Patients with chronic somatic conditions face unique challenges accessing mental health care outside of their homes due to symptoms and physical limitations. Internet-based cognitive behavioral therapy (ICBT) has shown to be effective for various psychological conditions. The increasing number of recent trials need to be systematically evaluated and quantitatively analyzed to determine whether ICBT is also effective for chronic somatic conditions and to gain insight into the types of problems that could be targeted.Our goal was to describe and evaluate the effectiveness of guided ICBT interventions for chronic somatic conditions on general psychological outcomes, disease-related physical outcomes, and disease-related impact on daily life outcomes. The role of treatment length was also examined.PubMed, PsycINFO, and Embase were searched from inception until February 2012, by combining search terms indicative of effect studies, Internet, and cognitive behavioral therapy. Studies were included if they fulfilled the following six criteria: (1) randomized controlled trial, (2) Internet-based interventions, (3) based on cognitive behavioral therapy, (4) therapist-guided, (5) adult (≥18 years old) patients with an existing chronic somatic condition, and (6) published in English. 23 randomized controlled trials of guided ICBT were selected by 2 independent raters after reviewing 4848 abstracts. Demographic, clinical, and methodological variables were extracted. Standardized mean differences were calculated between intervention and control conditions for each outcome and pooled using random effects models when appropriate.Guided ICBT was shown to improve all outcome categories with small effect sizes for generic psychological outcomes (effect size range 0.17-0.21) and occasionally larger effects for disease-specific physical outcomes (effect size range 0.07 to 1.19) and disease-related impact outcomes (effect size range 0.17-1.11). Interventions with a longer treatment duration (>6 weeks) led to more consistent effects on depression.Guided ICBT appears to be a promising and effective treatment for chronic somatic conditions to improve psychological and physical functioning and disease-related impact. The most consistent improvements were found for disease-specific outcomes, which supports the possible relevance of tailoring interventions to specific patient groups. Explorative analyses revealed that longer treatment length holds the promise of larger treatment effects for the specific outcome of depression. While the current meta-analysis focused on several chronic somatic conditions, future meta-analyses for separate chronic somatic conditions can further consolidate these results, also in terms of cost-effectiveness. Cognitive behavioral therapy (CBT) focuses on challenging cognitive distortions and dysfunctional underlying beliefs, and on teaching coping and problem solving skills . A varie. ICBT may be beneficial to both patients and therapists: it is more convenient, flexible, and reduces traveling time, costs, and waiting lists, enabling more patients to be reached and treated .-57.35-57In 74% (17/23) of studies, subjects were randomized to one of two conditions, 15 of which compared ICBT with a passive control condition: waiting-list (12 studies), care-as-usual (2 studies), and information-based psycho-education (1 study) . Three sA total of 70% (16/23) of studies were published between 2008 and 2011, and 52% (12/23) were carried out in Sweden. Eleven studies (48%) used intent-to-treat (ITT) analyses. The majority of these studies (6/11) used the last observation carried forward (LOCF) method, in which a participant’s missing values after dropout are replaced with the last available measurement . Four ofPatient populations included chronic pain , headache or migraine , tinnitus , irritable bowel syndrome , diabetes , breast cancer , epilepsy , fatigue in patients with chronic neurological disorders , and a heterogeneous patient population  . Twenty Interventions consisted of a variety of generic CBT-based techniques, often supplemented with specific approaches appropriate for the chronic condition under study. Interventions focusing on relaxation and psycho-education were included only when combined with other CBT techniques, that is, some form of cognitive reappraisal or restructuring . TreatmeInterventions were generally broad and multifaceted, targeting various aspects of chronic somatic conditions within one intervention . Incidentally, studies indicated that there was a specific primary aim, for example, to reduce depressive symptoms -57, distAll studies incorporated treatment-related contact options, usually in the form of (weekly) email contact with (psychology master students supervised by) licensed clinical psychologists. One study was based solely on therapist-patient contact via email without additional treatment components. Most studies did not report, or not in detail, the average time therapists spent on patients. The main mode of therapist contact was through asynchronous (email) messages, but in 3 of 23 studies (13%) telephone was the main contact option. Five studies (22%) used online group formats. A total of 43% (10/23) of studies included a bulletin board that enabled patients to interact with each other, as an addition to individual treatment tools.The authors’ judgments about risk of bias for each included study and presented as percentages across all included studies can be found in SMDs for the included outcomes are reported in k=16, 95% CI 0.09-0.55, P=.005, I2=78%).Sixteen of 17 studies comparing ICBT with a passive control condition included general psychological outcomes, 5 of which (31%) found greater improvements in the ICBT condition on at least one outcome see  and 4. IP<.001, I2=0%, k=3). Studies with an active control condition were not pooled due to a limited number of studies and comparable outcomes  finding effects in favor of the ICBT condition on at least one outcome see  and 4. PP<.001, I2=0%, k=4). Results from studies with an active control condition were not pooled due to a limited number of studies and outcomes. Individual study results can be found in Nine studies with a passive control condition included measures of disease-related distress or quality of life, of which 7 78%) found effects in favor of the ICBT condition on at least one outcome see  and 4. S% found e21=3.91, P=.05). Intervention duration did not influence effectiveness for other outcomes.Most interventions were relatively short, with little variability in treatment duration: 4% (1/23) of the interventions lasted 4 weeks, 48% (11/23) lasted 6 weeks, and 48% (11/23) lasted 7-24 weeks see . ConsequOur meta-analysis indicates that ICBT is effective for chronic somatic conditions regarding both general psychological outcomes and disease-specific outcomes. Effect sizes were generally small to moderate, with larger effect sizes occasionally found for disease-related outcomes, such as self-reported headache and IBS symptoms, and for disease-specific quality of life. These findings of larger effects on disease-specific outcomes may on the one hand reflect the larger sensitivity to change of these measures ,63 and oThe three included studies that compared ICBT with an active treatment condition showed that ICBT can be as effective as group-based face-to-face CBT, for example. However, two studies also found that ICBT and an informational website without CBT content were similarly effective. These results indicate a need for studies in which the effect of specific components of ICBT are more closely investigated. The role of one such component of ICBT was examined in this meta-analysis—intervention length—suggesting that interventions lasting longer than 6 weeks result in greater improvements in depression.Overall, results of this review extend previous reviews and meta-analyses, which concluded that ICBT may be a promising adjuvant treatment for psychological outcomes -16 and fSome potential limitations should be discussed. First, there are still a limited number of studies on ICBT in chronic somatic conditions, and sometimes only one study was available for a specific condition, which precludes drawing reliable conclusions about specific patient groups and generalizing across conditions. Over half of the studies were performed in Sweden by the same authors, but post-hoc analyses did not find differences in outcomes between the Swedish and other studies (data not shown). Women constituted a large proportion of most study populations, reflecting the often unequal gender distribution of different chronic somatic conditions. Second, studies were found to be of variable methodological quality, which may influence both individual study results and overall outcomes in meta-analysis. Although all studies had unclear or high risk of blinding bias, this is often unfeasible or very difficult to achieve in non-pharmacological behavioral interventions and thus may not be a valid indicator of study quality . In manyFinally, we used the pooled standard deviation based on pre- and post-intervention measurements in our meta-analysis. When using change scores in meta-analysis, the most appropriate measure would have been the standard deviation of changes. However, the included studies did not report sufficient information to calculate these standard deviations [29], which has been recognised as a common problem when using change scores. Our approach can, however, be considered as a conservative approach since the calculated standard deviations will be slightly larger than the standard deviations of changes would have been. Another alternative would have beento perform the meta-analysis based on post-intervention measurements, but such an approach does not take into account possible differences in baseline measurements. Nevertheless, we also performed a meta-analysis based on post-intervention measurements results. The results of this meta-analysis were very similar to the change score results reported in our study (data not shown), and would have led to similar conclusions.Results from this review suggest several areas for future research, related to study methodology and intervention design. More studies with adequate sample sizes focusing on a wider range of chronic somatic conditions with between-group long-term follow-up are needed. Only one study involved older patients , yet oldThe current review indicates that ICBT interventions improve both psychological and disease-related physical outcomes in patients with chronic somatic conditions, with small-to-medium effect sizes. Larger improvements are occasionally found for disease-specific outcomes related to daily-life impact of the illness, which underlines the importance of tailoring interventions to specific (patient) groups. Our results also indicate that interventions of longer duration may be more effective on psychological outcomes such as depression, which implies that tailoring the duration of interventions to specific problems may be appropriate.


Objectives. This study investigated serum thiobarbituric acid-reactive substances (TBARS) and free thiol levels in different subtypes of acute ischemic stroke (AIS) and evaluated their association with clinical outcomes.  Methods. This prospective study evaluated 100 AIS patients, including 75 with small-vessel and 25 with large-vessel diseases. Serum oxidative stress (TBARS) and antioxidant (thiol) were determined within 48 hours and days 7 and 30 after stroke. For comparison, 80 age- and sex-matched participants were evaluated as controls.  Results. Serum TBARS was significantly higher and free thiol was lower in stroke patients than in the controls on days 1 and 7 after AIS. The level of free thiol was significantly lower in the large-vessel disease than in the small-vessel disease on day 7 after stroke. Using the stepwise logistic regression model for potential variables, only stroke subtype, NIHSS score, and serum TBARS level were independently associated with three-month outcome. Higher TBARS and lower thiol levels in the acute phase of stroke were associated with poor outcome.  Conclusions. Patients with large-vessel disease have higher oxidative stress but lower antioxidant defense compared to those with small-vessel disease after AIS. Serum TBARS level at the acute phase of stroke is a potential predictor for three-month outcome. Stroke is a major cause of morbidity and mortality worldwide . InflammOxidative stress has been defined as “an imbalance between oxidants and antioxidants in favor of oxidants, potentially leading to damage” . To asseα-tocopherol, carotenoids, and uric acid [On the other hand, the antioxidant defense system has been studied in stroke patients as regards enzymes, including superoxide dismutase (SOD) and glutathione peroxidase , 16, andric acid , 17, 18.Under the hypothesis that the level of oxidative stress is increased and may be diverse in different subtypes of stroke, this study evaluated longitudinal changes in serum oxidant and antioxidant levels after ischemic stroke to determine their value in predicting short-term outcome. Serial changes of serum TBARS and free thiol were measured in different subtypes during the first month after stroke and the possibility of using these markers for predicting three-month outcome was assessed.From August 2010 to July 2012, consecutive patients with AIS who were admitted to the Neurology Department of Chang Gung Memorial Hospital-Kaohsiung were evaluated. Acute ischemic stroke was defined as an acute onset loss of focal cerebral function persisting for at least 24 hours. Diagnosis was based on clinical presentation, neurologic examination, and results of brain magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI). Patients aged 18–80 years with acute noncardioembolic ischemic stroke were included and divided into two major etiologic subtypes  according to the TOAST  classification . For comPatients with cardioembolic stroke, other determined causes and undetermined causes of stroke, and those with underlying neoplasm, end-stage renal disease, liver cirrhosis, and congestive heart failure were excluded. Clinical examination, electrocardiography, and cardiac ultrasound were conducted to exclude cardioembolic stroke. Patients with fever or any infectious disorder within the first week after acute stroke were also excluded.All of the participants underwent complete neurologic examination. Brain MRI with DWI, extracranial carotid sonography, and transcranial color-coded sonography were performed during the hospitalization. The therapeutic regimens for AIS were based on the American Heart Association (AHA)/American Stroke Association (ASA) guidelines . NeuroloBlood samples were collected by venipuncture of forearm veins from patients within 48 hours of the stroke (presented as day 1) and on days 7 and 30 after stroke. Serum MDA was measured using the TBARS assay. The concentration of TBARS was assessed based on the method of Huang et al. . TBARS r−1 cm−1).The ability of antioxidative defense in response to increased oxidative damage was evaluated by measuring the serum level of total reduced thiols because thiols were physiologic free radical scavengers. Serum free thiols were determined by directly reacting thiols with 5,5-dithiobis 2-nitrobenzoic acid (DTNB) to form 5-thio-2-nitrobenzoic acid (TNB). The amount of thiols in the sample was calculated from absorbance, as determined using the extinction coefficient of TNB .Data were presented as mean ± SEM. Continuous variables, including age, cell count, lipid profile, hemoglobin A1c (HbA1c), blood pressure, and serum free thiol and TBARS, were analyzed by independentP < 0.05. All statistical calculations were performed using the SAS software package, version 9.1 .Scheffe's multiple comparison was used to analyze the intraindividual courses of parameters over time. These were then compared among patients with small-vessel and large-vessel diseases. Multiple logistic regression analyses determined the independent influence of different predictive variables on clinical outcome. Statistical significance was set at n = 6), cardioembolic stroke (n = 5), end-stage renal disease (n = 5), and gastrointestinal bleeding in the acute stage (n = 4). The remaining 100 patients included 75 with small-vessel occlusion and 25 with large-vessel atherosclerosis. Based on their baseline characteristics and laboratory data . At the three different time points, the levels of TBARS were similar between patients with large-vessel disease and those with small-vessel disease.Serial changes in serum concentration of TBARS among patients groups and in the controls  revealedP < 0.05). Free thiol concentration was also significantly lower in the large-vessel disease group than in the small-vessel disease group on day 7 after stroke (P < 0.05). Thereafter, the level of free thiol gradually increased until it became similar to that of the controls on day 30 after stroke. Repeated ANOVA with Scheffe's multiple comparison showed significantly different free thiol levels between patients with small-vessel disease and those with large-vessel disease at three different time points (within 48 h and on days 7 and 30 after stroke) (P < 0.05).Serial changes in serum concentration of free thiol among patients with small-vessel and large-vessel diseases and in the controls  demonstrPotential prognostic factors of the 100 stroke patients were listed in P = 0.008), NIHSS score , and serum TBARS on day 7 after stroke  were independently associated with three-month outcome. Any increase in TBARS concentration by one μM/L worsens the poor outcome rate by 37%.Potential variables such as age, sex, stroke subtype, blood pressure, HbA1C, total cholesterol, HDL, LDL, and TBARS and free thiol levels on admission were analyzed using a stepwise logistic regression model. Only the stroke subtype . These levels gradually decreased thereafter and no significant difference existed between the two groups on day 30 after stroke. Repeated ANOVA with Scheffe's multiple comparison revealed significantly different serum TBARS levels on three different time points between the two groups (P < 0.05).Changes in serum TBARS between groups with good and poor outcomes  revealedP < 0.05). Repeated ANOVA with Scheffe's multiple comparison showed significantly different free thiol levels between the good and poor outcome groups at three different time points (within 48 h and on days 7 and 30 after stroke) (P < 0.05).Changes in serum concentration of free thiol among patients with good and poor outcomes, and in the controls  revealedThe present study has four major findings. First, patients with AIS in the acute phase had significantly higher TBARS and lower free thiol levels than the controls. Second, the level of free thiol is significantly lower in patients with large-vessel disease than in those with small-vessel disease on day 7 after stroke. Third, the higher TBARS and lower free thiol levels in the acute phase of AIS is associated with poor outcome. Lastly, the most important finding in this study is that TBARS level on day 7 after stroke is an independent predictive factor of three-month outcome.The results on the MDA level changes over time in stroke patients are controversial. Some researchers observed higher erythrocyte MDA levels in the very early phase of stroke, with subsequent decline in the levels of the controls , while oFurthermore, the current study demonstrates that antioxidant levels, measured by free thiol, are much lower in patients with large-vessel cerebral infarction than in those with small-vessel infarction on day 7 after stroke. The level of free thiol gradually increases until the difference is no longer significant one month after the stroke. These suggest that oxidant/antioxidant balance is related to the different pathogenesis in the two major subtypes of noncardioembolic stroke. The pathogenesis of small-vessel infarction is lipohyalinosis , while aOxidative stress is an important contributor to the pathophysiologic sequelae of stroke. A correlation of MDA level with infarct size, clinical stroke severity, and patient outcome has been observed , 25. SinOn the other hand, antioxidant vitamin concentrations are associated with neurologic damage and stroke prognosis , 30. TheAlthough other inflammatory biomarkers like high-sensitivity C-reactive protein (hs-CRP) and leukocytes have been reported to be useful in predicting clinical outcome after stroke , 32, theSome limitations of this study should be acknowledged. First, the measurement of only few biomarkers of oxidative damage cannot be considered a valid tool for exploring a multifaceted, complex oxidant/antioxidant imbalance after acute stroke. Second, the oxidant/antioxidant balance of stroke patients may be influenced by a multitude of parameters, including age, sex, smoking habit, alcohol consumption, physical activity, and vitamin supplementation. Third, oxidative stress may be influenced by other drugs . Since the use of these drugs depends on the preference of the attending physician, this may cause potential bias in statistical analysis and in drawing conclusions. Nonetheless, the sample size is not large and the number of variables considered in the stepwise logistic regression analysis is small. Hence, the maximum likelihood estimates of the coefficients are valid in the analysis.In conclusion, patients with AIS have significantly higher TBARS and lower free thiol levels than healthy controls. The level of free thiol is significantly lower in patients with large-vessel disease than in those with small-vessel disease in the acute phase of stroke. Serum TBARS on day 7 after stroke is an independent predictive biomarker of three-month stroke outcome.


The risk for herpes zoster (HZ) in acute kidney injury (AKI) survivors was never explored. We identified 2,387 adults in the Taiwan National Health Insurance Research Database who recovered from dialysis-requiring AKI and matched them with non-recovery and non-AKI patients by propensity score. During a mean follow-up of 2.7 years, the incidences of HZ were 6.9, 8.2 and 4.8 episodes per 1,000 person-years in AKI-non-recovery, AKI-recovery and non-AKI group, respectively. The recovery group was more likely to develop herpes zoster than those without acute kidney injury . Patients without acute kidney injury were less likely to develop herpes zoster than those AKI, recovered from dialysis or not . Dialysis-requiring acute kidney injury poses a long-term risk of herpes zoster after hospital discharge. Even patients who have recovered from dialysis still carry a significantly higher risk of developing herpes zoster. As the collaborative campaign  promoted by ISN  and IFKF  indicated, acute kidney injury (AKI) is now a growing global health alert. It is estimated to occur in 3–5% of the community population annually, and the rate is even higher in hospitalized (5–25%) or ICU patients 30–60%), causing great morbidity/mortality and medical expenses12350%, causi8101112Herpes zoster (HZ) is the reactivation of latent varicella-zoster virus infection in the nerve ganglia after primary infection, usually when the host’s cellular immunity declines. Herpes zoster and its consequence of post-herpetic neuralgia (PHN) can significantly compromise patients’ life quality and cause medical economic burden151618We identified 2,387 patients recovered from severe, dialysis-requiring AKI and matched them with the same number of non-recovery  and non-AKI patients in the Taiwan National Health Insurance database by propensity score matching. Baseline demography, Charlson morbidity index and index hospitalization conditions and transplant (solid organ other than kidney or hematopoietic) were identical in all groups after the matching process. There were slightly more patients with pre-existing liver disease in the control group (p = 0.043) , therefoDuring a mean follow-up of 2.7 years, the incidences of HZ were 6.9, 8.2 and 4.8 episodes per 1,000 person-years in AKI-non-recovery, AKI-recovery and non-AKI group, respectively. The recovery group was more likely to develop herpes zoster than those without AKI . On the other hand, patients without AKI were most unlikely to develop herpes zoster than both the AKI- recovery and non-recovery groups . In all three groups, HZ took place mostly within 5 years after index hospitalization . The mean time from index hospitalization to HZ was 2.7, 2.1 and 2.5 years for AKI-non-recovery, AKI-recovery and non-AKI group, respectively. Despite better renal outcome in the AKI-recovery versus non-recovery group (48.3% CKD plus ESRD versus 100% ESRD), the HZ incidence was not lower in the recovery group.Despite that the pre-discharge conditions were well matched, we observed higher prescription rates of steroids and immunosuppressant agents in AKI non-recovery and recovery groups after discharge. Therefore, to determine whether the higher HZ incidence was confounded by these medications, we performed a Cox proportional hazards model with steroids and immunosuppressant agents as time-dependent covariates . As expeAside from the known increased risk of HZ in CKD and ESRD population, we are able to demonstrate for the first time that AKI survivors are also at risk for HZ using one of the largest databases in the world. We also demonstrated that, using the Mahalanobis metric matching method, propensity score matching can be applied to three (or more than three) groups of patients to achieve quasi-randomization for further analysis. By this method, a novel platform for outcome comparison under similar baseline comorbidities was provided. Also, we pointed out that the risk of HZ was as high in AKI survivors even with renal recovery. Therefore, it is consistent with our hypothesis that the altered immune system during AKI, instead of the worsening renal function alone, is responsible for the increased risk of HZ. These findings are noteworthy for clinicians taking care for any individual who survived dialysis-requiring AKI.AKI can lead to a wide range of devastating short- and long-term sequels, in addition to the well-known risk of CKD development and mortality72126233031Our findings suggest that AKI patients should be closely followed-up even after recovery, because the risk of developing HZ in AKI patients was not significantly different between the recovery and non-recovery groups. In fact, the incidence was even higher in the AKI-recovery group versus non-recovery group , although not reaching significant difference. It is also consistent with the accumulating evidence which suggests that the presence of underlying CKD modifies the outcomes of AKI, but does not completely account for the impact of AKIet al had validated the diagnosis accuracy of ICD-9-CM codes for AKIThere are several limitations of our study. First, because the administrative data have varying sensitivity for diagnosis, we cannot completely exclude misclassification at baseline. Although Waikar et al. demonstrated that 95% of 100 clinically diagnosed HZ cases were positive for VZV viral DNA in the base of the blisters by PCR study, indicating that the clinical and virology diagnosis are concordant in most caseset al. also demonstrated excellent agreement between the ICD-9-CM diagnosis of herpes zoster and diagnosis by chart review37192039Another limitation is that the diagnosis of HZ is often made upon the clinical findings of typical skin rash and blisters alone in the dermatome without further tests or laboratory examinationsFrom a population-based perspective, we found for the first time that survivors after an episode of dialysis-requiring AKI are more likely to develop HZ than those without AKI. Furthermore, all patients with or without recovery from AKI are at the same risk of HZ reactivation, and this increased risk is irrelevant to post-discharge immunosuppressant agent use. Because HZ is a significant global health burden, our findings suggest that AKI patients should be closely followed-up after the insult for both renal and extra-renal disorders. It may be necessary to enhance the post-discharge follow-up of AKI patients, even among those who have recovered from temporary dialysis.All study cohorts were retrieved from the Longitudinal Health Insurance Database (LHID2005) in Taiwan. The National Health Insurance (NHI) program in Taiwan covers almost 99% of the entire population of 22 million people4344Informed consent was originally obtained by the NHRI, and since patients were anonymous in the present study, informed consent was not required. Also, since the identification numbers of all individuals in the NHRI databases were encrypted to protect the privacy of the individuals, this study was exempt from a full ethical review by the institutional review board of National Taiwan University Hospital (201212021RINC)de novo, those ever coded with AKI within 1 year prior to index admission  were also excluded, as well as those who ever received kidney transplant (n = 24) at any time point before. 12,216 patients who died shortly after discharge were excluded. The creation of an arteriovenous shunt/graft or the insertion of a Tenckhoff catheter during the index admission suggest that rapid renal function deterioration was expected and the patient might resume renal replacement therapy shortly, so these patients were also excluded . Finally, there were 8,720 patients whose renal function did not recover from dialysis-requiring AKI and went on subsequent maintenance dialysis , and 5,375 patients who recovered from dialysis-requiring AKI for at least 30 days after discharge without creating dialysis access during the index hospitalization were enrolled as the study group (recovery group). On the other hand, those with neither claims of HD/CRRT nor codes of AKI during an index admission less than 180 days were regarded as the control cohort. The exclusion processes were the same as study group. The index hospitalization dates of the matched control had to be within the same year as those of the study group. The negative predictive rate of ICD-9 coding for AKI was 96.1% according to previous studies35All adult patients who claimed for hemodialysis (HD) or continuous renal replacement therapy (CRRT) during an index hospitalization less than 180 days were considered eligible study subjects N = 42,483) . We did ,483 . WeIn order to validate the accuracy of diagnosing HZ, we performed separate chart reviewing of 110 patients with the coding of ICD-9 053.X in a single center of National Taiwan University Hospital, Hsin-Chu Branch. A hundred of the 110 patients were confirmed to have HZ reactivation by the description of typical blisters distributed over dermatomes or typical post-herpetic neuralgia, photography, or the prescription of antiviral agents. The validated positive predictive value to HZ using ICD-9 (053.X) was 90%.Each patient was followed after discharge until the development of herpes zoster, and censored at death or on December 31, 2009, whichever occurred first.To reduce the selection bias caused by the differences in the baseline risks for AKI, propensity score analysis was conducted. Briefly, we conducted a multivariable logistic regression model to estimate the probability of developing dialysis-requiring AKI for every patient with demographics, index hospitalization characteristics and operative categories (if applicable) listed in The sample variance of the logit (estimated propensity score) was 5.57, 3.61, and 5.71 for propensity scores of being AKI non-recovery, AKI recovery and non-AKI, respectively. The distribution of the logit of the estimated propensity scores before and after matching was shown in After making sure that the groups were perfectly matched, we went on comparing the incidence of herpes zoster by Poisson regression model. Finally, we performed a Cox proportional hazards model with time-dependent covariates (post-discharge steroids and immunosuppressant agents use) to identify factors influencing HZ risk. All analyses were performed using R statistical package version 2.15.2. Two-tailed P < 0.05 was considered statistically significant.How to cite this article: Yang, W.-S. et al. High Risk of Herpes Zoster among Patients with Advance Acute Kidney Injury – A Population-Based Study. Sci. Rep.5, 13747; doi: 10.1038/srep13747 (2015).


Functional magnetic resonance imaging (fMRI) studies traditionally use general linear model-based analysis (GLM-BA) and regularly report task-related activation, deactivation, or no change in activation in separate brain regions. However, several recent fMRI studies using spatial independent component analysis (sICA) find extensive overlap of functional networks (FNs), each exhibiting different task-related modulation , different from the dominant findings of GLM-BA. This study used sICA to assess overlap of FNs extracted from four datasets, each related to a different cognitive task. FNs extracted from each dataset overlapped with each other extensively across most or all brain regions and showed task-related concurrent increases, decreases, or no changes in activity. These findings indicate that neural substrates showing task-related concurrent but different modulations in activity intermix with each other and distribute across most of the brain. Furthermore, spatial correlation analyses found that most FNs were highly consistent in spatial patterns across different datasets. This finding indicates that these FNs probably reflect large-scale patterns of task-related brain activity. We hypothesize that FN overlaps as revealed by sICA might relate to functional heterogeneity, balanced excitation and inhibition, and population sparseness of neuron activity, three fundamental properties of the brain. These possibilities deserve further investigation. Blood oxygenation-level dependent (BOLD) functional magnetic resonance imaging (fMRI) studies traditionally use a general-linear-model-based analysis (GLM-BA) to interrogate BOLD time series. They often find task-related activation, deactivation, and no change in activation, with a mutually exclusive state associated with specific voxels within each brain region. While these findings help understand brain functional organization, they are not always consistent with data generated from other methods. For example, electrophysiological recordings from monkey brain often find that neurons showing task-related activation, deactivation, or no changes in activation intermix with each other in the same brain regions –4, in coDifferent from GLM-BA, spatial independent component analysis (sICA) is a multivariate approach and assumes that fMRI signal from each voxel represents a linear mixture of source signals; separates this signal mixture into spatially independent source signals using higher-order statistics; and groups all brain regions showing synchronized source signals into independent components (ICs) –7. ThereIn one of its earliest applications in fMRI, sICA allowed separation of BOLD signal from one voxel into as many as six ICs . Since tIn the two studies from our group ,26, GIFTA third study used GIFT to extract FNs from an fMRI dataset related to an anti-saccadic task and found extensive overlap of FNs showing task-related concurrent but different modulations . This stThe most recent study used MELODIC to extract FNs from fMRI datasets investigating speech (Speech), counting (Count), and decision-making (Decision) . They foIn summary, the main findings of the above reviewed studies include: 1) some FNs extracted by sICA overlap with each other extensively, 2) each of the overlapping FNs shows a unique timecourse and/or task-related modulation, 3) some overlapping FNs show opposite task-related modulation  simultaneously, and 4) GLM-BA may not detect task-related activity in these overlapping regions. These findings initially appear to be in conflict with the dominant existing fMRI data of separated activation and deactivation as revealed by GLM-BA, but they do provide an intuitive explanation for the observed brain activity. In addition, these findings of sICA are consistent with the intermixed activation and deactivation of different neurons in the same brain regions as revealed by electrophysiological recordings . These sBased on the afore-mentioned findings and the following discussions, we hypothesized that at least two functional properties of the brain as revealed by electrophysiological recordings and other methods might relate to FN overlap as revealed by sICA. The first is balanced excitation and inhibition (E/I). Within any cortical region, about 20% of all neurons are GABAergic inhibitory interneurons and 80% are excitatory pyramid neurons . These iThe second property is functional heterogeneity at cortical regions. Neurons within any cortical region including the primary sensory cortex are considerably heterogeneous in their functional properties ,39–43. FA typical voxel in the cortex with 3∼5 mm in each dimension contains hundreds of thousands of neurons ,54. The For further understanding FN overlap and how it might relate to brain functional organization, this study assessed the overlap of FNs extracted from four fMRI datasets, each related to a different cognitive task. The extent of overlap in FNs exhibiting significant task-related activation or deactivation was determined, as was whether there existed no identifiable task-related changes in activation. This study also compared data revealed by sICA and a GLM-BA for comparing findings generated by the two different approaches. It also assessed “goodness of fit” of FNs extracted from different datasets for estimating their consistency in spatial patterns. Studying in this manner multiple datasets employing different tasks should provide insight into whether FN overlap reflects a general property of brain functional organization and/or whether these features of brain activity relate to specific tasks. We selected four specific tasks because they taxed different aspects of brain function and were expected to activate and deactivate different FNs.Flanker task. This dataset was downloaded from https://openfmri.org (ds000102), a free open source for fMRI data [MRI data –58. PartFalse belief task (FBT). This dataset was downloaded from https://openfmri.org (ds000109) [s000109) . It has Attention task. This dataset has been described before [d before . It inclMonetary incentive delay task (MIDT). This dataset includes 70 healthy participants . The original study for acquiring this dataset was approved by Human Investigation Committee at Yale School of Medicine. All the participants gave written informed consent.Flanker task. This is a slow-paced task with inter-trial intervals ranging from 8s to 14s (mean = 12s). During each trial, five arrows were presented at the screen center and participants were required to press one of two buttons to indicate the direction of the central arrow. All arrows pointed in the same direction in the congruent condition, and the central arrow pointed to the direction opposite to the direction of other four arrows in the incongruent condition. Therefore, the congruent condition is a simple display-response task, while the incongruent condition involves interference control  and/or response inhibition.FBT. Participants read short scripts and answered questions during this task. It requires the participants to remember the content and answer questions about the mental status of a character described in the script [e script . The tasAttention task. The task uses a block design. Each block uses the same 16 faces, each of which was paired with a scene picture, as stimuli. The duration of each block was 19.2s (16 x 1.2s). The task has four levels of cognitive loads, one for rest (L0) and the remaining three for low (L1), medium (L2), and high (L3) levels of attention and working memory load. Participants rested during L0 and identified targets with 2, 3, and 4 facial features in conjunction during L1, L2, and L3, respectively [ectively . TherefoMIDT. In this version of the MIDT [the MIDT , each trFlanker task. The fMRI data were acquired using a 3T scanner with TR = 2000 ms, TE = 30 ms, flip angle = 80°, and a voxel size of 3x3x4 mm3. Each participant performed two functional runs, and each run acquired 146 volumes.FBT. Functional data were acquired using a 3T scanner with TR = 2000 ms, TE = 35ms, voxel size of 3x3x3 mm3, 0.54 mm skip, and 36 slice. Each participant had two runs and each run acquired 179 volumes.Attention task. Functional images were acquired using gradient-echo EPI scanning sequence with a Siemens Allegra 3T system. TR = 1500 ms, TE = 30 ms, Flip angle = 70°, voxel size of 3x3.125x3.125 mm3, 1.2mm skip, 26 slices. Each participant had three functional runs, and each run acquired 258 volumes.MIDT. Functional data were acquired using a 3T scanner and EPI gradient-echo sequence. TR = 1500 ms, TE = 27 ms, flip angle = 60°, voxel size of 3.4x3.4x4 mm3, 1mm skip, 25 slices. Each participant had two functional runs, and each run acquired 480 volumes.http://icatb.sourceforge.net/, version1.3h) was used to extract spatially independent components (ICs) from each dataset separately [Each BOLD time series was motion-corrected, normalized to the MNI  template, and smoothed with an 8-mm kernel using SPM5 . Group ICA algorithm  visually inspected each IC to separate artifacts from functional networks (FNs). Our diagnostic criteria for artifacts were consistent with the criteria used previously . ICs witSince each IC has a positive and a negative element, the above-described t-map of each IC contains significant clusters with positive and negative t values. In this paper, we call the positive and negative clusters in the t-map as positive and negative sub-networks, respectively, and each sub-network represents one FN. In the following text of this paper, the term IC will be used to refer to a component extracted by sICA, and each IC includes both positive and negative sub-networks. In contrast, FN will be used to refer to either the positive or negative sub-network of each IC.We converted each sub-network into a binary mask. Only significant voxels in each sub-network surviving the statistical threshold described above were converted into voxels with a value of one in the output mask, while all other voxels were converted into voxels with values of zero. Two masks were generated for each t-map: one for positive clusters and one for negative clusters. We added these masks together for assessing FN overlap in each dataset. Within the output map, any voxels with a value of two or higher number indicate that two or more sub-networks  overlap at this voxel.To examine task engagement of each IC, a design matrix for each participant was constructed using SPM5. This design matrix represents the onset of each trial or task block (details are presented in the next section). The temporal sorting function from GIFT was used to perform a multiple regression analysis between IC timecourse and the design matrix for each participant. For each IC, this regression generated a beta-weight value for each trial type of each functional run. These beta-weight values represent the correlations between IC timecourses and the canonical hemodynamic response model of task conditions, and index the engagement of ICs during specific task conditions . An incrThe beta-weights of each IC for each task condition across multiple runs of each subject were averaged, and then the group mean of averaged beta-weights for each task condition was tested against zero using SPSS one-sample t-tests. The significance threshold was p<.05, using FDR algorithm for correction of multiple comparisons due to multiple ICs. A positive beta-weight significantly different from zero indicates a task-related up-modulation of timecourse or increase in activity of the positive sub-network of the IC during a specific task condition relative to the baseline condition. Therefore, the positive sub-network of this IC was designated as a positive FN, and the negative sub-network as a negative FN. A significant negative beta-weight indicates a task-related down-modulation of timecourse or decrease in activity of the positive sub-network of the IC. Therefore, the positive sub-network of this IC was designated as a negative FN, and the negative sub-network as a positive FN. If the beta-weight was not significantly different from 0 after correction for multiple comparisons, then the IC is a neutral IC and both of its sub-networks are neutral FNs. Paired t-tests were used to compare beta-weights between two conditions within a task. The significance threshold was set at p<.05, using FDR algorithm for correction of multiple comparisons due to multiple ICs. Table A in In the current study, the beta-weights in congruent conditions in the Flanker task were used to assess congruent condition-related FN modulation. The beta-weights related to reading false-belief scripts in the FBT were used to assess reading false-belief script-related FN modulation. The beta-weights in low- and high-load conditions in the attention task were used to assess low- and high-load condition-related FN modulation. The beta-weights in W1 and W5 conditions in the MIDT were used to assess W1- and W5-related FN modulation.Spatial correlation tool provided with GIFT was used to assess “goodness of fit” of ICs extracted from the four datasets. This analysis will allow us to match ICs with similar spatial patterns from different datasets. Based on a recent publication , any paiFor GLM-based analyses, we used SPM5 to assess task-related changes in brain activity for each dataset. We used the same SPM5 design matrix created for temporal sorting as described above for these analyses. For the Flanker task, congruent and incongruent conditions were modeled as different event-related trials. For the FBT, scripts related to false belief and physical representations were modeled as different blocks, as were the blocks for answering related questions. For the attention task, the resting and low-, medium-, and high-load conditions were modeled as four different block conditions, while the instruction before each block was not explicitly modeled. For the MIDT, the trials of Win $0 and Loss $0 were used as baseline and not explicitly modeled. The first anticipation phase (A1) of trials for Win $1, Win $5, Loss $1, and Loss $5 were modeled as short blocks separately. The block durations were the intervals between cue onsets and target onsets. The second anticipation phase (A2) of trials for Win $1, Win $5, Loss $1, and Loss $5 were also modeled as short blocks separately. The block durations were the intervals between responses of participants and outcome onsets. The outcome phase of trials for Win $1, Win $5, Loss $1, and Loss $5 were modeled as event-related trials separately.For the first-level analysis of each subject, a contrast map was created for each task condition to assess significant changes in BOLD signal between task conditions for each participant. The contrast images generated from each participant were inputted into a second-level (random-effect) one-sample t-test for group means. We employed cluster p<0.05, family-wise-error (FWE) corrected in conjunction with voxel-height threshold p<0.01 to identify task-related significant changes in BOLD signal.In this paper, the voxels or FNs showing significant increases or decreases or no significant changes in BOLD signal during each task condition were termed as positive, negative, and neutral voxels or FNs, respectively. Below we first describe findings unique to each task and then findings across tasks.Flanker task. During the congruent condition, extensive brain regions showed significant increases, but only a small cluster showed decreases in BOLD signal as revealed by the GLM-BA  during reading the false belief script  of Win $1 (W1) and Win $5 (W5) trials. The GLM-BA revealed significant increases and decreases in BOLD signal at separated brain regions at W1 relative to control condition  of positive and negative FNs did not show significant changes in BOLD signal as assessed by the GLM-BA, indicating that the concurrent co-localized increases and decreases in source signals were equivalent and cancelled each other at these regions. However, the remainder of these regions showed significant increases or decreases in BOLD signal , indicating that either increases or decreases in source signals dominate over the opposite changes in these regions. Their exact locations were task-dependent as indicated by the GLM-BA. Their volumes ranged from 0% to 53% of the whole brain, and were often smaller than the volumes without significant changes in BOLD signal as revealed by the GLM-BA.SICA revealed neutral FNs across all task conditions Figs.  & 3. NeuRelative to the congruent condition of the Flanker task, both the low-load and high-load conditions of the attention task presented a greater demand on perception, attention, and working memory. However, both induced considerably less extensive increases in BOLD signal relative to the congruent condition of the Flanker task, as revealed by the GLM-BA. However, sICA found that both positive and negative FNs covered more extensive brain regions at the high-load condition of the attention task relative to the Flanker task. The fact that these datasets were acquired from different populations using different scanners prevented direct comparison using conventional statistical methods.ICASSO found that the stability indices of most ICs were > 0.8 and only 1 to 6 ICs from each dataset showed stability index between 0.6 and 0.8. Therefore, sICA generated stable ICs from each dataset in the current study.We identified 42 ICs from the attention dataset as FNs, the lowest number of ICs among the four datasets. Spatial correlation analyses were used to match each of the 42 ICs from the attention dataset to ICs from the other three datasets. This analysis generates six correlation coefficients (r) for each IC from the attention dataset and three matched ICs from other three datasets , and a tSICA extracted multiple positive and negative FNs from each dataset. Consistent with recent findings –10,26, tIn the current study, the attention task mainly demands central processes related to visual attention. The positive FNs covered about one third of the entire brain at the low-load condition, and about 80% of the whole brain during the high-load condition. Relative to the attention task, the MIDT requires reward anticipation in addition to visual attention and perception. This difference between the two tasks may contribute to the more extensive brain regions covered by the positive and negative FNs related to the low-value condition (W1) of the MIDT than those related to the low-load condition of the attention task. Both the positive and negative FNs related to the MIDT covered almost the entire brain even during W1, and these FNs could not expand to cover more brain regions as task load increased from W1 to W5 due to the ceiling effect. These findings indicate that neural substrates distributed across most of the entire brain are implicated during the performance of high-demand or complex tasks.Most brain regions showing overlap of task-related positive and negative FNs did not show significant changes in BOLD signal as analyzed using a GLM-BA. These data indicate that the task-related, concurrent, co-localized increases and decreases in source signals were equivalent or balanced and cancelled each other. Even though these regions did not show significant changes in BOLD signal when assessed using a GLM-BA, different source signals within them underwent significant task-related changes as revealed by sICA. These brain regions include both cortical and subcortical areas. Therefore, neural substrates related to positive or negative source signals in these regions were activated or deactivated during task performance, consistent with the notion that sICA may reveal task-related activity which is not detected by the GLM-BA .The GLM-BA in the current study revealed significant changes in BOLD signal in some areas, including those showing overlap of positive and negative FNs. For example, the GLM-BA revealed significant increases in BOLD signal in extensive brain regions but very limited decreases during the congruent condition of the Flanker task, whereas extensive decreases in BOLD signal with no significant increases during the low-load condition of the attention task. Therefore, these brain regions were dominated by either increases or decreases in source signals during different tasks. The exact locations of unbalanced changes in source signals were task-dependent as revealed by the GLM-BA. This finding indicates that not all brain regions maintain a balance of task-related activation and deactivation of neural substrates related to different source signals.In addition to the positive and negative FNs, sICA revealed multiple “neutral” FNs from each dataset. These “neutral” FNs covered most or all brain regions and overlapped with positive and negative FNs extensively. This finding indicates that some neural substrates related to these “neutral” source signals within each brain regions do not show task-related changes in activity. These “neutral” neural substrates distributed across almost the entire brain and intermixed with neural substrates showing more consistent task-related activation or deactivation.The GLM-BA and sICA identified common regions showing increases, decreases, or no changes in BOLD signal and source signals, respectively, indicating that the two approaches identified the same brain regions showing consistent changes in BOLD signal and source signals. Besides this similar finding, the two approaches have several important different findings. First, the GLM-BA revealed task-related increases, decreases, and no change in BOLD signals in separated regions without any spatial overlap among them, consistent with most previous findings of GLM-BA. This finding implies that neural substrates showing task-related activation, deactivation, or no changes in activation are segregated and distributed in different brain regions. In comparison, sICA finds extensive spatial overlap among source signals showing increased, decreased, or no changes in activation. These findings suggest that neural substrates showing task-related activation, deactivation, or no changes in activity intermix with each other in the same regions across extensive portion of the brain.Second, the finding of segregated brain regions showing task-related increases in BOLD signal as revealed by GLM-BA has been interpreted by some investigators as evidence supporting the view of modular processing in the brain . HoweverThird, the GLM-BA revealed activation in the striatum and deactivation in the parietal and occipital cortex during either the W1 or W5 conditions of the MIDT. This finding is consistent with most data from previous reward-anticipation-related fMRI studies using a GLM-BA and task analogs of the MIDT . HoweverFourth, the GLM-BA reveals significant deactivation without significant activation during the low-load condition of the attention task. It is unlikely that participants can successfully perform the task without activation of any brain regions relative to the resting condition. On the other hand, sICA found extensive increases in source signals in the frontoparietal and occipital cortex accompanied by concurrent co-localized decreases in source signals. The sICA data suggest that the frontoparietal and occipital cortex contribute to task performance, and that the negative finding of the GLM-BA may represent cancellation of opposite changes in source signals. Finally, the GLM-BA reveals a much smaller volume showing increases in BOLD signal (<10%) during the high-load condition of the attention task relative to the congruent condition of the Flanker task, even though the former task condition presents a greater demand on visual perception, attention, and working memory. On the other hand, sICA finds a greater volume showing increases in source signals during the high-load condition relative to the congruent condition, but also a greater volume of decreases in source signals. Therefore, the smaller volume of increases in BOLD signal during the high-load condition as revealed by the GLM-BA may reflect the cancellation of concurrent co-localized increases and decreases in source signals. These different findings suggest that sICA provides additional information related to task-related brain activity relative to the GLM-BA, and further support the view that sICA can reveal task-related activity hidden from GLM-BA .Several recent studies assessed the “optimal” model order  in each dataset and found high-order models involving between 70 and 80 ICs generated refined informative networks corresponding to known anatomical and functional segmentations ,69,77,78As discussed in the introduction, we hypothesized that balanced E/I and functional heterogeneity might relate to overlap of FNs showing concurrent opposite modulations. In the literature, balanced E/I mainly refers to the close relationship between excitation and inhibition within a neuron and among adjacent neurons in the same brain regions –35. HoweThe balanced E/I and functional heterogeneity combined with the unique capacity of separating signal mixture into source signals of sICA might explain differences in some findings between the GLM-BA and sICA in the current study. For example, the MIDT involved both reward anticipation and visual perception and attention. Reward anticipation induced activation in the striatum, thalamus, insula, and medial PFC, but may induce deactivation in the occipital and parietal cortex because of balanced E/I. The deactivation in these brain regions was probably greater than activation induced by visual perception and attention, and thus the GLM-BA found deactivation. In contrast, sICA revealed concurrent activation and deactivation in these brain regions.The current study found multiple neutral ICs from each dataset. We hypothesized that they might relate to another brain property, i.e., sparseness of neuron activities ,83. SparEven though the exact coupling between neural activity and BOLD signal is not clear yet, recent data indicate that BOLD signal increases are related to increased neuronal activity while BOLD signal decreases are related to reduced neuronal activity –90. ThesOne issue related to concurrent increases and decreases in BOLD signal is blood redistribution. The brain may have a limited volume of blood supply, and it is logical to suspect that increases in blood flow in some brain regions may lead to reduced blood flow in other brain regions. While it is not clear the extent of “blood redistribution” contributing to the current finding of concurrent increases and decreases in source signals, some data from this study indicate that it may not be the main factor contributing to source signal reduction as revealed by sICA. For example, GLM-BA revealed extensive BOLD signal increases, but only a very limited decrease during the congruent condition of the Flanker task, and extensive BOLD signal decreases but no significant increase during the low-load condition of the attention task. Therefore, task-related increases and decreases in BOLD signal may not always correlate with each other.The statistical threshold for defining the spatial extent of each FN may influence the spatial extent of FN overlap. More strict thresholds will lead to a smaller spatial extent of each FN and less spatial overlap of different FNs. Relative to the threshold regularly used in fMRI studies using GLM-BA, the current study used a very strict threshold, i.e., voxel level p <. 001, FDR corrected for multiple comparisons involved in voxel-wise whole brain analysis .One limitation of this study is that the precise number of ICs existing in each dataset is not known. The number of ICs generated by sICA will likely influence the number of FNs overlapping with each other. Another limitation is that there is no reliable fully objective method available for separating artifacts from real FNs. A third limitation is the uncertainty of an optimal statistical threshold for defining task-positive, task-negative, and task-neutral FNs. Using a strict threshold for positive and negative FNs may lead to a liberal threshold for neutral FNs and vice versa. Therefore, the number of FNs in each category may change depending on the selection of different thresholds. However, the final conclusion of extensive overlap of different FNs still holds at different thresholds.Finally, we emphasize here, even though this study hypothesizes that balanced E/I, functional heterogeneity, and population sparseness may relate to the extensive overlap of positive, negative, and neutral FNs, the exact relationships or the real neural substrates underlying this finding of sICA remains relatively speculative and should be investigated further in future studies. FN overlap as revealed by fMRI using sICA represents a feature of large-scale networks of brain activity, and the three brain properties  represent functional activity at the level of microcircuits. The exact relationships between large-scale networks and microcircuits activity are not clear yet.In summary, by revealing extensive overlap of positive, negative, and neutral FNs, findings from sICA indicate that neural substrates showing task-related activation, deactivation, and no change in activation intermix with each other and distribute across most or even the whole brain. This pattern of brain functional organization is different from the pattern of separated activation, deactivation, and no-change in activation as often revealed by the GLM-BA. We hypothesized that the extensive overlap of different FNs as revealed by sICA may relate to balanced E/I, functional heterogeneity, and population sparseness, three fundamental properties of the brain, and their exact relationships deserve further investigation.S1 FileFig. B, Matched ICs from different datasets. Table A, Beta weights at each task condition. Table B, Brain regions showing task-related changes in BOLD signal as assessed by SPM5.(DOCX)Click here for additional data file.


Previous studies have shown an association between gout and/or hyperuricemia and a subsequent increase in cardiovascular disease (CVD) outcomes. Allopurinol reduces vascular oxidative stress, ameliorates inflammatory state, improves endothelial function, and prevents atherosclerosis progression. Accordingly, we tested the hypothesis that a positive association between allopurinol therapy in gout patients and future cardiovascular outcomes is present using a population-based matched-cohort study design.Patients aged ≥40 years with newly diagnosed gout having no pre-existing severe form of CVD were separated into allopurinol (n = 2483) and non-allopurinol (n = 2483) groups after matching for age, gender, index date, diabetes mellitus, hypertension, hyperlipidemia, and atrial fibrillation. The two groups were also balanced in terms of uric acid nephrolithiasis, acute kidney injury, hepatitis, and Charlson comorbidity index.With a median follow-up time of 5.25 years, the allopurinol group had a modest increase in cardiovascular risk . A Cox proportional hazard model adjusted for chronic kidney disease, uremia, and gastric ulcer gave a hazard ratio (HR) for cardiovascular outcomes of 1.25  in gout patients receiving allopurinol compared with the non-allopurinol group. In further analysis of patients receiving urate-lowering therapy, the uricosuric agent group (n = 1713) had an adjusted HR of 0.83 (0.73–0.95) for cardiovascular events compared with the allopurinol group.The current population-based matched-cohort study did not support the association between allopurinol therapy in gout patients with normal risk for cardiovascular sequels and beneficial future cardiovascular outcomes. Several important risk factors for cardiovascular disease, such as smoking, alcohol consumption, body mass index, blood pressure were not obtainable in the current retrospective cohort study, thus could potentially bias the effect estimate. Gout is a common disease resulting from urate crystal deposition in joints, connective tissues, and parenchymal organs including the kidneys, which may present clinically as gouty arthropathy, accumulation of urate crystals in the form of tophaceous deposits in numerous tissues, gouty nephropathy, or uric acid nephrolithiasis.In a population-based cohort study, we showed that among non-diabetic individuals aged ≥50 years who had no pre-existing serious cardiovascular disease (CVD), those with gout were 1.1 times more likely than those without gout to die from CVD in the next 5 years.The causative role of elevated serum uric acid concentrations (hyperuricemia) in CVD is suggested by studies showing its deleterious effect on endothelial function, inducing production of pro-inflammatory and pro-oxidative substances and platelet adhesiveness.There are three main types of urate-lowering therapy in clinical practice: reduction of urate production by use of a xanthine oxidase inhibitor such as allopurinol; enhancement of urinary excretion of uric acid with uricosuric agents; or conversion of uric acid to the more soluble purine end product allantoin using exogenous urate oxidase, also known as uricase. Allopurinol, as an antihyperuricemic agent, has been demonstrated to protect the cardiovascular system by reducing vascular oxidative stress, ameliorating inflammatory state, improving endothelial function, and preventing atherosclerosis progression.The positive effect of allopurinol treatment on future cardiovascular risk among patients with chronic kidney disease (CKD) was shown in a small prospective randomized trial of 113 patients with estimated glomerular filtration rates of <60 milliliter/min. In this open label study conducted by Spanish investigators, patients were randomly assigned to treatment with allopurinol at 100 mg/day (n = 57) or to continue their usual therapy (n = 56). Allopurinol treatment slowed renal disease progression independently of age, gender, diabetes, C-reactive protein, albuminuria, or renin–angiotensin system blockers use. After a mean follow-up time of 23.4±7.8 months, allopurinol treatment reduced the risk of cardiovascular events by 71%  compared with the usual therapy.A cohort study using a record linkage database to study the impact of allopurinol treatment on cardiovascular and mortality outcomes showed that higher doses of allopurinol were associated with better control of urate and lower risks of both cardiovascular events and mortality. In this study, there was no significant increase in the risk of cardiovascular events for allopurinol users (n = 1035) when compared with non-urate-lowering therapy users . Compared with low-dose (100 mg) allopurinol users, high-dose (≥300 mg) users showed a significant reduction in the risk of cardiovascular events  and mortality .P<0.001) and all-cause mortality  among patients with a history of gout.An observational study using data from a Health Maintenance Organization evaluated the effect of uric acid and allopurinol use on clinical outcomes in 6204 patients with heart failure. This study demonstrated that high uric acid levels (>7.7 mg/dL or >458 µmol/L) were a predictor of increased mortality  and an increase in cardiac hospitalizations . An increase in uric acid levels during follow-up was also an independent predictor of mortality  and cardiac hospitalizations . With a median follow-up time of 498 days, treatment with allopurinol was independently associated with improved survival .Therefore, it would be of great interest and academic appeal to examine the hypothesis that among different urate-lowering therapies for gout patients, allopurinol therapy would have better cardiovascular outcomes than non-allopurinol treatments, including a uricosuric agent in matched patients with gout. We thus designed a large-scale population-based retrospective matched-cohort study to answer this question.We conducted a population-based retrospective matched-cohort study using the Taiwan National Health Insurance Research Database (NHIRD). The Taiwan National Health Insurance (NHI) program commenced on March 1, 1995. As of 2007, 98.4% of Taiwan's population of 22.96 million individuals was enrolled in this program. The NHIRD contains a number of computerized databases that incorporate files and original data on claims reimbursements derived from the insurance system held by the NHI Administration. These data have been provided to researchers for academic research purposes. The NHIRD comprises four main database files: ambulatory expenditures by visit, inpatient expenditures by admission, details of ambulatory care orders, and details of inpatient orders. These data files were de-identified by scrambling the identification codes of both individuals and medical facilities. The NHIRD is widely regarded as very accurate and complete and has become one of the largest and most comprehensive population-based databases in the world.This study used a dataset of one million randomly selected enrollees representing 4.5% of the Taiwanese population in the entire NHI enrollee profile. There was no significant difference in age or gender between the patients in the dataset used in this study and the population in the mother NHIRD, as verified by the National Health Research Institute (NHRI), Taiwan.Human Subjects Research Act enacted on December 28, 2011. This study adhered to strict confidentiality guidelines that are in accordance with the regulations set forth by the Personal Information Protection Act of Taiwan, amended on May 26, 2010. The research was conducted in accordance with the Declaration of Helsinki as revised in 1989.Because this study used only NHIRD data files that were de-identified by scrambling the identification codes of both individuals and medical facilities, this research fits the criteria for exemption from review by the Institution Review Board contained within the legal statements promulgated by the Ministry of Health and Welfare of Taiwan pursuant to Paragraph 1, Article 5 of the th Revision, Clinical Modification (ICD-9-CM). Under ICD-9-CM code 274, subjects with gouty arthropathy (code 274.0), gouty nephropathy (274.1), gouty iritis (274.89), gouty tophi (274.8), gouty tophi of ear (274.81), gouty tophi of heart (274.82), gout with other manifestations (274.89), and uric acid nephrolithiasis (274.11) were included. Gout and gout-related diagnoses are used interchangeably in this paper.We limited our study population to every individual diagnosed with gout in the years 1999 to 2008 . We defined individuals with gout as those with gout-related diagnoses according to code 274 of the International Classification of Diseases, 9From this pool of 46,586 subjects with gout, we excluded 7200 subjects who were <40 years old or whose gender was unknown; 10,420 who visited the clinic less than 2 times during the defined study period; 2904 who had a pre-existing severe form of hypertensive, cerebrovascular, or CVD; and 2033 who had pre-existing gout in the preceding 2 years. This process resulted in a target population of 24,029 patients aged ≥40 years, with newly diagnosed gout, having no history of pre-existing severe form of hypertension, cardiovascular, or cerebrovascular disease .The severe CVDs included malignant hypertension, hypertensive nephropathy, myocardial infarction, or any form of congestive heart failure, as well as a coronary artery bypass surgery or percutaneous transluminal coronary angioplasty. In addition, subjects with intracerebral hemorrhage, intracranial hemorrhage, occlusion/stenosis of pre-cerebral arteries, and occlusion of cerebral arteries were also excluded. The detailed list of the corresponding ICD-9-CM codes can be found in our previously published article.The study population was divided into two groups: those who received allopurinol treatment and those who did not. The allopurinol group consisted of 12,563 patients and the non-allopurinol group consisted of 11,466 patients. We then performed one-to-one matching by age at accrual, gender, index date of subjects in the allopurinol group, diabetes mellitus, hypertension, hyperlipidemia, and atrial fibrillation. After matching, we finalized two matched study group, an allopurinol group and a non-allopurinol group, each containing 2483 patients. Follow-up continued until the occurrence of a primary cardiovascular outcome, death, or the end of 2008 .A cardiovascular outcome is defined as an event requiring hospitalization during follow-up that is given a primary final diagnosis among several CVD-related diagnoses. These diagnoses included a spectrum of diseases from coronary heart disease (CHD) (ICD-9-CM codes 410–414) to hypertensive heart disease (401–405), heart failure (428), cerebrovascular disease (stroke) (430–438), and other CVDs .Demographic data such as age and gender, as well as medical comorbidities including hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation, uric acid nephrolithiasis, acute kidney injury, hepatitis, contact dermatitis and other eczema, CKD, uremia, and gastric ulcer were collected for baseline evaluation. The Charlson comorbidity index (CCI) was also calculated for each case in the two groups. Comorbid medical conditions, identified using their standard ICD-9-CM codes, were used to calculate cumulatively the CCI score for each individual. The established CCI, adapted from the Charlson index for use with ICD-9-CM coded administrative databases, contains 17 weighted categories related to chronic concomitant diseases and is able to predict the subsequent 1-year mortality among inpatients. Each category has a score between 1 and 6 points , and the sum of these scores is regarded as a measure of the burden of medical comorbidity.We assessed the use of uricosuric agents for urate-lowering therapy in the comparator cohort not receiving allopurinol. In Taiwan, three kinds of uricosuric agent are reimbursed: benzbromarone, probenecid, and sulfinpyrazone. The daily dose and duration of allopurinol use were also evaluated in this matched-cohort study.P<0.05 were considered statistically significant. The risk of cardiovascular outcomes associated with gout was evaluated using Cox proportional hazards analysis. All Cox regression models included the following covariates: CKD, uremia, and gastric ulcer. Adjusted hazard ratios (aHR) with a 95% CI were calculated. The relative risks of cardiovascular outcomes were calculated and analyzed using the Chi-square test (2×2). The distribution of comorbidity characteristics were compared between the two groups, and the differences were examined using the Chi-squared test and t test, as well as the Mann–Whitney U test , which is a non-parametric statistical hypothesis test for assessing whether one of two samples of independent observations tends to have larger values than the other. Variables such as age, sex, underlying comorbidity, daily dose of allopurinol, use of uricosuric agents, duration of allopurinol use, and follow-up in years are reported as percentages. StatsDirect statistical software  was used to provide relative risk values and Yate's corrected 2×2 test computations. The cardiovascular event-free cumulative survival probabilities were estimated in each group using the Kaplan–Meier method. The log-rank test was used to compare the significance of inequalities with respect to the cardiovascular event-free survival curves of each group.Pre-analysis data file merging and other data management operations before statistical analysis were performed using the SAS statistical package . Statistical analyses were performed using SPSS software . All statistical tests were two-sided. Values of P = 0.0296) , there was no statistically significant difference between these two groups in terms of these seven variables. Furthermore, there was no statistically significant difference in the frequency of uric acid nephrolithiasis, acute kidney injury, hepatitis, contact dermatitis and other eczema, as well as overall Charlson–Deyo comorbidity index . However 0.0296) . These mThe mean age (± standard deviation) of the study group was 61.84 (±12.13) years. Men accounted for 62.22% of the total cases. Slightly more than half of the patients in both groups had hypertension at accrual. Twenty three percent of the patients had been diagnosed with diabetes and approximately 31% had hyperlipidemia .In the allopurinol group, 85.54% of gout patients took allopurinol at a dose of >100 mg/day. Of these, 16% were treated with a dose of ≥300 mg/day. Among patients receiving allopurinol, 59% took allopurinol for >6 months. Of these, 9% took allopurinol for 0.5–1 year; 13% for 1–2 years; 9% for 2–3 years; 5% for 3–4 years and 23% for >4 years.In the non-allopurinol group, nearly 69% of the patients received a uricosuric agent. The most common uricosuric agent used was benzbromarone (66%), followed by sulfinpyrazone (3%), and probenecid (0.4%).Follow-up of the patients in the two groups was complete; there was no drop-out or loss to follow-up. The median follow-up time for the allopurinol group was 5.25 years , whereas it was 5.04 years  for the non-allopurinol group. There was no statistically significant difference in the follow-up time between these two groups . There wA Cox proportional hazards regression model established to calculate the effect of allopurinol therapy on future cardiovascular outcomes for gout patients aged ≥40 years, after adjusting for CKD, uremia, and gastric ulcer gave an aHR of 1.25  compared with the non-allopurinol therapy .With respect to the different forms of cardiovascular events, we further examined the effect of allopurinol therapy on subsequent hospitalizations due to CHD, cerebrovascular disease (stroke), hypertensive heart disease, heart failure, or other cardiovascular disorders. The HR and aHR for hospitalization due to each form of CVD are reported in We fit a Cox model for gout patients receiving urate-lowering therapy to determine if allopurinol provided protection against cardiovascular outcomes compared with uricosuric therapy consisting of benzbromarone, sulfinpyrazone, and probenecid. The results showed that when allopurinol therapy was regarded as a reference, uricosuric therapy was shown to have cardiovascular protection  .Taking all these results into account, allopurinol therapy did not provide cardiovascular protection and also led to adverse outcomes in patients with gout. With a median follow-up time of 5.25 years, the allopurinol group had a modest increase in cardiovascular risk . A Cox proportional hazard model adjusted for CKD, uremia, and gastric ulcer gave an HR for cardiovascular outcomes of 1.25 (1.10–1.41) in gout patients receiving allopurinol compared with those not receiving allopurinol. In a subgroup analysis of patients receiving urate-lowering therapy, the uricosuric agent group (n = 1713) had an aHR of 0.83 (0.73–0.95) compared with the allopurinol group.We also fit a Cox model examining the associations of low- and high-dose allopurinol therapy with subsequent cardiovascular risk. The model used a daily allopurinol dose of <100 mg, which had an incidence of cardiovascular events of 23.68%, as its reference for comparison . Using tTo the best of our knowledge, this is the first population-based study accruing a large number of patients with gout and including well-matched references that was designed to uncover an association between allopurinol therapy and subsequent cardiovascular risk. The quasi-experimental design of the study, with clear exclusion criteria and extensive matching, allowed profound control of variance by exclusion of subjects with pre-existing severe CVDs and control of known confounding variables. Excluding subjects with pre-existing severe CVD results in the exclusion of high-risk to very-high risk patients who are prone to experience a cardiovascular outcome during subsequent follow-up. The extensive matching process also allowed, in the early phase of the study, elimination of confounding variables other than age, gender, and index date only; thus, post-hoc statistical adjustments could be omitted.Selection bias was obviously avoided. The vast majority (84.5%) of the entire cohort received urate-lowering therapy , indicating that selection methodology for the gout patients was adequate. Allocation bias was also avoided, because positive or negative exposure to allopurinol was unambiguous in the database. Furthermore, our use of administrative-based data enabled us to study allopurinol exposure and cardiovascular outcomes without the influence of recall bias in both groups. There was no drop-out or loss to follow-up because complete tracking of study subjects was feasible, even when a patient relocated or received treatment in different hospitals. The follow-up time was considered long enough to allow a cardiovascular event to be observed.Using this study design, the results showed an association between allopurinol therapy for gout patients and increased CVD events. Allopurinol may have a harmful effect, with an increase in the risk of CVD even after adjustment for CKD and uremia. This means that a Taiwanese patient aged ≥40 years with newly diagnosed gout and hyperuricemia who is prescribed allopurinol therapy to lower urate levels is associated with a 25% increase in cardiovascular risk over the next 10 years of follow-up. This data is considered robust, with a narrow 95% confidence interval.It is noteworthy that a published cohort study, using a United Kingdom record linkage database, conducted in a population of patients aged ≥60 years who underwent urate measurements either at a hospital or a community clinic, demonstrated that there was a statistically insignificant increase in the risk of cardiovascular events for allopurinol users compared with subjects not receiving urate-lowering therapy  and with subjects not receiving urate-lowering therapy that had urate >6 mg/dL . Nevertheless, the study showed that compared with subjects receiving low-dose (100 mg) allopurinol, those receiving high-dose (≥300 mg) allopurinol showed a significant reduction in the risk of cardiovascular events .Another retrospective cohort study of patients with chronic heart failure that investigated the association between different durations (short-term versus long-term) and daily dosages [low-dose versus high-dose (≥300 mg)] of allopurinol therapy and cardiovascular mortality merits mention here.Thus, we believe that it is the dosage of allopurinol may make a difference when reduction of cardiovascular risk is the main therapeutic aim. Further prospective studies are needed to test this hypothesis.The mechanisms underlying the beneficial effect of higher daily dosage of allopurinol have been reported in recent years. Erdogan et al. published a single arm clinical trial of allopurinol at 300 mg/day for 3 months in patients diagnosed with dilated cardiomyopathy with concomitant hyperuricemia. Their results showed that this high dose of allopurinol can improve coronary microvascular and left ventricular function.There is also a possibility that our result, that allopurinol fared worse than the matched reference cohort consisting of uricosuric agent users (69%) and patients having no urate lowering therapy (31%), may have resulted just because of the capability of allopurinol therapy to serve as a prognostic factor suggesting a poorer cardiovascular outcome. However, this suggestion is only hypothetical.There are some potential limitations to this study. We did not have access to the relevant biochemical datasets incorporating urate measurements and personal lifestyle histories such as cigarette smoking and alcohol consumption history, abdominal obesity, consumption of fruits and vegetables, and records of physical activity. This is because individual identities are not available because of de-identification of the cases within the NHI databases. The lack of such information could potentially bias the effect estimate. Another potential limitation is that data for medication other than urate-lowering medications and the compliance and adherence to treatment were too complex to incorporate in the covariate analyses.In conclusion, allopurinol therapy as a urate-lowering treatment has previously been found to reduce cardiovascular risk, particularly in patients with coronary artery disease, heart failure, or CKD having concomitant hyperuricemia. Our large-scale study using population-based matched-cohort design in patients with gout and “normal risk” for cardiovascular events did not observe any beneficial effect of allopurinol, whereas the association with a modest increase in cardiovascular risk was detected. Several important risk factors for cardiovascular disease, such as smoking, alcohol consumption, body mass index, blood pressure were not obtainable in the current study, thus could potentially bias the effect estimate. A hypothesis-generating finding was suggested from a subgroup analysis of low- versus high-dose allopurinol therapy, showing a possible beneficial effect from high-dose therapy. Further prospective large-scale cohort studies or randomized controlled trials are needed.


However, the benefits of NIV in immunocompetent patients with ARF are debated. High flow nasal cannula oxygen therapy (High-Flow Oxygen) may offer an alternative in hypoxemic patients and we recently found in a randomized controlled trial including 310 patients with ARF that High-Flow Oxygen decreased mortality as compared to NIV , p = 0.005.In immunocompromised patients admitted to ICU for ARF, intubation and mortality rates were lower in patients treated with High-Flow Oxygen than in those treated with NIV as first-line therapy. The use of NIV was independently associated with day-28 mortality.