable metformin monotherapy who had been submitted to baseline measurements for interventional studies , and beat-by-beat finger blood pressure . We also measured brachial blood pressure with an automated oscillometric device . We recorded postganglionic, multiunit muscle sympathetic nerve activity (MSNA) from the peroneal nerve as described previously . Data weWe obtained fasted venous blood samples for glucose and hemoglobin A1c measurements. We measured body height with a medical gauge with shoes off and body weight on a calibrated scale with the patient in underwear. We also determined waist circumference and body composition (fat mass and lean body mass) with air displacement plethysmography .p-values were calculated to assess the relationship between the assessments. Statistical comparisons between subgroups (men/women) were done with unpaired Student’s t-tests.Descriptive statistics  were calculated for each parameter. Pearson’s correlation coefficients and corresponding We included 61 patients  with type 2 diabetes mellitus and good quality MSNA recordings in our study. Anthropometric data, resting blood pressure, heart rate, and hemoglobin A1c measurements in women, in men, and in both groups combined are provided in p = 0.55). MSNA expressed as burst incidence was 52.7 ± 2.0 bursts/100 beats in women and 59.2 ± 3.1 bursts/100 beats in men (p = 0.21). The area under MSNA bursts was 2.9 ± 0.5 arbitrary units in women and 2.4 ± 0.3 arbitrary units in men (p = 0.35). 2 in women, 61 years and 27 kg/m2 in men) showed large overlap with our study population. Five out of 39 men (12.8%) and two out of 22 women (9.1%) exhibited resting MSNA measurements above the 95th percentile for sex and age. Overall 11.4% of all patients with type 2 diabetes had an MSNA above the 95th percentile for sex and age.In the combined dataset, MSNA ranged between 15 and 75 bursts/min, MSNA burst incidence between 26 and 98 bursts/100 beats, and MSNA burst area between 0.44 and 9.5 arbitrary units. Mean MSNA was 37.5 ± 2.5 bursts/min in women and 39.0 ± 2.0 bursts/min in men . Furthermore, MSNA expressed as bursts/min did not predict systolic blood pressure  or diastolic blood pressure . Correlation analyses for MSNA bursts incidence (p = 0.41); body mass index was 28.9 ± 0.9 kg/m2 in the group with lower and 30.5 ± 0.6 kg/m2 in the group with higher MSNA (p = 0.13); blood pressure was 127 ± 2.8/76 ± 1.2 mmHg in the group with lower and 130 ± 2.6/78 ± 1.5 mmHg in the group with higher MSNA (p = 0.34/0.23). Similarly, there were no significant differences in waist circumference, body fat, or HbA1c between groups.In the pooled dataset, MSNA expressed as bursts/min was not correlated with body mass index, waist circumference, body fat, hemoglobin A1c, or diabetes duration (ncidence  and MSNAThe important finding of our study is that in most older patients with type 2 diabetes mellitus resting MSNA is within the reference range for age and gender. Only few patients exhibit resting MSNA measurements above this reference range. Moreover, the large interindividual variability in MSNA cannot be explained by gender, blood pressure, body mass index, or glycemic control suggesting that there must be hitherto unrecognized variables affecting sympathetic activity in this population.The sympathetic nervous system has a crucial role in cardiovascular and metabolic regulation and can contribute to cardiovascular disease progression and poor clinical outcomes. Yet, data on MSNA in patients with type 2 diabetes mellitus is surprisingly limited. For example, a recent meta-analysis on MSNA only included 35 patients with type 2 diabetes overall and 36 control persons from two studies . Our stuper se is unlikely to drive sympathetic activation. In fact, MSNA is not increased in patients with type 1 diabetes mellitus (Impaired glucose metabolism mellitus  and we dmellitus . Obesitymellitus  but not mellitus . Moreovemellitus . Yet, thmellitus . Moreovemellitus . We specmellitus .Insulin infusion elicits peripheral vasodilation, which acutely increases MSNA through baroreflex mechanisms . The abiSympathetic activation raises blood pressure, however, correlations between MSNA and blood pressure across populations are generally weak . Thus, aAn important limitation of our study is that we only measured sympathetic neural traffic directed to a relatively small vascular bed. Moreover, we cannot exclude that our results are affected by diabetic neuropathic changes in the peroneal nerve. We only assessed MSNA at rest and cannot exclude that the response to physiological stimuli may be perturbed. In fact, patients with type 2 diabetes may exhibit augmented sympathetic responses to physical exercise  with dimOur study, which comprises the largest sample of patients with type 2 diabetes mellitus with MSNA recordings, suggests that substantial sympathetic overactivity is not a general finding in older patients with type 2 diabetes mellitus. Instead, MSNA varies profoundly between patients and only few exhibit MSNA above the reference range. An important scientific and clinical implication is that recognition of variability in sympathetic activity could provide a frame for a more individualized treatment approach for cardiovascular and metabolic disease prevention and treatment. For example, high resting MSNA is associated with increased sympathetically mediated postprandial energy expenditure . At leasThe 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 North Rhine Medical Association. The patients/participants provided their written informed consent to participate in this study.KH and TH: study design, conduct, analysis, and manuscript writing. JT: study design and manuscript writing. AD: analysis and manuscript writing. AF and JJ: study design, analysis, and manuscript writing. All authors contributed to the article and approved the submitted version.


Diabetic kidney disease (DKD) is a serious complication that begins with albuminuria and often leads to a rapid progressive decline in renal function. Niclosamide is a potent inhibitor of the Wnt/β-catenin pathway, which controls the expression of multiple genes of the renin–angiotensin–aldosterone system (RAAS), which in turn is influences the progression of DKD. This study was conducted to evaluate the effect of niclosamide as adjuvant therapy on DKD.Out of 127 patients screened for eligibility, 60 patients completed the study. After randomization, 30 patients in the niclosamide arm received ramipril plus niclosamide, and 30 patients in the control arm received ramipril only for 6 months. The primary outcomes were the changes in urinary albumin to creatinine ratio (UACR), serum creatinine, and estimated glomerular filtration rate (eGFR). The secondary outcomes were measurements of urinary matrix metalloproteinase-7 (MMP-7), 8-hydroxy-2ʹ-deoxyguanosine (8-OHdG), and podocalyxin (PCX). Comparisons between the two arms were done using student t-test. Correlation analysis was done using Pearson correlation.Niclosamide decreased UACR by 24% (95% CI − 30 to − 18.3%) while there was a rise in UACR in the control arm by 11% (95% CI 4 to 18.2%) after 6 months (P < 0.001). Moreover, a significant reduction in MMP-7 and PCX was noticed in the niclosamide arm. Regression analysis revealed a strong association between MMP-7, which is a noninvasive biomarker predicting the activity of the Wnt/β-catenin signaling, and UACR. A 1 mg/dL decline in MMP-7 level was associated with a 25 mg/g lowering in UACR .The addition of niclosamide to patients with diabetic kidney disease receiving an angiotensin-converting enzyme inhibitor significantly reduces albumin excretion. Further larger-scale trials are needed to confirm our results.Trial registration: The study was prospectively registered on clinicaltrial.gov on March 23, 2020, with identification code NCT04317430. Diabeti or both .The mechanisms behind the pathophysiology of DKD are complex and not fully understood . The actRecently, it was found that multiple genes of RAAS are direct downstream targets of Wnt/β-catenin. In adult healthy kidneys, Wnt/β-catenin signaling is silenced . HoweverBlocking of RAAS activation by Wnt/β-catenin inhibition avoids the disadvantage of standard RAAS blockers, as the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) leads to compensatory upregulation of other RAAS components such as renin and leads to declined responsiveness in long-term . MoreoveNiclosamide, which is an antihelminthic drug approved by Food and Drug Administration (FDA) since 1982, has recently demonstrated activity in many disease models, ranging from cancer and metabolic diseases to multiple types of infections through various mechanisms . NiclosaMatrix metalloproteinase-7 (MMP-7), also known as matrilysin, is a secreted, zinc- and calcium-dependent endopeptidase that degrades a broad range of extracellular matrix substrates . MMP-7 ePodocalyxin (PCX) is a podocyte-specific protein that was reported to be an early marker for podocyte injury and diabetic nephropathy . It was Both ACEIs and ARBs reported to have almost the same efficacy in DKD . This clThis study was an open-labeled randomized controlled parallel clinical study designed to investigate the role of niclosamide in DKD. Eligible patients were randomly assigned to the niclosamide arm or the control arm. Randomization was carried out based on the days of the hospital visit every week. Patients in the niclosamide arm received ramipril plus niclosamide 1 g once daily, and patients in the control arm received ramipril only for 6 months. Ramipril was chosen as it is routinely used as standard therapy for diabetic patients with albuminuria in Internal Medicine Department, Tanta University Hospital, Tanta, Egypt.2), pregnancy or lactation, chronic heart failure, malignancy, inflammatory or autoimmune disease, and history of kidney disease other than diabetic nephropathy.Patients were recruited from Internal Medicine Department, Tanta University Hospital, Tanta, Egypt. Eligible patients were aged ≥ 18 years with a confirmed diagnosis of type 2 diabetes mellitus at least 6 months before screening and had stage 2 or 3 diabetic nephropathies  despite treatment with a maximum tolerated dose of ramipril for at least eight weeks before recruitment. Exclusion criteria were Type 1 diabetes mellitus, severe renal impairment , diabetes duration, and blood pressure data were recorded. Urine samples were collected at baseline and after 6 months to assess UACR, MMP-7, PCX, and 8-OHdG using enzyme-linked immunosorbent assay (ELISA) kits. Blood samples were also collected at baseline and after 6 months to assess fasting blood glucose, glycosylated hemoglobin (Hemoglobin A1c), and serum creatinine using standard colorimetric methods.The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiological Collaboration (CKD-EPI) equation as it is more accurate at higher levels of renal function and better to be used for clinical assessment of DKD . The eGFPatients had regular visits every month for medication refills and to report if there are any encountered side effects. As far as we know, niclosamide can be taken with or without food and there is no evidence that food affects niclosamide effect. To prevent GIT upset, we advised patients to take niclosamide after a light meal. Every month, all administered medications by each patient were reviewed to exclude any patients taking medications that induce albuminuria or interact with niclosamide.Statistical analysis was carried out using SPSS statistical package version 28.0, May 2021, IBM corporation software group, USA. A chi-square test was applied to compare categorical clinical variables between groups. The Shapiro–Wilk test was applied to the measured parameters before running parametric statistical analysis. Normality test results reveal the normal distribution of our data with a P-value greater than 0.05. Analysis of baseline characteristics and biomarkers was done using unpaired student t-test for parametric data. Comparing the two groups mean values and the percent change in variables were done using a student t-test with statistical significance being set at P < 0.05. Correlation analysis was done using Pearson correlation. Correlation coefficients are interpreted as weak (< 0.4); moderate (0.4–< 0.7), or strong relationship (> 0.9). . A lineaConsidering that the primary objective of this trial was to compare UACR between the niclosamide arm and control arm, we calculated the minimum number of patients needed to detect the 20% change in UACR. The lower limit of 20% UACR reduction was chosen as a cut-off point representing clinical relevance which is not likely to be subjected to variance error. The assumed mean of the control group was 300 mg/g, and the expected mean difference between the control and treatment groups was 60 mg/g. Assuming 80% power, a two-sided type I error rate of 0.05, an allocation ratio (r = 1), and a standard deviation equal to 75 mg/g. After applying a 15% dropout rate, 29 participants were needed in each arm of the trial. Therefore, it was planned to enroll 30 patients per arm for 1:1 randomization.From March 2020 to April 2022, a total of 127 patients were assessed for eligibility. As shown in the flow diagram , while there was a significant increase in the control arm. 16% . Similarly, the niclosamide arm showed a significant decline in PCX after 6 months, while the control arm showed a significant rise. Niclosamide had no apparent effect on 8-OHdG as no statistically significant difference can be detected in both groups at baseline and the end of the study (Table 1C was significantly reduced in the niclosamide arm from 9.7 to 9.1% compared to the control arm that changed from 9.4 to 9.9% (P < 0.001).Fasting blood glucose didn’t differ markedly between the two arms after 6 months (165 mg/dL (± 20) and 173 mg/dL (± 28) for the niclosamide arm and the control arm respectively. However, hemoglobin ASince hypertension and obesity may affect UACR, baseline values were investigated, and a sub-group analysis was performed. The mean UACR of the 22 obese patients was 232 mg/g (± 73) while the mean UACR of the 38 non-obese patients was 239 mg/g (± 87). No significant difference was revealed between the obese and non-obese patients with regards to the baseline UACR levels. Similarly, the baseline UACR of the 32 normotensive patients, was not statistically different from that of the 28 hypertensive patients (239 mg/g (± 80), vs 233 mg/g (± 84) respectively).Sub-group analysis showed that niclosamide significantly reduce UACR in both normotensive patients and the hypertensive patients  vs -17%  respectively). Furthermore, niclosamide showed significant UACR reduction in both non-obese and obese patients  vs − 21%  respectively) .Throughout the 6 months of the study, two patients in the niclosamide group complained of GIT upset. One of them was a 51 Y.O female who decided to discontinue niclosamide after taking it for 3 weeks and had declared that she had chronic dyspepsia before recruitment to the study and that taking that medication had exacerbated her condition. She withdrew from the study and was excluded from the analysis. The other patient was a 45 Y.O male who complained of mild GIT upset, he was advised, like other patients in the niclosamide arm, to take niclosamide just after meals and he continued taking niclosamide until the end of the study with no problems.No other treatment-related side effect was reported. No recruited patients chronically use NSAIDS, depression medications, acetaminophen, antihistamines, or any other drugs known to induce albuminuria. However, some patients in both arms had been administered analgesics on an as-needed basis to treat a mild condition such as headache.To our knowledge, this was the first randomized clinical trial to study the role of niclosamide on albuminuria in patients with DKD. This study demonstrated that niclosamide may reduce albuminuria in patients with type 2 diabetes mellites receiving ACEI. Patients in the niclosamide arm showed a significant decline in albumin excretion and were protected from the significant increase in albuminuria in the control arm. In addition, patients who received niclosamide preserved their serum creatinine and eGFR compared with the control arm.Those outcomes suggest that niclosamide may be a promising therapeutic approach to protect against the progression of DKD and positively affect patients’ quality of life. These findings are consistent with previous preclinical trials that reported the ability of niclosamide to improve DKD in mice , 14. BloDeterioration of albuminuria that occurred in the control arm despite using ACEI is in accordance with several studies that reported increase in albuminuria and progression of DKD despite using RAAS blocking agent –28.Furthermore, MMP-7 was found to be elevated in all analyzed patients than normal reported urinary MMP-7 level of healthy volunteers confirming the fact that MMP-7 is elevated in diseased kidney , 16, 29.The significant reduction in PCX level in the niclosamide arm, and the significant correlation between UACR and PCX level suggest that niclosamide may also protect against podocyte damage. Correspondingly, observations of a previous preclinical study reported niclosamide can recover podocyte dysfunction and ameliorate pathological renal injury . ConsistThe niclosamide arm showed slightly better glycemic control than the control arm which suggests that niclosamide may improve beta cell function. This finding is consistent with a previous preclinical study that reported the capability of niclosamide to improve pancreatic islet function, increase serum insulin levels and reverse hyperglycemia in mice with diabetes .Niclosamide was reported recently to be a well-tolerated drug with no limiting toxicities even if it administrated in a dose of 2 g daily, which is a higher dose than used in this study . CorrespThis study has some potential limitations including small sample size, short duration, exclusion of patients with stage 4 and 5 chronic kidney disease, and high dropout rate.The present randomized clinical trial revealed that niclosamide may be effective as an adjuvant to ACEI in reducing albuminuria in patients with type 2 diabetes mellites. Blocking of Wnt/β-catenin signaling, decreasing podocyte injury, and improving Beta cell function are the suggested mechanisms underlying niclosamide efficacy. Large-scale clinical trials with longer duration are urgently needed for confirming our findings.


The maintenance of blood pressure is pivotal in preventing sepsis with acute kidney injury (AKI). Especially in sepsis patients treated with vasopressors. The optimal the blood pressure has been controversial to maintain renal perfusion. This study aims to explore the blood pressure target in sepsis with AKI.We retrieved patient data from the MIMIC IV and eICU databases. The Lasso regression model was used to identify the relationship between blood pressure and sepsis in patients with AKI and remove collinearity among variables. Generalized additive models were used to estimate the blood pressure range in patients with sepsis with AKI. Statistical methods such as multivariable logistic regression, propensity score analysis, inversion probability-weighting, and doubly robust model estimation were used to verify the target blood pressure for patients with sepsis and AKI.In total, 17874 patients with sepsis were included in this study. the incidence of AKI may be related to the level of mean article pressure (MAP) and diastolic blood pressure (DBP) in sepsis patients. The range of MAPs and DBPs may be 65-73 mmHg and 50-60 mmHg in AKI patients without hypertension. The range of MAPs and DBPs may be 70-80 mmHg and 54-62 mmHg in AKI patients with hypertension. The prognosis of sepsis with AKI was unaffected by MAP or DBP. Systolic blood pressure is not associated with sepsis in patients with AKI.To ensure renal perfusion, AKI patients with hypertension may require a higher MAP [70-80] versus (65-73), mmHg] and DBP  than patients without hypertension. Acute kidney injury (AKI) has been a global concern in the field of acute and critical diseases . AccordiDespite receiving adequate fluid resuscitation and vasopressors, many patients with sepsis still suffer from organ hypoperfusion. Insufficient renal perfusion and low blood pressure are health risks that contribute to AKI. The Surviving Sepsis Campaign recommends that patients with low blood pressure receive vasopressors to raise their blood pressure  where laThe effects of MAP on renal injury have been studied through RCTs, but the effects of SBP and DBP have been poorly investigated. The effects of SBP and DBP have been studied in a small sample size but the impact of extremely high blood pressure on patients has rarely been considered. Thus, there are still no a large-scale study with comprehensive blood pressure assessments in patients with sepsis and AKI. The effect of blood pressure on kidney is still a hot topic and controversial. Sepsis patients with AKI with chronic hypertension may and without hypertension need different blood pressure levels to maintain kidney function. As a result of the above study, sepsis patients with AKI were categorized into patients with chronic hypertension and those without chronic hypertension. Through large multiple databases, we explored the blood pressure of sepsis patients with AKI who had hypertension and those who did not have hypertension using the incidence of AKI as the main research result, and atrial fibrillation as an adverse event caused by high blood pressure.This study was a large observational study from the multicenter database eICU Collaborative Research Database (eICU-CRD v2.0) from 2014 to 2015 and Medical Information Mart for Intensive Care IV (MIMIC-IV version 1.0) database from 2008 to 2019 , 12. TheThis study population conforms to the diagnostic criteria of sepsis 3.0 . In thisWe collected patient age, gender, coexisting illnesses, infection site, and microbiological infection type data. During hospitalization and treatment with vasopressor drugs, the mean value of vital signs and urine output as well as the worst laboratory parameters were recorded. Patient’s disease severity score, including SOFA and GCS. In addition to recording if the patients were treated with mechanical ventilation, the patients’ length of stay, length of stay in the ICU, and their hospital mortality were also recorded. Only the first admission was considered for patients who are admitted to the ICU repeatedly.The Shapiro Wilk test was used in this study to detect distributions of data. This study uses continuous variables with non-normal distributions. Several continuous variables are described by the median and interquartile range (IQR). There are also categorical variables that are expressed as a count and a percentage. The two groups of continuous variables were compared using a nonparametric test. The categorical variables were compared using Fisher’s exact test.To reduce multicollinearity between variables, the Lasso regression model was used to select variables that were significantly different from each other in We tested the relationship between blood pressure and AKI patients using a multivariate Logistic Regression model. An independent association between optimal blood pressure levels and patients’ AKI was inferred through the doubly robust estimation method . MultivaA total of 51395 sepsis patients were retrieved from MIMIC IV and the eICU databases. Of these, 33521 patients were excluded based on the exclusion criteria. A total of 17874 patients were included in the study. The number of patients with Sepsis with AKI was 5833 while the number of patients with sepsis without AKI was 12041 Figure 1In We divided the patients into two groups according to whether they had hypertension so that we could evaluate the SBP, DBP, and MAP of the incidence of AKI using a generalized additive model. According to the results of the study, MAP≥70 mmHg  mmHg, (54-62), and (92-101) mmHg, respectively. In patients with AKI without hypertension disease, the MAP, DBP, and SBP ranges (65-73) mmHg, (50-60) mmHg, and (94-108) mmHg, respectively. Moreover, we selected variables that were contained in the most streamlined model screened by Lasso regression for multivariate analysis Table 2.In terms of AKI incidence, the double-robust analysis showed that MAP, DBP, and SBP had a significant beneficial effect. A propensity matching scoring model was constructed using 29 covariates with statistically significant differences in In septic patients with AKI without chronic hypertension, MAP (65-73) mmHg and DBP (50-60) mmHg were associated with less atrial fibrillation and lower creatinine and blood urea nitrogen levels; whereas, among sepsis patients having AKI with chronic hypertension, MAP (70-80) mmHg and DBP (54-62) mmHg were linked to less atrial fibrillation, lower creatinine, and lower urea levels. There was no association with length of hospital stays, ICU stays, and hospital mortality in patients with sepsis AKI  mmHg and (50-60) mmHg in sepsis patients with AKI who did not have hypertension. The range of the MAP and DBP may be (70-80) mmHg and (54-62) mmHg in sepsis patients with AKI having hypertension. It was found that MAP and DBP were not linked with the prognosis of sepsis patients with AKI.Sepsis with AKI has always been a disease of global concern, it has a high incidence rate and is associated with poor clinical outcomes. Sean m Bagshaw et al. found that the incidence of AKI was 64.4% and AKI was mainly associated with significant ICU mortality and hospital mortality (OR 1.73 and OR 1.62), respectively , the resMost sepsis patients are known to have low blood pressure and insufficient tissue perfusion. These two parameters  are the important mechanisms of AKI in sepsis . It has The surprising finding of this study was that there was a nonlinear relationship between MAP, DBP, and the incidence of sepsis in patients with AKI without chronic hypertension. They did, however, have a linear relationship with sepsis patients with AKI with chronic hypertension. It may be attributed to the increase of anterior glomerular arteriole resistance and intraglomerular hypertension and the continuous increase of anterior glomerular artery resistance which brings the glomerular capillaries into a state of high perfusion, high filtration, and high transmembrane pressure and ultimately in the state of long-term chronic hypertension . GlomeruThrough a large observational study, we provide a reference range for blood pressure levels, but it is important to demonstrate the limitations of such studies. First of all, since this is a retrospective study, our results could not provide a causal relationship between the blood pressure level and AKI incidence in sepsis. Secondly, based on previous studies, we chose atrial fibrillation caused by high blood pressure to be the endpoint of blood pressure level control, which may have caused a deviation in the research results. Thirdly, the dose and type of the vasopressors, and the amount of fluid used for residence, were not included in this study, which are important for AKI of sepsis patients, their absence may cause information bias to the study results. We provide a certain reference range for the blood pressure level control of AKI patients based on large-scale data, but some patients don’t fit into this range.Based on previous studies, we reassessed the blood pressure range in sepsis patients with AKI using multiple large databases. Through this study, we recommend that the MAP range may be 65 to 73 mmHg and the DBP range may be 50 to 60mmHg in sepsis patients with AKI without chronic hypertension; however, the MAP range may be 70 to 80 mmHg and the DBP range may be 54 to 62 mmHg in sepsis patients with AKI with chronic hypertension.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by MIMIC-IV and eICU-CRD databases were approved by the institutional review boards of the Massachusetts Institute of Technology and Beth Israel Deaconess Medical Center. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.LZ, YL, and KX conceived the central ideas of the study. YF and ZWang collected the data. LZ wrote the first draft of the manuscript. YL and KX revised the paper, worked on the English, and drafted the final version of the manuscript. ZWei and YZ revised the paper. All authors contributed to the article and approved the submitted version.


TM) device has been granted SAPHRA approval for emergency COVID-19 pandemic use. The device has the potential to be used widely in the healthcare sector due to its efficient oxygen supply and adjustable wall positive expiratory pressure (PEP).Severe Coronavirus Disease 2019 (COVID-19) can develop pneumonia with severe complications. The Oxygen Efficient Respiratory Aid  exceeding 6.3 mmHg and above the 45 mmHg threshold. We also monitored changes in vital organ signs and assessed the pain and comfort of the participant at various intervals with changes in PEPs.We assessed whether the OxEraTM Device on 30 healthy participants at the ICU training centre of Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa. Each participant had basic vital-signs, ETCO2, and Oxygen saturation percentages (SpO2%) taken at baseline until the end of 2 h. In the first 20 min, the PEP was increased by 5 cmH20 until 20 min, then continued for the rest of the time on a PEP of 5 cmH20. At each interval, vital signs, subjective comfort, pain, and visual scores were measured.This was an experimental safety study of the OxEra2 from baseline until 2 h. No participant experienced an increase in measured ETCO2 greater than 45 mmHg and no increase in ETCO2 from baseline was greater than 6.3 mmHg. The median increase in ETCO2 over the study period was 2 mmHg. There were no significant changes in respiratory rate and blood pressure. The heart rate decreased significantly (73–68 bpm). The VAS and comfort score had a significant increase over the 2 h from baseline of 0–2 at maximum; however, the PAS scores showed no significant increase.Thirty healthy participants were enrolled. There was no significant difference in ETCOTM device achieved the safety endpoints set out. There was no sign of asphyxiation and there were appropriate physiological responses to changes in PEP once applied. The comfort of the mask did worsen over the 2 h; however, the scores were minimally worse on PEP application but improved once-off PEP. No adverse event was recorded at all.Overall the OxEra Coronavirus Disease 2019 (COVID 19) is a highly contagious disease caused by a new β coronavirus called Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV 2). This new coronavirus is closely related to the 2003 Severe Acute Respiratory Syndrome (SARS) and the 2012 Middle East Respiratory Syndrome (MERS) Coronavirus, of which caused severe respiratory distress, cytokine storm, and severe lung injury TM (OxEraTM) device, which is a simple CPAP device that only requires an oxygen flow rate of 15 L/min. The collaboration included engineers, doctors, designers, 3D printing specialists, and programme managers. The OxEraTM device has received approval by SAPHRA for emergency use in COVID-19 hypoxemic patients. While a multidisciplinary team at the CSIR has evaluated the device relating to the calibration and reliability of the device, there has been no clinical human evaluation.Non-invasive ventilation has had a successful role in the management of patients with acute hypoxemic respiratory failure TM device has a built-in safety valve to avoid rebreathing. In the case of rebreathing, a significant rise in ETCO2 will occur Most CPAP systems run the risk of inducing rebreathing in case of failure Another important challenge related to positive pressure ventilation delivered through a non-invasive device relates to patient comfort and acceptance TM device, we evaluated the device on a group of healthy volunteers and monitored ETCO2, oxygen saturation, physiological variables related to pain, and we performed an objective pain assessment using three different pain and comfort tools.Given the obvious potential for the widespread utilisation of this oxygen device in a resource-limited setting we performed a clinical assessment study. To evaluate the safety and patient acceptance of the OxEraTM device using a healthy volunteer population. The primary objective was to monitor for an increase in ETCO2 (less than 6.3 mmHg change from baseline ETCO2 and no ETCO2 above the 45 mmHg threshold). The secondary objective was to monitor changes in vital signs  and changes in blood pressure, mean arterial pressure, respiratory rate, and HR). The tertiary objective was pain and comfort score assessment .The aim was to assess the safety and user acceptance of the OxEraTM Device at the Intensive Care Unit training centre of the Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa. This is a large academic facility affiliated with the University of the Witwatersrand. The protocol was approved by the University of Witwatersrand's Human Research Ethics Committee (HREC No: M210222). National Research Database Reference Number GP 202107013. Written informed consent was obtained from each participant , pain assessment score (PAS), and the comfort score were also taken at each time point. See Appendix I and II for VAS and PAS scores.Study population, procedure, and data collection: Thirty healthy adult participants were included in the study. Exclusion criteria included smoking, pregnancy, body mass index (BMI) greater than 30, respiratory and cardiac comorbidities, beards, facial abnormalities, and previous thoracic surgery. An initial safety brief, demonstration, and face mask test to ensure an appropriate seal was followed by the application of the CPAP facemask, an oxygen flow rate of 15 l/min but no positive end-expiratory pressure (PEP = 0). Baseline data (T0) were collected. Data was then collected at the following time points; T1 , T2 , T3 , T4 , T5 , T6 , T7 , T8  and T9 . The data were collected by a trained study Doctor and Nurse. Demographic data of each patient included: height (cm), weight (kg), age (years), race, and gender. The following clinical data were collected at each study time point: ETCOp-value < 0.05 was considered significant.Statistical Analysis: All continuous data were described using median and interquartile range (IQR) while categorical data were described using number (n) and percentage (%). Dependent data were compared using the Wilcoxon matched-pairs test (2 groups) or the Friedman ANOVA tests for more than 2 groups. A 2 will occur 2 mean threshold value of 45 mmHg and a standard deviation of 6.3 mmHg. Using a 5% precision, we required a sample size of 30 participants.Sample Size: The sample size was based on the calculation of a single mean estimate. In the case of rebreathing a significant rise in ETCO2 using a threshold of 45 mmHg or an increment of 6.3 mmHg for the study duration. Secondary and tertiary outcomes included changes in pulse oximetry saturation readings, blood pressure, respiratory rate (RR), HR, and pain and comfort scores for the duration of the study.Outcomes: The main outcome was to determine if there was a significant increase in ETCO2, with interquartile ranges of 21.9–25.9 kg/m2.Participant Description: The thirty participants had a median age of 30, with the youngest being 25 years of age and the oldest being 41 years of age. The median weight was 71.5 kg with an interquartile range from 61 to 80 kg. The median height measured was 170 cm with an interquartile range of 167–176 cm. Therefore, the median Body Mass Index (BMI) was 24.7 kg/m2 from baseline until T9 at 2 h (p = 0.13). No participant experienced an increase in measured ETCO2 up to a value greater than 45 mmHg. No participant experienced an increase in measured ETCO2 greater than 6.3 mmHg. The median increase in ETCO2 (∆ ETCO2) over the study period was 2 mmHg . See Main Outcome: There was no significant difference in ETCO2%): Sixteen (16 out of 30) participants had a SpO2% reading of 100% at baseline, while 14 participants had a value of between 94 and 99% at baseline. Thirteen (13/14) had an increase in SpO2% by 5 min on the OxEraTM and one (1/14) had an increase by 20 min.Pulse Oximetry (SpOp = 0.32. See Respiratory Rate (RR. Friedman ANOVA): There were no significant changes in respiratory rate from baseline to 2 h (T9), p = 0.000. See HR: The median HR decreased significantly from 73 (IQR 65–87) at T0, to 68.5 (IQR 63–75) at T9, p = 0.21. See Mean Arterial Pressure (MAP): There were significant changes in the MAP from baseline to 2 h (T9), p = 0.14. See Systolic Blood Pressure (SBP): There were no significant changes in SBP from baseline to 2 h (T9), p = 0.33. See Diastolic Blood Pressure (DBP): There were no significant changes in DBP from baseline to 2 h (T9), p = 0.000. The worst median VAS score was 2 at T3, T4, and T5. This decreased to a median VAS score of 1 by T9. See VAS Score: The VAS score had a significant increase from T0 to T9, p = 0.09. See PAS Score: There was no significant increase in PAS scores from T0 to T9, p = 0.000. The worst median comfort score was 2 at T4 and T5 . This decreased to a median comfort score of 1 by T7. See Comfort Score: There was a significant increase in comfort scores from T0 to T9, TM device concerning the risk of rebreathing. This safety aspect is key amongst many characteristics on which a CPAP system is selected. In our limited resource setting, safety, portability, comfort, ease of use, and the ability to reduce oxygen requirements are key 2 that may be caused by rebreathing Safety: The main aim of this study was to assess the safety of the OxEra2 from baseline until the end of the study. No participant experienced an increase in ETCO2 above the upper reference limit. In addition, no participant experienced an increase in ETCO2 greater than the imprecision of the measurement device (capnography devices). This finding confirms the safety of the OxEraTM device concerning rebreathing.The main finding of our study showed no significant difference in ETCOTM device: Discontinuation of PEP will occur in a significant proportion of patients due to pain and discomfort. A recent study during the SARS CoV-2 pandemic demonstrated that 12% of patients on CPAP discontinued due to pain and discomfort Tolerance of OxEraA multi-variable approach to pain and discomfort may be superior to any one method of detection 2O TM device.Respiratory physiological changes of PEP are usually monitored in studies with invasive methods. These studies observed that the work of breathing is shown to be reduced in unhealthy patients with increases in PEP from as little as 5 cmH20. The combination of the lack of physiological changes of pain and the lack of significant indicators of pain using objective scoring systems suggest that the OxEraTM device was well tolerated on a positive pressure as high as 20cmH20, and discontinuation due the pain or discomfort is unlikely.Pain/discomfort: Pain and discomfort are notoriously difficult to assess in severe or critically ill patients TM device in our subjects; however, this has been previously done for SAHPRA approval. Lastly, we could have improved on the average age of participants. An older population would have distributed the sample size to a greater general population.Limitations: Although we used an imprecision documented in the literature, we did not measure this in the capnograph instrument used for the study. Secondly, we did not measure the positive pressure generated by the OxEraTM device is an innovative oxygen delivery device that has many benefits, especially in this era of COVID 19. Currently, it has SAPHRA approval to be used in the COVID 19 pandemic for emergency use.The OxEraTM device demonstrated safety in terms of risk of rebreathing and was well tolerated up to a positive pressure of 20 cmH20 in this clinical evaluation amongst healthy participants.The OxEraTM may have use in various fields of medicine involving respiratory diseases, specifically in resource and oxygen-limited settings.With approval for the safety of this device, the OxEraThe results of this study were presented as a Master of Medicine Report. The report will be displayed on a poster in the Witwatersrand University's School of Medicine, Bienniel Research Day on the 30th of September 2021.Authors contributed as follow to the conception or design of the work; the acquisition, analysis, or interpretation of data for the work; and drafting the work or revising it critically for important intellectual content: MTJ contributed 70% and SVB, SO and JB contributed 10% each. All authors approved the version to be published and agreed to be accountable for all aspects of the work.The authors declared no conflicts of interest.