To determine whether the delivery method is associated with the rate of anemia in later life, using the data from the Korea National Health and Nutrition Examination Survey (KNHANES).This study used data from the KNHANES 2010–2012. Among 25,534 participants, 8,126 cases were included in this study after exclusion of males and other inappropriate data. The study population was divided into three groups according to the delivery modes: vaginal delivery (VD) only group, single cesarean delivery (SCD) group and repetitive cesarean delivery (RCD) group. The primary outcome was anemia and iron deficiency. Anemia was defined as hemoglobin <12 g/dl in accordance with the World Health Organization criteria. Iron deficiency was defined as low transferrin saturation (TSAT) or ferritin levels. Multivariate analysis was used for determination of association between the delivery modes and anemia.P <0.001] and iron deficiency  compared to VD only. In the subgroup analysis, RCD was significantly associated with anemia in perimenopausal women, women with iron deficiency, those without any comorbidity and those without anemia-prone treatment.The mean age was 53.4 years and the median time from the last delivery to the survey was 25 years. The VD only group was composed of 6,493 (79.9%) women, while 685 (8.4%) were classified as the SCD group and 948 (11.7%) were classified as a RCD group. The rates of anemia were 11.8%, 13.9%, and 19.7% in VD only group, SCD group, and RCD group, respectively. However, those groups were significantly different in many confounding factors. Therefore, to adjust those factors, multivariate analysis and subgroup analysis were followed. The odds of SCD for anemia and iron deficiency were not different from those of VD only. However, RCD was independently associated with anemia [Odds ratio(OR) 1.47, 95% Confidence interval (CI) 1.21–1.79, Repetitive cesarean section may be a risk factor for future development of anemia in later life, especially in perimenopausal period. Therefore, evaluation and management of anemia in longer postpartum period should be considered for women who experience repetitive cesarean section. Although anemia is a benign condition, it largely affects the quality of life and is associated with various morbidities including cardiovascular complications , 2, renaThe study also demonstrated a bimodal distribution of anemia in women with peaks in age group 40–49 and over 80 years. About 20% of women experience excessive menstrual blood loss in their 40s and most of them are caused by bleeding abnormalities associated with uterine fibroids or anovulation . Two thiPregnancy is a well-known risk factor of iron deficiency anemia in women. During pregnancy, plasma volume and red blood cell mass simultaneously increase and hemodilution is resulted . This phThe average estimated blood loss at the time of delivery is about 500 mL . The amoThis study aims to determine whether the delivery method is associated with the rate of anemia in later life, using the data from the Korea National Health and Nutrition Examination Survey (KNHANES).The KNHANES has been performed periodically since 1998 to assess the health and nutritional status of the civilian in non-institutionalized Korean population. Participants were selected using proportional allocation systematic sampling with multistage stratification. This study used data from the KNHANES 2010–2012. Of 31,596 candidates, 25,534 people agreed to participate the KNHANES 2010–2012 (participating rate: 71.3%). The study protocol complied with the Declaration of Helsinki. Full approval of the study was obtained from the Institutional Review Board of the Korea Centers for Disease Control . All data were fully anonymized before we accessed them. KNHANES participants provided informed written consent to have their data used in research. The protocol comprised a health-questionnaire survey, health examination, and nutrition survey.Among 25,534 participants, we excluded 5,935 cases aged <19 years first. Of 19,599 adults aged ≥19 years, 8,461 men, 849 missing menstrual information, 8 missing exogenous estrogen exposure history, 38 missing obstetric information, 636 missing data regarding diagnostic studies on anemia , and 1,481 who have never been pregnant were excluded. This study therefore included 8,126 participants .2).A standardized interview was conducted in the homes of the participants to collect information including demographic variables, obstetrics and gynecologic history, medical history, medications used, and a variety of other health-related variables. Blood pressure (BP) was measured three times in accordance with the standard protocol, and mean values of the three measures were used as the representative BP. Height was measured to the nearest 0.1 cm using a portable stadiometer . Weight was measured to the nearest 0.1 kg using a Giant-150N calibrated balance-beam scale . Body mass index (BMI) was calculated by dividing the weight by the square of the height . The hemoglobin level was measured via the cyanide-free sodium lauryl sulphate method using a XE-2100D . Serum iron and ferritin levels were measured by a Bathophenanthroline direct method with a Hitachi Automatic Analyzer 7600  and an immunoradiometric assay with a 1470 WIZARD gamma counter , respectively. TSAT (%) was calculated as serum iron × 100/total iron binding capacity.Anemia was defined as hemoglobin <12 g/dl in accordance with the World Health Organization criteria. The definition of anemia-prone treatment was the ongoing treatment course of cardiovascular disease or arthritis. Iron deficiency was defined as low TSAT or ferritin levels. Since there is no agreed consensus of cut-offs for the low TSAT and ferritin levels in diagnosis of iron deficiency , we defiThe distributions of continuous variables were evaluated using histograms and Q-Q plots. Normally distributed continuous variables are expressed as mean ± standard deviation (SD), non-normally distributed continuous variables as median (interquartile range), and categorical variables as percentages. Difference was analyzed by one-way ANOVA for normally distributed continuous variables, Kruskal-Wallis test for non-normally distributed continuous variables, and a chi-square test for categorical variables. Post-hoc analysis was performed using Bonferroni method of one-way ANOVA for normally distributed continuous variables, Mann-Whitney U tests for non-normally distributed continuous variables, and chi-square tests for categorical variables.The relationship between TSAT and ferritin and anemia was plotted using the penalized smoothing spline method with the “pspline” package in R Statistics (version 3.03). The area under the curve (AUC) with its 95% confidence interval (CI) of receiver operating characteristic curve (ROC) was evaluated using R Statics (version 3.03) with “pROC” packages. The best cut-offs was calculated by obtaining the Youden index (sensitivity + specificity—1). Odds ratio and its 95% CI were calculated using logistic regression analysis.P-value of <0.05 was considered statistically significant. All analyses unless otherwise specified were performed using SPSS Version 22 .In multivariate analysis, covariates were chosen based on clinical relevance: age, comorbidity , smoking and drinking status, white blood cells counts, obstetric and gynecologic variables . A pmol/l. The proportion of oral pills usage was 17.2% and the history of estrogen replacement treatment was found in 10.3%. The rates of hypertension, diabetes, dyslipidemia, and cancer history were 33.8%, 10.0%, 21.6%, and 4.1%, respectively.In the total study population, the mean age was 53.4 years and the median numbers of delivery was two. The median time from the last delivery to the survey was 25 years. At the time of the survey, 57.2% women were at menopause. The VD only group was the largest and was composed of 6,493 (79.9%) women, while 685 (8.4%) were classified as the SCD group and 948 (11.7%) were classified as a RCD group. The rate of anemia was 12.9%. Mean ± SD value of TSAT was 32.3 ± 13.6% and median (interquartile range) of ferritin was 93.3 (47.9–157.6) pmol/l of ferritin were found to be associated with anemia best. The rates of low TSAT and ferritin levels defined as TSAT <20.6% and ferritin <22.6 pmol/l were 18.3% and 11.9%, respectively, and the rate of iron deficiency was 21.9% accordingly.We plotted the relationships between TSAT, ferritin, and anemia using the penalized smoothing spline analysis . TSAT shThe clinical characteristics according to the delivery modes are demonstrated . Women iP <0.001) higher odds for anemia and 1.422-times  higher odds for iron deficiency than VD only. In the subgroup analysis, RCD was significantly associated with increased odds for anemia in cases before menopause, those with iron deficiency, those without any comorbidity and those without anemia-prone treatment Click here for additional data file.S1 File(XLSX)Click here for additional data file.


Domestic incense burning is a common activity in China. Although it generates serious air pollution and has been linked to various health outcomes, it remains unknown whether it is associated with blood pressure and hypertension. A community-based survey including 1153 hypertensive subjects and 4432 normotensive participants in Guangdong (China) was used to examine this question. Two-level logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI). The analyses showed that, compared with non-users, OR of hypertension was 1.24 (95% CI: 1.03–1.50) for users, and 1.37 (95% CI: 1.04–1.80) for daily users with a clear dose-response relationship. The estimated increases in systolic and diastolic blood pressures were 1.02 mmHg (95% CI: 0.06–1.99) and 1.26 mmHg (95% CI: 0.69–1.83) for users, 0.67 mmHg (95% CI: −0.35–1.68) and 1.25 mmHg (95% CI: 0.66–1.85) for occasional users, and 2.09 mmHg (95% CI: 0.79–3.39) and 1.28 mmHg (95% CI: 0.52–2.05) for daily users, respectively. The results remained after adjusting for potential confounders and more pronounced associations were found among females. This study suggests that domestic incense burning may increase the risk of hypertension and blood pressure in the study population, and women are more vulnerable to these effects than men. Hypertension is a major public health problem with about one quarter of the population being affected in the world . As one Hypertension is one important public health issue not only for high income countries but also for developing countries, such as China, In China, the incidence of hypertension is expected to increase as a consequence of aging population and economic development ,4. It haGrowing evidence has suggested that indoor biomass burning is associated with elevated blood pressure ,8,9 and It is reasonable to hypothesize that exposure to indoor air pollution resulting from domestic incense burning is associated with higher blood pressure and risk of hypertension. In the present study we assessed the relationship of personal exposure to incense burning with blood pressure and hypertension in residents of Guangdong Province in southern China.We used information from a cross-sectional survey, which was conducted in 14 counties/districts of Guangdong Province, China . The surThe survey was conducted during the period from August to December 2013. Written informed consent was obtained before each interview. All eligible subjects were invited to attend face-to-face interviews and physical examinations. We used a standardized structured questionnaire to collect information mainly on basic socio-demographic characteristics, living condition, ventilation, domestic use of incense burning, and other potential confounding variables.The arterial blood pressure was strictly measured in accordance with the 1999 World Health Organization/International Society of Hypertension Guidelines for the Management of Hypertension . The staIn accordance with previous studies ,5, hyperInformation on incense burning habits at each residence was collected in terms of number of days per month with incense burning at home. One day with incense burning was defined as burning at least one stick at home in a particular day. Two questions were used to assess the incense usage at home: (1) does your family burn incense at home? (2) if yes, how many days in one month do your family burn incense at home? Based on the distribution and the local custom, the frequency of domestic incense burning was classified into three categories in this study: daily usage, occasional usage and never. Daily usage was defined as burning incense at home on a daily basis ; occasional usage was defined as only burning incense at home for some special days, such as Spring Festival Day, Mid-autumn Day, often less than five days a month. Twenty-five days per month used as a cut-point was based on our field survey experience and the local custom, we also did sensitivity analyses by changing the cut-point to check the robustness of the results.A number of covariate variables were collected, such as age, sex, weight, height, education, physical exercise, habits of tobacco smoking and alcohol consumption, dietary salt restriction, indoor biomass use, environmental tobacco smoking (ETS) exposure, and ventilation. Weight and height were measured when wearing light clothes but no shoes; body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. Ventilation was defined as whether they had ventilation facility used at their home. Physical exercise was defined as whether the subjects had a vigorous physical activity for at least 10 min each day. Dietary salt restriction was defined as whether they were undertaking salt intake restriction to limit daily salt intake less than 6 gram per individual as recommended by Chinese dietary guidelines . To obtahttp://cdc.cma.gov.cn/home.do), as previous studies have suggested that ambient temperature was inversely associated with blood pressure [We also obtained the daily mean temperature data for the study counties/districts during the survey date from the publicly accessible China National Weather Data Sharing System . The methods were carried out in accordance with the approved guidelines. All the data management and statistical analyses were performed using R software Version 3.1.0 . All statistical tests were two-sided and p = 0.01 for t-test); hypertensive subjects had higher BMI compared to normotensive subjects ; more hypertensive subjects were males, had low education level, used unclean fuels for domestic cooking; fewer hypertensive participants were alcohol drinkers, had ever experienced environmental tobacco exposure, vigorous physical exercises, better ventilation at home. However the distribution of household income, ambient temperature on the survey date, smoking status, and dietary salt restriction was not statistically different among the two groups.A total of 5600individuals were originally invited to participate in the cross-sectional survey, among which 5585 completed the interview, and were included in the subsequent analyses, yielding a response rate of 99.7%. Among them, 1153 were identified as hypertensive subjects based on the criteria described before. The distribution of socio-demographic characteristics and major risk factors of hypertension among hypertensive and normotensive subjects is shown in We also found significant associations of domestic incense burning with increased arterial blood pressures .Compared with non-users of incense, those with domestic incense burning had higher diastolic and systolic blood pressures, the estimates were 1.26 mmHg (95% CI: 0.69–1.83) and 1.02 mmHg (95% CI: 0.06–1.99), respectively. We also found a clear dose-response relationship between the frequency of domestic incense burning and the blood pressures, for example, people with daily exposure to incense burning had higher blood pressure, after controlling for potential confounding factors, the diastolic and systolic blood pressures among subjects with daily incense burning increased by 1.28 mmHg (95% CI: 0.5–2.05) and 2.09mmHg (95% CI: 0.79–3.39), respectively. Generally similar effects were observed for males and females, and generally more significant effects were observed for diastolic blood pressure; for instance, the estimated diastolic blood pressure effects of incense users were 0.95 (95% CI: 0.26–1.63) for males, 2.05 (95% CI: 1.00–3.10) for females, respectively; we did not find significant effect of incense burning exposure on systolic blood pressure among females, which might be due to relatively smaller sample size in this subgroup. In the sensitivity analyses, we found comparable effect estimates when controlling for the simulated family history of hypertension in the models (results not shown). Our analysis restricting to nonsmokers also yielded a similar result .This was the first study to provide epidemiologic evidence of the effects of domestic incense burning on risk of hypertension and arterial blood pressure. The findings supported our hypothesis of the presence of an association of domestic incense burning with elevated risk of hypertension and arterial blood pressure, and it seemed that women were more vulnerable to these effects than men.A few previous studies have linked exposure to indoor air pollution with risk of hypertension ,6,9,10, Findings from this study have some important public health implications. Though it is impractical to discourage this religious and ritual activity, findings from this study suggested that it is important to disseminate the results of the adverse health effects of incense burning to the users and provide appropriate methods to reduce the exposure and associated adverse health effects, and future studies are warranted to develop the least harmful types of incense as well as strategies to improve indoor air quality when burning incense indoors .Though we observed that the hypertensive subjects were relatively older than the normotensive subjects, our further analysis found a comparable prevalence rate of incense burning among the older (over 50 years) and younger (<50 years) groups (79.1% in older group vs. 73.4% in younger group for incense burning) and (17.5% in older group vs.19.6% in younger group for daily incense burning), indicating that age should not have distorted the results to a great degree.This study suggested a more pronounced hypertension associated with domestic incense burning among women. Similar findings have also been reported in previous studies on the effects of incense burning on lung carcinomas ,32, and 2.5) to far exceed the ambient concentration guidelines proposed by the World Health Organization [2.5 exposure and blood pressure among women in rural China, and found a significant association between PM2.5 exposure and increased systolic and diastolic blood pressures [2.5 and PM10 with arterial blood pressure and hypertension, and found that per 3.9 μg/m3 increase in PM10 was associated with increase of 1.1 mmHg and 0.8 mmHg in systolic and diastolic blood pressures, respectively. Using a large database from three northeastern Chinese cities, Dong et al., investigated the association between various air pollutants and blood pressure and hypertension, and found that exposure to PM10 was significantly associated with increased blood pressure and higher risk of hypertension [Some studies analyzing the emissions from incense burning have suggested volatile organic compounds and particulate matter to be the deleterious components ,43,44,45nization ,47, and nization ,49, whicressures . In a coressures  investigrtension ,51 and Drtension .The main strength of this study included its population-based study design, relatively large sample size, detailed information on lifestyle factors that were established or potential risk factors of hypertension. The use of domestic incense was quite common in the participants, providing a good opportunity to evaluate the association between incense use and hypertension, which has not been reported previously.A few limitations should be noted. First, due to cross-sectional nature of the study design, residual or unmeasured confounding was possible, and causality should be inferred with caution. Because incense burning was one practice related to religious and cultural brief, it was possible that there were some differences in other characteristics between the participants who used incense and those who did not, resulting in potential unmeasured confounding factors in our analysis. Second, selection and information biases were possible. However, we have attempted to reduce these biases as much as possible through strict quality control and assurance processes. The interviewers were strictly trained to conduct survey with the same degree of questioning for all participants, and the study was introduced as a general health study. Third, the information of family history of hypertension was not available to our analysis; our sensitivity analysis based on simulated information suggested that it should not have affected our result to a great extent. Finally, we did not collect the information on some important factors that were likely to influence the results, such as the type of incense, the duration of incense burning, isolation between incense burning room and living room, exposures at temples, time spent at home each day, survey time (morning or evening), noise, anxiety, psychological stress, work stress, anti-hypertensive medications and fasting status, more studies are needed to further investigate this research question.In summary, our study provides epidemiologic evidence that exposure to smoke from domestic incense burning may contribute to the risk of hypertension and increased blood pressure, and women were more vulnerable to these effects than man.


P < 0.001]. After 1:1 matching, the incidence of postoperative acute kidney injury was still significantly lower after laparoscopic liver resection than after open liver resection . The postoperative inflammatory marker was also lower in laparoscopic liver resection than in open liver resection in matched set data . Our findings suggest that the laparoscopic technique, by decreasing the inflammatory response, may reduce the occurrence of postoperative acute kidney injury during liver resection surgery.The inflammatory response has been shown to be a major contributor to acute kidney injury. Considering that laparoscopic surgery is beneficial in reducing the inflammatory response, we compared the incidence of postoperative acute kidney injury between laparoscopic liver resection and open liver resection. Among 1173 patients who underwent liver resection surgery, 222 of 926 patients who underwent open liver resection were matched with 222 of 247 patients who underwent laparoscopic liver resection, by using propensity score analysis. The incidence of postoperative acute kidney injury assessed according to the creatinine criteria of the Kidney Disease: Improving Global Outcomes definition was compared between those 1:1 matched groups. A total 77 (6.6%) cases of postoperative acute kidney injury occurred. Before matching, the incidence of acute kidney injury after laparoscopic liver resection was significantly lower than that after open liver resection [1.6% (4/247) vs. 7.9% (73/926),  As one of the most complex major abdominal surgeries, laparoscopic liver resection (LLR) is arguably the last frontier in minimally invasive surgery. Recently, owing to advances in surgical techniques, the use of LLR has been increasing rapidly . AlthougPostoperative acute kidney injury (AKI) is a serious postoperative complication with a detrimental impact on patient outcomes –9. AfterOne of the underestimated advantages of laparoscopic surgery is that it results in less immunologic modulation ,18. The After this retrospective observational study was approved by the institutional review board of Asan Medical Center, the data of all patients who underwent either OLR or LLR for primary hepatocellular carcinoma were reviewed. Informed consent was waived due to the retrospective nature of our study. LLR has been performed in Asan Medical Center since July 2007. Considering the learning curve of the surgeon, we included LLRs performed between January 2008 and October 2015. OLRs performed during the same period were also included. All surgeries were performed consecutively by a single surgeon (KHK). Of the 1184 identified patients, we excluded those with chronic kidney disease (CKD) of stage 3 or higher, as determined by the consulting nephrologists (n = 11) . As the We collected the patients’ baseline characteristics, laboratory variables, and perioperative variables by using our institution’s patient record system. The baseline characteristics included patient age, sex, body mass index (BMI), model for end-stage liver disease (MELD) score, Child-Turcotte-Pugh grade, and comorbidities . Variables related to the patients’ tumor characteristics included the largest tumor size and alpha-fetoprotein level. Laboratory data included hemoglobin, platelets, prothrombin time, serum creatinine, erum albumin, total bilirubin, white blood cell (WBC) count, aspartate transaminase, alanine transaminase, sodium, potassium, glucose, and total cholesterol. Intraoperative data included the extent of resection (major and minor), year of surgery, volume of infused fluids , amount of transfusion, urine output, and operation time. Blood tests including serum creatinine, complete blood cell, and liver function tests were routinely conducted preoperatively as part of patient evaluation. Baseline laboratory values including kidney function were determined as the most recent measurements before the surgery.®; Fresenius Kabi, Bad Homburg, Germany)] were infused depending on individual practitioner preferences. The total volume of hydroxyl ethyl starch did not exceed 20 mL/kg. Packed red blood cells were transfused when the patient’s hemoglobin was <8 mg/dL. For patients with a history of ischemic heart disease, hemoglobin levels were maintained at >10 mg/dL. Central venous pressure was maintained at <5 mmHg. If the mean arterial blood pressure was <65 mmHg, vasoactive drugs  were administered.General anesthesia was conducted with thiopental sodium 4–5 mg/kg, fentanyl 1–2 μg/kg, and rocuronium 0.6–1.2 mg/kg. Anesthesia was maintained with sevoflurane 2–4 vol% in 50% air/oxygen. Invasive arterial and central venous pressure monitoring were routinely conducted. Crystalloids  and colloids  after adjustment for clinical covariates (P = 0.004), albumin concentration , and transfusion amount  were also independently associated with the occurrence of postoperative AKI.In multivariable analysis, LLR was found to be an independent contributor to the lower occurrence of postoperative AKI [odds ratio (OR) 0.228; 95% confidence interval (CI) 0.082–0.635, variates . Higher P = 0.094). The numbers of patients with CKD stage 3, 4, and 5 were 1 (0.5%), 1 (0.5%), and 2 (0.9%) after LLR and 24 (2.6%), 3 (0.3%), and 11 (1.2%) after OLR, respectively. ICU admission, length of hospital stay, and mortality were not statistically different between the LLR and OLR groups  patients in the LLR group and in 38 (4.1%) patients in the OLR group  vs. 14/222 (6.3%), P > 0.100 for all).Postoperative outcomes including CKD, renal replacement therapy, hospital stay, ICU admission, and mortality were not significantly different between the two groups after matching . This result remained consistent after adjustment for important preoperative and intraoperative confounders with propensity score matching analysis. The significance of LLR was consistently found during multivariable analysis. In addition, there was a significant association between LLR and lower WBC count before and after matching.To date, only a few studies have reported the exact incidence of AKI after LLR despite the recent increase in the number of LLR surgeries performed. Our results showed that the incidence of AKI after LLR was 1.6% according to the KDIGO criteria. In a previous literature review of a total of 2804 patients undergoing LLR, only one case of renal failure was reported . HoweverAlthough the exact cause of AKI in patients with LLR has not been established, we presumed that the attenuation of the postoperative inflammatory response might have affected the occurrence of postoperative AKI after LLR. Previous studies have shown that laparoscopic surgery, by decreasing surgical trauma, induces less systemic inflammatory response than open surgery . Some stThere are theoretical concerns that the laparoscopic technique may predispose patients to AKI during liver resection, because LLR is not only technically difficult to perform but also needs a long duration of pneumoperitoneum. Previous studies have shown that creatinine clearance and urine output were decreased during pneumoperitoneum . In addiP < 0.001) [Transfusion has been known to be one of the major contributors to postoperative AKI development. A recent study demonstrated that the maximum postoperative creatinine level of the LLR group was significantly lower than that of the OLR group  ,40. The The current study also showed that diabetes, higher BMI, and lower postoperative albumin are risk factors for postoperative AKI. Diabetes is a well-known risk factor for AKI after various types of surgery including liver resection . In termThe association between postoperative AKI and long-term adverse renal outcomes including CKD has been demonstrated in previous studies ,44. The The current study has several limitations. First, as this study was retrospective in nature, we used propensity score matching to mitigate selection bias. However, not all confounding factors could be controlled. Second, because the current findings were from an observational analysis, we could not verify the causal relationship between LLR and its protective effect against postoperative AKI. Third, as this was a single-center study with all surgeries conducted by one experienced surgeon, caution should be exercised when interpreting the results of this study.In conclusion, this propensity score-matched observational study showed that the incidence of postoperative AKI was lower after LLR than after OLR. The laparoscopic technique may play a protective role against the occurrence of postoperative AKI during liver resection surgery.S1 FileWe provide complete data set of our study after anonymization.(XLSX)Click here for additional data file.


To examine the distribution of intraocular pressure (IOP) in a normal population and the associations of IOP with other ocular and systemic parameters.Out of 3468 participants of the population-based cross-sectional Beijing Eye Study 2011 we selected those individuals without glaucomatous optic neuropathy. The study particpants underwent a detailed ophthalmologic and systemic examination. IOP was measured by air puff non-contact tonometry.P<0.001), higher blood concentration of glucose (P = 0.03) and triglycerides (P<0.001), higher diastolic blood pressure (P<0.001), higher pulse rate (P = 0.003) and higher quantity of alcohol consumption (P = 0.004), and with the ocular parameters of larger central corneal thickness (P<0.001), more myopic refractive error (P = 0.01) and steeper anterior corneal curvature radius (P = 0.006). IOP decreased significantly by 0.50 mmHg and 0.76 mmHg for each increase in age by 10 years and each increase in corneal curvature radius by 1.0 mm, respectively. The range of the mean ± 2 standard deviations of the IOP adjusted for the parameters of the multivariable model was 9.0 to 18.1 mmHg versus 9.2–20.2 mmHg for the unadjusted IOP. In the age group of 50 to 55 years, the age-adjusted IOP range (mean ± 2 standard deviations) was 9 to 18 mmHg, and in the age group of ≥75 years, it was 8 to 18 mmHg.The study included 3135 eyes of 3135 participants with a mean age of 64.1 ± 9.6 years (mean ± standard deviation). The mean IOP was 14.7 ± 2.8 mmHg. The 95% percentile and 97.5% percentile of the IOP distribution decreased from 20 mmHg / 21 mmHg in individuals aged 40 to 54 years to 18 mmHg / 19 mmHg in individuals aged ≥80 years. In multivariable analysis, higher IOP was associated with the systemic parameters of younger age (IOP physiologically depends on a multitude of systemic and ocular factors including age and blood pressure. These physiological associations of the IOP may be taken into account in the definition of the normal range of the IOP. Glaucoma can be defined as an optic neuropathy in eyes in which the intraocular pressure (IOP) is higher than the pressure tolerance of the retinal ganglion cells axons in the lamina cribrosa in the optic nerve head . The traThe definition of the normal range of IOP was based on a large-scaled hospital-based study performed by Leydhecker and colleagues in 1958, and on an investigation conducted by Hollows and Graham in 1966, who used a rigorous population-based sampling method , 7. ThesIf a variable such as the IOP is taken to define the presence of a disease and if this variable in the normal population shows physiological associations with a variety of other parameters, primarily not correlated with the disease itself, these associations should be taken into account when the normal range of the variable is defined and used for the definition of a disease. Previous studies on normal-pressure glaucoma did not always consider the physiologic associations between IOP and the other ocular and systemic parameters , 5, 19. The Beijing Eye Study 2011 is a population-based cross-sectional study which was carried out in a central region of Beijing (Haidan region) and in a rural area South of Beijing . The Medical Ethics Committee of the Beijing Tongren Hospital approved the study and written informed consent was obtained from all participants. All inhabitants of the study regions with an age of ≥ 50 years  were eligible to participate.The study population included 3468 individuals (1963 (56.6%) women) (response rate: 78.8%) with a mean age of 64.6 ± 9.8 years . The series of examination started with an interview containing standardized questions on the socioeconomic background including the family status, level of education  and self-reported income, on previous and current consumption of alcohol, smoking habits, and on the history of major systemic diseases such as arterial hypertension, diabetes mellitus, hyperlipidemia, cardiovascular disorders and cerebral infarction. We measured the body height and weight, the blood pressure and the concentrations of lipids, glucose, glycosylated hemoglobin HbA1c, creatinine and C-reactive protein in blood samples obtained under fasting conditions. Diabetes mellitus was defined as a plasma glucose concentration of ≥7.0 mmol/L or by a self-reported history of physician-based diagnosis of diabetes mellitus or by a history of medical treatment of diabetes. Arterial hypertension was characterized by a systolic blood pressure of ≥140 mm Hg and/or a diastolic blood pressure of ≥90 mm Hg, and/or a self-reported current treatment of arterial hypertension. The mean blood pressure was calculated as the sum of the diastolic blood pressure plus one third of the pressure amplitude.The ophthalmological examinations consisted of refractometry, non-contact tonometry , slit lamp examination of the anterior and posterior segment of the eye, digital photography of the cornea, lens, macula and optic disc , spectral domain optical coherence tomography  of the macula and optic nerve head, and biometry for measurement of the central corneal thickness and corneal curvature, anterior chamber depth, lens thickness and total axial length . Tonometry and refractometry carried out by an experienced technician were performed three times, and the means of the measurements were taken for further statistical analysis.2] + 0.16 x Diastolic Blood Pressure [mmHg]– 0.18 x Age [Years] - 1.91” [The degree of cataract was determined using the lens photographs. The degree of nuclear opacities was assessed in 6 grades using the grading system of the Age-Related Eye Disease Study . On the  - 1.91” . Glaucom - 1.91” , 26. RelThe only exclusion criterion for the present study was the presence of glaucoma. The data of the right eye of each study participant was taken for statistical analysis.Adjusted = IOPMeasured−((Non-Standardized Correlation Coefficient B) x ) + Intercept of the Regression Line of the Y-Axis”. We determined the standardized regression coefficient beta, the non-standardized regression coefficient B, and the 95% confidence intervals (CI). All P-values were two-sided and considered statistically significant when the values were less than 0.05.The statistical analysis was carried out using a software package . In a first step, we calculated the mean values ± standard deviations of the main parameters, and we determined the normal range of the IOP defined as the mean ± 2 standard deviations. In a second step, we assessed associations between the IOP and other ocular and systemic parameters in a univariate mode. In a third step, we re-tested in a multivariate analysis the associations between IOP and all parameters which were significantly associated with the IOP in the univariate analysis. Out of the list of independent parameters, we first dropped step by step parameters with a high collinearity (defined as a variance inflation factor (VIF) of higher than 5), before we deleted those parameters which were no longer significantly correlated with the IOP. In a fourth step, we used the final model to adjust the raw IOP readings for their dependency on the parameters of the final model. We applied the general formula “IOPP <0.001), less myopic , and had a shorter axial length .Out of the whole population of the Beijing Eye Study (n = 3468), 3135 eyes of 3135 participants (90.4%) fulfilled the inclusion criteria. The age (mean ± standard deviation) was 64.1 ± 9.6 years (range: 50–93 years), and the mean refractive error was -0.17 ± 2.03 diopters (range: -21.0 to +7.00 diopters) . Axial lIn the whole study population, the mean IOP was 14.45 ± 2.70 mmHg (mean ± standard deviation). The IOP range defined as the mean ± 2 standard deviations was 9.17–19.74 mmHg) . The IOPP<0.001) (P<0.001), heavier body weight (P<0.001), higher body mass index (P<0.001), larger waist and hip circumference (P<0.001), higher blood concentrations of glucose (P<0.001), glycosylated hemoglobin HbA1c (P<0.001), low-density lipoproteins (P<0.001), triglycerides (P<0.001) and cholesterol (P<0.001), lower blood concentrations of high-density lioproteins (P<0.001), higher prevalence of diabetes mellitus (P<0.001), higher systolic, diastolic and mean blood pressure (P<0.001) (P<0.001), higher pulse rate (P<0.001), higher number of smoking package years (P<0.001), smoking ever (P<0.001), and higher frequency and quantity of alcohol consumption (P<0.001). Higher IOP was correlated with the ocular parameters of thicker cornea (P<0.001) (P = 0.022), shallower anterior chamber depth (P = 0.002), thinner lens thickness (P = 0.001), and higher prevalence of diabetic retinopathy (P = 0.042)   Figs 2  P<0.001 P<0.001) , rural rP<0.001) , higher P<0.001) , more my= 0.042) .P = 0.86), lens thickness (P = 0.87), anterior chamber depth (P = 0.46), ever smoking (P = 1.00), glycosylated hemoglobin HbA1c (P = 0.59), blood concentration of glucose (P = 0.85), hip circumference (P = 0.16), alcohol consumption frequency (P = 0.82), history of arterial hypertension (P = 0.12), and smoking package years (P = 0.20). In the final model, higher IOP was associated with the systemic parameters of younger age (P<0.001), higher blood concentration of triglycerides (P<0.001), higher mean blood pressure (P<0.001), higher pulse rate (P = 0.001), higher drinking quantity of alcohol (P = 0.006) and higher prevalence of diabetic mellitus (P = 0.004), and with the ocular parameters of larger central corneal thickness (P<0.001), more myopic refractive error (P = 0.01) and steeper anterior corneal curvature radius (P<0.001) .The multivariate analysis included IOP as the dependent variable and all those parameters as independent variables which were significantly associated with the IOP in the univariate analysis. Due to collinearity, we first dropped the parameters with a VIF higher than 5, including body weight (VIF: 141), body mass index (VIF: 107), blood concentration of low-density lipoproteins (VIF: 28.7), blood concentration of cholesterol (VIF: 35.4), blood concentration of high-density lipoproteins (VIF: 6.5), and waist circumference (VIF: 5.1). Due to lack of statistical significance we then dropped step by step the parameters of rural/urban habitation (P<0.001) . If refrP<0.001), higher mean blood pressure (P<0.001), higher pulse rate (P<0.001), higher prevalence of diabetic mellitus (P = 0.004), more myopic refractive error (P = 0.001), larger central corneal thickness (P<0.001) and flatter cornea (P<0.001) . Using the model, the equation for adjusting the IOP readings to the single individual was: “IOPAdjusted = IOPMeasured + 0.054 x (Age (Years)– 64.15) - 0.033 x (Mean Blood Pressure (mmHg) - 90.25) - 0.017 x (Pulse Rate (Beats/min) - 72.56) - 0.426 x -0.148) + 0.071 x (Refractive Error (Diopters)—(-0.17)) - 0.038 x  - 532.3) + 0.756 x  - 7.61) -0.908”. The mean adjusted IOP was 13.6 ± 2.3 mmHg, and the range of the mean ± 2 standard deviations was 9.0 to 18.1 mmHg  with younger age (P<0.001) . If refr8.1 mmHg .In our population-basd study on non-glaucomatous individuals, higher IOP was associated  with younger age, higher blood concentration of glucose and triglycerides, higher mean blood pressure, history of diabetes mellitus, higher pulse rate and higher drinking quantity of alcohol, thicker central corneal thickness, more myopic refractive error, and smaller anterior corneal curvature radius. Mean IOP decreased by 0.50 mmHg mmHg for each decade increase in age. It further decreased by 0.76 mmHg for each increase in corneal curvature radius by 1mm. IOP increased by 0.33 mmHg, 0.17 mmHg, 0.43 mmHg and 0.38 mmHg for each increase in mean blood pressure by 10mmHg, pulse rate by 10 beats/min, presence of diabetes mellitus and central corneal thickness by 10μm, respectively. After adjusting the raw IOP readings for their associations with parameters measurable under routine clinical conditions, the range of IOP within the range of the mean ± 2 standard deviations was between 9.0 and 18.1 mmHg.The findings confirmed results obtained in previous hospital-based and population-based investigations and extend them for associations of IOP with a panoply of ocular and systemic variables. The mean value of the raw IOP readings of 14.5 ± 2.7 mmHg with a ±2 standard deviations range of 9.2–19.7 mmHg in our study population agreed with the normal range of IOP readings for Caucasians as reported by Leydhecker and colleagues with a mean IOP of 15 to 16 mmHg and a range of 10 to 21 mmHg in their classical study dating back to the year of 1958 .Our study also confirmed previous studies in which higher IOP was correlated with higher blood pressure, such as in the Beaver Dam Study, the Blue Mountains Study, the Tanjong Pagar Study, the Los Angeles Latino Eye Study, the Singapore Malay Eye Study and a recent investigation using the UK biobank , 27–29. The relationship between higher IOP and thicker central corneal thickness has long been described and several equations have been postulated to correct the measured IOP reading for its dependence on central corneal thickness , 32–36. The association between higher IOP and more myopic refractive error or longer axial length is in agreement with previous studies , 18. TheThe inverse relationship between higher IOP and older age may be of clinical importance , 18, 29.Limitations of our study should be discussed. First, IOP was measured by air puff non-contact tonometry. Previous studies have shown that IOP readings obtained by non-contact tonometry can differ from those measured by Goldmann applanation tonometry. Second, a major concern in any population-based study is nonparticipation. The participation rate in the Beijing Eye Study 2011 of 78.8% was however relatively high so that it may be unlikely that non-participation had a major effect on the results. Third, our investigation had a cross-sectional design so that the relationships found between the IOP and other parameters could be described only as associations and not as causal relationships. Fourth, several parameters such as socioeconomic factors were assessed in an interview with questionnaires. Fifth, the individuals included into our study and those not included differed in some baseline characteristics such as age, refractive error and axial length . These dIn conclusion, IOP depends on a multitude of factors including age and blood pressure. These associations may be taken into account in the definition of the normal range of IOP and in the definition of so called normal-pressure glaucoma.


The aim of this study is to characterize the presence of exercise oscillatoryventilation (EOV) and to relate it with other cardiopulmonary exercise test(CET) responses and clinical variables.2 > 34 and peak VO2 < 14 ml/kg/minwere used to assess patients' severity.Forty-six male patients  with heart failure were recruited toperform a maximal CET and to correlate the CET responses with clinicalvariables. The EOV was obtained according to Leite et al. criteria andVE/VCO2 > 34 and peak VO2 < 14 ml/kg/min in14 and 10 patients, respectively. There was no difference in clinical andCET variables of the patients who presented EOV in CET when compared tonon-EOV patients. Also, there was no difference in CET and clinicalvariables when comparing patients who presented EOV and had aVE/VCO2 slope > 34 to patients who just had one of theseresponses either.The EOV was observed in 16 of 24 patients who performed the CET, as well asVE/VCO2 and higher VE/VCO2 slope values, butthey showed no difference on other prognostic variables. As well, there wasno influence of the presence of EOV on other parameters of CET in thispopulation, suggesting that this variable may be an independent marker ofworst prognosis in HF patients.The present study showed that there was an incidence of patients with EOV andlower peak VO An important outcome of this peripheral musculardysfunction is the reduced functional capacity, negatively affecting the patients'autonomy and consequently their quality of life.Cardiovascular ischemic events are the leading cause of chronic heart failure (CHF),which is a syndrome that is generally characterized by the classic left ventricularsystolic impairment with consequent muscular peripheraldysfunction because it may reflect the inspiratory muscleweakness, usually witnessed in them. Furthermore, the handgrip strength has alsobeen reported as an isolated parameter of CHF severity. In this context, we mayhighlight the significance of the cardiopulmonary exercise test (CET). It is auseful tool that induce physiological responses in exercise conditions that mightnot appear at rest conditions.Many parameters are known as independent markers of severity and predictors ofmorbidity and mortality in this group of patients. The maximal inspiratory pressurehas been shown as an independent variable to quantify the survival rate of thesepatients2),6. Another powerful CET variable that may reflect theseverity of these patients and, more specifically, the pulmonary congestion is theventilation production (VE)/ carbon dioxide production (VCO2) slope,which shows the ventilatory inefficiency, mainly in those who have values > 34,strongly characterizing pulmonary congestion,8. Also, the presence of oscillatory ventilationin rest or during exercise is being considered as an important variable withprognostic value of CET,10. Besides this importance, there is still nostandardization for obtaining and interpreting exercise oscillatory ventilation(EOV).From the parameters obtained in the CET, many of them have been described asnegatively influenced by CHF progression. It is quite well known that patients withCHF present low functional status and exercise capacity, with reduced peak oxygenconsumption , exercise-inducedasthma, unstable angina or significant cardiac arrhythmias, and myocardialinfarction within the previous six months; also, none of the subjects weretobacco users, alcohol dependents, or users of addicting drugs. No patient hadbeen submitted to cardiovascular rehabilitation. All subjects presented the sameclinical management, optimized medications, and were clinically stable. Theeligible participants signed a written informed consent and the study protocolwas approved by the Ethics Committee of Institution (protocol 238/06 andprotocol 970.098).Forty-six men with CHF were recruited by clinical assessment. Inclusion criteriawere previous history of stable symptomatic CHF due to left ventricular systolicdysfunction, documented for at least six months (left ventricular ejectionfraction [LVEF]: < 45%), New York Heart Association (NYHA) class betweenII-III, and clinical stability for at least three months. Patients were excludedfrom study if they had clinical and/or functional evidence of obstructivepulmonary disease . In the day before the test,patients were warned to avoid the intake of stimulating drinks, not to performphysical activity, and to have light meals and at least 8 hours of sleep. First,the volunteers were familiarized with the experimental set and involvedresearchers. Before the test begun, the patients were examined to verify if therecommendations were followed. Then, the systolic and diastolic arterial bloodpressure and the peripheral oxygen saturation were measured, and it wasperformed auscultation.1, and FEV1/FVC ratio, were carried out using theCardiO2 System .For comparative purposes, reference values from Knudson etal., expressed in body temperature pressurestandard (BTPS) conditions, were used. Carbon monoxide diffusion capacity (CMDC)was assessed by simple respiration model and static volumes were assessed bywhole-body plethysmography. Technical procedures and the acceptability andreproducibility criteria were defined according to norms recommended by theAmerican Thoracic Society.Pulmonary function tests, measuring slow vital capacity (SVC), FVC,FEV2 System), using the BreezeSuite 6 software package. Tidal volume was obtained by a Pitot pneumotachometerconnected to the CardiO2 System and attached to a facial mask - whichwas selected considering the volunteer's face size and providing an adequate fitin order to avoid air leakage. The device presents in real time applied powervalues (W) and pedaling speed (rpm), as well as VO2, VCO2,minute ventilation (VE), heart rate (HR), and blood oxygen saturation(SpO2). Ventilatory equivalent values (VE/VO2 andVE/VCO2), respiratory exchange ratio (RER), end-tidal partialpressure of oxygen (PETO2) and carbon dioxide(PETCO2), flow-volume (FV), and respiratory rate (RR)were also calculated and registered. The power applied to the cycle ergometerduring exercise protocols was controlled by the system through an interface withthe bicycle.Ventilatory and metabolic variables were obtained by a computer connected to anergospirometric measurement system  under the following situations: 1) V-slope: breaking point fromlinearity in VO2 and VCO2 correlation curves; 2)VE/VO2: nadir point of this ratio, ensuring that a systematicincrease occurs from it; and 3) PETO2: nadir point ofthis variable, from which a systematic increase begins. The CET data wereset from the beginning of the ventilatory and metabolic variables responsesto power output increments till the end of the exercise. Analysis of eachobserver was performed in an independent manner, on a 15 inches monitor connected to the MedGraphics software.Visual analysis of VO.The presence of periodic breathing was obtained by the analysis ofventilation data, and it was confirmed if there were three consecutivecycles with minimal average amplitude of 5 l in these data , as suggested by Leite etal.2 data were analyzed from the beginning of the exercisetill peak. Data were input into spreadsheet software (Microsoft Excel) tocalculate VE/VCO2 slope via least squares linear regression .VE and VCO2 > 34 and peak VO2 < 14 ml/kg/min wereused to assess patients' severity.VE/VCOStatistical analyses were performed using the SigmaPlot version 11.0.0.007 (forWindows(r)) with level of significance set at 0.05. Data were submitted to anormality test (Shapiro-Wilk). As a normal distribution was observed, parametricstatistical tests were used. For intergroup comparisons, the t-Student paredtest was applied. Demographics, anthropometrics, and clinical data werepresented as means with standard deviation.Forty-six male patients were recruited; 22 patients were excluded and 24 wereincluded in the present study .and VE/VCO2 slope> 34 when compared to patients with EOV or VE/VCO2slope > 34, as shown on Also, there was no difference on age, clinical variables and parameters of the CETdata obtained from patients with EOV and VE/VCO2 >34 and those with EOV or VE/VCO2 > 34; iii) thepresence of EOV and peak VO2 < 14 ml/kg/min in 25% of the patients, aswell as EOV and VE/VCO2 > 34 in 46% of them.The present study's main findings are: (i) no difference between CET variables inpatients with EOV and non-EOV; (ii) the absence of difference on functionalvariables between CHF patients with EOV 2 (15.1 ml/kg/min), presenting low peak workload values. Theliterature shows that CHF patients exhibit a low peak VO2 as amarker of exercise intolerance caused by many factors of this disease as the lowcardiac output, pulmonary congestion, and alterations of metabolism on peripheraland ventilatory muscle fibers that lead to a muscular dysfunction with impact onexercise tolerance. Peak VO2 is also a prognostic variable ofCET,6.Anthropometric data of CHF patients showed that they were overweight and that 15 ofthe 24 evaluated patients were classified as NYHA functional class III. Furthermore,they had a poor exercise performance on CET, which can be seen by the value of peakVO2 > 34 and peak VO2< 14 ml/kg/min. One study has showed that the presence of thecombination EOV and VE/VCO2 > 34 is particularly more alarming becauseof the risk for adverse cardiac events. Otherwise, our results do not agreewith the literature when it comes to the worst response of CET variables on EOVpopulation, described as lower peak VO2, higher VE/VCO2 slope,and lower rest and peak PETCO2, when compared to non-EOVpopulation. Hypotheses for these findings are theheterogeneity of exercise protocols in the literature and the absence of a goldstandard to verify the presence of EOV in patients with profile and clinical statussimilar to our subjects. In a meta-analysis about the assessment of EOV, Cornelis etal.have suggested the use of Corrà et al. criteria, although none of thecriteria available appears to be superior. This criterion should be applied to aconstant load protocol since the VE data may not vary more than 15% compared to themean of rest VE data, which is a physiological response expected on the incrementalexercise protocol. Also, the presence of EOV may be longer than 60% of the exercisetime. For the results presented, we used Leite et al. criteria because theseare not so subjective since the presence of EOV is not calculated through time, butas a continuous variation of the VE data with an waxing and waning pattern, and itis not influenced by the time of its appearance, but by its amplitude. Finally, webelieve that Leite et al. criteria could be more appropriate to assess EOVduring incremental exercise test.Other CET variables showed similarities between our study and the literature,specifically when it comes to the coexisting presence of EOV and other badprognostic variables, such as VE/VCO. The reduced cardiac output leads to adelayed lung-chemoreceptor circulation ; this and theinefficient control of VE caused by increased chemosensitivity lead to anexaggerated response of the ventilation. From the hemodynamic view, there isan uncoupling on the right ventricle to lung circulation, and a pulmonary edema dueto a high ventricle filling pressure even when these patients are clinically stableand on optimized drug therapy.Even though the trigger mechanisms of EOV are not totally understood, the mainhypotheses are circulatory delay, increased chemosensivity, increased ergoreflexsignaling, and/or pulmonary congestion2 slope. Additionally, the presence of EOV combinedwith higher values of VE/VCO2, mainly > 34, is even more alarming andpowerful to predict adverse cardiac events on CHF population, characterizing thatthese two ventilatory variables reflect the worst control on ventilation andventilatory inefficiency and may be translated into a better prognosticdefinition. In the present study, the comparison betweenpatients with EOV and VE/VCO2 > 34 and patients with only one of theseshowed no statistical difference on CET ventilatory variables, age, nor theirclinical status, such as LVEF. It is already known that the presence of EOV is notaltered by LVEF, since Guazzi et al. showed no difference in incidence of EOV in CHFpatients with normal or reduced LVEF. It suggests the power of EOV as an independentCET marker of worst prognostic because it represents the poor hemodynamic andventilatory adjust to physical exercise and did not correlate with other ventilatoryand metabolic CET variables with prognostic values.Studies that evaluated the prognostic power of EOV obtained by the analysis ofventilatory pattern of CHF patients when submitted to a CET suggest that thisvariable seems to be the most important in the CET, even with better prognosticvalues than VE/VCO and selectivepulmonary vasodilator (sildenafil) have shown some attenuation on EOV. In anotherstudy based on aerobic training, for three months, 71% of the patients with stablecongestive heart failure showed a good EOV response. These studiesevaluated stable patients on optimized drug therapy, which suggests that maybe EOVdoes not respond to standard treatment for CHF, requiring other approaches thanpharmacological interventions, such as physical exercise.Some studies focused on treatment of EOV and showed that the pathological pattern ofventilation in EOV population can be modulated and even disappear. Three studiesevaluating pharmacological therapy with inodilator Based on the present study's findings, it is important to encourage further studiesabout EOV in CHF and other patients for a better comprehension of the role of EOV,as well as to establish a gold standard pattern to verify the presence of thisvariable in different diseases and levels of severity. Finally, this knowledgeimproves therapeutic strategies.The absence of gold standard in obtaining EOV must be considered, also some toolto evaluate peripheral muscular strength would give information that could helpthe interpretation of the findings. Results may not be extrapolated to moresevere patients. Finally, this study was made with a convenience sample and moresubjects should be recruited to consolidate our findings.2 and higher VE/VCO2 slope values, but there was nodifference on other prognostic variables. In addition, no influence of the EOVpresence on other parameters of CET in this population was observed, suggesting thatthis CET variable may be an independent marker of severity in CHF patients.The present study showed that there was an incidence of patients with EOV and lowerpeak VO


Microalbuminuria (MA) is the earliest clinical evidence of diabetic nephropathy, but most patients in sub-Saharan Africa (SSA) only have access to much cheaper dipstick proteinuria as a means to screen for diabetic nephropathy. The aim of this study was to determine the prevalence and associations of MA among proteinuria-negative type 2 diabetic patients in a SSA setting.In this cross-sectional study, patients with type 2 diabetes screened negative for dipstick proteinuria in a primary healthcare hospital were assessed. Detection of microalbuminuria was carried out in two steps: qualitative detection using special microalbumin urine strip, and quantitative laboratory measurement and calculation of urinary albumin-to-creatinine ratio (UACR). Microalbuminuria was defined as UACR of 30–300 mg/g.A total of 162 type 2 diabetic patients were included. Using quantitative assessment, the prevalence of microalbuminuria was 14.2% (95% CI 8.8–19.6) whereas 26.5% (95% CI 19.8–34.0) had microalbuminuria with urine strip. The mean systolic blood pressure (p = 0.032), diastolic blood pressure (p = 0.032) and serum creatinine concentration (p < 0.001) were higher in people with microalbuminuria as compared to those with normoalbuminuria, whereas the mean body mass index (p = 0.046) and mean eGFR (p < 0.001) were lower in the albuminuria group. In multiple linear regression, eGFR (p = 0.001) and serum creatinine concentration (p = 0.003) were independently associated with increased UACR.One in every seven proteinuria-negative type 2 diabetic patients has microalbuminuria in primary care setting in Cameroon; microalbuminuria is associated with higher systolic and diastolic blood pressure, and declining kidney function. Our results emphasize the urgent need to increase the accessibility to microalbuminuria testing to ensure that all diabetic patients with negative dipstick proteinuria can benefit. Diabetic nephropathy (DN) is a kidney disease characterized by persistent albuminuria, progressive decline in glomerular filtration rate (GFR) and raised arterial blood pressure . DiabetiMicroalbuminuria, an early marker of diabetic nephropathy can progress to macroalbuminuria and ESRD –8 but eaThe aim of this study was to determine the prevalence of microalbuminuria and to identify associated factors, in patients with type 2 diabetes who screened negative for dipstick proteinuria, in the two regional hospitals of the South West Region of Cameroon.This was a hospital-based cross-sectional study conducted at the diabetic clinics of Buea and Limbe regional hospitals. These are the two regional hospitals of the South West Region of Cameroon. Consenting participants coming for routine diabetes follow-up were consecutively recruited. Patients who presented with a febrile illness, overt proteinuria, urinary tract infection, pregnancy, diagnosed or suspected renal, hepatic or other systemic disease were excluded from the study. Those who had done intensive physical activity within the preceding 72 h were ask to come back after 72 h without intensive exercise, for inclusion.2 and classified based on WHO classification fication .A second morning mid-stream urine sample (10 mL) was collected in a container with no preservatives. Collected urine was put immediately into a cooler containing ice pack, and transported to the laboratory for analysis. Samples not analysed on the day of collection were stored at 2–4 °C.® Urinalysis Reagent Strips with 11 parameters. Participants whose samples tested positive for leukocytes, nitrites or glycosuria were treated and urine recollected after 3 weeks, while those with overt proteinuria were excluded. The same urine sample used to assess for proteinuria was used to assess for microalbuminuria. All proteinuric patients tested positive for albuminuria, and they were excluded from the study.During analysis, urine samples were first screened for any urinary indicator of urinary tract infection , overt proteinuria and glycosuria using ACONTwo screening methods  were used to screen for microalbuminuria using the same urine sample. Qualitatively, special microalbumin semi-quantitative urine-testing strips (CYBOW™2MAC) were used to test for microalbuminuria according to manufacturer’s instructions .Quantitatively, microalbuminuria was assessed by determining urine albumin-to-creatinine ratio (UACR) from values obtained from measurements of urine creatinine and urine albumin. Urine creatinine was analysed using the modified kinetic Jaffé method while urine albumin was detected by using acid precipitation reaction between urine albumin and 12% trichloroacetic acid. The turbidity of the precipitate formed was measured spectrophotometrically. UACR was calculated and categorised as microalbuminuria if it was between 30–300 mg/g and normoalbuminuria if it was <30 mg/g based on the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF/KDOQI) guidelines . A seconSerum total cholesterol, high density lipoprotein-cholesterol (HDLc), triglycerides, serum creatinine, and plasma glucose were measured by spectrophotometry and expressed in mg/dL. Low density lipoprotein-LDL (LDLc) was calculated using the Friedewald equation. Renal function was assessed using the estimated glomerular filtration rate (eGFR) calculated from the modification of diet in renal disease (MDRD) formula .α/2 is a constant dependent on the CI, 1.96. And q = 1−p (0.873). Computing the foregoing yields a minimum sample size of 147 participants.The minimum sample size (n) was calculated using the following formula: be 10.7% , E repreData were analyzed using SPSS  Version 17.0 and STATA version 10.1. Results are presented as counts, percentages, means and standard deviations where applicable. Factors associated with microalbuminuria were investigated using linear regressions. A p value <0.05 was considered statistically significant.Of the 162 consenting participants included, 67.3% (109) were females. Participants’ age ranged from 24 to 70 years, with mean age of 55.3 ± 10.2 years ] were positive for microalbuminuria, while quantitative analyses showed that 23 participants [14.2% (95% CI 8.8–19.6%)] had microalbuminuria (UACR 30–300 mg/g). In 28 participants [17.3% (95% CI 7.9–26.8%)], the eGFR was <60 mL/min/1.73 mThe mean systolic blood pressure (p = 0.032), diastolic blood pressure (p = 0.032) and serum creatinine concentration p < 0.001) were higher in people with microalbuminuria as compared to those with normoalbuminuria , higher diastolic blood pressure (p = 0.015), higher serum creatinine (p < 0.001) and lower eGFR (p < 0.001) as shown in Table In multivariable linear regression, only eGFR (p = 0.001) and serum creatinine concentration p = 0.003) were independently associated with increased UACR  is a predictor of rapid progression of microalbuminuria in patients with well-controlled blood pressure. However, like in other studies , 22, 24,Poor glycemic control favors the progression of diabetes complications . AlthougIt is evident that microalbuminuria is a significant problem amongst Cameroonian type 2 diabetic patients in a primary care setting and as such routine screening for microalbuminuria which heralds severe renal dysfunction should be instituted universally in Cameroon. This is important because subtle derangements in kidney function  are potentially preventable and/or reversible by judicious use of angiotesin-converting-enzyme inhibitors for optimal blood pressure control in type to diabetic patients .We acknowledge the following potential limitations: the role angiotensin converting enzyme inhibitor or angiotensin receptor blockers on prevalence of microalbuminuria was not assessed. Also, we could not use HbA1c to evaluated glycemic control because it is not available in these regional hospitals. However, this study to the best of our knowledge is amongst the rare studies in Cameroon that has assessed epidemiology of microalbuminuria in diabetic patients with negative dipstick proteinuria in a primary healthcare setting.One in every seven proteinuria-negative type 2 diabetic patients attending the out-patient diabetic clinics in a primary care setting in Cameroon has microalbuminuria. Microalbuminuria is associated with elevated blood pressure and low eGFR. This study emphasises the urgent need to increase the access to microalbuminuria testing so as to allow all diabetic patient with negative dipstick proteinuria to benefit. It also raises the importance of optimal blood pressure control in diabetic patients so as to prevent associated renal and cardiovascular complications.


CKIP-1 nonsynonymous polymorphism rs2306235 (Pro21Ala) contributes to risk and prognosis of chronic heart failure in a Chinese population.A total of 923 adult patients with chronic heart failure and 1020 age- and gender-matched healthy controls were recruited. CKIP-1 rs2306235 polymorphism was genotyped using PCR-restriction fragment length polymorphism. Additional follow-up data for 140 chronic heart failure patients was evaluated. The rs2306235 G allele was associated with an increased risk of chronic heart failure , especially in patients with hypertension  and coronary heart disease  after adjustment for multiple cardiovascular risk factors. However, rs2306235 polymorphism was not associated with cardiovascular mortality in chronic heart failure (p = 0.875). CKIP-1 rs2306235 polymorphism may be a risk factor for chronic heart failure in a Chinese Han population.Pathological cardiac hypertrophy is an independent risk factor for chronic heart failure. Casein kinase-2 interacting protein-1 (CKIP-1) can inhibit pathological cardiac hypertrophy. Therefore, we investigated whether  Chronic heart failure (CHF) is a complex clinical syndrome with a multifactorial etiology including genetic factors –6. NeverCKIP-1 exhibit hypersensitivity and resistance to pathological cardiac hypertrophy induced by pressure overload, respectively [The pleckstrin homology domain-containing protein casein kinase-2 interacting protein-1 (CKIP-1) was originally identified as a casein kinase-2 α-subunit (CK2α) interacting protein . CKIP-1 ectively . Also, Cectively .CKIP-1 may represent a potential candidate gene for CHF. However, there is no report about association between CKIP-1 polymorphisms and risk of CHF yet. By using the 1000 genome data, we observed rs2306235 polymorphism (Pro21Ala) in CKIP-1, and the 21st amino acid locates in the PH domain of CKIP-1. The PH domain is essential for localization of CKIP-1 in the plasma membrane (PM) and recruitment of multiple proteins to the PM [CKIP-1 rs2306235 polymorphism, we herein performed a case-control study to investigate the association between CKIP-1 rs2306235 polymorphism and risk of CHF in a Chinese population.Pathological cardiac hypertrophy is an independent risk factor for CHF. Considering the crucial role of CKIP-1 in inhibiting pathological cardiac hypertrophy, Baseline characteristics of the study participants were shown in Table p = 0.896 and 0.728, respectively). The frequency of rs2306235 GC and GG genotype was significantly higher in CHF patients than in the controls (Table p = 0.010). After adjustment for age, gender, smoking status, and dyslipidemia, the association was still significant .The rs2306235 genotype distribution was shown in Table p = 0.011; coronary heart disease: OR = 1.37, 95% CI = 1.07-1.76, p = 0.014). Also, rs2306235 G allele was associated with increased risk of CHF in nondiabetic patients . After adjusting for age, gender, smoking status, and dyslipidemia, the association was still significant . However, rs2306235 polymorphism was not associated with risk of CHF in patients without hypertension and coronary heart disease .Echocardiographic examination was performed only in 839 CHF patients. Comparisons of NYHA class, left ventricular ejection fraction (LVEF), and left ventricular end-diastolic diameter (LVEDD) among rs2306235 genotypes were presented in Table p = 0.875, Figure A total of 140 patients were followed up for a median period of 38.7 months. No significant difference in cardiovascular mortality was observed between rs2306235 genotype groups  in f CKIP-1 . This PHCKIP-1 polymorphism may be a potential risk factor for CHF in patients with hypertension and coronary heart disease.Considering that hypertension, coronary heart disease, and diabetes are important risk factors for heart failure , stratifCKIP-1 should been evaluated for their association with CHF. In addition, fewer patients were followed up in a relatively short period of time. Further study with larger patients and long term follow up is needed. Finally, functional assessment of rs2306235 polymorphism was not performed. Therefore, further investigations are necessary to clarify the exact relationship between this variant and heart failure.Several limitations of this study deserve consideration. First, we only enrolled Han Chinese participants with relatively limited sample size. As MAF of rs2306235 varies among different ethnicities, whether our results are generalized to other ethnicity still needs to be clarified. Second, only rs2306235 polymorphism was investigated in the present study, other potentially functional polymorphisms in CKIP-1 rs2306235 polymorphism with an increased risk of CHF in Chinese Han populations. Further investigations in larger cohorts may be required to verify our findings. More comprehensive survey and functional experiments are also needed to illuminate the exact mechanism behind our findings.In conclusion, we firstly revealed the association of A total of 923 patients with CHF were recruited between November 2011 and December 2014 from Xiangya Hospital, Central South University. The eligibility criteria were described previously . PatientA group of 1020 age- and gender-matched healthy controls were also enrolled in physical examination center of the same hospital. The subjects were apparently healthy as assessed by physical examination, serum biochemical testing, and electrocardiogram. Hypertension was defined as participants with a systolic blood pressure (SBP) ≥ 140 mmHg and/or a diastolic blood pressure (DBP) ≥ 90 mmHg or those who received at least one antihypertensive medication. Coronary heart disease (CHD) was defined as luminal stenosis ≥ 50% in at least one major coronary artery branch or myocardial infarction. Diabetic mellitus was diagnosed as a fasting plasma glucose ≥ 7.0 mmol/L or under diabetes medication. The healthy controls had no histories or symptoms of hypertension, CHD, diabetes mellitus, or any other cardiovascular diseases.All subjects were Han Chinese origin as ascertained by their resident identity card. The study protocol was approved by the ethic committee of School of Pharmaceutical Sciences, Central South University and registered in Chinese Clinical Trial Registry (registration number: ChiCTR-RCC-12002817). Informed consent was obtained from each participants prior to enrollment.http://browser.1000genomes.org), a total of seven tag polymorphisms with minor allele frequency (MAF) > 0.05 were identified using Haploview 4.2 software. Among them, only rs2306235 polymorphism is located in CKIP-1 exon. This polymorphism results in replacement of proline by alanine at the 21 amino acid (Pro21Ala). This amino acid is located in the CKIP-1 PH domain [Based on the CHB population  of 1000 Genomes project . Five microliters of PCR products was digested with Pst I restriction enzyme  overnight at 37°C. The digested PCR products were then analyzed on an agarose gel followed by ethidium bromide staining. Additionally, a random selection of 5% of the samples was also genotyped by Sanger sequencing with the ABI PRISM 3730XL DNA sequencer  and the genotyping were confirmed in 100%.Venous blood samples were collected into EDTA tube and stored at -20°C. Genomic DNA of each subject was extracted from peripheral blood leukocytes using the standard phenol/chloroform protocol. CKIP-1 polymorphism and the risk of CHF was estimated by unconditional logistic regression analysis adjusting for multiple cardiovascular risk factors. The effect of CKIP-1 polymorphism on disease survival was estimated using Kaplan-Meier curve and Cox proportional hazards regression model. The statistical analysis was performed with SPSS software . A two-sided p value < 0.05 was considered to be statistically significant.Continuous values were expressed as mean ± SD and categorical variables as numbers and percentages. Patient characteristics were compared using Chi-square test for categorical variables and independent sample t test or one way analysis of variance for continuous variables. Hardy-Weinberg equilibrium of genotypic distribution was evaluated using a Chi-square test. The association between


Hypotension during anaesthesia for hip fracture surgery is common. Recent data suggest that there is an association between the lowest intra-operative blood pressure and mortality, even when adjusted for co-morbidities. This is consistent with data derived from the wider surgical population, where magnitude and duration of hypotension are associated with mortality and peri-operative complications. However, there are no trial to data to support more aggressive blood pressure control.We are conducting a three-centre, randomised, double-blinded pilot study in three hospitals in the United Kingdom. The sample size will be 75 patients (25 from each centre). Randomisation will be done using computer-generated concealed tables. Both participants and investigators will be blinded to group allocation. Participants will be aged >70 years, cognitively intact , able to give informed consent and admitted directly through the emergency department with a fractured neck of the femur requiring operative repair. Patients randomised to tight blood pressure control or avoidance of intra-operative hypotension will receive active treatment as required to maintain both of the following: systolic arterial blood pressure >80% of baseline pre-operative value and mean arterial pressure >75 mmHg throughout. All participants will receive standard hospital care, including spinal or general anaesthesia, at the discretion of the clinical team. The primary outcome is a composite of the presence or absence of defined cardiovascular, renal and delirium morbidity within 7 days of surgery . Secondary endpoints will include the defined individual morbidities, mortality, early mobility and discharge to usual residence.This is a small-scale pilot study investigating the feasibility of a trial of tight intra-operative blood pressure control in a frail elderly patient group with known high morbidity and mortality. Positive findings will provide the basis for a larger-scale study.ISRCTN89812075. Registered on 30 August 2016.ISRCTN Registry identifier: The online version of this article (doi:10.1186/s13063-017-2066-5) contains supplementary material, which is available to authorized users. It occurs 30 days after the intervention and so will be affected by any number of other factors that are unrelated to anaesthesia . Other rOn the basis of this body of research, we hypothesise that intra-operative hypotension causes critical ischaemia/hypoperfusion of the brain, heart and kidneys in older, frailer patients with hip fracture who have co-morbidities, producing measurable post-operative alterations in organ function and resulting in poorer outcome, We propose a prospective, multicentre, randomised controlled trial comparing protocolised intra-operative control of blood pressure with standard treatment, using a composite of defined cardiovascular, renal and delirium outcomes within 7 days as the primary outcome and 30-day post-operative mortality, fitness for hospital discharge, return to baseline mobility level and return to independent living as secondary outcomes. This paper describes the protocol for an internal pilot feasibility study prior to the main trial.see Additional file The trial protocol has been prepared and is reported in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidance , 14 , randomised controlled clinical trial. Three centres will participate. Recruitment commenced on 22 December 2016, and total recruitment is expected to take 12 months.The study setting comprises three U.K. secondary hospitals providing acute care for patients with hip fracture. Each hospital admits over 400 patients with hip fracture each year.Randomisation (on a one-to-one basis) will be carried out via security-sealed, sequentially numbered opaque envelopes containing details of group allocation. The sequence generation and preparation of envelopes are done by an individual not involved in the trial. Randomisation is computer-generated in blocks of unequal size using a random seed known only to this individual. Randomisation is stratified by intended mode of anaesthesia  and Nottingham Hip Fracture Score (NHFS) (≤4 vs ≥5) . The seqThe investigators, patients, nurses and data-collecting staff will all be blinded to treatment allocation. The attending anaesthetist will not be blinded to treatment allocation.Assessment of mobility will be made by the ward physiotherapists treating the patient. Patients are declared medically fit for discharge by the multi-professional team when all are satisfied that the participant has no ongoing needs for acute hospital care. This team is blinded to participant allocation.Participants will be identified by emergency department staff, trauma co-ordinator nurses and the orthopaedic and anaesthesia clinical teams, which will then inform a member of the research team about the presence of the patient. Once the patient is identified, a member of the research team will approach the patient, conduct initial screening and take consent from of the patient. Active participation in the study will be until the 30-day follow-up phone call.Participants will be informed that participation is voluntary and that they are free to withdraw at any time without affecting their care. Data on time to discharge and mortality are routinely collected for all patients with hip fracture at each institution, and participation in the trial will involve consent for this data to be used. Patients unable to provide informed consent will be excluded from the trial. Patients for whom language will be a barrier will also be excluded, owing to the small-scale nature of the study; patient information will not be available in languages other than English. In practice, non-English speakers represent a very small number of patients in this population group.Primary hip fracture listed for surgical repairAged >70 yearsAble to give informed consentAny condition or impairment which, in the view of the investigator, would prohibit the patient from full participation in the studyStandard care will be identical in both groups. Only the control of intra-operative blood pressure will be different.All patients are admitted to dedicated trauma wards and cared for in units that have written processes for administration of pre-operative fluids, choice of orthopaedic repair, and early mobilisation. All three units have policies mapped to national U.K. standards  in all patients.Blood transfusion will be started in recovery if deemed clinically necessary.All patients will be encouraged to eat and drink as soon as possible following surgery.Regular paracetamol will be prescribed (dose adjusted if necessary).Rescue analgesia will be prescribed, avoiding non-steroidal anti-inflammatory drugs.In both groups, the attending anaesthetist will be responsible for provision of adequate analgesia and anaesthesia and appropriate post-operative fluid, haemoglobin and pain management. At a minimum, the following will be done:Displaced intra-capsular fracture: cemented hemiarthroplastyExtracapsular fracture: dynamic hip screwSub-trochanteric fracture: dynamic hip screw or femoral nailSurgical technique will be in line with standard national policies, though individual patient circumstances may require deviation from these on occasion, as follows:Analgesia will be provided in accordance with normal practice at the study centre. Non-steroidal anti-inflammatory drugs are not routinely prescribed for this group of patients, owing to side effects. Other medications will be prescribed by the attending medical staff as appropriate for each individual. Thromboprophylaxis with subcutaneous low-molecular-weight heparin is routine.Anaesthesia will be at the discretion of the attending anaesthetist; both spinal and general anaesthesia may be used. Peri-operative use of nerve blocks  is encouraged but not mandated in all of the units. Other post-operative therapies, such as physiotherapy, will be applied in accordance with routine hospital practice at the relevant centre.Patients randomised to standard blood pressure control will receive routine care. Fluids and vasopressor drugs will be used as deemed clinically appropriate by the attending anaesthetist.Systolic arterial pressure >80% of baseline pre-operative valueMAP >75 mmHg throughoutPatients randomised to tight blood pressure control or avoidance of intra-operative hypotension will receive active treatment as required to maintain both of the following:Fluid bolus to ensure adequate intra-vascular volume (associated with reduced requirement for vasoactive drugs )Combined β-/α-1-adrenergic agonist (ephedrine)More selective α-1-adrenergic agonist (metaraminol)These targets have been purposefully set relatively high because we anticipate that, although there may be failure to achieve this target in all patients, intervention groups will be less likely to fall below thresholds with stronger associations with a poor outcome. The order and doses of treatments to achieve this will depend upon the clinical scenario but will include the following:Baseline pre-operative blood pressure will be defined as the mean of two readings taken at least 5 minutes apart after the patient has arrived in the induction room for anaesthesia. Patients will receive any anaesthetic technique deemed suitable by the attending anaesthetist in consultation with the patient and/or the patient’s relatives. Blood pressure will be measured using standard non-invasive equipment every 2.5 minutes or continuous non-invasive blood pressure monitoring in the intervention group. The frequency of blood pressure monitoring will be at the attending anaesthetist’s discretion in the control group, but at least every 5 minutes.Delirium using the 4 A’s Test (rapid assessment test for delirium) (4AT) tool: The 4AT is a four-question screening tool for delirium that will be performed by either the ward nursing staff or a member of the research team.Blood tests for renal function (including estimation of glomerular filtration rate) and troponin I: These blood tests will be ordered with routine clinical care tests to reduce any additional burden for participants. Blood tests are typically ordered on 3 or 4 of the first 7 post-operative days.In addition to their normal care, each participant will be screened daily for the following:A telephone follow-up call will be made to the patient  at 30 days to determine place of residence and functional status. Mortality status will be determined from administrative records at 1 year.Data will be recorded for pre-operative and intra-operative characteristics listed below.Usual place of residenceDate/time of admissionMobility prior to fractureMedical co-morbiditiesFrailty score : 35-poinNHFS , 22–24Full blood countUrea and electrolytesLast ward measurementMean of two measurements 5 minutes apart in anaesthesia room before induction of anaesthesiaArterial blood pressure Timing/duration of surgery and anaesthesiaMode of anaesthesia and analgesiaor ≥0.3 mg/dl (≥26.5 μmol/L) increaseStage 1: An increase in serum creatinine (sCr) of 1.5 to 1.99 times baseline Stage 2: An increase in sCr of between 2 to 2.99 times baselineor increase in sCr to ≥4.0 mg/dl (≥353.6 μmol/L) after previous stage 1 or initiation of renal replacement therapy (a retrospective staging)Stage 3: An increase of three times or more baseline Incidence of acute kidney injury in the first 7 days, defined as follows:Incidence of delirium in the first 7 days, defined using the AT4 , 27 deliIncidence of myocardial injury after non-cardiac surgery in the first 3 days, defined as troponin >0.03 ng/ml judged to be due to myocardial injury in the absence of other causesStroke: Embolic, thrombotic or haemorrhagic cerebral event with persistent residual motor, sensory or cognitive dysfunction Length of hospital stayIn-hospital mortality, 5- and 30-day mortalityQuality of life recorded by EQ-5D  at 30 da1-year mortalityAbility to mobilise on 4-point scale compared with pre-morbid mobilityComplications will be categorised according to European Perioperative Clinical Outcome (EPCO) definitions  as folloNadir blood pressure (single lowest post-induction blood pressure)Absolute time below blood pressure limitsProportion of intra-operative time below blood pressure limitsThe ability of intervention group participants to achieve blood pressure limits will be assessed using a variety of methods:orMyocardial injury following non-cardiac surgery orStroke orAcute kidney injury DeliriumThe primary outcome is a composite of presence or absence of defined cardiovascular, renal and delirium morbidity within 7 days of surgery:Presence or absence of each of the defined cardiovascular, renal and delirium morbidity within 7 days of surgery5-day post-operative mortality30-day post-operative mortalityOperation to fit-for-discharge timeOperation to up-and-walk timeProportion returning to pre-operative place of residencePrevalence of bone cement implantation syndrome Secondary outcomes are as follows:t or Mann-Whitney U test will be used). Mortality data will be analysed both as a binary outcome  and using survival analysis (Cox regression). No formal interim analyses are planned.The primary outcome is a composite binary outcome and will be analysed using chi-square statistics. Most of the supportive secondary outcomes are also binary outcomes and will be analysed similarly. Time data  will be tested for normality. It is expected that reciprocal or logarithmic transformation will be required. Appropriate independent group tests , then 1We are conducting a small-scale pilot feasibility study. Although there is mounting evidence of the association between intra-operative hypotension and worse outcome, there are few data demonstrating a causal link or that intervention is beneficial. Recent studies of cardiac output-guided fluid therapy in patients with hip fracture have provided inconclusive results , 33.We have deliberately chosen a pragmatic intervention to manage intra-operative blood pressure. Hypotension during surgery and anaesthesia is multi-factorial, with a combination of previous and ongoing blood loss, dehydration, vasodilation  and myocardial depression resulting from general or spinal anaesthesia, and concomitant drug therapy. The choice of fluids and vasoactive drugs for use in management is therefore dependent on the patient, the attending anaesthetist and the dynamic clinical situation. We therefore feel it is inappropriate, and also impractical, to protocolise how blood pressure is managed during anaesthesia.The patients at greatest risk of complications following hip fracture are the frailer patients. Because this is a pilot study, patients who lack capacity are not being included. This therefore excludes the group that may have most to gain from the intervention . We hopeThe study is unavoidably not blinded for the attending anaesthetist, and there is of course a risk that practice will drift towards the intervention practice. However, the high rates of hypotension observed during the ASAP study suggest that widespread ‘normal’ practice is not currently particularly effective at preventing hypotension. Intra-operative blood pressures are being recorded to assess the separation between groups.There are myriad definitions of intra-operative hypotension. For this pilot study, we have chosen plausible, and we believe achievable, targets. Prior to a full study, these targets will be reassessed in light of information gained from the pilot study. Similarly, there is no single agreed definition of ‘normal’ blood pressure, particularly in the emergency patient, who may be affected by pain, anxiety, dehydration and hypovolaemia. The protocol explicitly allows for the attending anaesthetist to over-ride the anaesthesia room blood pressures (before the intervention starts) if these are felt to be non-representative.We have chosen to limit the duration of the intervention to solely during anaesthesia, and not in the recovery or ward phases. Although hypotension in the recovery/post-anaesthesia care unit and the ward are anecdotally relatively common we felt it inappropriate to extend the intervention. This was for two reasons. First, in practical terms, during the period of anaesthesia and surgery, patients receive one-to-one care from a physician with the skills and resources to promptly and effectively prevent and treat cardiovascular disturbances. This is not the case in the ward, so an extended intervention period would not be practical outside a trial environment. Second, if the intervention is effective, then we anticipate that some of the causes of post-operative hypotension will have been mitigated before the post-operative period.The anaesthetic and surgical episode is only a relatively brief period in the longer course of post-injury rehabilitation. Although it is possible that intra-operative management has no effect on longer-term outcome, the data derived from the ASAP study and other studies of intra-operative hypotension support the premise that it may have effects well beyond the immediate post-operative period. Improvements in hip fracture outcome have been associated with greater standardisation of surgical care and orthogeriatric care. Anaesthesia currently has relatively limited evidence on which to base standards . The resWe have chosen a composite of four plausible, medically important complications. There is no good mechanistic reason to choose any one ahead of the others, and we therefore feel this is an appropriate approach. We hope that if this study shows positive effects, it will serve as a guide for larger studies investigating blood pressure control in both patients with hip fracture and more widely in older patients.As of 14 July 2017, 22 of the planned 75 participants had been randomised.Additional file 1: Figure S1.SPIRIT schedule of enrolment, interventions and assessments. (DOCX 78 kb)Additional file 2:SPIRIT checklist. (DOCX 60 kb)