Mean blood pressure was significantly higher at visit 1 than visits 2 and 4 (P < 0.01), but higher at visit 3 than visit 2 (n = 0.02). Mean blood pressure was higher in males (n = 0.01), and males were more likely to be categorized as borderline hypertensive/hypertensive or severely hypertensive (n = 0.01). Number of vocalizations was significantly associated with waiting room by FFP interactions (P < 0.01), with fewer vocalizations associated with bypassing the waiting room and when FFP was provided. In conclusion, although we found some behavioral evidence supporting stress reduction when feline patients bypass the waiting room and are provided with FFP, these interventions did not result in lower blood pressure in a clinical setting.Obtaining accurate blood pressure measurements in cats is challenging due to the stressful nature of clinic visits. The objective of this study was to evaluate the effects of veterinary clinic waiting experiences and a feline pheromone spray on blood pressure in the cat. We hypothesized that reduced stress associated with bypassing the waiting room and use of synthetic feline facial pheromone (FFP) spray would result in lower blood pressure. A 2 × 2 factorial design involved two rooms and two FFP treatments. Thirty-nine healthy adult cats were recruited and were systematically assigned to four treatment combinations administered over four visits in 2016 and 2017. Cats were kept in the hospital waiting room or were taken directly to the exam room, with or without FFP treatment. All cats were then acclimated to the exam room for an additional 10 min, where vocalizations were recorded manually, before blood pressure measurements were collected using Doppler ultrasonography. Data were analyzed using generalized linear mixed models, with room × FFP interaction, visit, sex, and trial year in the model. There was no significant effect of waiting room by FFP interaction on blood pressure ( Systemic hypertension (high blood pressure) is a common complication of diseases seen frequently in aging cats, particularly chronic kidney disease and hyperthyroidism –5. The aAccurate diagnosis and monitoring of hypertension presents particular challenges to feline practitioners, because cats often experience fear and anxiety during veterinary visits –11. FeliAmerican Association of Feline Practitioners (AAFP) and International Society of Feline Medicine (ISFM) have developed guidelines for reducing fear and anxiety associated with veterinary visits . While tThe primary objective of this study was to examine the effects of two “feline friendly” recommendations, minimized waiting room experience, and FFP, on blood pressure measurements. We hypothesized that bypassing the waiting room and the use of FFP would be associated with lower blood pressure values. We also hypothesized that cats would acclimate to the experience over time, resulting in lower blood pressure values over subsequent clinic visits.This research was reviewed and approved by the Institutional Animal Care and Use Committee at Iowa State University (Protocol ID#: 4-16-8249-F).A 2 × 2 factorial design was used to compare effects of patient waiting location and exposure to a spray containing a synthetic analog of the F3 fraction of FFP  on blood pressure in cats. To control for potential effects of individual cats, including their temperament, all cats received all treatments. Additionally, treatment order for each cat was randomized. Randomization procedures were completed using a random number generator. To avoid subjective bias, personnel collecting blood pressure data were blind to treatment allocations for all cats; for practical reasons, cat owners, and personnel collecting vocalization data could not be blinded to treatment. All cats received treatments singly, and hence cat was the experimental unit.This study was conducted at the Lloyd Veterinary Medical Center, Iowa State University (ISU) College of Veterinary Medicine (CVM) during normal business hours from 1,300 to 1,700 h, 2016 and 2017.Treatments were administered in the following combinations, with cats arriving in and remaining in carriers provided by their owners. Waiting room (WR+) treatment consisted of a 10-min dwell time in the designated hospital waiting room, after which the client and patient were escorted to the examination room. The carrier was placed on a chair with the carrier door facing outwards to the waiting area. Bypassed waiting room (WR–) treatment consisted of a 10-min dwell time in the examination room. In the examination room, the carrier was placed on a chair with the door facing outwards toward interior of the room. A large beach towel, provided by the researchers and sprayed with FFP, was placed over the carrier during the dwell time (FFP+). Control (FFP–) treatment consisted of an identical beach towel without FFP spray in 2016, and no beach towel or FFP spray in 2017. No instructions were provided to owners regarding provision of FFP, bedding, or towels inside the carriers. During the 10-min dwell period, the owner filled out a brief patient medical history. If an owner arrived much earlier than scheduled, a neutral holding place  was provided for them until the cat could be enrolled in its assigned treatment. Following the 10-min dwell period, the carrier was placed on the examination table, and an additional 10 min (the “acclimatization period”) was provided to allow the cat to acclimate before the exam. This was done because a 5–10 min acclimatization period to the measurement room is recommended prior to blood pressure evaluation  in 2016 and in 46 out of 68 visits (68%) in 2017. The tail base or rear leg was measured to determine cuff size (40% of appendage circumference) . The taiLow Stress Handling for Dogs and Cats® , and training was provided by a veterinarian (JC), Certified Silver level in this program (2015) and certified in the Cat-Friendly Practice® AAFP program (2015).After the blood pressure measurements were recorded, a brief physical exam was performed, including heart rate, respiratory rate, body condition score, and body weight. Heart rate was determined by auscultation with a stethoscope with the number of beats counted in 15 s and multiplied by four. Respiratory rate was determined by observing thoracic excursions and counting the number of complete breaths (inspiration and expiration) in 15 s and multiplying by four. Body condition score was determined using a nine-point scale . Blood pCats were recruited from faculty, staff, and students of ISU in summer 2016 and 2017, with the following inclusion criteria based on owner self-reporting: at least 1 year of age, no chronic illnesses, not on medications with potential to affect blood pressure, and no history of aggressive behavior during routine veterinary visits. All owners provided written, informed consent at the first appointment.A priori sample size calculations determined that 31 cats would provide 80% statistical power to detect a 15 mmHg difference in blood pressure. Published feline blood pressure data  were analyzed using SAS® software with generalized linear mixed models (GLIMMIX) to compare differences in outcomes based on WR and FFP treatments. A Gaussian distribution was used for blood pressure, heart rate, and respiration rate. A binary distribution was used to analyze occurrence of vocalization (Yes/No), and a Poisson distribution was used for frequencies of vocalizations. Time to collect blood pressure was analyzed separately for each year as the methodology for collecting these data differed between the 2 years.The statistical models included the fixed effects of WR and FFP interactions, visit, year, and sex, with the exception of time to collect blood pressure, which included the fixed effects WR and FFP interactions, visit, and sex. Cat age and weight were included as covariates, but were later removed from the models due to lack of significance. Cat ID was included in the model as subject in the random statement.P ≤ 0.05 was considered significant.The I-Link option was used to transform LSMeans and standard errors back to original units for respective measurements and subsequent reporting. Forty-eight cats were enrolled in the study . Nine cats were ultimately excluded from the study . One cat was removed from the study at the owner's request after the first visit when hypertension was discovered and anti-hypertensive therapy was implemented. Another cat was removed due to extreme resistance to handling. The remaining cats were removed because they did not complete all four visits. Hence, 39 cats remained in the dataset for the final analyses .n = 3 visits in 2016) were kept in a neutral holding area. Minimal restraint included toweling during 18 visits in 2016 (21% of visits), whereas toweling was used only three times in 2017 (4% of visits). Scruffing was used for one cat during one visit in 2016 (1% of visits), and on 14 visits (21% of visits) in 2017. Full body restraint was not used on any cats. For one cat, blood pressure data could not be collected on visit 1 due to equipment malfunction, but all other parameters were measured.Cats that arrived at the clinic prior to their assigned appointment (n = 0.95). Similarly, blood pressure did not differ by year . Blood pressure differed by visit (P < 0.01), but not in a consistent manner. Higher blood pressure was associated with visit 1 relative to visit 2 (P < 0.01) and visit 4 (n = 0.01), whereas higher blood pressure was associated with visit 3 relative to visit 2 (n = 0.02). Males displayed higher blood pressure than females .Blood pressure data were statistically analyzed using all six readings, as well as using only readings 2–6 as per clinical recommendations; since no statistical differences were identified for these approaches, results from readings 2–6 are reported. Differences in blood pressure were not associated with WR by FFP interactions (P > 0.09). Blood pressure categories differed between males and females, with males having a greater probability of being placed in a higher blood pressure category than females .Out of a total of 155 visits during which blood pressure was successfully measured, cats were categorized as NT during 97 visits, BHT/HT during 39 visits and SHT during 19 visits. Of those cats receiving a classification of BHT/HT during the study, 14 cats received this classification once, nine cats on two visits, one cat on three visits, and one cat on four visits. Of the cats receiving a classification of SHT during the study, six cats received this classification on one visit, five cats on two visits, and one cat on three visits. There were no observed effects of WR by FFP interactions, visit or year on blood pressure categories (P < 0.01) and there was a trend for males to take longer than females . In 2017, no differences were observed for visit or sex .The time (in minutes) needed to obtain the blood pressure measurements was not associated with WR by FFP interaction . In 2016, visit 1 (8.4 ± 0.7) was significantly longer than subsequent visits . Similarly, respiratory rate was not associated with WR by FFP interaction or visit . Respiration rate differed by sex, with males having a lower respiration rate (55.3 ± 3.33) than females . Respiration also differed by year, with 2016 having higher respiration rates (72.3 ± 2.98) than 2017 .Heart rate was not associated with WR by FFP interaction, visit, year, or sex  or visit (n = 0.72). However, probability of vocalizing was higher in 2016 (0.73 ± 0.09) than 2017 . Conversely, number of vocalizations (P < 0.01), with fewer vocalizations associated with WR– and FFP+ treatments (P < 0.01). Number of vocalizations was associated with visit (n = 0.02); fewer vocalizations were observed on visits 1 and 2 than visit 3 . Number of vocalizations was not associated with sex (n = 0.20), but more vocalizations were observed in 2017 (3.09 ± 1.7) than in 2016 .Probability of vocalizing  was not izations  was signBlood pressure measurement in the cat is a process that is fraught with difficulty. In the stress of a clinical setting, blood pressure can increase above what may be considered normal in a home environment , 12, makBlood pressure measurements obtained in this study were similar to or slightly higher than those reported using Doppler in healthy cats , 24, 25.For the purposes of our study, we classified blood pressure according to the following categories: <150: NT; 150–179: borderline hypertensive/hypertensive (BHT/HT); ≥180: SHT. This is roughly based on ISFM guidelines and historic American College of Veterinary Internal Medicine (ACVIM) hypertension guidelines, although the updated ACVIM guidelines now classify 140–159 mmHg as pre-hypertensive , 7, 29. We anticipated that bypassing the waiting room and the use of FFP would reduce stress in feline patients, translating to lower and more reliable blood pressure measurements. There was some evidence to support this assumption of reduced stress, in terms of vocalizations. Struggling and vocalization in cats have been associated with sympathoadrenal stimulation, and hence expected to result in an increase in blood pressure .Vocalizations occurred in one-third to two-thirds of all visits, and the number of vocalizations performed were roughly three times greater when cats did not bypass the WR and were not provided with FFP. Since our experimental design and statistical analysis controlled for confounding effects associated with individual cat responses to stress, these differences were likely driven by the treatment interventions. However, it is important to note that vocalizations were collected during the waiting period, and were not recorded during the physical exam or blood pressure measurement procedures. Treatment differences were not observed for physiological responses to stress, including blood pressure, during the examination itself. Hence, if indeed bypassing the waiting room and use of FFP reduced stress in the feline patients, the effects if present may be short lived and did not translate to improved blood pressure as we had hoped.Although not significant, occurrence of vocalization numerically showed similar but opposite associations with treatment combination; vocalizations were less likely to occur when cats did not bypass the WR and were not provided with FFP. It is possible that distress may have suppressed vocalization occurrence entirely, whereas vocalization frequency was exacerbated for individuals that displayed this behavior. Relationships between vocalizations and distress in cats are variable in the scientific literature. Some researchers reported vocalization score was a reliable indicator of stress when cats were restrained in a handling carrier, showing intra-cat response consistency over repeated exposure to this acute stressor . In contThe WR is identified as a source of stress in cats during visits to the veterinary clinic, which may alter physiologic parameters such as blood pressure, and has been associated with increased stress behaviors as perceived by cat owners, particularly in response to the presence of dogs and other animals . While nIt is possible that WR had no effect on blood pressure in this study because the experiences associated with the waiting and exam rooms may not have sufficiently differed. This study took place at a large veterinary referral hospital that has a partitioned WR intended to separate species. Efforts were made during our study to have cats wait in an environment that would be typical of a small waiting area in a veterinary clinic that includes other cats, dogs, and other species in close proximity. Because study cases were seen in the afternoon when hospital caseload was often lighter, it is possible that the WR environment was unnaturally quiet. This information was not recorded, and would have aided interpretation of our findings.It is also possible that WR did not affect blood pressure in the cats in this study because they were allowed an acclimation period once they entered the exam room. In a previous study evaluating 24-h ambulatory blood pressure in cats, transitions into the waiting room and into the exam room were both associated with a transient increase in blood pressure . NoveltyStudies evaluating whether FFP can help reduce behavioral indictors of stress in a veterinary setting have shown mixed results. Griffith et al. showed a decrease in anxiety-related behavior and increased food intake in a hospital setting in association with FFP . Some stOther factors associated with the visit, independent of WR and FFP may have contributed to the cats in our study being maximally stressed and unaffected by these interventions. Cats have been shown to experience stress during all stages of the veterinary visit, including transportation to the clinic and the time leading up to departure from the home environment , 12. WhiThere was a significant difference in vocalizations by year with fewer vocalizations across visits and treatments in 2016 than in 2017. This is particularly noteworthy since time to collect blood pressure measurements was more than twice as long in 2016. Conversely, the likelihood that cats would vocalize at least once during the visit was higher in 2016. Several factors that may have contributed to these discrepancies, including the possibility that the cohort of cats in 2017 were inherently more vocal. In response to novel stimuli in test situations, feral cats display a higher vocalization rate than socialized house cats, in conjunction with extreme aggressive and defensive behaviors consistent with fear and distress affective states . These vMean blood pressure did differ across visits, with mean blood pressure in visit 1 significantly higher than mean blood pressure in visits 2 and 4, but not visit 3. While a higher blood pressure in visit 1 could suggest acclimation to multiple veterinary visits over a short period of time, the fact that there was not a progressive decline in mean blood pressure and that blood pressure in visit 3 did not differ from visit 1 suggests that cats did not acclimate. These results are consistent with a previous study, in which cats did not have a lower blood pressure with multiple simulated veterinary visits . AdditioIn conclusion, results of this study suggest that the use of FFP and bypassing the WR do not result in lower blood pressure measurements in cats. Although we found a large number of clinically healthy cats presenting with blood pressure measurements high enough to warrant treatment, these values were infrequently repeatable across multiple visits, suggesting blood pressure measurement should be interpreted with caution in the absence of risk factors for hypertension. While blood pressure was not affected, we cannot decisively comment on the stress experienced by cats in this study, and the degree to which these interventions mitigated stress. More detailed analysis of stress, including behavioral responses, physiologic responses, and cognitive effects could be evaluated in future studies to inform best practices for mitigating fear and distress in the clinical environment.The original contributions presented in the study are included in the article/The animal study was reviewed and approved by Institutional Animal Care and Use Committee at Iowa State University. Written informed consent was obtained from the owners for the participation of their animals in this study.The idea for the study and the experimental design were developed by JC, SM, and LV. Data was collected by MR, JC, RP, and LV. Data was analyzed by SM and RP. All authors contributed to writing and final approval of the manuscript.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.


This study aims to explore risk factors for direct coercive measures  in a high risk subpopulation of offender patients with schizophrenia spectrum disorders.Five hundred sixty nine potential predictor variables were explored in terms of their predictive power for coercion/no coercion in a set of 131 (36.6%) offender patients who experienced coercion and 227 who did not, using machine learning analysis. The dataset was split (70/30%) applying variable filtering, machine learning model building, and selection embedded in nested resampling approach in one subset. The best model was then selected, and the most important variables extracted on the second data subset.In the final model the following variables identified coercion with a balanced accuracy of 73.28% and a predictive power  of 0.8468: threat of violence,  violence toward others, the application of direct coercive measures during past psychiatric inpatient treatments, the positive and negative syndrome scales (PANSS) poor impulse control, uncooperativeness, and hostility and the total PANSS-score at admission, prescription of haloperidol during inpatient treatment, the daily cumulative olanzapine equivalent antipsychotic dosage at discharge, and the legal prognosis estimated by a team of licensed forensic psychiatrists.Results confirm prior findings, add detail on factors indicative for the use of direct coercion, and provide clarification on inconsistencies. Limitations, clinical relevance, and avenues for future research are discussed. For a uniform definition of direct  coercive measures in psychiatry it has been proposed to encompass restraint, seclusion, and involuntary medication –3: restrTwo recent studies used machine learning to explore factors predicting the use of any direct coercive measures  or mechaThe purpose of the current study is to employ machine learning for the analysis of 569 potential predictors of direct coercive measures in 370 Swiss forensic offender patients with a schizophrenia spectrum disorder during their involuntary inpatient treatment. By selecting a sample in which the presence of those factors most frequently and consistently identified to predict coercive measures  are present in all cases, we aim to identify more subtle and detailed predictors of coercion.In our retrospective study design, directed qualitative content analysis  was usedAnalysis of all cases included in this study was approved by the Zurich Cantonal Ethics Committee.a priori  and numerous other variables are tested for their ability to predict this outcome. Thus, ML means a computer algorithm  is developed which uses all variables available  in order to try predict the outcome variable for any given patient.Supervised machine learning (ML) is suitable for explorative analyses such as in the current study. In ML, a so-called outcome variable is defined In contrast to conventional (hypothesis testing) statistical methods, ML is able to uncover hidden interrelationships in data sets, can explore a larger set of variables at once, and can use various (linear and non-linear) algorithms, which can be evaluated quantitatively by transcending p-value thresholds. One of the most significant risks in ML is overfitting. This means that the mathematical algorithms depend heavily on the data structure and are sensitive to “noise” within the data, which leads to overestimation in the prediction. Especially if the study population is small and many variables are explored, there is a substantial risk for overfitting. Techniques designed to minimize the risk for overfitting include splitting the data to obtain a separate set of data for testing ML-results, cross-validation of ML results, regularization, or a reduction of the (predictor) variables explored.Despite such safeguards against overfitting, ML results from one data set should be treated with caution and need further confirmation by new data and perhaps more conservative statistical approaches before they can be considered to be generalizable –58.All raw data was first processed for machine learning  experienced one or more direct coercive measure, which corresponds with rates of coercion reported in extant literature, ranging from 21 to 59% of patients . The occMost patients were subjected to a combination of two or more measures of direct coercion. Just 31 (8.66%) patients were subjected only to seclusion and 12 (3.35%) only to involuntary medication. Physical restraint is not used in Switzerland and mechanical restraint was always used in combination with seclusion and/or involuntary medication.Next, the initial dataset was randomly divided into two subsets (see All of the following Steps under above heading where performed with the training data set (251 patients) only, while the data set for validation (107 patients) remained untouched:One main objective of the present study was to identify the most important predictor variables from the multitude of 569 possible variables. In addition, a reduction of variables was intended to counteract overfitting and keep computing times in initial model building at an acceptable level. Therefore, chi square testing was applied to the initial 569 predictor variables to filter for their 10 most predictive variables for further model building  this also led to a disbalance in the calculated sensitivity/specificity of the models, so the smaller subset (coercion experienced) was oversampled by a rate of 2.Since the distribution of the outcome coercion/no coercion was not balanced  was imputed with the stored weights from Step 3b by mean and mode. Then, the best previously identified model was applied to the data and again the performance measures of this final model were assessed  can be seen in The 10 most indicative variables  identified through chi square testing and subsequently used for model building can be withdrawn from The final naïve Bayes model using these variables applied to the validation subset  yielded a balanced accuracy of 73.28% and an AUC of 0.8468  were least important for the final model.Testing for multicollinearity showed no dependencies between the variables  also exploring direct coercive measures with machine learning  in a set of 358 offender patients with a schizophrenia spectrum disorder during forensic psychiatric inpatient treatment. The best identifiers out of a set of 569 potential variables were : threat of violence and actual violence toward others during inpatient treatment, direct coercive measures in the past, poor impulse control and uncooperativeness at admission, the prescription of haloperidol during inpatient treatment, the total PANSS-score at admission, the daily cumulative olanzapine equivalent antipsychotic dosage at discharge, hostility at admission, and the legal prognosis as estimated by a team of forensic psychiatrists upon discharge based on all available information in a patient's file. Based on these variables the model was able to predict the occurrence of coercion or absence of coercion in over 70% of cases, which, however, also means it was unable to do so in almost 30% of cases as an important limitation requiring further research in order to avoid severe consequences in clinical practice. Furthermore, due to the retrospective nature of the present study, future research should focus on those parameters indicating a high risk of coercion before its occurrence, as only these parameters may become of clinical value in preventing coercion. As detailed in ning see , 30, whining see , architening see  related Adding credibility to findings of the present study, the most frequently identified parameters correlating with coercion in prior research were confirmed, including (threat of) violence , 36–40 aSomewhat resolving inconsistent results of prior studies, gender was not identified in the current study, which may however also be due to the small number of female patients in the sample studied here or in prior research. In this context it is interesting to note, that research exploring predictors for mechanical restraint in 5050 patients  in Denmark also could not identify gender as a significant predictor . On the In addition, future research should address those limitations inherent to retrospective file analysis, including the use of a PANSS-adopted scale for content analysis of psychopathological data, which in some cases was recorded before the publication of that instrument. It should also take caution of selection effects due to data for this study stemming from only one forensic psychiatric institution in Switzerland (monocentric study) and a relevant subgroup of Swiss offender patients being unable to receive treatment in any forensic psychiatric facility due to their relative scarcity . Hence, The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.The study was reviewed and approved by the Cantonal Ethics committee of Zurich, Switzerland (Ref.-No. KEK-ZH-NR 2014-0480).via questionnaire was preformed independently by both JK and SL. All statistical analyses were carried out by JK. The first draft of the manuscript was done by MG and JK. SL and MG edited multiple drafts and supervised the statistical analyses.MG, JK, and SL designed the study and protocol. The survey of the data 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.


Background: This study aimed to explore the effects of sodium-glucose co-transporter 2 (SGLT2) on hemoglobin levels in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease.Methods: PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, the China National Knowledge Infrastructure database, Wanfang Digital Periodicals Database (WFDP) and the Chinese Biological and Medical database (CBM) were searched for randomized trials of SGLT2 inhibitors in patients with T2DM and chronic kidney disease up to July 25, 2020. A total of four studies that included 19,259 patients were identified.Results: Compared to control patients, SGLT2 inhibitors were shown to increase hemoglobin levels in patients with T2DM and chronic kidney disease .Conclusion: SGLT2 inhibitors may bring additional benefits to patients with T2DM and chronic kidney disease. In the past ten years, the incidence of type 2 diabetes mellitus (T2DM) has been increasing  which inSodium-glucose co-transporter 2 (SGLT2) inhibitors are a newly approved class of oral hypoglycemic agents that increase the excretion of glucose in the urine by inhibiting the reabsorption of urine glucose in the proximal tubules of the kidney, thereby reducing blood glucose levels, weight and blood pressure . In addiIn this study, we aimed to ascertain the effects of SGLT2 inhibitors on the hemoglobin levels in patients with T2DM and chronic kidney disease.The PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, the China National Knowledge Infrastructure (CNKI) database, Wanfang Digital Periodicals database (WFDP), the Chinese Biological and Medical database (CBM) were searched. The following Medical Subject Headings (MeSH) terms and free-text terms were applied: “Sodium-Glucose Transporter 2 Inhibitors”, “Sodium Glucose Transporter 2 Inhibitors”, “SGLT2 Inhibitors”, “SGLT-2 Inhibitors”, “SGLT 2 Inhibitors”, “Gliflozins”, “Renal Insufficiency, Chronic”, “Chronic Renal Insufficiencies”, “Renal Insufficiencies, Chronic”, “Chronic Renal Insufficiency”, “Kidney Insufficiency, Chronic”, “Chronic Kidney Insufficiency”, “Chronic Kidney Insufficiencies”, “Kidney Insufficiencies, Chronic”, “Chronic Kidney Diseases”, “Chronic Kidney Disease”, “Disease, Chronic Kidney”, “Diseases, Chronic Kidney”, “Kidney Disease, Chronic”, “Kidney Diseases, Chronic”, “Chronic Renal Diseases”, “Chronic Renal Disease”, “Disease, Chronic Renal”, “Diseases, Chronic Renal”, “Renal Disease, Chronic”, “Renal Diseases, Chronic”. All publications up to July 25, 2020 were selected without the restriction of origins, countries, languages or article types.Published articles that were included in the analysis were required to meet the following criteria: 1) the eligible subjects were men and women with T2DM and chronic kidney disease; 2) interventions involved treatment with SGLT2 inhibitors alone or with other hypoglycemic agents; 3) studies compared placebo control or standard of care; 4) outcomes reported changes in hemoglobin levels from baseline; 5) studies that were randomized controlled trials (RCTs); 6) studies with follow-up times of 12 weeks or longer. Observational studies, non-randomized trials and uncontrolled trials were excluded from the analysis.Two investigators extracted the following data independently from eligible publications: first author, publication year, study design, inclusion criteria, sample size, patient characteristics, interventions (types and doses of SGLT2 inhibitors), comparison (placebo control or standard care), follow-up duration and outcomes (changes in hemoglobin levels from baseline). The unit of hemoglobin levels was uniformly converted into g/l. Discrepancies were resolved by the discussion between two investigators. The Cochrane risk-of-bias tool was adopted to assess randomization, masking of treatment allocation, blinding, adherence and withdrawals for each of the RCTs .p values (<0.05) were considered to represent statistically significant publication bias.Data analysis was performed using Stata version 12.0 software. The effect sizes on scores were presented as the standard mean difference (SMD) and 95% confidence intervals (CIs). The Chi-squared test based on Q-statistic and I2 statistics was used to estimate the heterogeneity  . A fixedA total of 579 references were retrieved and finally, four studies  met the With the exception of one open-label study, the other three studies on random sequence generation were fully considered. The studies were all double-blind trials but there was no further explanation on the details of allocation concealment. There were no incomplete outcomes and selective reporting in the four studies. Based on the characteristics, we believe that the included studies had a low risk of bias.p < 0.0001) and so the random-effects model was used. The pooled effect size showed significant differences in hemoglobin levels  in favor of the experimental groups compared to the control groups (Four studies (Four publications) investigated a total of 19,259 participants  and reported hemoglobin levels. There was high heterogeneity ; thus, the fixed-effects model was used. The pooled effect size showed a significant difference in Hematocrit  in favor of experimental group, compared with the control group  reported Hematocrit. There was no heterogeneity . Subgroups were divided as to eGFR based on 30 ≤ eGFR <60 ml/min/1.73 mA sensitivity analysis was conducted by sequentially removing one study to observe the influence of each of the included studies on the overall pooled SMD. No single study was found to significantly influence the overall pooled SMD indicating that the results were stable.p = 0.161 (>0.05)) and Egger’s linear regression test ).In assessing publication bias, a funnel plot for the four studies analyzed was constructed. The shape of the funnel plot was symmetrical indicating the absence of publication bias. No significant bias was observed using the Begg’s rank correlation test , the differences were statistically significant.This article conducted a meta-analysis of four randomized controlled studies to explore the effects of SGLT2 inhibitors on hemoglobin levels in diabetic patients with chronic kidney disease. The results showed that the hemoglobin levels of patients after treatment with SGLT2 inhibitors increased from baseline and the differences were statistically significant. The hematocrit levels of patients after treatment with SGLT2 inhibitors increased from baseline and the differences were statistically significant. Whether it was different type and dosage of the drug , or different eGFR (30 ≤ eGFR <60 ml/min/1.73 mMost of the observations from previous reports in the literature and meta-analysis demonstrate the effects of SGLT2 on blood sugar levels, cardiovascular events and renal outcomes. There are very few studies that have analyzed the effects of SGLT2 inhibitors on hemoglobin levels or have performed meta-analyses of these effects across multiple RCTs.SGLT2 inhibitors protect patients with T2DM and chronic kidney disease through several different mechanisms. First, in diabetic patients, upregulation of SGLT2 increases the reabsorption of sodium and glucose by the proximal tubules, SGLT2 inhibitors lower blood sugar by blocking the glucose reabsorption of SGLT2 in the proximal renal tubules. Second, SGLT2 inhibitors also have a certain effect on renal hemodynamics. SGLT2 inhibitors block the reabsorption of glucose and sodium in the proximal tubules and increase the transport of sodium to the macula densa, thereby restoring impaired tubuloglomerular feedback. Thus, SGLT2 inhibitors can alleviate glomerular filtration in the early stage of diabetic nephropathy, reduce albuminuria, and delay the decline of renal function for a long time . BesidesThe mechanisms by which SGLT2 inhibitors improve hemoglobin levels in patients with diabetes and chronic kidney disease are not fully understood. It has been reported that SGLT2 inhibitors have diuretic-like effects and reduce plasma volume . It has 2. This meant that a small number of patients with normal renal function may have been included. In addition, the population included in the study did not have obvious renal anemia before SGLT2 inhibitors treatment. Therefore, for patients with significant renal anemia, the benefits of SGLT2 inhibitors need to be further investigated.Several limitations of this study should be noted. Firstly, a total of four articles were included in the analysis which is a small sample size, however, the total number of patients included was nor large. Secondly, the majority of the subjects were Caucasian and so the applicability of the data to other races including Asians requires further investigation. Thirdly, although we concluded that hemoglobin levels increased after treatment with SGLT2 inhibitors, we did not observe differences in the effects of different types of SGLT2 inhibitors on hemoglobin levels, the relationship between the increase in hemoglobin level and the duration of medication. Fourthly, among the populations included in the study, some had eGFR ≥ 60 ml/min/1.73 mIn summary, patients with T2DM and chronic kidney disease have increased hemoglobin and hematocrit levels after treatment with SGLT2 inhibitors. SGLT2 inhibitors may bring additional benefits to patients with T2DM and chronic kidney disease.


Background and Objective: The routine practice of self-medication of blood pressure (BP) not oriented with pulse devices may not be precisely useful in the control of BP and can lead the patient to self-medicate in error. Thus, we need to evaluate the non-oriented self-assessment of BP in real-life circumstances in hypertensive patients. The objective of this study was to evaluate in hypertensive patients the association of BP self-measurement with its control, as well as the presence of anxiety disorders, the occurrence of unscheduled visits to the emergency room, and self-medication. Materials and Methods: An observational study was carried out with 1000 hypertensive volunteers (age: 61.0 ± 12.5). Using a questionnaire, sociodemographic and clinical data on BP control were collected. Anxiety was assessed by the State-Trait Anxiety Inventory (STAI). Results: The group that performed non-oriented self-measurement of BP, showed that they had higher frequencies of self-medication  and more unscheduled visits to the emergency room . In addition, a lower level of BP control  was associated with higher levels of anxiety  in the group that performed non-oriented self-measurements of BP. Conclusion: The practice of non-oriented self-assessment of BP was associated with negative factors such as high levels of anxiety and higher frequencies of self-medication and unscheduled emergency visits. Systemic arterial hypertension is considered a public health problem because it is associated with a high risk of mortality . FactorsOne of the strategies used by hypertensive patients to achieve these goals is self-measurement of BP at home with the aid of digital devices. Some studies have shown that BP self-measurement allows for a better and/or similar BP prognosis and control than measurements performed in a health care setting ,6,7,8. IStudies indicate that this self-measurement procedure, when controlled and instructed by the clinician, has positive effects on the diagnosis and adherence to the patient’s treatment ,12,13, oTherefore, the present study aimed to evaluate in hypertensive patients the association of BP self-measurement with its control, as well as the presence of anxiety disorders, the occurrence of unscheduled visits to the emergency room, and self-medication.The present study was characterized as cross-sectional and observational with an analytical character, carried out between June 2017 and October 2019 in the city of Aracaju-Sergipe, Brazil. The sample was carried out in a non-random manner with the evaluation of 1000 consecutively selected patients to minimize sampling bias. As an inclusion criterion, patients from 18 years of age, both sexes and diagnosed with systemic arterial hypertension were defined. Those with mental disorders that could compromise the answers to the questionnaires were excluded. Initially, 1507 subjects were invited to participate in the research and 1000 responded that they would accept it. It was found that there were no duplicate or incomplete responses, and 1000 responses were readable for the final analysis . The claData collection was performed through the application of a specific questionnaire for research, which included data related to the patient’s sociodemographic and clinical aspects, quantification of unscheduled visits to the emergency services, self-medication and BP self-assessment. Self-medication related to antihypertensive treatment was considered as the use by the patient of an extra dose of an antihypertensive without a recommendation by a health care professional, the use of another non-prescribed antihypertensive, the non-use of an antihypertensive or not following the prescribed dose. The criterion for a self-measurement was the patient’s report of their frequency of use of the blood pressure (BP) measuring device per day and/or week. An unscheduled visit to the emergency room was based on the patient’s report of visits to the emergency room because of high BP in the last 12 months, as confirmed by their medical records. The control of BP was defined by means of ambulatory blood pressure monitoring (ABPM) or the average of the measurements in the last three consultations that were taken by three assistant physicians according to the College of Cardiology and the cardiology guidelines.The State-Trait Anxiety Inventory (STAI) was applied by a trained psychologist and information on clinical data and patient identification was collected by a nurse at the Federal University of Sergipe.The sample consisted of hypertensive patients aged 18 or over, of both sexes, followed up on an outpatient basis at three hospital institutions in the city of Aracaju-Sergipe, Brazil. One of these institutions exclusively serves users of the public health service and two serve the private sector. Those diagnosed with a mental disorder based on the answers to the questionnaires were excluded from the research. Patients who consented to participate in the present study signed an Informed Consent Form. This study was approved by the Research Ethics Committee involving human beings under the number CAAE: 60473316.9.0000.5546.Data collection was performed through the application of a specific questionnaire covering the following topics: (1) Patient identification and sociodemographic elements . The social class and education were inserted in the questionnaire according to the classification used by the Brazilian Institute of Geography and Statistics (IBGE). IBGE is a public institute of the Brazilian federal administration, which provides the geographic and statistical information of Brazil and classifies the social class by family income group, in which class A corresponds to above 20 minimum wages; B: 10 to 20 minimum wages; C: 4 to 10 minimum wages; D: 2 to 4 minimum wages; E: Up to 2 minimum wages. Education is classified as: elementary, high school, university, graduation program and never studied. (2) Clinical data: a cardiologist evaluation based on the average of the last three measurements performed in the last three consultations according to the College of Cardiology and the cardiology and/or ABPM guidelines for the classification of controlled and uncontrolled BP, in addition to the identification of the comorbidities of such patients. BP values were considered for the diagnosis of systemic arterial hypertension (SAH) according to the recommendations of the 2017 guideline, in which the American Society of Cardiology  classifit test for independent data in the case of quantitative variables. The Breslow–Day test was applied to assess whether the intensity of the relationship between anxiety (trait and state) and gender is dependent on the age groups. To analyze the factors associated with the outcome variables , the logistic regression technique was used using the “forward stepwise” and “backward stepwise” method, considering entry in the model p = 0.25 and remaining in the model p = 0.05. Then, simple and adjusted odds ratios were calculated. The Statistical Package for Social Sciences version 24.0 was used to perform the statistical calculations for testing. The estimates were made with the following parameters: power = 80%. The effect size  was defined as small (<0.20), medium (between 0.20 and 0.50), large (between 0.50 and 0.80) and very large  [The continuous variables were described as mean and standard deviation. As for the categorical variables, absolute frequencies and percentages, and 95% confidence intervals were used to summarize them when relevant. The Shapiro–Wilk test was used to assess the assumption of normality. To test hypotheses related to categorical variables, Pearson’s chi-square test or Fisher’s exact test were used when most appropriate. The comparison between groups  was performed using Student’s  . The twoThe patients had a mean age of 61.0 ± 12.5 with a minimum of 27 years and a maximum of 100 years. It was observed that 50% of the patients were followed up in the cardiology outpatient clinic of the Teaching Hospital of the Federal University of Sergipe and the other half in the supplementary network. The clinical characteristics shown in It was observed during the study period that there was a high frequency of self-measurement of BP (44.7%), uncontrolled hypertension (36.8%), self-medication (41.3%), unplanned visits to the emergency room (38.4%), and anxiety (51.6%), as shown in The data of patients with and without self-measurement of blood pressure in relation to sociodemographic characteristics by age groups can be seen in Data from patients with and without self-measurement of blood pressure in relation to clinical characteristics is shown in Data from patients with and without self-measurement of blood pressure in relation to clinical characteristics age groups was showed in The values of patients with controlled BP and uncontrolled BP in terms of sociodemographic characteristics, are shown in The values of patients with controlled BP and uncontrolled BP in terms of sociodemographic characteristics by age groups, as shown in The values of patients with controlled and uncontrolled BP in terms of clinical characteristics are seen in The values of patients with controlled and uncontrolled BP in terms of clinical characteristics by age group, are seen in In In multivariable logistic regression, the factors associated with non-BP control were: self-measurement, self-medication, unscheduled visits, state anxiety, a female prevalence, the presence of comorbidities, the use of medication for comorbidities and trait/state anxiety .The odds ratio of not BP and trait anxiety and state anxiety controlled for gender, use of medication for comorbidities, self-measurement of BP, self-medication and state anxiety or trait anxiety respectively were estimated . It was BP measurement is an important procedure that must be performed for any medical evaluation, regardless of specialty , and in The result of this research differs from some studies ,21,22,23Research has shown that women constitute the majority of the hypertensive population followed in primary health care ,24. ThusOne of the main causes of self-medication is the need to relieve symptoms  and psycIn some studies that analyzed the profile of individuals who seek health services in this country, it was observed that there is a predominance of users who seek urgent care with chronic diseases, such as arterial hypertension, with greater severity due to their lack of control of the condition ,35.It needs to be taken into account that hypertension is the main treatable cardiovascular risk factor ,37,38. HRegarding the limitations of this study, it should be noted that there was no randomization for the use or non-use of the blood pressure device because the devices used were obtained by the patients, which can lead to errors resulting from the use of the device, mistakes regarding knowledge about the device and other distortions.Another limitation of the study is that there was no standardization regarding the performance of ABPM, since not all patients underwent the exam which can interfere with some results. It is suggested for future work, randomized studies to assess the influence of self-measurement with self-medication, unscheduled visits to the hospital and anxiety disorders.Patients who self-assessed BP had the lowest blood pressure control, self-medicated more frequently, had a greater presence of state anxiety and had more emergency room visits because of their blood pressure. The factors associated with non-BP control were: self-medication, unscheduled visits to the hospital, state of anxiety, prevalence of females, the presence of comorbidities, especially diabetes mellitus and dyslipidemia, and the use of medications for comorbidities.Thus, the lack of knowledge about the disease and its implications, as well as the wrong guidance on the use of the pressure device are key factors in this chain of events and not BP control. Therefore, it is wise to discourage the use of digital pressure devices in patients to whom adequate guidance has not been given and the clinical picture has been observed, especially if such a patient suffers from an anxiety disorder. In addition, it is wise to invest in public policies aimed at capacitors, informing the population about the proper use of the blood pressure device and pointing out the importance of a multidisciplinary approach in the management of hypertensive patients with anxiety disorder.


Hypertension remains the leading risk factor for death and disability in China, and the ability of hypertensive patients to pay for outpatient care and medication has become a critical issue. To report the effect of an outpatient copayment scheme on health outcomes of hypertensive adults in a community-managed population in Xinjiang, we compared changes in outcomes between insured and uninsured groups from baseline to the first follow-up appointment in a community-managed hypertensive population and evaluated these changes based on propensity score matching and the difference-in-difference method. A total of 1,095 individuals in a community-managed hypertension population were selected for investigation at baseline, among which 805 (73.5%) had follow-up data and 749 (68.4%) were included in our analysis. After accounting for the self-reported severity of hypertension and individual characteristics, there were statistically significant improvements in drug treatment of hypertension and self-reported health. We also found increases in drug treatment for hypertension between groups, after correcting for confounding variables , and in self-reported health between groups after correcting confounders . Adjusted estimates (confounding variables) were corrected for age, sex, income, marital status, education level, employment, family size, self-reported severity of hypertension, course of hypertension, and number of medications. As a result, decreased outpatient copayment was associated with an increase in antihypertensive treatment coverage, and an improvement in self-reported health among community-managed hypertensive populations in Xinjiang, China. Hypertension remains the leading risk factor for death and disability in China , 2. The In 2014, the average copay of hypertensive patients in China from the outpatient and pharmacy departments was more than 60% , 13. TheFor Urban Employee Basic Medical Insurance (UEBMI) in China, the outpatient copayment scheme for eligible patients with chronic diseases, such as hypertension, replaced Medical Savings Accounts (MSAs) . MSAs weOften, health insurance may help hypertensive patients because long-term treatment is unaffordable , 23. TheThe 2016 outpatient copayment scheme ceiling rose from ¥2,000($301) to ¥3,000($452) in a region of Xinjiang, China, which decreased outpatient copayments . We hypoWe used a quasi-experimental design to measure the effects of the outpatient copayment scheme for eligible hypertensive patients (“the intervention”) in blood pressure, health-related quality of life (HRQOL), blood pressure control, drug treatment of hypertension, and self-reported health within a community-managed population. We compared outcomes from baseline at six months after the policy change (June—July 2016) with outcomes at 18 months after the policy change (June—July 2017) between insured and uninsured groups. We also considered the difference in changes from baseline to follow-up between the insured and uninsured groups to depict the intervention effect in Ordinary Least Squares regression models and logistics regression models.The study population was diagnosed with hypertension by clinical doctors. A follow-up survey was conducted by administering an original questionnaire to five communities at the Eighth Division of Xinjiang Production and Construction Corps, China, from June to July 2016 and from July to August 2017. The authors designed the questionnaire specifically for this study. To be included in the study, individuals had to be (1) hypertensive patients who live long-term in selected communities, (2) insured with the UEBMI, (3) managed by a community health institution, (4) insured by an outpatient copayment scheme before 2016 for eligible patients with hypertension in the insured group, and (5) never insured by an outpatient copayment scheme for eligible patients with hypertension in the uninsured group. Exclusion criteria comprised the following: those who (1) had communication difficulties, (2) exhibited severe cognitive impairment or were diagnosed with severe dementia and mental disorder, (3) were too sick to finish the interview, (4) were uncooperative, (5) passed away, and (6) in the uninsured group applied for the outpatient copayment scheme in 2017 successfully. At baseline, we selected 1,095 community-managed patients with hypertension from five communities in the Eighth Division of Xinjiang Production and Construction Corps, China, between June and July 2016.Using a multistage sampling method based on socio-economic status, population size, and reimbursement level within the outpatient copayment scheme for eligible patients in different regions of Xinjiang, we selected five communities in one region for the study sample. The level of reimbursement differs across the regions of Xinjiang. Therefore, it was problematic to select multiple regions for evaluation to reflect the effects of policy. Ultimately, we selected the Eighth Division, a region with a high level of economic development and a dense population. These five communities in the Eighth Division also have strong chronic disease management and services, and they meet the sample size requirements. In 2016, 4/5th of the Eight Division had an urban population while 1/5th had a rural population. . At the We performed sample-size calculations at a conventional power of (1-beta) 0.80 and alpha of 0.05 (two-sided testing), which revealed that a minimum of 150 participants was required to ensure efficacy. Thus, the calculations confirmed that our sample size was large enough for effective data analysis.Trained interviewers administered an original questionnaire to collect demographic, socio-economic, clinical, and medical information. The questionnaire asked about health outcomes, including blood pressure, health-related quality of life (HRQOL), blood pressure control, drug treatment of hypertension, and self-reported health. The data were collected through 10–15-minute face-to-face interviews. Blood pressure was measured three times on the upper left arm after at least 10 minutes of rest, using a mercury sphygmomanometer administered by a clinician-trained investigator. We assessed HRQOL using the EQ-5D, a generic measure of HRQOL, which can address these health issues . The EQ-Ethical clearance was obtained from the ethical review committee of Shihezi University. The study was funded and approved by the National Natural Science Foundation of China (Project Identification Code: 71363047). Participants were assured, via a formal written release or an informed consent statement, that their answers in this study would not impact their subsequent medical benefits. Informed consent was obtained from all participants by signature or by fingerprint on the consent form or written release.Blood pressure control (“control”) was defined as a measured systolic blood pressure of less than 140 mm Hg and a measured diastolic blood pressure of less than 90 mm Hg. Drug treatment of hypertension (“treatment”) was defined as individual-linked hypertension medication observed in the medicine cabinet, or the self-reported hypertension medication use portion of the study interview questionnaire , 29. TheThe goal of this analysis was to examine whether or not enrollment in the outpatient copayment scheme for eligible patients with hypertension was associated with decreased blood pressure as compared to similar patients that did not participate in the study during the same time period. A difference-in-differences approach was used, which is an econometric method for evaluating changes in outcomes occurring after the implementation of a policy , 35. ThiHowever, insured individuals may not be representative of all individuals with hypertension. The outpatient copayment scheme for chronic diseases has a series of application conditions, one of the most important of which is the severity of the disease. Therefore, we used two separate strategies to adjust for the potential differences between insured and uninsured groups. First, propensity scores matched the insured and uninsured groups on baseline patient demographics, clinical characteristics, and medication. Second, multivariate adjustment accounted for all observable individuals and patient characteristics that were included in the propensity score model. To ensure that individuals in the insured and uninsured groups were on the same trajectory for severity of hypertension at baseline, they were matched for self-reported hypertension severity, course of hypertension, and number of medications with the uninsured individuals. This matching ensured that the influence of confounding variables and the bias introduced by self-selection into (or out of) the program can be reduced in the pre-enrollment period, which is one of conditions of a difference-in-differences methodology , 37.We analyzed the data using commercially available statistical software . We examined population characteristics of the participants with hypertension in the insured and uninsured groups, comparing the statistics using the following bivariate analyses: the Kruskal-Wallis test for continuous variables and the chi-square test or Fisher’s exact test for categorical variables.To create propensity scores for observations matching at baseline, we created a logistic regression model with outpatient medical insurance for hypertension participation (versus not participating) as the dependent variable. Independent variables included age, sex, annual household income, marriage, education, employment, family size, self-reported hypertension severity, course of hypertension, and number of medications. For matching, we used caliper matching with one-to-one matches based on the propensity score without replacement .To perform the difference-in-differences analysis, we used regression models to evaluate the relationship between each dependent variable  and enrollment in the outpatient copayment scheme , 38. TheBetween July and August of 2016, 1,095 individuals in the community-managed hypertensive population were observed at baseline, including 329 insured and 766 uninsured patients. Between July and August of 2017, 805 (73.5%) individuals were followed up with during the first follow-up survey, including 248 of the insured population and 557 of the uninsured population. A total of 290 individuals were excluded from the first follow-up survey in 2017. Of these, six moved away, 24 refused to cooperate with the survey, and 260 missed their interview appointment. Of the 805 patients who completed follow-ups in 2017, 45 uninsured group members were eligible for insurance, but five patients died, while six members of the insured group died. Longitudinal data were available for 749 individuals (68.4%), of which 242 (73.5%) were in the insured group and 507 (66.2%) were in the uninsured group . EventuaSeeSeeOur study showed that the outpatient copayment scheme had no significant effect on systolic blood pressure, diastolic blood pressure, blood pressure control, EQ-5D index, or EQ-VAS, but it increased the coverage of drug treatment for hypertension and led to a substantial improvement in self-reported health. With respect to clinically measured health, this pattern of findings—an improvement in an individual’s recollection of their health status, yet no improvement in their physical health See—was mirrTo evaluate the extent to which these improved outcomes were independently associated with enrollment in the outpatient copayment scheme, we matched each insured individual with one control uninsured individual who had similar characteristics and severity of hypertension at baseline. These findings are consistent with previously published results conducted approximately one year after the policy changed. Using the control group of uninsured individuals, the independent association of enrollment in the outpatient copayment scheme with adverse outcomes and the UEBMI payments could be isolated, removing any confounding background trends toward biased outcomes. These findings show that enrollment in the outpatient copayment scheme may improve the self-reported health of hypertensive individuals but may be insufficient to reduce blood pressure in our study population.Sustained drug treatment for hypertension is vital for prevention of cardiovascular disease (CVD) , 40, parThis study demonstrates that outpatient copayment schemes result in an increase in the use of antihypertensive drugs, indicating better chronic care for patients. We hypothesized that decreased outpatient copayment would result in better quality drugs and greater self-reported health with better chronic care in the insured group compared with the uninsured group. Evidence from ten years of the highest quality research summarized in a review of the literature has indicated that health insurance programs significantly increase family economic security, chronic illness treatment, and access to medications . Those iHealth insurance programs could significantly increase family economic security, chronic illness treatment, and access to medications . These cPatients with better health literacy, more health-seeking behavior, and more severe diseases may be more likely to enroll in an insurance program. They may also be more likely to start and adhere to a treatment regimen, independent of their insurance status. For example, in rural Nigeria, the CBHI program was associated with a significant longer-term reduction in blood pressure in a hypertensive population after 5 years of coverage . AlthougBlood pressure, EQ5D index, VAS, controlled hypertension, treatment of hypertension, and self-reported health constitute a subgroup of the set of health outcomes potentially affected by health insurance , 43. We Our study has several limitations. First, antihypertensive drug use was self-reported, and no information about the quality and continuity of treatment was available. Sustained improvements in health require access to quality care, a continuous supply of guideline-based drugs, and adherence to treatment regimens , 41, 42.A decreased outpatient copayment scheme was associated with an increase in antihypertensive treatment coverage and an improvement in self-reported health in hypertensive populations in Xinjiang, China. The outpatient copayment scheme was not associated with improvements in blood pressure, EQ5D, controlled hypertension after 18 months. Our study highlighted the potential of outpatient copayment schemes to reduce or eliminate the cost of medications for a community-managed population with hypertension and, in turn, improve their treatment of hypertension. Further consideration should be given to raising the level of reimbursement for outpatient copayment schemes in order to combat the increasing costs of outpatient services.S1 File(DOC)Click here for additional data file.S2 File(DOC)Click here for additional data file.S3 File(DOC)Click here for additional data file.S1 Ethics statement(PDF)Click here for additional data file.


Background: Preterm infants are at an increased risk of developing hypertension and chronic kidney disease later in life. No recommendations exist for blood pressure (BP) and renal follow up for these patients. Aim: To compare BP and serum and urinary kidney markers between preterm-born adolescents and term-born controls. Methods: BP measurements in 51 preterm-born  and 82 term-born adolescents at the age of 10–15 years were conducted. Stepwise regression analysis explored the association between BP and participant characteristics. Kidney markers measured in the serum and urine were creatinine, neutrophil gelatinase-associated lipocalin (NGAL), and uromodulin. Kidney markers measured in the serum were cystatin C, beta-2 microglobulin, and beta trace protein. Results: Systolic BP was significantly higher in preterm boys compared with term boys, but not in girls, and low birth weight was associated with higher BP in boys. In the preterm group, maternal hypertension/preeclampsia and adolescent height were associated with higher systolic BP. Serum creatinine and NGAL were significantly higher in the preterm group. Conclusions: Our study confirms an inverse sex-dependant relationship between birth weight and BP at adolescent age. The higher serum creatinine and NGAL in the preterm group may indicate that premature birth affects kidney function in the long term. Infants born at a very young gestational age (GA) and a very low birth weight (VLBW) are at risk for developing renal and cardiovascular diseases when they grow up to adolescents and young adults . Large sThis study compared BP in a cohort of adolescents born preterm with term controls to test our hypothesis that preterm birth leads to increased BP. We explored pre-, peri-, and postnatal risk factors associated with higher BP; and we present profiles of established and newer glomerular and tubular kidney markers, some of which have not been described in this population: creatinine (Crea), CysC, NGAL, B2M, BTP, and Uromod in serum and Crea, NGAL, and Uromod in urine.This was a cross-sectional analysis embedded in the longitudinal cohort of the Basel Study of Preterm Children (BSPC). Previous reports of the first and second study waves have described recruitment procedures ,10. In b2. A BMI ≥ 85th and <95th centile for age and sex defined overweight, while a BMI ≥ 95th centile for age and sex defined obesity.Study participants were visited at home. Weight was measured on digital calibrated scales. Height was measured with a folding rule. Body mass index (BMI) was calculated as BMI = weight [kg]/(height [m])Upper arm circumference (measured mid-way between the acromion and olecranon with a non-elastic tap measure) on the non-dominant arm determined the BP cuff size. After a seated rest period of 10 min, BP was measured twice with one minute between measurements . The average systolic and diastolic BP from the two measurements were used for data analysis. Elevated BP was defined according to the 2017 American Academy of Pediatrics (AAP) guidelines as BP > 90th and <95th centile and hypertension-level BP was defined as BP ≥ 95th centile for age, sex, and height centiles . Study pStudy participants presented to the ambulatory study facility at the University of Basel Children’s Hospital for blood collection. Topical anaesthetic cream was applied one hour prior to collection of 10 mL of blood into EDTA vacutainers via direct venepuncture. Blood samples were centrifuged immediately and then frozen at −20 °C. After all lab visits had been completed, blood samples were sent in one batch on dried ice to the analysis facility. After thawing of samples, laboratory analysis of serum Crea, CysC, BTP, B2M, NGAL, and Uromod was performed in one batch in fully automated analysers according to methods specified in To identify factors associated with BP, we obtained pre-, peri-and postnatal data for each study participant born preterm from discharge summaries of their NICU admission. These included pregnancy complications and treatments , (complete or incomplete course of) antenatal steroid administration); delivery details ; and neonatal details , diagnosis of bronchopulmonary dysplasia , necrotizing enterocolitis (any stage according to Bell staging criteria), retinopathy of prematurity (any degree), intraventricular haemorrhage (any degree), persistent ductus arteriosus and its treatment with non-steroidal anti-inflammatory agents, hypotension , antibiotic treatment (no further specification of antibiotic class available in discharge summary), and treatment with postnatal steroids. For the term group, only information from official birth notifications was available, including GA at birth, BW, and z-score for BW, but no further details on pre-or perinatal details. Small for gestational age (SGA) was defined as a z-score for birth weight of below −1.28.R statistical software package . Descriptive data were displayed using means (±standard deviations) for normally distributed variables and medians (with interquartile ranges (IQRs)) for other continuous variables. Differences in characteristics between the preterm and term groups were assessed using Wilcoxon‘s rank sum test and Student’s t-test depending on the distribution of variables. We then built multivariable regression models to assess associations between systolic or diastolic BP and participant characteristics using the Akaike information criterion (AIC) for step-wise model selection. The first model was performed over the whole cohort, using the characteristics available for both the preterm and term groups ; the regression analyses were performed over the whole cohort. For this model, BW and GA were dichotomized as <2500 g or >2500 g and preterm or term. As this analysis of BP differences demonstrated a significant difference in preterm and term boys, but not in girls, this analysis was extended to explore sex differences by building separate models for each sex. The second model included additional characteristics only available for the preterm group . GA and BW were used as continuous variables. To avoid overfitting, variables with less than 10 events per variable and group were not used in the regression analysis. Due to the small sample size, this analysis was not performed separately for each sex.Statistical analysis was performed using the For kidney markers, analysis was restricted to descriptive statistics due to small sample size.Fifty-one former preterm-born adolescents and 82 term-born controls consented to either both or one of the study components. Forty-six urine samples and 26 blood samples were obtained from study participants in the preterm group, and 65 urine samples and 52 blood samples were obtained from the term group . The adoFor the preterm group, Systolic and diastolic BP values were similar in the preterm group and the term group, with a similar prevalence of elevated and hypertension-level BP . HoweverRegression models for all girls showed that age and height at assessment were significant predictors of systolic BP . None of2, which is the functional criteria for CKD if present for longer than 3 months, as defined in the KDIGO  guidelines [Serum Crea and NGAL were significantly higher in the preterm group compared to serum Crea and NGAL in the term group . eGFR waidelines . All othIn this cohort, the average systolic BP was higher in preterm-born adolescent boys compared with term-born adolescent boys. Only body weight at the time of BP assessment was predictive of systolic and diastolic BP in boys, while age and body height at BP assessment were predictive of systolic BP in girls. For the group of preterm-born study participants, we found associations between systolic BP and maternal hypertension or preeclampsia and body height at the time of BP assessment, and between diastolic BP and GA and antenatal steroid cover. The group of pretermborn adolescents had higher serum Crea and NGAL values compared with the term-born adolescents.Our finding of higher systolic BP in preterm-born boys contrasts with other studies, where preterm-born women were found to be at a higher risk for developing hypertension, but the association between preterm birth and high BP was present in both sexes . There iThe association of lower BW and GA with increased BP later in life has been described previously . A similOur study found a higher serum Crea level in the preterm-born adolescents, but no difference in eGFR. The bulk of evidence has identified preterm birth and/or LBW or VLBW as risk factors for lower eGFR by the time patients reach young adulthood , althougSerum and urine NGAL have been used to diagnose acute kidney injury and predict the progression of CKD . IncreasEqually, serum and urine B2M and Uromod have not been reported before in the adolescent age bracket after preterm birth. B2M reflects GFR independent of sex and body weight in adults  but is p2. Additionally, the differences between the study participants who provided blood and/or urine samples and those who did not provide either of the samples may have led to a degree of selection bias. It is challenging to infer the influence of these inconsistent inter-group differences on the study results, particularly with the small number of participants in some of the groups.Our study has a few limitations. Firstly, study participants were recruited for both BP measurements through kidney function testing and psychological testing, requiring a sufficient level of verbal communication. Therefore, adolescents with severe cognitive impairment were not invited to participate in the study. Children with severe developmental sequelae after preterm birth may have suffered from the most severe neonatal morbidities, with presumably more severe impacts on kidney development and function. This recruitment bias may have led to an attenuation of the difference in BP and kidney markers in comparison with the control group. Secondly, we did not have access to neonatal data for the term-born control group (other than GA and BW) or recent medical history and drug exposure in both groups. Therefore, we were unable to exclude any study participant with a history of kidney disease or other illness or drug exposure impacting renal function or BP. However, none of the adolescents had eGFR < 70 mL/min/mThirdly, we did not measure proteinuria or albuminuria. Albuminuria as a marker for glomerular filtration barrier injury or dysfunction has been incorporated into the defining criteria of CKD in the KDIGO definition . This prPreterm birth presents a multitude of risk factors for elevated BP in adolescence. The males in our cohort appeared to be more vulnerable to long-term cardiovascular sequelae after preterm birth. To date, no kidney marker has been shown to reliably identify declining renal health years after the interruption of kidney development by preterm birth and associated neonatal morbidities. Large scale prospective studies are required for serial follow up of children born at low GA and VLBW to validate individual kidney markers in urine or serum and identify those at increased risk for CKD.


We compared the sodium intake and systolic blood pressure (SBP) relationship from complete 24-h urine samples determined by several methods: self-reported no-missed urine, creatinine index ≥0.7, measured 24-h urine creatinine (mCER) within 25% and 15% of Kawasaki predicted urine creatinine, and sex-specific mCER ranges . We pooled 10,031 BP and 24-h urine sodium data from 2143 participants. We implemented multilevel linear models to illustrate the shape of the sodium–BP relationship using the restricted cubic spline (RCS) plots, and to assess the difference in mean SBP for a 100 mmol increase in 24-h urine sodium. The RCS plot illustrated an initial steep positive sodium–SBP relationship for all methods, followed by a less steep positive relationship for self-reported no-missed urine, creatinine index ≥0.7, and sex-specific mCER ranges; and a plateaued relationship for the two Kawasaki methods. Each 100 mmol/24-h increase in urinary sodium was associated with 0.64  mmHg higher SBP for self-reported no-missed urine, 0.68  mmHg higher SBP for creatinine index ≥0.7, 0.87  mmHg higher SBP for mCER within 25% Kawasaki predicted urine creatinine, 0.98  mmHg change in SBP for mCER within 15% Kawasaki predicted urine creatinine, and 1.96  mmHg higher SBP for sex-specific mCER ranges. Studies examining 24-h urine sodium in relation to health outcomes will have different results based on how urine collections are deemed as complete. High systolic blood pressure (SBP) is the largest single risk for death globally . High inAccurate measurement of daily sodium intake is critical to evaluate the effectiveness of population-based sodium reduction interventions . Sodium The accuracy and usefulness of creatinine-based criteria to evaluate the completeness of 24-h urine collection has been systematically reviewed ,12. HoweWe compiled data of three cohort studies from Bangladesh, carried out by the International Centre for Diarrhoeal Disease Research, Bangladesh . The study protocols were reviewed and approved by the Ethical Review Committee of ICDDR,B (PR-15096 and PR-18004). Informed written consent was obtained from all participants. The studies were predominantly implemented in southwest coastal Bangladesh where communities are exposed to brackish drinking water . In tota® HEM–907  digital monitor [We used a validated Omron monitor  and an aWe collected participants’ demographics  information, and their self-reported data on smoking, work-related physical activities, alcohol consumption, and sleep hours during all visits. Participants’ weight was measured in all visits, but height was measured once. To calculate households’ wealth, we collected information on households’ ownership of refrigerators, televisions, mobile phones, motorcycles, bicycles, sewing machines, chairs, tables, wristwatches, wardrobe wooden cots, motor pumps, rice husking machines, motorized rickshaw, cars, and access to electricity .We collected participants’ 24-h urine at all visits. Each participant received a 4-L container for urine collection, and a small container to transfer the voided urine to the 4-L container. Participants were instructed not to collect their 1st-morning urine and to start urine collection by collecting and transferring the 2nd-morning void, and all voids up to and including the next morning’s 1st void. In the second and third cohort studies, participants or a family member who could read or write received a small questionnaire to record the times of the first and last void, and to report any missed voids. Field research assistants recorded the collected 24-h urine volume and then obtained a 15-mL urine sample from the 4-L container after stirring. They transported the urine samples to a field laboratory at 2–8 °C. Direct ion-selective electrode (ISE) methods were used to measure the urinary sodium with a semi-auto electrolyte analyzer . Creatinine was measured by the Jaffe reaction . We determined the completeness of 24-h urine collection based on self-reported information and creatinine-based methods. Two self-reported methods were considered: (1) Participants reported no missed voids, and (2) a 22–26 h interval between the time of the first and last urine void plus no missed voids. For the 2nd self-reported method, we standardized the urine volume for 24 h. We considered four creatinine-based methods: creatinine index ≥0.7 , measureWe derived the household wealth score by the principal component analysis using the household asset ownership data . We thenIn a post hoc analysis, using data from all methods of assessing complete 24-h urine samples, we plotted the restricted cubic spline  to examip-value for the linear trend determined by the orthogonal polynomials [We also modeled urinary sodium as a categorical variable using tertiles of urinary sodium. Similar multilevel linear models to those described above were used to determine the associations of quartile 2, and 3 urinary sodium with BP compared to quartile 1. We reported the ynomials . Since wOf the total of 9804 person-visits with 24-h urine collections, 7176 (73%) reported no missed voids, and 5524 (56%) reported 22–26 h of urine collection and no missed voids . The creIn total, 96% of the samples selected by mCER within 15% of Kawasaki predicted urine creatinine, and 94% of samples selected by mCER within 25% of Kawasaki predicted urine creatinine were also included by creatinine index ≥0.7. All (100%) of the samples selected by mCER within 15% of Kawasaki predicted urine creatinine were also selected by mCER within 25% of Kawasaki predicted urine creatinine. In total, 73% of the samples included by the sex-specific range were included by creatinine index ≥0.7, and 67% included by mCER within 15% of Kawasaki predicted urine creatinine were included by the sex-specific mCER range.2) and the lowest (22.4 ± 4.1 kg/m2) for the creatinine index ≥0.7 criteria (The mean age of the person-visits was the highest (44.3 ± 14.6 years) for the sex-specific mCER ranges, and the lowest (42.3 ± 14.2 years) for the creatinine index ≥0.7 criteria . The procriteria .p < at the significance level of 0.05) (The sex-specific mCER ranges had the lowest mean urine sodium excretion (137 (±66) mmol/24-h) and the creatinine index ≥0.7 method had the highest mean urine sodium excretion (169 (±74) mmol/24-h). Compared to the 158 (± 76) mmol/24-h mean urine sodium of the self-reported no missed urine (the reference method), all methods had a statistically different mean measured 24-h urine sodium (of 0.05) . The Kerof 0.05) . Women hof 0.05)  in samplof 0.05) . Men conof 0.05) . For all methods, the covariates-adjusted restricted cubic spline plots illustrated an initial steep positive sodium–SBP and sodium–DBP relationship . AfterwaIn the fully adjusted model using tertiles of 24-h urinary sodium, there was a graded increase in BP with increases in sodium. Compared to the tertile 1 person-visits, those in tertile 3 had 3.36  mmHg higher SBP for the sex-specific mCER ranges, 2.97  mmHg higher SBP for the mCER within 15% of Kawasaki predicted creatinine, and 1.55  mmHg higher SBP for the mCER within 25% of Kawasaki predicted creatinine . In the In the full-adjusted model, each 100 mmol/24-h increase in urinary sodium was associated with 0.68  mmHg higher SBP and 0.09  mmHg higher DBP for the creatinine index ≥0.7 method, 0.98  mmHg change in SBP and 0.30  mmHg higher DBP for mCER within 15% Kawasaki predicted urine creatinine, 0.87  mmHg higher SBP and 0.29  mmHg higher DBP for mCER within 25% Kawasaki predicted urine creatinine, and 1.96  mmHg higher SBP and 0.88  mmHg higher DBP for the sex-specific mCER range .Twenty-four-hour urine collection is considered the most accurate method to assess dietary sodium intake. However, incomplete collection of urine samples is very common, particularly in population-based studies. Researchers across the world have used various methods to exclude incomplete 24-h urine samples. Our study demonstrates that the use of different methods led to significant differences in mean 24-h urine sodium excretion and altered the association of excreted sodium with BP, including the shape, magnitude, and significance levels. These differences were observed in all modeling strategies we assessed. Furthermore, we found a sex-specific difference in the urine sodium excretion and BP relationship. The different methods of assessing incomplete 24-h urine samples resulted in the exclusion of different proportions of urine collections. Additionally, the different methods resulted in differences in which specific collections were included or excluded. Likely, the indirect methods we evaluated may not effectively exclude all of the true incomplete 24-h urine samples and, at the same time, some complete 24-h urine samples may have been excluded in this Bangladeshi population. Since we did not have the gold standard PABA method, we are unable to determine which method performed the best.The creatinine index ≥0.7 excludes samples with low urine creatinine, which is analogous to the exclusion of samples based on urine creatinine below 15 mg/kg/24-h . The othCreatinine-based methods exclude samples if measured urine creatinine excretion levels are outside of the sex-specific physiological ranges; however, these methods consider neither participants’ age nor muscle mass, protein intake, and other variables influencing measured urine creatinine excretion. These methods were developed from a small number of participants; therefore, they may not reflect population-level characteristics and variability. For example, the creatinine index ≥0.7 was evaluated in 541 participants, the Kawasaki equation of completeness evaluation was developed from 487 participants, and the sex-specific mCER ranges was evaluated in 104 participants ,12,29. SWe identified a plateaued relationship between the urine sodium and systolic blood pressure relationship above the 50th percentile distributions of urine sodium. Randomized controlled trials, in contrast, show a mostly linear relationship between dietary sodium intake and blood pressure, with potentially a steeper relationship at sodium intake below100 mmol/day. Residual confounding, with physical activity and other variables that co-relate with blood pressure and sodium intake may explain some of the plateauing. One of the other possibilities includes the presence of blood pressure-lowering minerals  in the brackish water. In other analyses reported elsewhere , we idenThe sex-specific mCER ranges method excluded samples when measured urinary creatinine was low or high. The mean urine sodium excretion for the sex-specific mCER ranges was the lowest of all the methods, suggesting sex-specific mCER ranges included more data-points with low urine sodium excretion. Since the urine sodium and blood pressure relationship plots had a steep slope in the early segment of the plots, it also explains a higher magnitude of urine sodium and blood pressure association for sex-specific mCER ranges in linear analyses.The study population had high sodium intake, compared to the WHO-recommended daily intakes of less than 2000 mg/day or 87 mmol/day. Only 8% of person-visits had urine sodium within 1500 mg/day or 65.2 mmol/day, the recommended daily intake by the Dietary Approaches to Stop Hypertension (DASH) study. We consistently found a steep slope of the urine sodium and blood pressure relationship curve in the spline plots’ initial sections. This suggests reducing daily sodium intake below the recommended daily intakes may reduce the population’s mean blood pressure markedly, albeit a small portion of person visits were within the recommended urine sodium excretion.® HEM–907 rather than using different instruments would have provided standardized blood pressure measurements, reducing the measurement errors in blood pressure measurement. Twenty-four-hour urine collection studies are recommended to incorporate estimation of the completeness of 24-h urine in a subsample using para-aminobenzoic acid [Our study has several important strengths and limitations. We had cross-sectional sodium exposure and blood pressure outcome data for several visits for the same individual. Many hemodynamic changes associated with salt load occur within 24 h. Therefore, blood pressure, along with sodium intake, measurement is particularly advantageous instead of a time lag between sodium intake and blood pressure measurement. We had a relatively large sample size that provided enough power for analyses, even after excluding samples by more restrictive methods of complete 24-h collection evaluation. Inclusion of participant-, household-, and community-level random intercepts largely captured time non-variant unmeasured confounders at each level and therefore minimized the bias. The use of Omronoic acid , a gold oic acid ,43,44. Woic acid , howeveroic acid ,47. Highoic acid . Hence, oic acid . We wereOur findings suggest that the results of epidemiological studies evaluating the health effects of sodium intake can be influenced by different methods of evaluating the completeness of 24-h urine samples. It is therefore possible that other studies using 24-h urine collections without considering the completeness of urine samples may also have provided altered and unreliable associations between sodium and health outcomes. Low-quality epidemiological studies lead to more debates causing controversy and could impact public health policy on sodium reduction. It is vital to ensure the 24-h urine collections are complete in epidemiological studies, preferably using para-aminobenzoic acid to assess the completeness of the collected urine samples, so as to provide robust evidence on sodium intake and health outcomes. Further research on the evaluation of indirect methods of complete 24-h urine samples is needed, particularly to compare them with para-aminobenzoic acid excretion.