Background: Albuminuria is strongly associated with future risk for cardiovascular and kidney outcomes, and has been proposed to be included in the classification of chronic kidney disease (CKD) along with glomerular filtration rate (GFR). Few data are available on whether albuminuria is associated with concurrent complications of CKD. Methods: A cross-sectional analysis of 1,665 participants screened for the Modification of Diet in Renal Disease (MDRD) study was performed to examine the association between albuminuria ) and measured GFR  with anemia, acidosis, hyperphosphatemia, and hypertension. Results: Mean GFR (± SD) was 39 ml/min/1.73 m2 (± 21) and the median (25 – 75th percentile) ACR was 161 (38 – 680) mg/g. In multivariable models adjusted for age, sex, race, kidney disease etiology, and GFR, higher ACR levels were not associated with any complication. For example, comparing ACR > 300 mg/g vs. < 30 mg/g, the prevalence ratio (95% CI) for anemia was 0.98 (0.81 – 1.20), acidosis 1.13 (0.86 – 1.48), hyperphosphatemia 1.69 (0.91 – 3.17), and hypertension 1.04 (0.97 – 1.12). Lower levels of GFR were associated with all complications. For example, GFR levels < 30 ml/min/1.73 m2 vs. GFR levels 60 – 89 ml/min/1.73 m2 were associated with prevalence ratios (95% CI) of anemia 4.35 (3.18 – 5.96), acidosis 5.31 (3.41 – 8.29), hyperphosphatemia 23.8 (7.71 – 73.6), and hypertension 1.21 (1.10 – 1.32). Conclusions: Albuminuria is not associated with complications after controlling for GFR in patients younger than 70 years of age with non-diabetic CKD and GFR less than 90 ml/min/1.73 m2 and thus would not affect clinical action plans for decisions regarding evaluation and treatment of complications in similar populations.  We cate female] , 23. GFR 125I-iothalamate, as has been previously described [2 [2 were excluded due to the small number of individuals with this level of GFR. Participants with a GFR of 15 – 29 ml/min/1.73 m2 and GFR < 15 ml/min/1.73 m2  were combined into one category due to the small number of participants in Stage 5. Since the entry criteria in the screening phase required creatinine clearance of < 70 ml/min/1.73 m2, GFR category 60 – 89 essentially consisted of patients with GFR 60 – 70 ml/min/1.73 m2 only. GFR was measured using urinary clearance of escribed . Based oOther variables Kidney disease was initially classified into 23 etiologic categories based on history, biopsy, and physician diagnosis but for this analysis it was collapsed into 3 broader categories as previously defined : glomeruThe definitions of anemia, acidosis, and hyperphosphatemia were based on accepted cut-offs for patients with CKD , 26, 27.th – 75th percentiles for skewed variables. The trends across the ACR categories for the characteristics were tested using Spearman rank correlation for continuous variables and Cochran Armitage trend test for categorical variables. We summarized clinical characteristics according to ACR categories using proportions for categorical variables and means and standard deviations (SD) for normally distributed continuous variables or medians and the 25We first explored the optimal functional form for ACR using generalized additive models of log ACR for association of each outcome. Since we did not find any non-linear relationships between albuminuria and any of the complications we used the categories of ACR described above in the primary analysis. 2, as the reference groups. We wanted to express results using prevalence rations as the number of individuals with specific complications was high, and under this circumstance prevalence ratios as obtained by log-binomial regression are preferable. Models were initially unadjusted, but sequential models adjusted for age; age, sex, race, and GFR (or ACR); and age, sex, race, kidney disease etiology, and GFR (or ACR). P-values for linear trend were calculated by modeling category of ACR and GFR as continuous variables in the log-binomial models. We then analyzed the prevalence of the complications across the joint distribution of the ACR categories and GFR categories. We tested the interaction of ACR and GFR categories for modification of the effect of ACR on the complications by level of GFR. We used log-binomial regression to evaluate the association between ACR category and GFR category, separately, to each of the complications, using ACR < 30 mg/g and GFR 60 – 89 ml/min/1.73 mIn sensitivity analyses, we repeated the analyses using proteinuria in place of ACR, categorizing proteinuria by < 200 mg/24 h, 200 – 999 mg/24 h and ≥ 1,000 mg/24 h . We alsoStatistical analyses were performed using SAS (version 9.2). A two-tailed p-value of < 0.05 was considered statistically significant. 2, median (25th – 75th percentiles) for ACR and proteinuria were 161 mg/g (38 – 680) and 320 mg/24 h , respectively. Patients with higher ACR were younger, less likely to be white and male and had lower GFR . A higher proportion of glomerular disease was noted in the higher ACR category. The baseline characteristics of the study population according to the ACR categories are listed in The prevalence of anemia, acidosis, hyperphosphatemia, and hypertension was 43%, 31%, 16%, and 81%, respectively. There was a graded increase in the prevalence of anemia, acidosis, hyperphosphatemia and hypertension with increasing levels of albuminuria . After aThe prevalence of anemia, acidosis, hyperphosphatemia, and hypertension increased with decreasing GFR (p-trend < 0.001 for each complication) . In age-2, but not 30 – 59 or 60 – 89 ml/min/1.73 m2, increasing levels of albuminuria were associated with a higher prevalence of anemia, hyperphosphatemia, and acidosis. However, the interaction between ACR categories and GFR categories was not significant  for each outcome. In sensitivity analysis, the results using proteinuria were similar to those using ACR . For exaIn this study of participants with predominantly non-diabetic CKD, after adjustment for age, race, sex, GFR, and etiology of kidney disease, there was no association between ACR and concurrent complications of CKD, and ACR did not appear to modify the effect of GFR on complications. In contrast, consistent with previous reports, we observed strong associations between lower levels of GFR and each complication studied , 29. The2 and ACR ≥ 10 mg/g were independently associated with all-cause and cardiovascular mortality risk in the general population [Many studies have demonstrated that albuminuria is an independent predictor of mortality, cardiovascular outcomes, and progression of CKD , 30, 31.pulation . In a gepulation . The keypulation , 34, 35.There are several possible mechanisms by which albuminuria could be also associated with CKD complications. First albuminuria has been associated with systemic inflammation, which could contribute to the development of anemia and hypertension , 37. PosThe strengths of this study include the analysis of a large number of individuals from a well-established cohort with moderate-to-severe CKD, availability of measured GFR, detailed ascertainment of confounding variables including CKD etiology, and use of clinically relevant ACR cut-offs that allows for comparability with future studies from other cohorts and thus allow for generalizability of study results to the current era. The study population is restricted mostly to patients with progressive CKD not due to diabetes and therefore is a unique and homogenous population. The cross sectional study design is appropriate as the question being asked refers to point of care in the management of patients with CKD. 2. A significant proportion of patients have CKD based on proteinuria alone. The results will need to be reproduced in other populations such as diabetic kidney disease and other kidney diseases not represented in the MDRD study. There are several limitations to our study. First, ACR was not measured directly but rather derived from 24-hour urine protein excretion using a relationship observed between ACR and 24-hour protein excretion in the IDNT study, a study of diabetic nephropathy, where albumin is the predominant urinary protein. The MDRD Study, consisted of non-diabetic kidney disease and the total urine protein in this population likely contains in addition to albumin, non-albumin proteins such as β-2 microglobulin, retinol binding protein, and other low-molecular weight proteins . Thus, tIn conclusion, ACR does not provide any additional information about CKD complications beyond what is already known with GFR. These findings should be taken into account when considering the inclusion of albuminuria level along with GFR in the development of clinical action plans associated with the proposed new classification of CKD. GFR and albuminuria represent different aspects of kidney disease and management decisions should be based on their individual association with complications and ability to predict adverse outcomes and should be assessed separately for their clinical utility. Research Support: This research is supported by a National Kidney Foundation/Amgen Research Fellowship grant to Dr. Viswanathan. Dr. Inker is supported by a grant K23-DK081017. Dr. Sarnak is supported by K24DK078204. None declared.


Xu and colleagues evaluated the impact of increasing mean arterial blood pressure levels through norepinephrine administration on systemic hemodynamics, tissue perfusion, and sublingual microcirculation of septic shock patients with chronic hypertension. The authors concluded that, although increasing arterial blood pressure improved sublingual microcirculation parameters, no concomitant improvement in systemic tissue perfusion indicators was found. Here, we discuss why resuscitation targets may need to be individualized, taking into account the patient’s baseline condition, and present directions for future research in this field. Critical Care, Xu and colleagues [In a recent article in lleagues  evaluatelleagues .The concept of individualizing the MAP targets for patients with septic shock is certainly laudable. Several aspects of the study design and methodology should be considered in the interpretation of the results. First, patients were enrolled in a late phase of resuscitation, after an average of 16 h from the beginning of shock, with an unknown period of time spent with an MAP under 65 mmHg . Thus, oIn a recent large trial on septic shock, more than 40 % of patients had a history of chronic hypertension . PatientSmall prospective cohort studies –9 and twTaken together, the available evidence reveals that targeting higher MAP levels during the initial resuscitation of septic shock has variable effects on microcirculatory parameters and organ function, which may also be dependent on patients’ usual blood pressure level. However, it should be noted that targeting higher blood pressure increases patients’ exposure to fluids and vasopressors, which may have detrimental effects .What do we learn from the study by Xu and colleagues? It is well known that patients admitted to the intensive care unit vary widely in terms of age, number and type of comorbidities, and functional status . Such vaFurther research is needed to address the impact of individualized MAP targets on tissue perfusion, organ function, inflammatory response, and exposure to vasopressors and fluids and, more importantly, on the outcomes. The development of new technologies may help clinicians to evaluate, at the bedside, the impact of achieved MAP targets on microcirculatory parameters and organ function. Finally, the individualized approach may allow us to identify non-hypertensive patients who may tolerate lower mean arterial and perfusion pressure levels to maintain their organs’ function. In such patients, a decreased exposure to vasopressors may limit their side effects and improve outcomes.


Objective. The aim of this study is to define the normal range for average real variability (ARV) and to establish whether it can be considered as an additional cardiovascular risk factor. Methods. In this observational study, 110 treated hypertensive patients were included and admitted for antihypertensive treatment adjustment. Circadian blood pressure was recorded with validated devices. Blood pressure variability (BPV) was assessed according to the ARV definition. Based on their variability, patients were classified into low, medium, and high variability groups using the fuzzy c-means algorithm. To assess cardiovascular risk, blood samples were collected. Characteristics of the groups were compared by ANOVA tests. Results. Low variability was defined as ARV below 9.8 mmHg (32 patients), medium as 9.8–12.8 mmHg (48 patients), and high variability above 12.8 mmHg (30 patients). Mean systolic blood pressure was 131.2 ± 16.7, 135.0 ± 12.1, and 141.5 ± 11.4 mmHg in the low, medium, and high variability groups, respectively (p = 0.0113). Glomerular filtration rate was 78.6 ± 29.3, 74.8 ± 26.4, and 62.7 ± 23.2 mL/min/1.73 m2 in the low, medium, and high variability groups, respectively (p = 0.0261). Conclusion. Increased values of average real variability represent an additional cardiovascular risk factor. Therefore, reducing BP variability might be as important as achieving optimal BP levels, but there is need for further studies to define a widely acceptable threshold value. Until now, the goal of antihypertensive treatment was to obtain the optimal blood pressure (BP) value defined by international guidelines . HoweverIn this observational study, a number of 110 treated hypertensive patients were included who were referred to the County Clinical Hospital Tîrgu Mureş to adjust antihypertensive therapy. At the inclusion, from each patient, written informed consent was obtained and approved by the Local Ethic Committee, according to the International Ethical Guidelines and Declaration of Helsinki. Inclusion criteria were diagnosis of hypertension based on ABPM with mean BP values greater than 130/80 mmHg and ability to sign informed consent. Patients with cardiac arrhythmias, congestive heart failure NYHA class III/IV, and type 1 diabetes mellitus, shift workers, and pregnant women were excluded from the study.N represents the number of BP measurements in a given subject and BPk is the blood pressure at measurement number k [N is the number of valid BP measurements and Scr is serum creatinine in mg/dL. One factor concerning the race of the patient was omitted from the above formula, as it did not hold for any of the patients.Circadian BP profile was assessed with validated devices  applied on the nondominant arm of the patient. Monitoring began between 8 and 10 am and measurements frequency was set at 20 minutes daytime (06:00–21:59) as well as nighttime (22:00–05:59). Daytime and nighttime systolic/diastolic BP values, pulse pressure, diurnal/nocturnal index, morning surge, and standard deviation were provided automatically by the measurement device. The ABPM validation criteria were the presence of at least 70% of the scheduled measurements and at least 48 BP values over 24 hours . The 24-readings . The estreadings : (3)eGFRc-means (FCM) algorithm [After calculating ARV, the fuzzy lgorithm  was applp value less than 0.05 was considered statistically significant with a confidence interval of 95%.In order to assess cardiovascular risk, laboratory analysis was performed. Data were collected as raw data and statistical analysis was performed using Matlab. Numerical data are represented as mean ± SD. Means were compared using one-way ANOVA test and Chi-square test for categorical variables. To assess the individual contribution of various risk factors, multivariate linear regression was employed. A Based on the 24-hour systolic BP variability defined with ARV, fuzzy membership functions and patient groups were obtained by the FCM algorithm as presented in p = 0.0028). The highest values of the systolic blood pressure were found in the HV group. The highest pulse pressure was also recorded in the HV group with 69.7 ± 13.2 mmHg, compared to 60.5 ± 11.4 mmHg in the MV, and 55.8 ± 15.5 mmHg in the LV group (p = 0.0003). Further significant differences were recorded in daytime systolic BP, systolic BP standard deviation, and the estimated glomerular filtration rate  display greater cardiovascular risk compared to those with normal variability. In contrast to the study conducted by Mena et al., where high variability was defined as ARV exceeding 9.86 mmHg, in our study population the threshold value was 12.8 mmHg [The assessment of ambulatory monitoring derived blood pressure variability could represent an additional cardiovascular risk factor in hypertensive patients and could be of importance in individual risk stratification. Therefore, in high risk hypertensive patients, lowering of BP variability might be as important as achieving optimal BP levels. Although there are different threshold values to define high variability, there is need for a widely accepted value.


Sepsis-induced acute kidney injury (SAKI) remains an important challenge in critical care medicine. We reviewed current available evidence on prevention and treatment of SAKI with focus on some recent advances and developments. Prevention of SAKI starts with early and ample fluid resuscitation preferentially with crystalloid solutions. Balanced crystalloids have no proven superior benefit. Renal function can be evaluated by measuring lactate clearance rate, renal Doppler, or central venous oxygenation monitoring. Assuring sufficiently high central venous oxygenation most optimally prevents SAKI, especially in the post-operative setting, whereas lactate clearance better assesses mortality risk when SAKI is present. Although the adverse effects of an excessive “kidney afterload” are increasingly recognized, there is actually no consensus regarding an optimal central venous pressure. Noradrenaline is the vasopressor of choice for preventing SAKI. Intra-abdominal hypertension, a potent trigger of AKI in post-operative and trauma patients, should not be neglected in sepsis. Early renal replacement therapy (RRT) is recommended in fluid-overloaded patients’ refractory to diuretics but compelling evidence about its usefulness is still lacking. Continuous RRT (CRRT) is advocated, though not sustained by convincing data, as the preferred modality in hemodynamically unstable SAKI. Diuretics should be avoided in the absence of hypervolemia. Antimicrobial dosing during CRRT needs to be thoroughly reconsidered to assure adequate infection control. Both sepsis and acute kidney injury (AKI) are diseases of major concern in critically ill patients. Severe sepsis is often complicated by AKI –4. The oThe pathophysiology of SAKI is much more complex than previously anticipated . PrimaryThe old “credo” stating that fluid harms the lung but benefits the kidney should be revised . LiberalHypotension and hypovolemia during sepsis may cause or worsen AKI. Evidence is accumulating suggesting that crystalloid but not colloid solutions should be used for initial intravascular volume expansion in septic patients at risk for AKI –20. The ®) are associated with less occurrence of AKI than isotonic salt solutions [Balanced crystalloid perfusions  [Lactate levels more appropriately reflect arterial perfusion than oxygen supply, especially when accounting for the high level of intra-renal oxygen shunting . LactatecvO2 . LactatecvO2 . JanssencvO2 . In contre (MAP) . More ouFor decades, clinicians estimated that preload was the main determinant of kidney function. Increasing preload was thought to increase renal blood volume and flow. Although a “critical” CVP level is required to ensure optimal renal function, unrestrained preload increase may harm the kidneys by enhancing venous congestion and blocking venous outflow . Recently, higher CVP levels were found to be associated with an increased incidence and morbidity of AKI during septic shock . RelativNa) and urea (FEUrea) are highly prevalent during the initial phase of sepsis. Oliguria is an earlier sign of impending SAKI than the increase in serum creatinine. It is assumed that high FENa and low FEUrea values are associated with intrinsic SAKI whereas high values of both FENa and FEUrea concur with transient or functional SAKI. However, a definite discriminative power of these urinary indices has not been established [SAKI may present either as a functional or structural entity. The difference is clinically relevant since functional SAKI can be reversed completely by early adequate treatment whereas structural kidney damage will mostly require RRT. Discriminating functional from structural SAKI at the bedside, however, remains challenging. Low fractional excretions of sodium  and its most dreaded presentation, the abdominal compartment syndrome (ACS), are frequently associated with AKI in surgical and trauma patients. Because signs and symptoms are non-specific and laboratory and imaging studies often remain inconclusive, the diagnosis of AKI as a manifestation of IAH requires a high index of clinical suspicion. Early recognition and treatment improve clinical outcome . IAH hasHigh-volume hemofiltration offers no mortality benefit in SAKI , 87, 88.(C)RRT should be initiated when fluid overload is poorly tolerated and only partly or not responsive to a diuretic challenge . The IVOProwle and Bellomo reported that hemodynamically unstable patients with SAKI treated with CRRT remained significantly less dialysis-dependent than those receiving intermittent hemodialysis (IHD) . A recenThe use of diuretics to induce or increase urine production in the absence of hypervolemia is associated with increased mortality  and shouCRRT significantly influences the pharmacokinetic and pharmacodynamic behavior of most antimicrobial agents. This is insufficiently anticipated by currently recommended dosing guidelines. Patients are particularly at risk for underdosing which may cause treatment failure and enhanced resistance. An in-depth discussion of antimicrobial handling during CRRT is beyond the scope of this review. Table Several strategies are under investigation including newly designed membranes , apheresA small randomized phase I trial showed that adjunctive treatment with recombinant alkaline phosphatase (RAP) could prevent SAKI and even reversed some cases of advanced SAKI . A phasecvO2 monitoring performs better than lactate clearance rate or renal Doppler for monitoring kidney perfusion. Lactate clearance rate, however, is better correlated with SAKI-related mortality. High filling pressures must be avoided in light of the detrimental effects imposed by an increased kidney “afterload”. Noradrenaline remains the vasopressor of choice for preventing SAKI. Vasopressin or analogs need further investigation. IAH is a potential, yet often overlooked, trigger of SAKI. Early initiation of RRT is indicated when fluid overload is excessive or refractory to diuretics. CRRT is increasingly considered as first-choice therapy in hemodynamically unstable SAKI. Expanding its use to “stable” SAKI patients is attractive but not supported by current literature. Except for life-threatening hypervolemia, diuretics have no place in prevention or treatment of SAKI. Most antimicrobials require dose adaptation during CRRT.Prevention of SAKI starts with early and adequate fluid resuscitation. Crystalloids are preferred over colloids but balanced crystalloids do not appear superior to classic crystalloids for counteracting SAKI. Synthetic colloids and starches in particular should be withheld. No data support the use of albumin in patients with SAKI. Regarding SAKI prevention, S


Hypertension is the most prevalent cardiovascular disease, and various risk factors are known to be involved in it. Cervical spondylotic myelopathy (CSM) is the most common non-traumatic cause of myelopathy, which displays neurological symptoms and may induce systemic symptoms. To date, it is still unknown whether CSM is associated with hypertension, and if so, whether the decompression operations can attenuate CSM associated hypertension. Here, a total of 309 patients with CSM who received anterior or posterior decompression surgery were enrolled as subjects. Blood pressure measurements were performed before and within one week after the surgery. Among the 309 subjects, 144 (46.6%) of them exhibited hypertension before surgery, a significantly higher ratio than that of the whole population. One week after surgery, blood pressure of 106 (73.6%) patients turned back to normal. Blood pressure of another 37(25.7%) patients decreased with different degrees, although still higher than normal. Moreover, it appears that both approaches were effective in improving blood pressure, while the posterior approach was more effective in decreasing systolic blood pressure. We speculate this type of hypertension might result from hyperactivity of sympathetic nervous system as the heart rate of these patients decreased after surgery as well. Collectively, compression of spinal cord in CSM patients might be associated with hypertension, and decompression surgery largely attenuated this type of hypertension. These findings prove CSM to be a potential associated factor of high blood pressure and may shed light on therapies of hypertension in clinics. Hypertension is a most prevalent disease in clinics, and as a chronic pathological condition, it can result in a variety of serious complications , 2. DespCervical spondylotic myelopathy (CSM) is a dominant non-traumatic type of myelopathy, caused by cervical intervertebral disc herniated into vertebral tube and squeezed spinal cord . CSM canTreatment strategies for CSM depend on the severity of myelopathy, the extent of the disease process and a number of patient etiological factors . It is wIn this study, we found a large part of patients that suffered from CSM also exhibited hypertension, and drug intervention is sometimes required to control the high blood pressure. Intriguingly, blood pressures of these patients were decreased after the decompression surgery for CSM, and the posterior approaches seemed to be more effective in decreasing systolic blood pressure. Moreover, heart rate decreased along with the blood pressure as well. Taken together, we deduced this CSM associated hypertension may derive from hyperactivity of sympathetic nervous system. These results provided a potential index when selecting surgical strategy and a novel mechanism of increased sympathetic nervous activity.Given the retrospective nature of the study, written consent was not obtained. However, we got the oral consent from all participants in the study by telephone contact, and patient records were anonymized and de-identified prior to analysis. Then related data were extracted from hospital’s electronic and written medical records. The study was reviewed and obtained the approval from Institutional Review Board of Qilu Hospital, Shandong University.From January 2011 to May 2014, three hundred and thirteen patients visited the authors’ department who met the following criteria were selected: (1) Patients of 18 years or older, had symptomatic CSM confirmed by CT and MRI imaging. As chronic pain attributes to hypertension [The blood pressure data are presented as average early morning values within a week before and after surgery. Blood pressure data on the day of surgery was excluded as anesthesia may decrease blood pressure. The blood pressure measurements were determined by the average results of 2 readings of systolic and diastolic blood pressure obtained at five minutes intervals using an electronic sphygmomanometer by trained nurses. A third measurement was performed when there was a difference more than 5mmHg between the two measurements. Blood pressure was assessed after five minutes of rest in the sitting position using appropriate size cuffs before taking any antihypertensive drugs. According to the Sixth Report of the Joint National Committee (JNC) , which cThe heart rate data are presented as average early morning values within a week before and after surgery. As the electronic sphygmomanometer that measuring blood pressure records the current heart rate as well, the heart rate measurements were determined by the average results of 2 readings, recorded along with blood pressure.Data are expressed as mean value and the standard deviation (SD). Paired t-test was used for the analysis of the blood pressures before and after surgery. For the comparison of anterior and posterior approaches, unpaired t-test was used. Chi-square test was used to analyze the proportion among different hypertension stages. P-values<0.05 were considered to be statistically significant. All statistical analyses were conducted using SAS version 9.2 .Of the 309 subjects, 144 patients were diagnosed with hypertension before surgery according to values of their blood pressure, which means that 46.6% of our CSM patients were combined with different degrees of hypertension. It indicated the ratio of hypertension was significantly elevated in CSM patients compared with the average prevalence of the same age group in the same region as reported .As is shown in In addition, there were another 14 of the 309 patients that belong to prehypertension state, and surgery for the treatment of CSM diminished the blood pressure of these patients from 131.2/76.6mmHg to 117.8/67.9mmHg, which made all these patients become real normotensive.As is shown in As shown in From the perspective of anatomical positional relationship, we speculate CSM associated hypertension may results from the irritation of sympathetic nervous system. To confirm our speculation, we analyzed the changes of heart rate after surgery, as heart rate could represent sympathetic nerve activity to some extent. Consistent with the changes of blood pressure, surgery for CSM significantly decreased heart rate of hypertensive patients.  MeanwhilTo date, the prevailing treatment of hypertension is pharmacologic therapy and a large number of drugs are currently available for improving blood pressure. In many cases, drug combinations are required, as more than two-thirds of patients with hypertension cannot be controlled on one type of such drugs. Moreover, most of them face a lifetime medication in order to avoid the severe complications of high blood pressure. Therefore, the etiology and relevant therapy remains to be further investigated. Here we reported a potential etiology of hypertension—CSM associated hypertension, a kind of hypertension that might be cured by decompression surgery.This retrospective observation and statistic work demonstrates that a large part of CSM patients also suffered from hypertension. Moreover, both anterior approach and posterior approach decompression surgeries decreased blood pressure of these patients to a certain degree. What’s more, surgeries had no effect on blood pressure in normotensive patients. Hypertension in these patients were improved or even cured after the surgery, and the blood pressure of some patients with uncontrolled hypertension became stable and controlled following the decompression operation. Furthermore, according to our findings of this study, the posterior group appeared to be more effective in decreasing SBP. CSM is known to be the most common cause of acquired neurological disability in those older than 50 years . Both CSIt is reported that anterior and posterior surgical approaches have equivalent efficacy in treating CSM . Here weOur study has a number of limitations that warrant mention. Given the retrospective nature of this study, more detailed data that could reflect the sympathetic nerve activity such as norepinephrine and MSNA are lacked. Besides, other compounding factors that may contribute to the pathogenesis of hypertension are not put into this study. In addition, the long-term effect of decompression surgery on blood pressure requires further observation. To aid the evidence of CSM associated hypertension, whether hypertension develops following the occurrence of CSM deserves to be further investigated. Animal experiments as well as prospective randomized controlled clinical trials are warranted in order to figure out the pathogenesis and mechanism of CSM associated hypertension.


Studies worldwide show insufficient blood pressure control rates, and effective management of hypertension remains a challenge in general practice. Although structured forms of care improved blood pressure in randomized controlled trials, little is known about their effects under routine primary care. This cluster randomized trial (CRT) evaluates the effects of a modern interactive medical education series for general practitioners on hypertension management, including practice redesign strategies.For this CRT, 24 primary care academic teaching practices of the University of Duisburg-Essen, Germany, are randomized into two study arms. With the objective of improving hypertension control, general practitioners of the intervention group participate in a three-session medical education program on structured hypertension management. The program aims at changing physician awareness and practice design. Various practice tools are provided: for example, checklists on valid blood pressure readings, medication selection, detection of secondary hypertension, and patient education. General practitioners of both study groups include hypertensive patients with and without hypertension-related diseases such as angiographically proven coronary disease, and peripheral or cerebral vascular disease. Blood pressure is measured by 24-hour readings. Analyses will focus on differences in blood pressure control and changes of practice management between intervention and control group.The study will determine the effectiveness of our practice redesign intervention on hypertension control. The intervention addresses general practitioners and practice assistants, while aiming at benefits on the patient level. Therefore, the cluster design is used to evaluate the effects.DRKS00006315 (date of registration: 14 July 2014). According to a World Health Organization (WHO) report, hypertension is the single most important risk factor, accounting for 13% of mortality worldwide . A CochrInternationally, primary care is delivered in various organizational settings ranging from one- or two-physician offices scattered in urban or rural areas to large-sized multi-physician practices and health maintenance organizations. Therefore, strategies to improve hypertension control are needed that are applicable in various clinical scenarios .This cluster randomized trial evaluates the effectiveness of a modern medical education series for primary care physicians about structured hypertension management on blood pressure control in hypertensive patients. The intervention follows a modern didactic concept with evidence-based, interactive case discussions and practice redesign strategies. Primary care academic teaching practices are randomized into intervention group (education on hypertension management) and control group (no education).The study is designed as a cluster randomized trial with primary care practices as the unit of randomization. The cluster design is used because the intervention (education) addresses practice teams, and thereby aims to improve patient outcomes indirectly . AdditioPractices from both arms will receive the intervention, but sequentially, with control practices receiving the intervention after the follow-up data collection in both study groups.The study is conducted in the practice network of 180 primary care academic teaching practices of the University Duisburg-Essen, Germany. These practices are distributed in urban and rural regions of North Rhine-Westphalia with a distance of 5 to 150 kilometers to the Institute for General Medicine in Essen, Germany. All practices belong to the Association of Statutory Health Insurance Physicians North Rhine and Westphalia-Lippe. All practices are requested to take part in one of two network meetings of the institute yearly. Each practice is allowed to choose which meeting to attend: the spring or the fall meeting. All practices that participated in the spring meeting 2013 were asked to participate in this study (n = 51). Interested physicians are contacted by telephone to check practice inclusion criteria. Practices are eligible for participating in the study if they provide health services to hypertensive patients and are equipped with at least one calibrated 24-hour blood pressure monitoring device. A total of 24 practices volunteered for participation and fulfilled the inclusion criteria. These practices were randomized in two study arms of equal size. All participating physicians are asked to sign an informed consent form. Patients are recruited by these physicians.Patients are eligible for recruitment if 1) they are ≥18 years old and 2) their blood pressure is uncontrolled according to current guidelines: ≥140/90 mmHg in office readings, and/or ≥130/80 mmHg in 24-hour ambulatory measurements (based on the average 24-hour blood pressure), and/or ≥135/85 mmHg in patient self-measurements at home (based on the mean of a one-week protocol with at least two measurements daily) . PatientThe primary endpoint of the study is the change of the blood pressure control rate, defined as percentage of patients with an average 24-hour blood pressure <130/80 mmHg. The key secondary endpoints are the changes in average systolic and/or diastolic blood pressure (in mmHg) and changes in practice-specific hypertension management stratified by the intervention status of the practice. All outcomes are measured at baseline (before the intervention) and at follow-up (3 months after the last education session) in both study arms. This results in an average follow-up period of 5 months per patient.To determine the interventional effectiveness on the patients’ level, each study patient receives a 24-hour ambulatory blood pressure monitoring at baseline and at follow-up. To control for confounding, general practitioners complete a questionnaire on medical characteristics of each study patient . Study patients complete a self-administered paper and pencil questionnaire on individual characteristics such as sociodemographic characteristics, risk factors , medication adherence, and management of blood pressure self-readings at baseline and follow-up.At baseline, general practitioners complete a questionnaire on personal characteristics , medical degree(s), additional qualifications, and individual attitudes toward hypertension treatment (motivation and self-efficacy). To determine practice changes after intervention, the follow-up questionnaire focuses on changes in daily practice routines and determines which of the hypertension management strategies are implemented by the practices.current hypertension guidelines ,10-step checklist how to obtain standardized upper arm office blood pressure readings according to guidelines ,template of a blood pressure documentation sheet for serial documentation of blood pressure values by patients,list of electronic blood pressure devices that carry the quality seal of the German Hypertension League,prescription template detailing how to prescribe an electronic blood pressure device,prescription template detailing how to prescribe relaxation training programs (progressive muscle relaxation and autogenous training),checklists to assist in the diagnosis of secondary hypertension,templates for specialist referral sheets for the work-up of secondary hypertension,overview sheet specifying the mechanism of action of the various antihypertensives,information sheets on blood pressure lowering effects (in mmHg) of different single and combined blood pressure lowering measures such as regular physical activity or intensified pharmacotherapy , andpatient information leaflet about hypertension.General practitioners of the intervention group participate in a modern education on strategies of structured hypertension management in primary care. It is conducted as an in-class, three-session medical education program. Central elements of the education are 1) training on valid upper arm blood pressure readings; 2) evidence-based information on resistant hypertension, secondary hypertension, and modern pharmacotherapy, in the form of presentations and group discussions of actual cases; and 3) the introduction and distribution of practice tools to facilitate the long-term implementation of hypertension management. The following practice redesign tools are provided in print and electronic versions:All information sheets are written in an easily understandable language and designed in a clear layout so that they can be used for patient information and education. General practitioners and practice assistants participate in the session on blood pressure measurements, while all other sessions are offered to physicians only. The education sessions are supported by hypertension specialists from the German Hypertension League.Participating general practitioners are free in their choice of diagnostic and therapeutic strategies. Patient responsibility remains solely in the hands of the general practitioner in charge. Due to the physician-centered approach, study patients receive an indirect intervention.General practitioners of the control group are offered the same education sessions, but only after completing the follow-up data collection in both study arms. Control group patients receive treatment as usual.Despite this sequential design, it cannot be excluded that study participation, 24-hour blood pressure measurement at baseline and follow-up, and completing a questionnaire at baseline and follow-up might influence the physicians’ and patients’ awareness for hypertension in both study arms.The concept of this structured hypertension management for primary care, which is introduced during the education sessions, was developed in one exemplary teaching practice in our practice network. It combines guideline-based therapy, patient information on physical activity and diet, checklists for work-up of secondary hypertension, and patient supervision on blood pressure self-measurements according to standard. Patients were instructed about the documentation of blood pressure readings and how to react in case of blood pressure extremes. Patients with uncontrolled hypertension were scheduled for repetitive appointments to adjust the medications until blood pressure was in the target range or until other factors limited control. A phone recall to reschedule an appointment was performed for patients who had missed an appointment for blood pressure control. The retrospective evaluation of this hypertension management concept used in the model practice demonstrated that this strategy is effective: within one year blood pressure control rate of high-risk hypertensive patients increased from 46% to 74%  and for For the primary endpoint, a blood pressure control rate of 35% is assumed for the control group, while a blood pressure control rate of 70% is assumed for the intervention group ,9. AssumQuality controls are conducted during all study phases. After recruitment, physicians’ and patients’ inclusion criteria are controlled. Consent forms are checked for completeness. After baseline and follow-up data collection, quality controls are conducted to assure that required data collection documents are complete. Baseline and follow-up data of each study patient are checked using birth date to ensure that data are merged correctly.The data are entered manually in an electronic database with restricted access. To control for input errors, 10% of the data are entered twice. An error rate of 5% is accepted; otherwise all values are entered twice. The data are checked for plausibility using simple frequencies.P value <0.05 will be considered significant.The primary endpoint (differences in the blood pressure control rate between intervention and control group) will be analyzed using a chi-square test. A For analyses of secondary endpoints, average blood pressure levels at baseline and at follow-up will be determined for all study patients and separately for patients of both study arms. Differences between baseline and follow-up will be tested for significance within each study arm using paired t-tests. Differences in the mean systolic and diastolic blood pressure level of patients of the intervention group and patients of the control group will be tested for significance using an adjusted t-test for independent samples, which accounts for the intra-cluster correlation .The analysis will determine which elements of hypertension management have been implemented into everyday routine during the study period and which of them are regarded as being helpful. To describe the effect of single hypertension management strategies on blood pressure, bivariate analyses will be conducted.A generalized linear mixed model will be performed to identify predictors on blood pressure control at follow-up. The model will include patient level covariates such as age, sex, lifestyle, comorbidities, and changes in each patient’s hypertension management as well as cluster-level covariates such as changes of hypertension-related diagnostic and therapeutic strategies. Modeling will account for cluster effects by random effects modeling. Statistical analyses will be performed using IBM SPSS Statistics for Windows, Version 22.0 .Study conduction complies with the ethical principles of the World Medical Association Declaration of Helsinki . EthicalStudies have identified various barriers for hypertension control in regular care that are structured in physician-, patient-, health care delivery and health care system-related factors . Our cluet al. introduced calibrated 24-hour blood pressure monitor devices in primary care practices, while Reuther et al. introduced strategies to organize hypertension management in primary care [Cluster randomized trials from different countries evaluated various educational and organizational approaches to improve blood pressure control rates in primary care -24. Mostary care ,24. The ary care  and −1.7Interventions aimed at changing regular care need to be based on an in-depth understanding of the health care system that they are addressing . We desiMethodologically, we will address this expected inter-cluster variance by three strategies. First, for each practice we will obtain the hypertension management strategies at baseline and follow-up: this will allow us to assess which strategies are newly tried. In addition, the practices will be asked which strategies they will continue to use for their hypertension management. Second, based on this information we will outline typical patterns of hypertension management for inter-cluster analyses. Third, for each patient we will obtain the information in which changes in diagnostic, therapeutic and educational interventions occurred between baseline and follow-up. Depending on the frequencies and potential effects on hypertension control in bivariate analyses, we will include an appropriate selection of single measures or patterns of redesign aspects in the final regression model to describe the effects of the relevant hypertension management strategies on hypertension control in primary care patients.The study began in September 2013. Baseline data collection was completed in January 2014. Follow-up data collection was completed in August 2014. Data management, including quality control, is ongoing. Results are expected in summer 2015.


Background: Phenylketonuria (PKU) is caused by the inherited defect of the phenylalanine hydroxylase enzyme, which converts phenylalanine (Phe) into tyrosine (Tyr). Neonatal screening programs and early treatment have radically changed the natural history of PKU. Nevertheless, an increased risk of neurocognitive and psychiatric problems in adulthood remains a challenging aspect of the disease. In order to assess the vulnerability of complex skills to Phe, we explored: (a) the effect of a rapid increase in blood Phe levels on event-related potentials (ERP) in PKU subjects during their second decade of life; (b) the association (if existing) between psychophysiological and neurocognitive features.Methods: Seventeen early-treated PKU subjects, aged 10–20, underwent ERP  recording before and 2 h after an oral loading of Phe. Neurocognitive functioning, historical and concurrent biochemical values of blood Phe, Tyr, and Phe/Tyr ratio, were all included in the statistical analysis.Results: Event-related potential components were normally detected in all the subjects. In subjects younger than 13 CNV amplitude, W2-CNV area, P3b latency, and reaction times in motor responses were negatively influenced by Phe-loading. Independently from the psychophysiological vulnerability, some neurocognitive skills were more impaired in younger patients. No correlation was found between biochemical alterations and neurocognitive and psychophysiological findings.Conclusion: The vulnerability of the emerging neurocognitive functions to Phe suggests a strict metabolic control in adolescents affected by PKU and a neurodevelopmental approach in the study of neurocognitive outcome in PKU. Phenylketonuria  is an inherited metabolic cause of mental disability due to the defect of the phenylalanine hydroxylase (PAH) enzyme that converts phenylalanine (Phe) into tyrosine (Tyr). Neonatal screening programs and early treatment have radically changed the natural history of PKU  and psycWithin this frame, the aims of the present study were: (a) exploring the effect of rapid variations in blood Phe on psychophysiological components involved in attention and information processing in early-treated young PKU subjects during their second decade of life; (b) assessing the association (if existing) between psychophysiological vulnerability, biochemical control and neurocognitive functions.The experimental design scheduled two subsequent steps. The neurocognitive assessment was performed at Examination 1. Examination 2, 2 or 3 weeks later, was dedicated to the psychophysiological study (see below), which was performed before (T1) and 2 h after (T2) an oral loading of Phe (100 mg/kg). The time span between T1 and T2 recordings was based on H-MRS studies, which showed a pick of brain Phe concentration 1–4 h after an oral loading of Phe , 12. As Phe, Tyr levels, and Phe/Tyr ratio were assessed on dry blood spot on the day of neuropsychological assessment, and before T1 and T2 examinations.The study was approved by the medical ethical committee and a written informed consent was obtained from patients or patients’ parents (for minors).PAH; (b) early diagnosis, by neonatal screening program, and treatment; (c) aged 10–20; (d) IQ ≥80; (e) availability of biochemical data covering the patient’s history from the diagnosis up to the study; (f) absence of medical condition, other than PKU, affecting neuropsychological and/or psychophysiological functions; (g) no history or clinical evidence of consumption of drugs or medicaments interfering with neurocognitive and/or psychophysiological functions; and (h) no pregnancy.Seventeen subjects were sampled among the PKU patients in charge of the Department of Paediatrics and Child Neurology and Psychiatry in Rome, according to the following criteria: (a) genetically confirmed defect of Demographic and clinical characteristics of the sample are shown in Table E); (c) visuospatial and visual memory functions . To the aim of the present study the accuracy scores for the copying and immediate recall were analyzed; (d) sustained and shared attention, memory functions (Leiter-R test attention and memory battery). These Leiter subtests contribute to five composite scores: memory screener, recognition memory, memory span, attention composite, and memory process.The Neurocognitive assessment was focused on the following functions: (a) IQ [Wechsler intelligence scale for children-III (WISC-III) for patients aged 6–16 and Wechsler adult intelligence scale-revised (WAIS-R) for patients ≥17 years]; (b) cognitive flexibility and rule shifting [Wisconsin card sorting test (WCST)]. The following domains of WCST were measured: perseverative responses (PR), perseverative errors (PE), non-perseverative errors (NE), and total number of errors : mismatch negativity (MMN); auditory P300 ; contingent negative variation (CNV); and intensity dependence of auditory evoked potentials (IDAP). The brain functions potentially probed by the ERPs and the related behavioral tasks are reported in Table Participants were seated on an anatomic chair in a faradized and light-attenuated room. The electrophysiological signals were recorded by Ag/AgCl electrodes fixed on the scalp at the F3, Fz, F4, C3, Cz, C4, P3, Pz, and P4 sites, according to the International 10–20 System, referred to linked mastoids and grounded at Fpz. The bipolar electrooculogram (EOG) was recorded from above and below the left eye. All inter-electrode impedances were kept below 3 KΩ. EEG signals and EOG were filtered using a 0.01–30 Hz bandpass . A notch filter was also applied. The data were entered via an analog/digital converter at a sampling rate of 1024 Hz and stored in a hard disk. A Mizar Sirius EEG-EP multifunctional system was used.All auditory signals were visually inspected and revised by one investigator (F.F.) blinded to the patient’s age and clinical data.Trials containing eye movements were automatically rejected. A further selection was performed in the offline analysis in order to reject other kinds of artifacts, according to the clinical guidelines .With regard to MMN, ERPs were obtained by averaging EEG epochs separately for all deviant and standard tones. Difference waveforms were calculated by subtracting the ERPs of standard stimuli from those elicited by each deviant stimulus. The MMN latency and amplitude for each deviant stimulus were measured from the most negative peak detected between 100 and 250 ms post the onset of the stimulus difference, at Fz, on the difference-wave.With regard to the P3 paradigm, in the target response, the N1 component was identified as the most negative peak between 75 and 140 ms, while the P3b components were defined as the largest positive deflections between 250 and 500 ms on the stimulus onset. The amplitude of these components was identified by means of baseline-to-peak measurements. For the sessions, counting responses and mean reaction times (RTs) of correct responses were calculated (range for correct responses 100–1000 ms).The CNV amplitude was measured as the total area (negative shift between S1 and S2) and as two temporal windows of interest: the early orienting window – W1 (between 500 and 700 ms after S1), and the late window – W2 (200 ms preceding S2) . The RT With regard to IDAP, the epoch analysis for each AEP was of 600 ms with a 100 ms pre-stimulus baseline. Amplitudes of the N1 (between 50 and 150 ms post-stimulus) and P2 (between 90 and 230 ms post-stimulus) peaks were measured. The IDAP was calculated as the linear amplitude/stimulus intensity function (ASF) slope for block averages (mV/10 dB).All ERP recorded at T1 and T2 were compared with those obtained in healthy age matched internal controls in our lab. Moreover, as the T2 recording was concerned, each subject acted as control of himself.t-test for continuous variables (unpaired and paired samples) and an exact Fisher test for categorical variables. A correlation analysis between demographic, clinical, biochemical, and neuropsychological and neurophysiological variables was also performed by means of Pearson’s index.The statistical analyses have been performed using p value ≤0.05 was considered to indicate statistical significance.In order to explore the possible influence of the age on neurocognitive and psychophysiological performances, the sample was sub-grouped in tertiles according to the patients’ age and each subgroup was compared with each other with respect to neuropsychological and neurocognitive performances. All data were analyzed with SPSS (version 21.0). A Neurocognitive assessment was accomplished in all subjects Table . The mear = 0.595; p = 0.012), WCST E , WCST PE , and WCST NE . IQ and EFs were not significantly different in subjects on and out diet when the study was performed and neither of them was correlated with subjects’ age, and historical and/or concurrent biochemical alterations.Intelligence quotient was correlated with: WCST PR (p < 0.001).Mean blood Phe concentration at T1 and T2 was 571.64 μM (±192.92) and 1129 μM (±177.31), respectively . A further marginal negative correlation emerged between IQ and P3 latencies at T2 .The P3 components were well represented in all the subjects. No differences were found in the N1 and P3b (counting and motor response) amplitudes and in latencies between T1 and T2 recordings. Moreover, the number of correct responses and RTs were comparable in both the electrophysiological recordings. No correlations emerged between the P3 parameters and other clinical, biochemical, and neuropsychological data, except for a negative correlation between age and P3b latency either in counting or in motor response in T2 recording session , as well as the W2-CNV area at the Pz site (p = 0.05) were smaller at T2 than T1. RT values were comparable between the two ERP recording sessions.Contingent negative variation waves were elicited with a well detectable shape  in all tp = 0.05). Moreover in the same patients, the total CNV  and the W2-CNV areas  were smaller after Phe-loading than in basal condition ; RCFC trial (p = 0.04) and immediate recall trial (p = 0.03); Leiter-R attention sustained subtest (p = 0.027); and spatial memory subtest (p = 0.039). They had also a relatively lower IQ . Moreover, a positive correlation between IQ and RCFC  was observed only in this group. The differences among subgroups (younger and older than 13) could not be explained on the base of any of demographic and treatment variables showed in Table Re-examining neurocognitive results in the light of the psychophysiological data, patients younger than 13 were more impaired in the following tests: WCST total number of errors  , 39 poteIn all subjects, we recorded a normal pattern of the CNV waves in basal condition. However, a couple of hour after Phe-loading, a derangement of the total CNV amplitude emerged suggesting a suppression of the cerebral on-going activity thought to prepare the attentional system for a rapid motor response after a warning signal . Such alIndependently from psychophysiological alterations, patients younger than 13 showed some impairment in tests exploring visual-spatial and visual memory, sustained and shared attention. The occurrence of neurocognitive disorders in early-treated PKU has been the object of several studies over the last 10 years . A meta-While the low numerousness of the sample requires cautions in the interpretation of our results, the pattern of vulnerability we detected was congruous with other previous clinical observations.In conclusion, our data showed that two independent measures of brain functioning, one exploring complex neurocognitive skills, the other the sensibility to a rapid increase of Phe of specific information processing networks, are impaired in younger but not in older PKU patients.Such age-related vulnerability recommends a continuous dietary control in PKU patients during adolescence, and supports a pathogenetic model based on the relative vulnerability of the emerging functions to Phe suggesting a neurodevelopmental approach to the study of the neurocognitive outcome in PKU.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Extended criteria donor (ECD) and donation after circulatory death (DCD) kidneys are at increased risk of delayed graft function (DGF). Experimental evidence suggests that erythropoietin (EPO) attenuates renal damage in acute kidney injury. This study piloted the administration of high dose recombinant human EPO-beta at implantation of ECD and DCD kidneys, and evaluated biomarkers of kidney injury post-transplant.Forty patients were randomly assigned to receive either rhEPO-b  , or placebo (n = 20) in this, double blind, placebo-controlled trial at Manchester Royal Infirmary from August 2007 to June 2009. Participants received either an ECD (n = 17) or DCD (n = 22) kidney. Adverse events, renal function, haematopoietic markers, and rejections were recorded out to 90 days post-transplant. Biomarkers of kidney injury  were measured in blood and urine during the first post-operative week.The incidence of DGF (53% vs 55%)  and slow graft function (SGF) (32% vs 25%)  respectively, serum creatinine, eGFR, haemoglobin and haematocrit, blood pressure, and acute rejection were similar in the 2 study arms. High dose rhEPO-b had little effect on the temporal profiles of the biomarkers.High dose rhEPO-b appears to be safe and well tolerated in the early post- transplant period in this study, but has little effect on delayed or slow graft function in recipients of kidneys from DCD and ECD donors. Comparing the profiles of biomarkers of kidney injury  showed little difference between the rhEPO-b treated and placebo groups. A meta-analysis of five trials yielded an overall estimate of the RR for DGF of 0.89 , a modest effect favouring EPO but not a significant difference. A definitive trial based on this estimate would require 1000-2500 patients per arm for populations with base DGF rates of 50-30% and 90% power. Such a trial is clearly unfeasible.ISRCTN85447324 registered 19/08/09.EudraCT Number 2006-005373-22 ISRCTN  In 2011-2012, 34% of UK deceased donors were over the age of 60 yrs while 40% were donation after circulatory death (DCD) donors . In addiBased on results from clinical trials including 1725 patients approximately 8% of patients treated with NeoRecormon® are expected to experience adverse reactions. Undesirable effects are observed predominantly in patients with chronic renal failure or underlying malignancies and are most commonly an increase in blood pressure or aggravation of existing hypertension and headache. The therapeutic margin of NeoRecormon® is very wide. Even at very high serum levels no symptoms of poisoning have been observed .Against this background of evidence supporting the theory that administration of rhEPO after injury may be beneficial, we performed a pilot study to assess the safety of administering high dose rhEPO-beta to ECD and DCD kidney recipients intra- and peri-operatively, to obtain preliminary data on efficacy, and to evaluate changes in three extensively reported biomarkers of kidney injury in blood and urine: NGAL ,16, IL-1Eighty-two recipients were screened Figure  providinIn the rhEPO-b group 5/19 received 2 hours of haemodialysis and one patient received rapid cycling peritoneal dialysis with varying degrees of ultrafiltration immediately prior to surgery. Of these, four patients subsequently developed DGF. In the placebo group 4/20 received 2 hours of haemodialysis prior to surgery and all developed DGF. Of interest, 17/21 patients on maintenance haemodialysis prior to surgery developed DGF, as opposed to 3/15 patients on maintenance peritoneal dialysis .There were two deaths due to sepsis in the placebo group. Hypertension occurred in 6 rhEPO-b recipients and 5 patients in the placebo group . One patient in the rhEPO-b group developed a generalised tonic-clonic seizure due to severe hypertension, attributed to hypervolaemia and the cessation of anti-hypertensive medication peri-operatively (unit policy). In the opinion of the respective attending consultants and the independent trial data monitor, none of the observed adverse events was attributable to rhEPO-b treatment.Numbers and duration of dialysis episodes were similar in both groups Table . DCD kidSequential serum creatinine and 4-variable MDRD eGFR are shown in Figure vs 11.3 ± 0.4 g/dl, respectively; p = 0.78). The number of blood transfusions required during the in-patient stays did not differ significantly between groups (p = 0.20) and the groups had similar levels of maintenance rhEPO-b usage post- transplant , Kidney Injury Molecule-1 (KIM-1) and, IL-18 are shown in Figure A meta-analysis Figure  includinThis pilot study supported the view that the intra- and peri-operative intra-venous administration of high dose rhEPO-b  appeared to be safe in the early post-transplant period. The study reports only small effect sizes of rhEPO-b on adverse events, renal function, haematopoietic factors, acute rejection episodes, and the profiles of biomarkers of kidney injury post-transplant.The dose regimen in our study was adapted from Ehrenreich et al. , where h4 IU; n = 45) or placebo  on 3 consecutive days, starting 3–4 h before the transplantation and 24 h and 48 h after reperfusion. Results showed no differences in the incidence or duration of delayed graft function and/or primary non-function  though Epoetin treatment significantly increased the risk of thrombotic events at 1 month and 1 year .Song et al.  administIn patients with an acute ST-segment elevation myocardial infarction a single intravenous bolus of EPO-alpha within 4 hours of percutaneous coronary intervention did not reduce infarct size .Two other randomised controlled trials investigating high dose EPO in renal transplantation have been published recently. Sureshkumar et al.  conducteIn the second study Hafer et al.  evaluateThe doses of rhEPO used by Sureshkumar et al.  and Hafer et al.  were similar to our study . It is conceivable that a lack of efficacy is a consequence of the timing of EPO administration. Injury prior to reperfusion is multi-factorial and due to recurrent insults to the kidney rather than a single ischaemia reperfusion event. Typically injury begins with peri-mortem events including, severe hypertension or hypotension and nephrotoxic agents. Retrieval of the kidneys is associated with warm ischaemia, cold ischaemia and the anastomotic ischaemic phase. The lack of efficacy in these studies may be due to the delay in rhEPO-b administration until reperfusion. However, therapeutic intervention in the donor, prior to organ retrieval and storage, would impact on all organs donated and prevent any potential recipients from declining involvement in the study without declining organ transplantation. It was not possible to intervene during cold storage firstly because we did not have access to machine perfusion technology at the time, and secondly the potential recipient would not have been able to decline involvement in the study. We decided to intervene immediately prior to reperfusion, with the knowledge that significant injury to the kidney may have already occurred, but based on the experimental evidence, intervention could still be beneficial to the graft. The participants in our study received kidneys from DCD and ECD donors. In the study from Sureshkumar et al. the kidneys were from ECD donors in only 46% of the cases. The donor details were not presented in the study from Hafer et al., though their exclusion criteria included immunological loss of a previous graft, and cold ischaemic time of longer than 24 hours.Taking the five studies together, a range of quality of donated kidneys has been examined and the evidence appears convincing that high dose rhEPO in deceased kidney transplants, although well tolerated, has little effect on DGF, early or later allograft function, graft histology, or levels of biomarkers of kidney injury, including NGAL, IL-18 and KIM-1. Additionally, concerns were raised over the increased number of thrombotic events in the EPO treated groups in some of the trials. A meta-analysis of the five trials yielded an overall estimate of the RR for DGF of 0.89 , a modest effect favouring EPO but not demonstrating a significant difference. At a time when there is obvious need to maximise the lifespan of donated organs it is disappointing that the promising experimental evidence of rhEPO tissue protection does not readily translate into the clinical setting of transplantation.The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and was consistent with the International Conference on Harmonization of Good Clinical Practice. The clinical and research activities reported are consistent with the Principles of the Declaration of Istanbul as outlined in the Declaration of Istanbul on Organ Trafficking and Transplant Tourism. The study was approved by the Central Manchester Research Ethics Committee (07/Q1407/94), the Medicines for Human use Regulatory Authority (EuDract no. 2006-005373-22), and registered with the ISRCTN . Informed consent was obtained from each patient. The manuscript adheres to CONSORT guidelines for reporting clinical trials [Patients were eligible if aged 18 years or more, able to give consent, and in receipt of a Maastricht category III, , a Maastricht category IV (cardio-circulatory death in a brain dead donor), a kidney from an extended criteria donor . Exclusion criteria included inability to consent, pregnancy, breastfeeding, acute infection, previous intolerance of the trial drug, a diastolic blood pressure > 100 mm/Hg pre-transplantation, or initially a haemoglobin level = or > 13 g/dl. However, it became clear that a haemoglobin cut-off of 13 g/dl would exclude approximately one third of otherwise eligible participants. A review of the pre-operative haemoglobin levels of adults transplanted at this centre in 2007 reported a mean pre-op haemoglobin of 12.2 g/dl, with a range of 7.4-17.7 g/dl, and a mean decrease of 2.4 g/dl within 24 hours of surgery. As a result, the haemoglobin exclusion criterion was reset to ≥15 g/dl, as a substantial amendment to the protocol with ethical and regulatory authority approval. All patients received immunosuppression as per unit protocol. Induction immunosuppression consisted of basiliximab 20 mg intravenously on day 0 and day 4, as well as a single dose of methylprednisolone 1 g given intra-operatively. Maintenance immunosuppression consisted of tacrolimus (Prograf®), prednisolone and mycophenolate mofetil (Cellcept®). DGF was defined as the need for haemodialysis or peritoneal dialysis within the first seven days post transplantation, and slow graft function was defined as a creatinine reduction ratio at day 7 of <70% [Eligible patients were randomly assigned by the trial Pharmacy using a computer-generated list to receive either rhEPO-b (Neorecormon® Roche) or 0.9% saline. All study participants and the clinical team were blinded to the trial drug for the duration of the study. Pharmacovigilance was undertaken by PDMS Roche Products Limited.The first dose of rhEPO-b  (Neorecormon® Roche) or 0.9% saline were administered intra-operatively in a 100 ml intra-venous infusion over 15 minutes, as clamps were released to allow graft reperfusion. The second and third infusions  were given at 24 hour intervals post-operatively, making a total rhEPO-b dose of approximately 100,000 iu over approximately 48 hours. Prior to reperfusion, a 20 ml systemic blood sample was collected via the central line (the pre-reperfusion sample). The post-reperfusion 20 ml blood sample was collected approximately 15 minutes following reperfusion. 10 ml blood samples were collected at 2, 8 and 24 hours, and daily for the first 7 days post-operatively, coinciding with venepuncture for routine care where possible. Blood samples were centrifuged at 2000 rpm for 10 minutes to separate the plasma, which was aliquoted and stored at -80C. Urine samples were collected at similar time points where possible, centrifuged at 2000 rpm for 5 minutes, aliquoted and stored at -80C. Samples were batched for analysis of biomarkers.Plasma NGAL (pNGAL) and urine NGAL (uNGAL) were measured by immunoassay using the Duoset DY1757, and urine KIM-1 (uKIM-1) using the duoset DY1750, R&D Systems, OXON UK, following the manufacturer’s guidelines. Mature IL-18 in plasma and urine was measured using an in-house immunoassay . Sample concentrations in all assays were calculated from a 4-parameter standard curve . Biomarkers in urine were corrected for creatinine concentration in the sample. An internal standard was included on each assay plate confirming an inter-assay coefficient of variation (CV) of <20% and an intra-assay CV of <10%.As a pilot, the study had no formal power calculation, but was designed to test the safety of delivering the intervention, to describe effect sizes on the measured variables , and to evaluate the profiles of three biomarkers of kidney injury. A sample size of 20 per arm was chosen on the basis of feasibility and to gather sufficient data to design and power a definitive trial .Data analysis was performed using GraphPad Prism 5. Results were presented as median ± interquartile range, or as percentages as appropriate. Mann-Whitney U tests were used to compare continuous variables between groups. Categorical data was analysed using a Fisher’s exact test to generate a risk ratio (RR) and confidence interval (CI). Clinical and biomarkers assessed at multiple times were compared using mixed-effect ANOVA models to allow for correlations between repeat measures using the lmer package in the R statistical environment . A meta-


Aside from the overall amplitude, the response may vary across cognitive states, tasks, brain regions, and subjects with respect to characteristics such as rise and fall speed, peak duration, undershoot shape, and overall duration. Here we demonstrate that the fixed-shape (FSM) or adjusted-shape (ASM) methods may fail to detect some shape subtleties . In contrast, the estimated-shape method (ESM) through multiple basis functions can provide the opportunity to identify some subtle shape differences and achieve higher statistical power at both individual and group levels. Previously, some dimension reduction approaches focused on the peak magnitude, or made inferences based on the area under the curve (AUC) or interaction, which can lead to potential misidentifications. By adopting a generic framework of multivariate modeling (MVM), we showcase a hybrid approach that is validated by simulations and real data. With the whole HDR shape integrity maintained as input at the group level, the approach allows the investigator to substantiate these more nuanced effects through the unique HDR shape features. Unlike the few analyses that were limited to main effect, two- or three-way interactions, we extend the modeling approach to an inclusive platform that is more adaptable than the conventional GLM. With multiple effect estimates from ESM for each condition, linear mixed-effects (LME) modeling should be used at the group level when there is only one group of subjects without any other explanatory variables. Under other situations, an approximate approach through dimension reduction within the MVM framework can be adopted to achieve a practical equipoise among representation, false positive control, statistical power, and modeling flexibility. The associated program  When a region in the brain is activated, oxygen and glucose demands lead to blood vessel dilation, followed by increased blood to the tissue (neurons and astrocytes) under stress. The onset of a neuronal activity triggers a sequence of physiological events in the blood vessels of the surrounding area, typically characterized by the changes in cerebral blood flow as well as concentration fluctuations of deoxyhemoglobin and oxyhemoglobin. The blood oxygenation level dependent (BOLD) signal from the FMRI scanning mainly captures the concentration changes of deoxyhemoglobin; that is, the BOLD signal is a surrogate and signature of neuronal activations plus various sources of noise . As an indirect measure of neuronal activity, the shape of the BOLD response may hold some crucial features about brain function. However, the cascade of events from neural activation to measurable MRI signal is complex and nonlinear under certain regimes  that corresponds to a stimulus with a theoretically instantaneous duration and unit intensity. The voxel-wise EPI signal is then modeled through time series regression with explanatory variables (or regressors) of interest, each of which is constructed through the convolution between the stimulus timing and the IRF. In a block design, each task or condition has a duration of more than two seconds. As each block can be approximately considered as a sequence of events with an interval of scanning repetition time (TR), the theoretical HDR is usually hypothesized as the integral or linear summation of the consecutive IRFs, or the convolution of IRF over the stimulus duration.m) per condition or task, resulting in m regression coefficients which need to be considered simultaneously at the group level. In addition to the aforementioned TENT basis set, options for ESM at the voxel level include cubic splines, Legendre polynomials, sines, or user-defined functions in AFNI, and finite impulse function (FIR) in SPM, FSL, and NIPY, inverse logit  to approximate the HDR based on the experimental data with the assumption of linearity and time-invariance (or stationarity)  to obtain the area under the curve (AUC)  of the two or three effect estimates  include the need for a larger number of kernel coefficients that need to be estimated. They requires 3, 24 contiguously interleaved axial slices, and TR of 1250 ms . Six runs of EPI data were acquired from each subject, and each run lasted for 380 s with 304 data points. The task followed an event-related design with 96 trials in each run, with three runs of congruent stimuli interleaved with three runs of incongruent stimuli . Subjects used a two button box to identify the large letter during global runs and the component letter during local runs. Each trial lasted 2500 ms: the stimulus was presented for 200 ms, followed by a fixation point for 2300 ms. Inter-trial intervals were jittered with a varying number of TRs, allowing for a trial-by-trial analysis of how the subject's BOLD response varied with changes in reaction time (RT). The experiment protocol was approved by the Combined Neuroscience Institutional Review Board at the NIMH, and the National Clinical Trials Identifier is NCT00006177.To demonstrate and compare various modeling approaches at the group level, we adopt the same experimental data used in our previous paper  at a voxel size of 3.5 × 3.5 × 3.5 mmAt the group level, it is the BOLD effects associated with the average RT that are of interest here. In addition to the estimated HDR profiles, three other explanatory variables considered are: a) between-subjects factor, Group (two levels: children and adults), b) within-subject factors, Condition (two levels: congruent and incongruent), and c) quantitative covariate, age. The focus is on the interaction of HDR between Group and Condition: Do the two groups differ in the HDR profile contrast between the two conditions?3dClustSim in AFNI, Forman et al., This paper is a sequel to our previous exploration  and upper (X) cases for column vectors and matrices respectively. The word multivariate is used here in the sense of treating the effect estimates from the same subject or from the levels of a within-subject factor as the instantiations of simultaneous response (or outcome) variables . This usage differs from the popular connotation in the FMRI field when the spatial structure (multiple voxels) is modeled as the simultaneous response variables, including such methods as multivariate pattern analysis  stand for scalars, boldfaced italic letters in lower . For example, the effect estimates from the multiple basis functions under ESM or ASM can be considered the response values associated with the levels of a within-subject or repeated-measures factor (termed Component hereafter). When multiple within-subject factors occur, all their level combinations for each subject are flattened from a multi-dimensional space onto a one-dimensional row of B. It is noteworthy that the within-subject factors are expressed as columns in B on the left-hand side of the model (1), and only between-subjects variables such as subjects-grouping factors , subject-specific measures  and their interactions are treated as q explanatory variables on the right-hand side. The same linear system is assumed for all the m response variables, which share the same design matrix X is assumed to have full column-rank q. Each column of the regression coefficient matrix A = (αhj) corresponds to a response variable, and each row is associated with an explanatory variable. Lastly, the error matrix nm-dimensional Gaussian: vec(D) ~N, where vec and ⊗ are column stacking and direct (or Kronecker) product operators respectively. As in univariate modeling (UVM), the assumptions for model (1) are linearity, Gaussianity and homogeneity of variance-covariance structure . When only one group of subjects is involved (q = 1), the parameter matrix A becomes a row vector  that is associated with the m levels of a within-subject factor.The As demonstrated in Chen et al. , MVM hasm basis functions at the individual subject level: a) one group of subjects with the associated effects at the group level expressed as α1, α2, …, αm under (1), and b) either two groups or two conditions and the two sets of effect estimates for HDR are αj1 and αj2 respectively, j = 1, 2, …, m. To simplify geometric representations, we assume equal number of subjects across groups in the case of group comparison, but the assumption is not required from the modeling perspective. The various modeling strategies discussed below for these two cases can be easily extended to situations with more explanatory variables, including factors and quantitative covariates.Here we exemplify two simple and prototypical cases with the HDR profile modeled by t-tests under UVT, the two prototypes can be expressed with the following null hypotheses,As the analogs of one- and two-sample or paired m regression coefficients associated with the m basis functions from each subject are brought to the group level and treated as the instantiated values of m simultaneous variables. When the effect estimates associated with the basis functions of ESM or ASM are treated as the values of m simultaneous response variables, the hypothesis (2a) or (2b) can be analyzed through MVT under the model (1). Geometrically, the data for 1, α2, …, αm) in the m-dimensional real coordinate space ℝm  and , and the corresponding two-sample Hotelling T2-test is conducted to see if the hypothesis (2b) about the two centroids can be rejected. The hypothesis (2b) can be easily generalized to the situation with more than two groups of subjects  as well as more than one subject-grouping variable  through the formulation of general linear testing  with an intercept of 0. That is, the m effects are coded by m indicator variables instead of any conventional contrast coding. Suppose that the m effect estimates associated with the m basis functions from the ith subject are βi1, βi2, …, βim, the LME model can be specified as,i characterizes the deviation or shift of the ith subject's HDR from the overall group HDR, the residual term ϵij indicates the deviation of each effect estimate βij from the ith subject's HDR, and the indicator variables xij take the cell mean coding,j, j = 1, 2, …, m capture the overall group HDR. The significance of the overall HDR at the group level can be tested through LME on the same hypothesis as (2a),As demonstrated in Chen et al. , linear It is of note that the LME approach does not work when other explanatory variables  are involved because (2a) or (2b) cannot be formulated due to the parameterization constraint through dummy coding. For instance, when there are two groups involved, the typical contrast coding for the two groups renders one dummy variable ; however, such a coding strategy relies on the existence of an intercept in the model. If the two groups are coded by two indicator variables, the model matrix would become overparameterized.The multiple estimates associated with the multiple basis functions can be reduced to a single value, which is the area under the curve of the estimated response function. The AUC hypotheses for the two prototypes (2a) and (2b) becomem coefficients (or area under the HDR curve) is used to summarize the overall response amplitude per subject in one- or two-sample t-test at the group level. The AUC hypotheses (4a) and (4b) are essentially a zero-way interaction (or intercept) and a one-way interaction (or the main effect of Group or Condition) respectively and can be performed under the AN(C)OVA, GLM, or MVM framework. Their geometrical interpretations are as follows (cf. Table m−1 isosurface (or hyperplane) α1 + … + αm = c, and the associated test for AUC (4a) is executed on the distance between the data isosurface and the null isosurface α1 + … + αm = 0. As the correct null hypothesis for MVT (2a) is only a subset of AUC (4a), the rejection domain of AUC (4a) is only a subset of the rejection domain for MVT (2a), leading to a misrepresentation in (4a) and a detection failure when a data point lies on α1 + … + αm = 0 but not at the origin . Similarly for That is, the sum of the L2 distance (L2D) for ESM can be formulated respectively asAs an alternate dimension reduction approach, the null hypotheses associated with the Euclidean or L2-distance of the m regression coefficients from no response, and then performs one- or two-sample t-test on the distances.In other words, one captures the overall magnitude for each subject using the For ASM, the null hypotheses with the focus on the canonical basis aresgn is the sign function. That is, the L2D for ASM is similar to the L2D for ESM, but using the two or three weights associated with the two or three basis functions in ASM and assigning the sign of the canonical response to the resultant L2-distance.And the null hypotheses for L2D  is executed on the radius of the ℝm−1 iso-sphere, leading to no geometrical distortion . On the other hand, the data for m−1 iso-sphere surfaces, and the associated test for (5b) acts on the radius difference between the two ℝm−1 iso-spheres, resulting a detection failure when the two HDR curves have roughly the same radius.Their geometrical interpretations are as follows Table . The datm effect estimates from ESM as m levels of a within-subject factor Component, one can test the hypothesis for the effect-by-component interaction (EXC); that is, the m regression coefficients associated the m basis functions are taken to the group level without any condensation:By treating the m components in (9) by treating them as the m levels of a within-subject factor in an AN(C)OVA or univariate GLM platform. In contrast, the equality among the m components in (9) is tested in XMV as m simultaneous variables in an MAN(C)OVA or multivariate GLM (Appendix B).As discussed in Chen et al. , EXC (9)m. The associated test for (9a) is executed on the distance between the data line and the null line . As the correct null hypothesis (2a) is only a subset of The geometrical interpretations of the hypotheses are the following Table . EXC (9am−1 planes and sphere surfaces respectively). We need to address the question of whether the geometric accuracy order translates to statistical power through simulations and to performance when the methods are applied to real data.Among all the testing strategies, LME and MVT are the most precise  structure for their variance-covariance matrixAs the spatial extent of FMRI data analysis is independently controlled through false positive rate or family-wise error, the simulations here were performed at a voxel to examine and compare the false positives and power performance among the testing methods. Simulated data were generated with the following parameters, imitating a typical FMRI group analysis with six scenarios  and Component (within-subject factor with 7 levels that are associated with the 7 basis functions). False positive rate (FPR) and power were assessed by counting the datasets with their respective F- or t-statistic surpassing the threshold corresponding to the nominal significance level of 0.05. Similarly, one- or two-sample t-test was performed on the AUC and L2D values respectively.The choice of a simple Σ structure here is to allow manageable number of simulations while in the same time providing a reasonable structure similar to the one adopted for the Gaussian prior in Marrelec et al.  that guaAmong the six scenarios, all the testing methods showed proper control of FPR except for L2D with one group of subjects. L2D exhibits high power but at the cost of poor FPR control. This is in part due to the reduction of effect estimates to a positive value regardless the signs of the individual components in ESM. It is possible to reduce this problem in ASM when the sign of the principal kernel is assigned to the resulting L2D measure as shown in (7) and (8). Also, L2D achieved the lowest power with two groups of subjects. AUC simply sums over all the components, significantly misrepresenting the effects when the undershoot becomes moderate. This is reflected in the results where reasonable power is achieved when the undershoot is small and lower power is obtained when the undershoot is moderate. With two groups, AUC performed well in power when the two groups had the same HDR shape, but behaved as poorly as L2D when the two groups had different HDR shapes. As expected, AUC is only sensitive to peak amplitude differences, but is insensitive to shape subtleties. Except for L2D and AUC, the other methods tend to converge in power when the sample size is large enough . With one group, LME outperformed all other candidates. XUV had a balanced performance on power among all the scenarios, constantly surpassing XMV. Lastly, MVT was slightly more powerful than XUV with two groups when their HDRs were of the same shape with a large number of subjects .In summary, our simulations show that LME is preferred when there is only one group of subjects with no other explanatory variables present. Under other circumstances, XUV is the preferred choice, especially with the typical sample size of most studies, while MVT, AUC, and XMV may provide some auxiliary detection power.3dMVM on the ESM data presented in the Introduction section with n = 50 (2 groups: 21 children and 29 adults), m = 20 (2 conditions with each having 10 component estimates at 10 TR grids) and design matrix X of q = 4 columns in the MVM (1): all ones (intercept associated with the average effect across groups), effect coding for the two groups, the average age effect between the two groups, and the interaction group:age (or group difference in age effect). The age values were centered within each group so that the group effect can be interpreted as the difference between the two groups at their respective average age. The effect of interest was on the interaction of group and condition: Did the two groups have the same HDR profile difference between the two conditions? Five F-statistics from MVT, XUV (with sphericity correction), AUC, L2D, and XMV, were obtained and then, due to different degrees of freedom, converted to Z-values for direct comparisons  function through the hypothesis (6b) was adopted  with the three SPM curves covering 32 s or 25 TRs, the model would contain too many parameters relative to the data size; b) the effect estimates after the first 10 TRs were mostly negligible. Two tests, XUV and AUC, were performed while MVT and XMV were impossible because the rank was 3 among the 10 effect estimates from the linearly reconstructed HDR per condition.With the ASM analysis results, five tests were performed using d Figure  bottom. 0 and L2D with ASM was very low  played a supplementary role when XUV failed  are a priori ignored. That is, activation detection intuitively focuses on the estimated magnitude around the activation peak while statistical inference on the whole HDR shape is generally considered a daunting hurdle. FSM may work well for situations such as a contrast between a condition and fixation. However, it would fail to detect shape subtleties such as prolonged plateau at the peak, slower or faster rise or fall, bigger or longer undershoot, or overall duration. Therefore, FSM through a presumed HDR  is very crude even in an experiment with a block design  would be the most accurate approach in terms of hypothesis characterization. However, in practice the number of subjects is usually not large enough for MVT due to resource limitations , leading to an underpowered performance of MVT as shown in our simulations and real data. Among all the workaround methods through dimensional reduction, XUV has the least hypothesis distortion and the lowest power loss. With one group of subjects and no other explanatory variables present, XUV surpasses MVT, XMV, and AUC in power. However, with an accurate representation of the hypothesis, LME is slightly more efficient than XUV, and should be considered as the first choice . MVT for the components from ESM presents a unique challenge when one or more within-subject factors are included in the model, and we offer a testing strategy that still fits in the MVM framework (Appendix B). As an alternative, these tests could be conducted in the traditional univariate GLM except for the two multivariate methods, MVT and XMV. In other words, some of the testing methods (MVT and XMV) are truly multivariate, while others  are essentially univariate. However, as we demonstrated in Chen et al. , a non-linear approach is usually difficult to handle and still requires some extent of prior information about the HDR shape. Furthermore, the ESM approach is generally considered to be susceptible to noise or effects unrelated to the effects of interest . In other words, the confounding effects may leak into the HDR estimation through over-fitting. However, the false positives from the potential over-fitting at the individual level is less a concern at the group level for the following reasons: a) the likelihood is reduced unless most subjects systematically have similar or same confounding effects; b) cluster-based inferences may reduce the risk of false positives; and most importantly c) examination of the estimated HDR profiles offer an extra safeguard to filter out the potential false positives.It is noteworthy that the reliability information from the individual subject analysis is not considered at the group level with the modeling methods discussed here, unlike the mixed-effect multilevel analysis  or the effects for both time and dispersion derivatives (8)  of the dimensional reduction methods for ESM discussed here have been sporadically and individually applied to real data in the literature. For example, a popular practice with ASM is to solely focus on the coefficient of the principal basis function  with other coefficients  being a priori abandoned. As our results with real data showed, the investigator may fail to detect most activations when the effect lies in the HDR shape nuances but not the peak. One suggestion for ASM was to extend the definition of amplitude in (6) to the Similarly for ESM, two dimensional reduction methods have separately been adopted in data analyses. For example, AUC was employed in Beauchamp et al. , Greene m to the three quantities  in ℝ3 might be compromised in power when detecting the shape subtleties—this point can be highly dependent on the experiment. Secondly, the reliability for the estimation of the three characteristics was suboptimal. For example, the lackluster performance of ESM in Lindquist et al.  or adjusted-shape (ASM) method may fail to detect most of the shape subtleties  in hemodynamic response (HDR). In contrast, the estimated-shape method (ESM) through multiple basis functions would more accurately characterize the cerebral blood flow regulation, and significantly improve the detection power at both individual and group levels. In addition, we propose an analysis scheme for ESM that still fits within the conventional two-tier analysis pipeline and achieves higher statistical power than the alternatives: one performs regression time series analysis separately for each individual subject, and then conducts group analysis with the individual effect estimates. For one group of subjects, a linear mixed-effects (LME) model is preferred if no other explanatory variables are present. In all other scenarios, statistical inferences on the HDR shape can be achieved through a hybrid combination of multivariate testing (MVT) and dimensional reduction approaches with a multivariate model (MVM). Simulations are shown in terms of controllability for false positive rate (FPR) and power achievement among various testing methods. The strategy was applied to a dataset from a real experiment to compare among different testing strategies in terms of power assessment. In addition, we showcase that the MVM flexibility allows any number of explanatory variables including between- and within-subject factors as well as between-subjects covariates.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.