Among patients with end-stage renal disease (ESRD), few studies have examined the use of complementary and alternative medicine (CAM) and patients' interest in learning mind-body interventions to address health issues. We surveyed 89 adult patients (response rate 84%) at an outpatient hemodialysis center in Brookline, MA, USA regarding the utilization of CAM, including mind-body practices, and willingness to learn mind-body practices. Of respondents, 47% were female, 63% were black, and mean age was 62 years. 61% reported using CAM for health in their lifetime, and 36% reported using CAM within a month of the survey. The most frequent CAM modalities reported in ones' lifetime and in the last month were mind-body practices . Overall lifetime CAM use did not differ significantly by sex, race, dialysis vintage, diagnosis of ESRD, employment status, or education level. Subjects reported that mind-body interactions were very important to health with a median score of 9 on a 10-point Likert scale (ranging from 0 for not important to 10 for extremely important). Most patients (74%) reported interest in learning mind-body practices during maintenance hemodialysis. In summary, CAM use, particularly mind-body practice, is frequent among patients with ESRD providing opportunities for future clinical research. Over half a million individuals in the USA have end-stage renal disease (ESRD), and about 400,000 receive maintenance hemodialysis (MHD) to sustain their life . Despite Complementary and alternative medicine (CAM) may provide new therapeutic options for patients with ESRD with the goal of improving symptoms and quality of life. CAM, as defined by the National Center for Complementary and Alternative Medicine, is “a group of diverse medical and health care systems, practices, and products that are not generally considered to be a part of conventional medicine” . Based oAll patients with ESRD receiving MHD at a private dialysis center in Brookline, MA, USA, affiliated with a large academic medical center from September 2009 to July 2010 were approached to participate in the study. Potentially eligible patients were approached chair side during their dialysis session and asked to participate in the study. Subjects were excluded from the study if they were younger than 18 years, non-English speaking, or had a diagnosis of dementia. Willing patients gave verbal consent to participate. A 40-item questionnaire was administered by the principal investigator (GB) to subjects face-to-face, chair side, during MHD . Individual CAM therapies were grouped into 5 major categories as defined by the National Center for Complementary and Alternative Medicine: (1) biologically-based practices ; (2) manipulative- /body-based practices ; (3) mind-body-based practices ; (4) alternative medical systems ; and (5) energy healing (Reiki). For analyses, we excluded vitamins from biologically based practices since vitamins are usually prescribed as a conventional therapy for MHD patients in the USA. All CAM therapies were combined to a single category to identify any CAM use in a lifetime and the last month. Continuous variables were reported as medians with 25th and 75th interquartile ranges and categorical variables as frequencies and proportions. Categorical variables were compared with Fischer's exact test. The study was approved by the Institutional Review Board at Beth Israel Deaconess Medical Center.P = 0.02), alternative medical systems (P = .03), and manipulation and body-based practices (P = 0.01) were used most commonly by patients aged between 50 and 64 years  and by only 36% of patients of age 80 years or older. While CAM use was more common in females than males  and those with college or higher education than those with high school or less education , observed differences did not reach statistical significance. In the last month, 36% of patients reported using some type of CAM. The most frequent CAM modality used in the last month by patients was mind-body practice (27%), while biologically based practices excluding vitamins were used in the last month by 15% of patients.Among 106 eligible subjects approached, 89 subjects were willing to participate corresponding to a response rate of 84% see . The mosn = 21), lack of time (n = 5), and perception of inability to learn (n = 4). Subjects reported the perception that mind-body interactions were important to their health with a median score of 9  on a 10 point Likert scale from 0 to 10. In our sample population, 61% of patients with ESRD on MHD reported a lifetime use of CAM with 36% reporting use within a month of the survey. The most common modality used by patients in a lifetime or during the last month was mind-body practices. A majority of patients felt that the mind-body connection was very important for their health. An estimated 3 out of 4 patients were interested in learning mind-body practices and participating in research regarding mind-body practices during MHD. n = 356) reported 12% prevalence of CAM use [Limited studies have been conducted identifying patterns of CAM use among patients with chronic disease. National surveys have reported a high overall prevalence of CAM use among patients with arthritis (60%), lung disease (55%), cardiovascular disease (46%), and diabetes (41%) . Prior s CAM use . These sOur results suggest a positive perception of and willingness to learn mind-body practices among patients on MHD, including during hemodialysis, especially among those patients who have familiarity with CAM. Three small studies have suggested that mind-body practices may be useful for patients with ESRD –27. HoweAbout 1 out of 4 patients on MHD were not interested in learning mind-body practices. Only about half of patients of age 80 years and older or those who had never used CAM expressed interest in learning. This is consistent with national data from the general population where fewer elderly patients reported using any CAM or mind-body techniques; only 24% and 10% of individuals of age 85 years and older reported use of CAM and mind-body practices, respectively, in the last 12 months . PotentiOur study has several limitations. Since our sample population was small and derived from a single dialysis center, our results may not reflect CAM use in other regions or nationally. In comparison to national data of the outpatient dialysis population, our sample had a higher proportion of black patients, while it had a similar distribution in age, sex, and causes of ESRD . Data coIn summary, CAM use is common among patients with ESRD on MHD, in particular mind-body practices, and is used by a greater percentage of females than males, middle-aged than elderly, and patients with higher education levels. Patients largely expressed interest to learn and participate in studies of mind-body therapies. While CAM use, including mind-body therapies, is frequent in the general population and patients with chronic diseases, there exists limited evidence on their therapeutic efficacy . Further


In classical conditioning, proactive interference may arise from experience with the conditioned stimulus (CS), the unconditional stimulus (US), or both, prior to their paired presentations. Interest in the application of proactive interference has extended to clinical populations as either a risk factor for disorders or as a secondary sign. Although the current literature is dense with comparisons of stimulus pre-exposure effects in animals, such comparisons are lacking in human subjects. As such, interpretation of proactive interference over studies as well as its generalization and utility in clinical research is limited. The present study was designed to assess eyeblink response acquisition after equal numbers of CS, US, and explicitly unpaired CS and US pre-exposures, as well as to evaluate how anxiety vulnerability might modulate proactive interference. In the current study, anxiety vulnerability was assessed using the State/Trait Anxiety Inventories as well as the adult and retrospective measures of behavioral inhibition . Participants were exposed to 1 of 4 possible pre-exposure contingencies: 30 CS, 30 US, 30 CS, and 30 US explicitly unpaired pre-exposures, or Context pre-exposure, immediately prior to standard delay training. Robust proactive interference was evident in all pre-exposure groups relative to Context pre-exposure, independent of anxiety classification, with CR acquisition attenuated at similar rates. In addition, trait anxious individuals were found to have enhanced overall acquisition as well as greater proactive interference relative to non-vulnerable individuals. The findings suggest that anxiety vulnerable individuals learn implicit associations faster, an effect which persists after the introduction of new stimulus contingencies. This effect is not due to enhanced sensitivity to the US. Such differences would have implications for the development of anxiety psychopathology within a learning framework. In classical or Pavlovian conditioning, a conditioned response (CR) develops after repeated presentations of a conditioned stimulus (CS) and an unconditional stimulus (US). Relative to rates of acquisition when the stimuli are novel, prior experience with the CS, US, or both, results in proactive interference, or degraded acquisition of the CR. Eyeblink conditioning is an excellent platform to study proactive interference in both clinical and non-clinical subjects due to its procedural simplicity and detailed understanding of neural substrates modulating response acquisition , or degraded acquisition after prior experience with the CS. Robust LI has been shown in rabbits  and 10 to 21 (M = 15.1 ± 1.9), respectively. Informed consent was obtained in accordance with procedures approved by the Rutgers University Institutional Review Board.Participants completed the State/Trait Anxiety Inventory  activity was the same as previously used , US pre-exposure (US), CS + US pre-exposure (CS + US), or pre-exposure to the experimental Context for an equivalent time period (Context). Final numbers of participants prior to signal processing were: CS = 41, US = 39, CS + US = 43, Context = 37. Once consent was obtained, participants were asked to complete the STAI, AMBI, and RMBI questionnaires. Participants were then fitted with the eyeblink testing equipment and asked if they were ready to begin. Upon verification of EMG signal quality, the conditioning program was started.Each session began with three US-alone trials to allow for a measure of unconditional response (UR) magnitude in all subjects free from the influence of pre-exposures. Next, the pre-exposure period consisted of either 30 CS-alone , 30 US-alone , 30 CS and 30 US explicitly unpaired stimuli, pseudorandom order (with no more than three consecutive occurrences of either stimulus in a row), or the experimental Context without presentation of discrete stimuli. For the CS-alone and US-alone pre-exposures, the inter-trial interval (ITI) ranged from 25 to 35 s; for explicitly unpaired pre-exposures, the ITI ranged from 10 to 20 s, keeping the total time in the experimental Context during pre-exposure equal between groups (approximately 15 min). Immediately following the pre-exposure period, all participants received 60 paired trials in a delay conditioning paradigm (US overlapped and co-terminated with CS). The ITI varied between 25 and 35 s for the paired conditioning period. During the entire testing session, all participants watched a silent movie from a limited selection  to alleviate boredom and help maintain a forward-facing gaze.EMG data was evaluated on a trial-by-trial basis for all participants. The raw files were rectified then subjected to local smoothing with a sliding window covering 10 samples (20 ms). For an eyeblink to be counted, smoothed EMG activity in a 500-ms window beginning at the onset of the CS had to exceed the mean activity, plus four times the standard deviation, of the activity in a 125-ms comparator window that immediately preceded the CS window. Those sessions with excessive signal noise  or incomplete session data , were discarded and not used for further analysis. This inspection of the eyeblink conditioning sessions resulted in rejection of data from 28 participants . The resulting number of participants in each group was: CS = 33, US = 33, CS + US = 34, Context = 32.p > 0.25). The Trait anxiety inventory was positively correlated with the AMBI , and RMBI , and State inventory . The AMBI and RMBI were also positively correlated , which is consistent with published standards  = 5.65, p < 0.001, and Block, F = 26.74, p < 0.001, as well as interactions of Group × Block, F = 2.00, p < 0.05 and Vulnerability × Block F = 2.88, p < 0.05. The main effect of Block indicated that CR acquisition increased over the training session. Post-hoc analysis of the group main effect revealed that group Context demonstrated significantly greater CR acquisition overall (53%) than groups US (34%), and CS + US (36%). The Group × Block interaction indicated that the greatest amount of inhibition occurred in the US pre-exposure group over training blocks, while groups CS and CS + US significantly increased CR acquisition over the training session. This additionally shows that pre-exposure to combined CS + US did not result in greater learning interference than pre-exposure to either the CS- or US-alone. With respect to anxiety vulnerability, the Vulnerability × Block interaction revealed that high trait anxious individuals demonstrated faster acquisition over the training session compared to the low trait anxious individuals  × 2 (Vulnerability) × 6 (block) mixed analysis of variance (ANOVA). The analysis revealed a main effect of Group, Post-hoc analyses comparing groups Context and CS revealed that %CRs differed on block 2 for high trait anxious individuals, but did not differ on any block for low trait anxious individuals. When groups Context and US were compared, %CRs differed on blocks 2–6 for high trait anxious individuals, with no differences between groups for low trait anxious individuals.Furthermore, trait anxious individuals demonstrated enhanced proactive interference compared to low trait anxious individuals relative to their respective Context pre-exposure groups. Since we had an a priori hypothesis that higher trait anxiety would be associated with enhanced acquisition during standard delay conditioning, we examined group Context across a range of low, moderate, and high trait anxiety. If facilitated acquisition apparent in the top one-third of the scoring distribution could alternatively be explained as poor acquisition in the extreme lower end of the distribution, those falling in between should look similar to our High Trait Anxiety group. However, in this analysis, the high scoring group still showed faster acquisition compared to groups moderate and low, which acquired at similar rates Figure . SpecifiT-test comparing UR magnitudes between vulnerable and non-vulnerable groups revealed no significant differences prior to the pre-exposure session. As such, US sensitivity was not likely influencing the differences found in CR acquisition between groups.We examined unconditioned response magnitude to three US pre-exposures obtained prior to training to discern whether pre-existing differences in reactivity might account for acquisition differences apparent in those classified as anxiety vulnerable. Assessment of reactivity was confined to the US, since the rise/fall and decibel level of the CS used does not induce any appreciable responses in eyelid EMG. A Additional analysis of UR magnitude was conducted on the two groups receiving US pre-exposures (US and CS + US) to ascertain that peripheral sensory habituation to the US was not accounting for the proactive interference occurring during paired training. An ANOVA comparing the average of the last three US pre-exposures before the start of paired training was conducted. The 2 (pre-exposure group) × 2 (Vulnerability) ANOVA revealed no significant main effects or interactions.In the present study, proactive interference of the conditioned eyeblink response was assessed in human participants after pre-exposure to equal numbers of CS, US, or explicitly unpaired CS and US presentations. Interference was evident as reduced CR acquisition in all three pre-exposure groups relative to a Context pre-exposure condition. The combined pre-exposure to both CS and US did not result in greater interference than either stimulus alone. As prior work in humans has only examined these conditions independently, this represents the first study to both compare and successfully demonstrate proactive interference across stimulus conditions with equal stimulus pre-exposures. Additionally, since proactive interference is shown to be sensitive to anxiety, the results were examined with respect to anxiety vulnerability as indexed by the Trait Anxiety Inventory in non-clinical individuals. Faster learning was apparent over the training session in high trait anxious relative to low trait anxious individuals, which supports early eyeblink conditioning work in non-clinical participants. Furthermore, greater interference after stimulus pre-exposure was seen in anxiety vulnerable relative to non-vulnerable groups compared to the Context pre-exposure condition. These findings have important implications regarding the acquisition of cue-outcome associations in anxiety etiology.The phenomenon of LI has been tested extensively in animal preparations using classical conditioning of the eyeblink response. In the human literature however, the appearance and degrees of LI are inconsistent Lubow, . Early eSimilar to the CS pre-exposure condition, robust proactive interference was apparent after pre-exposure to the US, the degree of which appears to be greater than what may be expected from 30 US pre-exposures. In a prior study manipulating US number, learning interference was apparent with 70 US pre-exposures but not 35 Hobson, . In otheMatching the number of US pre-exposures with that of CS pre-exposures from prior LI work also enabled us to examine if unpaired CS and US presentations resulted in equal or greater inhibition than that of pre-exposure to CS or US alone. Previous work in animal preparations has reported greater inhibition after combined CS and US pre-exposures (Siegel and Domjan, When individuals were sorted on anxiety vulnerability as indexed by trait anxiety, interesting patterns of proactive interference emerged with respect to CS and US pre-exposures. Individuals reporting high trait anxiety exhibited faster rates of CR acquisition than that reporting lower trait anxiety. Additional analyses confirmed that enhanced acquisition was indeed a function of those individuals scoring higher in trait anxiety, with individuals scoring in the moderate and low range acquiring at a similar, slower rate. These individuals also demonstrated greater PI over the training session, particularly in the US pre-exposure condition. Prior work in humans examining inhibition of learning acquisition in psychopathology has reported reduced LI in instrumental learning or cognitive tasks (Zalstein-Orda and Lubow, It is possible that proactive interference observed in the current study is a result of non-associative processes like habituation or attention (Lubow et al., For combined CS and US pre-exposures, theoretical accounts posit that interference should be at least similar in magnitude to the strongest interference of CS or US pre-exposure alone. Additionally, the degree of interference would be expected to exceed these component values if the properties of the combined exposure differ appreciably from those attributable to the separate components (Siegel and Domjan, Taken together, enhanced acquisition and proactive interference in anxiety vulnerable individuals suggests a greater susceptibility to acquire cue-outcome associations with mildly aversive stimuli, a characteristic that would potentiate the development of anxiety. Although this learning process has been discussed in the etiology of anxiety disorders with implications for therapy, these data suggest that learning differences are traceable as a predisposing factor. With respect to anxiety vulnerability, stimulus pre-exposure, associability, and their relationship to attention might interact to modulate CR interference. Further work is necessary to understand exactly what components might be involved in the regulation of proactive interference, and if those might be compromised—or enhanced—in anxiety vulnerable individuals. The ability to reliably examine degrees of proactive interference in normal and anxiety vulnerable populations allows for a more critical assessment of learning and stimulus processing differences in trait anxiety and inhibited individuals. Thus, there is greater potential to understand anxiety development as a learning process, with specific and quantifiable features.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.


Porcine kobuvirus was first identified in early 2007 in Hungary. Originally thought to be confined to the intestine, almost 2 years later the virus was found in the blood of clinically healthy pigs on the same farm. Porcine kobuvirus may be widely distributed on pig farms worldwide. Picornaviridae) are small, nonenveloped viruses with single-stranded, positive-sense genomic RNA; they are divided into 12 genera: Aphthovirus, Avihepatovirus, Cardiovirus, Enterovirus, Erbovirus, Hepatovirus, Parechovirus, Sapelovirus, Senecavirus, Teschovirus, Tremovirus, and Kobuvirus  characterized from fecal samples from domestic pigs in Hungary  has not been reported. We report the endemic circulation and in vivo evolution of porcine kobuvirus on a pig farm where the virus was originally discovered and virus escape from the gastrointestinal tract, resulting in viremia in domestic pigs.In February 2007, a total of 39 (65%) of 60 fecal samples from clinically healthy domestic pigs on a farm in eastern Hungary were positive (by reverse transcription–PCR) for porcine kobuvirus . In NovePorcine kobuvirus RNA was detected in 32 (53.3%) of the 60 fecal samples and 16 (26.6%) of the 60 serum samples collected in November 2008 . PorcineThe complete genetic sequence of strain kobuvirus/swine/K-30-HUN/2008/Hungary, detected in a fecal specimen from a 3–4-week-old pig in 2008, was determined and compared with the prototype strain kobuvirus/swine/S-1-HUN/2007/Hungary . In the We report the endemic circulation and natural interhost evolution of porcine kobuvirus among domestic pigs on a pig farm within a 21-month period. This follow-up study indicates that domestic pigs are generally infected with porcine kobuvirus. It is likely that porcine kobuvirus is not restricted geographically and is widely distributed on pig farms worldwide. According to a veterinarian’s clinical report, no clinical signs were associated with the endemic kobuvirus infection. In this closed-animal community, the susceptible young host generations were continuously infected; the length of the cycle interval when the virus is outside the host  is probably short. However, the number of nucleotide changes is consistent with rates observed for other picornaviruses  in humans (Similar explanations for the pathogenesis of many picornaviruses exist. Escape from the gastrointestinal tract into the bloodstream was probably the situation for the bovine kobuvirus detected in culture medium supplemented with cattle serum (


Many patients have serious depression that is nonresponsive to medications, but refuse electroconvulsive therapy (ECT). Early research suggested that isoflurane anesthesia may be an effective alternative to ECT. Subsequent studies altered drug, dose or number of treatments, and failed to replicate this success, halting research on isoflurane's antidepressant effects for a decade. Our aim was to re-examine whether isoflurane has antidepressant effects comparable to ECT, with less adverse effects on cognition.Patients with medication-refractory depression received an average of 10 treatments of bifrontal ECT (n = 20) or isoflurane (n = 8) over 3 weeks. Depression severity  and neurocognitive responses  were assessed at Pretreatment, Post all treatments and 4-week Follow-up.Both treatments produced significant reductions in depression scores at Post-treatment and 4-week Follow-up; however, ECT had modestly better antidepressant effect at follow-up in severity-matched patients. Immediately Post-treatment, ECT (but not isoflurane) patients showed declines in memory, fluency, and processing speed. At Follow-up, only autobiographical memory remained below Pretreatment level for ECT patients, but isoflurane patients had greater test-retest neurocognitive score improvement.Our data reconfirm that isoflurane has an antidepressant effect approaching ECT with less adverse neurocognitive effects, and reinforce the need for a larger clinical trial. Although antidepressant medications are effective for many patients with depression, the rate of response to the first agent administered can be as low as 50%. For nonresponders to the first agent, the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial showed that the remission rate decreased from 37% to 13% as successive medication alternatives were tried It would be highly desirable to establish an alternative therapy that has similar benefits to ECT while minimizing any adverse neurocognitive effects and having wider social acceptability. One alternative meeting these criteria that has some prior data supporting its potential effectiveness in depression is deep inhalation anesthesia with isoflurane (ISO). Like ECT, deep anesthesia with ISO induces a brief state of electrocortical quiescence ), but does so without inducing convulsions or other seizure symptoms. Based on two preliminary studies directed by Langer, et al in Europe Given the large number of patients with medication-refractory depression , and improvements in medical monitoring and management of patients during deep anesthesia, a renewed effort to evaluate ISO anesthesia as an effective alternative therapy to ECT is warranted. As a small open-label comparability study, the present study's primary objective was to examine whether deep ISO anesthesia shows similar efficacy to ECT in alleviating moderate to severe depression in medication-refractory patients. The secondary objective was to evaluate whether a series of 10 treatments with deep ISO anesthesia over a 3 week period results better neurocognitive function at 24–48 hours after the last treatment and 4 weeks later than treatments with bifrontal ECT, a form of ECT previously shown to have lesser effects on memory on cognition than bitemporal ECT Participants included 28 patients aged 18–65 years with moderate to severe depression . They were recruited from among patients referred for ECT to the University of Utah Neuropsychiatric Institute (UNI) based on unsatisfactory response and/or intolerance to multiple antidepressant pharmacological interventions, and included 21 with a primary diagnosis of major depressive disorder (MDD) and 7 with a diagnosis of bipolar disorder (BPD). After evaluation by the study psychiatrist (HW), patients were offered enrollment and the opportunity to choose either the standard treatment, ECT, or the investigative treatment, ISO anesthesia. Exclusions included: 1) primary psychotic disorder, dysthymia, or personality disorder; 2) significant premorbid cognitive impairment ; 3) unstable cardiovascular or cerebrovascular disease, 4) any other contraindication to ISO anesthesia; 5) pregnancy or 6) inability to consent. Enrolled patients continued their usual pharmacotherapy and psychotherapy, except for anticonvulsants which were discontinued see  while unThis study was approved by the University of Utah Institutional Review Board (IRB Protocol No. 00025750) and all participants provided written informed consent.depressive symptoms assessed by clinical assessment using the HRSD-24 by blinded investigators, and patient self-ratings on the 16-item Quick Inventory of Depressive Symptomatology Self Report (QIDS-SR16); 2) neurocognitive function assessed by tests of memory, executive function, and processing speed. HRSD-24 and cognitive assessments were completed 3 times: 1) Pretreatment, 2) 24–48 hours after the last treatment session (Post-treatment), and 3) 4 weeks after the last treatment session (Follow-up). In 12 ECT and all 8 ISO patients, QIDS-SR16 assessments of depression were obtained just prior to each treatment session, to provide a more continuous picture of the rate of symptom change.The design was an open-label, two-arm treatment trial, comparing 8–12 sessions of ECT vs. 10 sessions of ISO anesthesia treatments over a 2.5–3.5 week period. Primary outcome measures included: 1) Procedures for the ECT treatment group: Induction was performed by an anesthesiologist (KS) with methohexital (1–3 mg/kg IV). A tourniquet was inflated around a hand followed by neuromuscular blockade using succinylcholine . Then, 60–120 seconds later, the bifrontal ECT stimulus was administered . Visual evidence of tonic-clonic seizure was confirmed by observation in the hand that remained isolated from the systemic circulation. ECT procedure time averaged 20 min, with 30–45 min required for post-procedure recovery. ECT treatments were repeated approximately every other day for a total of 8–12 treatments  0.34), based on clinically determined need. Procedures for the ISO treatment group: As with ECT, anesthetic induction was achieved with methohexital (1–3 mg/kg IV) and neuromuscular blockade was accomplished with succinylcholine . Patients were infused with 500 ml of lactated Ringers solution to help reduce risk of hypotension. The patient's airway was secured via endotracheal intubation. The EEG-derived bispectral index (BIS) was monitored continuously using an Aspect A1000 monitor , along with end-tidal concentration of isoflurane, carbon dioxide and oxygen. Isoflurane concentration was initially at 4% with high flow oxygen until >80% EEG burst suppression; it was then decreased to 2 times the age-adjusted Minimum Alveolar Concentration (MAC) for the patient and oxygen flows reduced. This level of burst suppression was maintained for 15 minutes  that rapidly removes residual inhaled anesthestics, reducing post-procedure recovery time to 15–20 min. Significant hemodynamic alteration (change in heart rate or blood pressure more than 20% from baseline) was treated in standard fashion with appropriate agents  as per the anesthesiologist's (KS's) discretion. ISO treatments were repeated approximately every other day for a total of 10 treatments.Patients received standard monitoring as recommended by the American Society of Anesthesiologists (ASA). At Pretreatment, all patients completed the Mini-mental Exam and the Wechsler Test of Adult Reading (WTAR) to confirm that intellectual levels were within normal limits and generally comparable across groups. Mini-mental scores were all >26 and did not differ for the ECT-All, ECT-Matched and ISO groups . WTAR scores and age also did not differ significantly p>0.12; , but theAt Pretreatment, Post-treatment and Follow-up, the following battery of tests were completed. To assess retrograde amnesia, subjects completed the Autobiographical Memory Interview-Short Form (AMI) Two sets of analyses were performed. First, ECT-All patients (n = 20) were compared with the ISO patients (n = 8) for HRSD-24 scores and for each of the neurocognitive performance scores at Pretreatment, Post-treatment and Follow-up using a mixed model repeated measures ANCOVA with Group (2) as a between-subjects factor and Time (3) as a within-subjects factor. For the QIDS-SR scores, which were obtained before and throughout the ECT and ISO treatment series, a Group (2)×Time (4) analysis was used, where sampling times were before the first, fourth, seventh and tenth/last treatment. When ANCOVAs indicated significant effects, between-group and within-group comparisons among means were performed, including comparisons between ECT-All vs. ISO groups and between ECT-Matched vs. ISO groups. For the Pretreatment neurocognitive measures, these means were adjusted for age and WTAR. To examine relative changes in performance after treatment between groups, Post-Treatment and Follow-up neurocognitive means were compared between-groups after adjustment for the Pretreatment score on that test as well as WTAR. Alpha level was set at p<0.05 two-tailed, even where our predicted outcomes were directional (ISO > ECT for neurocognitive measures following treatment), in an effort to limit the increase in false positive findings associated with multiple dependent variables. Cohens d estimates of effect sizes were also generated (using pooled standard deviations) for each significant group difference.For the HRSD-24 scores, a main effect of Times  and a significant Group X Time interaction was obtained . Subsequent comparisons showed that although the ECT-All group initially had higher depression severity than the ISO group , the HRSD scores of both groups decreased significantly to similar levels at Post-treatment .These significant decreases in HRSD-24 scores persisted at 4-week Follow-up . When ECT-All was compared with the ISO group, they did not differ significantly in HRSD-24 at Post-treatment or Follow-up, with both groups reducing mean symptom severity to the mild range . The ECTUsing the definition of 50% reduction in HRSD-24 depression score to identify treatment responders, 90% of ECT-All patients (18 of 20), 88% of ECT-Matched patients (7 of 8) and 75% of ISO patients (6 of 8) met this criterion at Post-treatment . These gAfter adjustment for differences in age and WTAR, a significant Group×Time interaction was obtained for 6 of the 8 neurocognitive measures: Hopkins Immediate Recall and Discrimination, Logical Memory I and II, Fluency and AMI . For the PSI, this interaction approached significance (p = 0.067), but the main effect of Group was more robust . For Hopkins Delayed Recall, no reliable effects were seen (p>0.15). Subsequent analyses focused on comparisons of adjusted means in the 7 neurocognitive measures where overall analyses were significant see . All meaFor age- and WTAR-adjusted AMI scores, no group differences were obtained at Pretreatment, but the ISO group had significantly better recall for dates and details of real-life autobiographical events at Post-treatment and Follow-up than both the ECT-All and the ECT-Matched groups . Within-For the Verbal Fluency measure, no group differences were significant at Pretreatment or Follow-up, but the ISO group had significantly better performance immediately Post-treatment . These PAmong the Hopkins Verbal Learning measures, which involve memory for spoken word lists, there were no significant group differences at Pretreatment after adjustment for age and WTAR . After fFor the Logical Memory Tests I and II, which involve immediate and delayed recall of spoken passages, respectively, no significant group differences were obtained at Pretreatment after adjustment for age and WTAR . At bothFor the Processing Speed Index scores, the ISO group had significantly better performance than ECT-All at Pretreatment, Post-Treatment and Follow-up even with adjustment for WTAR and age p<0.03;  but wereThe results of this open label study supported our primary hypothesis that a series of 10 sessions of deep anesthesia with ISO is effective as an antidepressant intervention for patients with medication-refractory depression. The improvement in HRSD-24 scores (including percent of patients achieving remission) and QIDS-SR16 scores immediately after completion of treatment was similar in the nonstandard ISO treatment compared to the standard ECT treatment. Although there was somewhat better maintenance of the decrease in HRSD-24 depressive symptom scores among the 8 severity-matched ECT patients one month later, the ISO group still showed significant improvement even at that later time point.™.The antidepressant effect of ISO indicated by these observations is very similar to the original reports by Langer et al The neurocognitive assessments made as part of this study indicate that even with 10 sessions of ISO anesthesia over a 3 week period, there was no significant performance decrement on any of the traditional neurocognitive measures. In fact, the ISO patients showed significant improvements in word fluency, nonverbal processing speed, logical memory, and immediate and delayed recall of newly learned verbal material after the intervention. These improvements are probably a result of the combined effects of decreased depressive state (which has been linked to response slowing and other performance deficits) and practice The effectiveness of bifrontal ECT on depressive symptoms was never in doubt There are several study limitations to acknowledge. The study was open-label rather than randomized, and the group sizes were modest. Replication in a larger clinical trial is needed to confirm these findings. More of the severely depressed patients chose ECT than ISO, which was managed by creating a smaller ECT-Matched subgroup to examine along with the full ECT and ISO groups. The effectiveness of ISO for the most severely depressed patients is still uncertain. Also, some of the ECT patients had 8 or 12 rather than 10 treatments, titrated to clinical effectiveness, but our IRB approval restricted the ISO treatment series to 10. This factor may have contributed to the slightly better antidepressant outcome for the ECT-Matched patients at 4-week follow-up. Finally, all of the patients in the study had medication-refractory moderate to severe depression, so that future research is needed to examine whether ISO anesthesia may be an effective treatment in milder and medication-responsive depression. This small open-label study indicates the ISO may be another option for patients with moderate to severe depression (both with MDD and BPD diagnoses) who find medications ineffective or are unable to tolerate their side effects. Like transcranial magnetic and direct current stimulation, magnetic seizure therapy and other novel treatment options, it is important to explore the comparable efficacy as well as side effect profiles of novel alternatives to ECT for seriously depressed patients This small study counters intervening negative studies and confirms the original research showing that a series of 10 treatment sessions with deep inhalation isoflurane anesthesia has an antidepressant effect in moderate to severe medication-refractory depression approaching that of bifrontal ECT. Neurocognitive performance of ISO-treated patients was superior to ECT-treated patients immediately after the last treatment (when only ECT was associated with worsened performance relative to pretreatment). ISO patients continued to perform better 4 weeks later, although performance in ECT patients showed considerable improvement between those tests. With this additional supportive evidence, a larger clinical trial is strongly indicated, preferably one designed to examine whether ECT and ISO have their effects through shared physiological pathways.


Previous observational studies have shown that insulin therapy may modify the risk of prostate cancer (PCa). However, these studies yielded controversial results. Thus, we performed this meta-analysis to determine whether insulin use was associated with PCa risk in patients with diabetes mellitus (DM).A literature search was carried out in PubMed, EMBASE, and Cochrane Library Central database between January 1966 and January 2013. Fixed-effect and random-effect models were used to estimate pooled relative risks (RR) and corresponding 95% confidence intervals (CIs). Subgroup analyses and sensitivity analyses were also performed. A total of 11  studies published between 2007 and 2013 were included in the meta-analysis, representing data for 205,523 male subjects and 7,053 PCa cases. There were five studies investigating the influence of insulin and other glucose-lowering agents on the risk of PCa , and six studies investigating the influence of glargine and non-glargine insulin. Insulin use was not associated with PCa risk when compared with other glucose-lowering agents . Use of insulin glargine did not contribute to susceptibility to PCa as compared with use of non-glargine insulin . Sensitivity analysis confirmed the stability of present results, since no individual study affected the pooled result significantly. Our results suggest that, there may be no significant association between insulin use and risk of PCa as compared with other glucose-lowering agents in patients with DM, and there was no substantial evidence for increase risk of PCa among insulin glargine users as compared to non-glargine insulin users. Further studies are warranted to validate these conclusions. Prostate cancer (PCa) is the sixth leading cause of cancer death in males worldwide and is tWhether insulin treatment increases risk of cancer is an important issue because almost all patients with DM will eventually require insulin treatment. The assThis meta-analysis was conducted following guidance provided by the Cochrane Handbook and was Two reviewers(CQ and CY) independently selected eligible trials. Disagreement between the two reviewers was settled by discussing with the third reviewer(WZ). Studies were selected if they met our criteria for study design , population (patients with DM), outcome (PCa incidence reported) and one or both of our comparisons of interest(1): insulin vs. other glucose-lowering agents; and (2) insulin glargine vs. all other types of insulin. Studies without PCa assessment were excluded. When there were multiple publications from the same population, only data from the most recent report were included in the meta-analysis and the others were excluded. Studies reporting different measures of RR like risk ratio, rate ratio, hazard ratio (HR), and odds ratio (OR) were included in the meta-analysis. In practice, these measures of effect yield a similar estimate of RR, since PCa is not common among patients with DM -30.The following data was collected by two reviewers(CQ and CY) independently using a purpose-designed form: name of first author, publishing time, country of the population studied, study design, study period, duration of follow-up, number of male subjects, number of PCa cases, type of DM, mean age of participants, cancer diagnosis methods, data ascertainment methods, the relative risk (RR) estimates and its 95 % confidence intervals (CIs), confounding factors for matching or adjustments. Newcastle-Ottawa scale(NOS) was used to assess the methodologic quality of cohort and case–control studies. The NOS contains eight items that are categorized three categories: selection , comparability , and exposure/outcome . A ‘‘star’’ presents a ‘‘high-quality’’ choice of individual study. Two reviewers(CQ and CY) assessed the methodological quality independently. Disagreement between the two reviewers was settled by discussing with the third reviewer(WZ).2 statistics. For the Q statistic, a P value<0.10 was considered statistically significant for heterogeneity; for the I2 statistic, heterogeneity was interpreted as absent (I2: 0%–25%), low (I2: 25.1%–50%), moderate (I2: 50.1%–75%), or high (I2: 75.1%–100%)[Heterogeneity was assessed using the Cochran Q and I.1%–100%). The ove.1%–100%) was repo.1%–100%) was repo.1%–100%). A univa.1%–100%),36. Furt.1%–100%). All ana2 =29.6%, p = 0.224), the fixed-effects model but not the random-effects model was chosen to provide a appropriate estimate of pooled RR and its 95% CI, and we found that, compared with other glucose-lowering agents, insulin use was not associated with risk of PCa , which indicated that this study was the main source of heterogeneity. After excluding this study, the result was still insignificant . Moreover, no significant variation in combined RR was found by excluding any of other studies.To test the robustness of association and clarify possible sources of statistical heterogeneity, sensitivity analyses were carried out by excluding studies one-by-one and analyzing the homogeneity and effect size for all of rest studies. When we excluded the study by Carstensen B et al, the het2=63.4%, q=0.018) was observed, the random-effects model was applied and we found that use of insulin glargine was not associated with increased risk of PCa in patients with DM as compared with use of non-glargine insulin , which differs from human insulin by replacing asparagine with glycine in position 21 of the A-chain and by carboxyterminal extension of B-chain by 2 arginine residues, is widely used as a long-acting insulin analogue in the treatment of DM. Previous experimental studies have shown that glargine may have potential carcinogenic effects for its higher mitogenic potency compared with non-glargine insulin,17. HoweThe strength of the present meta-analysis lies in inclusion of 11 studies and 205,523 male subjects. Most of the included studies(8 of 11) were published after 2010. This study included our report of two different exposure comparisons measures (insulin vs. no insulin and insulin glargine vs. other insulins). However, limitations of this meta-analysis should also be noted. First, we did not search for unpublished studies, so only published studies were included in our meta-analysis. Therefore, publication bias may have occurred although no publication bias was indicated from both visualization of the funnel plot and Egger’s test. Second, we allowed for exposure to any combination of other medications, including oral glucose-lowering agents, which may leads to over- or under-estimation of the true cancer risk,42,43. NIn conclusion, our results suggest that, there may be no significant association between insulin use and risk of PCa as compared with other glucose-lowering agents in patients with DM, and there was no substantial evidence for increase in PCa risk among insulin glargine users as compared to non-glargine insulin users. More studies, especially high quality cohort studies with larger sample size, well controlled confounding factors and longer duration of follow-up are needed to confirm these conclusions.Table S1PRISMA checklist.(DOC)Click here for additional data file.


Objective. Patients with schizophrenia residing at institutions often suffer from negative symptoms, motor, and functional impairments more severe than their noninstitutionalized counterparts. Tai-chi emphasizes body relaxation, alertness, and movement coordination with benefits to balance, focus, and stress relief. This pilot study explored the efficacy of Tai-chi on movement coordination, negative symptoms, and functioning disabilities towards schizophrenia. Methods. A randomized waitlist control design was adopted, where participants were randomized to receive either the 6-week Tai-chi program and standard residential care or only the latter. 30 Chinese patients with schizophrenia were recruited from a rehabilitation residency. All were assessed on movement coordination, negative symptoms, and functional disabilities at baseline, following intervention and 6 weeks after intervention. Results. Tai-chi buffered from deteriorations in movement coordination and interpersonal functioning, the latter with sustained effectiveness 6 weeks after the class was ended. Controls showed marked deteriorations in those areas. The Tai-chi group also experienced fewer disruptions to life activities at the 6-week maintenance. There was no significant improvement in negative symptoms after Tai-chi. Conclusions. This study demonstrated encouraging benefits of Tai-chi in preventing deteriorations in movement coordination and interpersonal functioning for residential patients with schizophrenia. The ease of implementation facilitates promotion at institutional psychiatric services. Schizophrenia affects about 24 million people worldwide. Despite a low incidence rate 3/10,000) [0,000 [1,Under the medical model, the primary focus of care and research on patients prioritizes illness management, self-care, and functioning abilities while physical or psychological well-being falls secondary. Patients with schizophrenia have comparatively shorter life expectancies due to poor physical health (higher incidence of cardiovascular and metabolic diseases) and psychological health (depression and suicide) –5. HowevThere are a number of known benefits of exercise to patients' psychosocial well-being and their symptoms of psychiatric disorders. Levin and Gimino  indicateExercises based upon Eastern health philosophy like Tai-chi stress the interrelated body and mind. Besides being a form of light-to-moderate intensity physical exercise , 15 whicThe present study explored the effectiveness and implementation feasibility of Tai-chi (Wu-style Cheng form) on the movement coordination, negative schizophrenic symptoms, and general functioning disabilities for residential schizophrenic patients. This pilot trial was conducted for patients with schizophrenia residing at residential rehabilitation facilities. Halfway houses and long-stay care homes offer training on illness management and life skills so as to facilitate community reintegration . This reThe primary aim of this pilot trial is to examine the effectiveness of a 6-week Tai chi program as an adjunctive intervention in a residential rehabilitation setting. The secondary objective is to explore the benefits and disadvantages of such intervention, thereby, informing the feasibility for promotion and areas for improvement.The pilot trial recruited thirty residential patients with chronic schizophrenia from the Sheng Kung Hui Providence Garden for Rehab, a mental health rehabilitation complex in Hong Kong providing both long-stay care and halfway house services to enhance the heterogeneity of the sample. Potential participants were invited to participate by their social workers based on the following inclusion and exclusion criteria. 30 participants were recruited so as to ensure an optimal group size of 12 after randomization  and a drThe inclusion criteria included the following. (a) A diagnosis of schizophrenia according to the DSM IV-TR criteria. (b) Age between 18 to 65 years. (c) Ability to understand and speak Cantonese. (d) no prior experience in learning Tai-chi. Participants were excluded if (e) diagnosed with acute schizophrenia requiring hospitalization; (f) suffering from severe schizophrenic symptoms  that would limit their ability to interact or participate in the class; (g) suffering from physical disabilities that would limit Tai-chi practice ; (h) Suffering from other severe illnesses which may impair cognitive or visuomotor functioning, cause physical pain or limit life expectancy to 10 years or less.Ethical approval for this study was granted by the Human Research Ethics Committee for Non-Clinical Faculties at the University of Hong Kong. Written informed consent was solicited from all participants.This Tai-chi class was based on the Wu-style Cheng-form Tai-chi Chuan  led by mRandomization of participants was done using random numbers. The waitlist group received their standard residential care which includes a 30-minute daily morning stretching routine for both the Tai-chi and control participants.Both the Tai-chi and waitlist groups were assessed (i) before intervention (T1), (ii) within 1 week after the 6-week intervention (after intervention T2), and (iii) within the 6th week after the intervention (maintenance T3). Qualitative feedback on learning and practising Tai-chi were collected with a structured interview schedule at T3 on their perceived benefits and difficulties of practising Tai-chi. Responses were recorded on paper by the interviewer.A series of patient assessments were administered by trained research assistants who were blinded to the group assignment of participants.Measurements of arm-hand dexterity and rapid eye-hand coordination were assessed using the Minnesota Rate of Manipulation Test (CMDT) , which iThe SANS  was usedTo ensure inter-rater reliability, the first 5 interviews were conducted with multiple interviewers and final ratings were given after deliberation by the team. The rated scores would subsequently be discussed with psychiatric social workers providing care to the participants to ensure that ratings given closely reflected their actual symptom levels.The WHODAS-II  measuresThe interviewer-administered 36-item version was adopted. Items were translated and back-translated by the research team into Chinese to facilitate participants' understanding. Certain items including “staying by yourself for a few days” and “sexual activities” were dropped for a lack of relevance at the studied residential facility. Higher scores denote greater functioning disabilities.Patients' sociodemographic and clinical information were solicited from personal and medical records. This included their age, gender, education level, martial status, and employment. Their period of psychiatric diagnosis, medication, and consecutive lengths of stay at residential facilities were collected as clinical data. Structured interview questions requiring participants to list their subjective advantages and disadvantages of Tai-chi were posed at the maintenance assessment. U tests, respectively, using the Statistical Package for Social Sciences version 18.0. Analyses were conducted on all three time points for intervention and maintenance effects. All statistical significance tests are two-sided, at the level of significance of P ≤ 0.05. Effects sizes were calculated according to [r = 0.3 and r = 0.5, respectively. Missing variables were replaced with the median of the respective subscale if the number of missing variables did not exceed half of the subscale. Qualitative feedback was analyzed using theme analysis.Intention-to-treat analysis was employed, such that participants with missed Tai-chi sessions or data were still included in the final analysis. Due to the small sample size, nonparametric techniques were adopted. Within and between-group comparisons were conducted with the Wilcoxon signed ranks the Mann-Whitney rding to , where m30 participants fulfilling the inclusion and exclusion criteria were invited to participate into the study .Participants had a mean age of 53 years and were diagnosed for about 28 years. The average consecutive length of stay at rehabilitation residencies was 11.8 years. All participants were receiving antipsychotic medication.On Chi-square and Mann-Whitney tests, the Tai-chi and the waitlist groups were comparable on their sociodemographic and clinical statues as well as the assessment variables . The solZ = −0.591; P = 0.555) [Z = −0.537; P = 0.592). Approximately 57% of the participants (n = 17) were taking atypical antipsychotics.Antipsychotic medication use at baseline (T1) did not differ significantly between the two groups which were assessed based on chlorpromazine equivalents which reflects medication dosage (= 0.555) . The aveZ = 2.22; P = 0.026; r = 0.57), the displacing test  and the one-hand test . Motor dexterity and eye hand coordination (CMDT) after attending the Tai-chi class (T2) was not vastly different from baseline (T1). But the waitlist group experienced significant deterioration on 3 of the 5 tests of the CMDT, the turning test  and marginal significance the one-hand test . Therefore, the Tai-chi class buffered from deteriorations in movement coordination but effects were not sustained at maintenance (T3).There is a significant difference in how the Tai-chi group and the waitlist group faired on the displacing test . The Tai-chi participants also found fewer difficulties with community participation at T2 . The waitlist group, however, experienced greater disruptions in interpersonal functioning at T2  and sustained at T3 . Between group differences in interpersonal functioning were marginally significant between baseline and T2  and significant between baseline and T3 . Performance outcomes of the two groups are detailed in Fewer disruptions in life activities functioning was observed for the Tai-chi group at maintenance (T3)  can be better cultivated in a group than by a single person alone. Therefore, the Tai-chi class allows for both verbal and nonverbal connections among participants. Another study on yoga intervention for patients with schizophrenia proposed the role of improved emotional recognition to enhancing social functioning [Exercise-related benefits to interpersonal functioning are particularly relevant to group exercises like Tai-chi. Despite focusing on the inner self , traditictioning . Being sctioning . Yet, itctioning .Participant feedback provided anecdotal suggestions for the possible mechanisms of the benefits of Tai-chi. Similar to yoga, Tai-chi distinguishes itself from other forms of physical exercises. Recognizing the mind-body nature of this activity, some participants expressed appreciation for both physical and mental benefits. They experienced improvements in health, flexibility, assured of the benefits for bones and ligaments. On the cognitive and psychological level, some participants were happier, more relaxed, alert, thinking more openly, and feeling more regulated. A hallmark disability of schizophrenia is poor learning and memory, believed to arise from hippocampal atrophy. With a high cognitive component involving the memorization of movement sequence, it can possibly help instigate hippocampal neurogenesis, hence, leading to cognitive improvements . Future From this preliminary study, Tai-chi supplementing regular antipsychotic and rehabilitation care has a protective effect for institutionalized patients. It is also a sustainable form of treatment that may offer a sense of mastery towards illness control. A persistent obstacle is participants' low motivation to continue practising independently. Tai-chi calls for mental endurance and patience, which proved challenging for some who found it mundane, or experience difficulty remembering the movements. Consequently, trainer-led weekly practice sessions could be helpful. Outside residential facilities however, practice sessions may become less feasible in the community, where preintervention psychoeducation on the health benefits of exercise and enhancing self-efficacy may improve participation rates . In addiDespite numerous studies demonstrating the effects of exercising and Tai-chi, this is one of the few randomized controlled trials on Tai-chi for patients with schizophrenia. However, this remains a small-sampled pilot study, which is confounded by the lack of a group exercise control condition to account for the possible effects of exercise or peer gathering. Another limitation lies in the assessment of functioning disability, WHODAS-II which was translated to Chinese but has yet to be validated in the population. Two items were also removed from the scale for their irrelevancy to the context but should also be assessed in a larger study with both residential and community patients. Notwithstanding such limitations, Tai-chi proved promising in areas where psychotropic medication currently has limited effectiveness. As the rehabilitation of mental illness gradually moves away from the medical model, Tai-chi can be promoted as an adjunct to improving patients' general functioning.


Chronic heart failure (CHF) is a public health priority. Its age-standardized prevalence has increased over the past decade. A major challenge for the management of CHF is to promote long-term adherence to self-care behaviors without overtaxing available health care resources. Counseling by multidisciplinary health care teams helps to improve adherence to self-care behaviors and to reduce the rate of death and hospitalization. In the absence of intervention, adherence to self-care is below recommended standards.This trial aims to establish and evaluate a Canadian e-platform that will provide a core, standardized protocol of behavioral counseling and education to facilitate long-term adherence to self-care among patients with CHF.P<.05.Canadian e-Platform to Promote Behavioral Self-Management in Chronic Heart Failure (CHF-CePPORT) is a multi-site, double blind, randomized controlled trial with a 2 parallel-group  by 3 assessments  design. We will identify subjects with New York Heart Association Class II or III systolic heart failure from collaborating CHF clinics and then recruit them (n=278) by phone. Subjects will be randomized in blocks within each site . The primary outcome will be improved quality of life, defined as an increased number of subjects with an improvement of ≥5 points on the summary score of the Kansas City Cardiomyopathy Questionnaire. We will also assess the following secondary outcomes: (1) diet habits, depression, anxiety, smoking history, stress level, and readiness for change using self-report questionnaires, (2) physical activity level, current smoking status, and vagal-heart rate modulation by physiological tests, and (3) exercise capacity, prognostic indicators of cardiovascular functioning, and medication adherence through medical chart review. The primary outcome will be analyzed using generalized estimation equations with repeated measures on an intention-to-treat basis. Secondary outcomes will be analyzed using repeated-measures linear mixed models with a random effects intercept. All significant main effects or interactions in the statistical models will be followed up with post hoc contrasts using a Bonferroni correction with a 2-sided statistical significance criterion of This 3.5-year, proof-of-principle trial will establish the e-infrastructure for a pan-Canadian e-platform for CHF that is comprised of a standardized, evidence-based protocol of e-Counseling.CHF-CePPORT is designed to improve long-term adherence to self-care behaviors and quality of life among patients with CHF. It will demonstrate a distinct Canadian initiative to build capacity for preventive eHealth services for patients with CHF.ClinicalTrials.gov NCT01864369; http://clinicaltrials.gov/ct2/show/NCT01864369 (Archived by WebCite at http://www.webcitation.org/6Iiv6so7E). Chronic heart failure (CHF) is a progressive clinical syndrome in which the heart is unable to pump oxygenated blood sufficiently to meet metabolic demands during exercise or at rest . It is aA key challenge is to improve quality of life and long-term adherence to self-care behaviors for patients with CHF without overtaxing health care resources. In the absence of intervention, adherence to self-care is problematic with regard to medications (50%-96%), physical activity (9%-53%), dietary restriction of sodium 20%-71%), and daily monitoring of weight 20%-80%)  is  is .kg-1 to 1.4) . With al to 1.4)  and in o to 1.4) . When co to 1.4)  and 21% Our team will recruit subjects from CHF clinics in tertiary care hospitals where we hold senior positions. It is feasible to recruit 278 subjects across 3 sites: (1) Vancouver , (2) Toronto (UHN), and (3) Montreal –Years 1 and 2=248 subjects/3 hospitals/2 years=41 subjects per hospital, per year. Additionally, 30 subjects  will be recruited in the first quarter of Year 3. The research clerk at the Behavioral Cardiology Research Unit, UHN, Toronto will perform coordination and monitoring of recruitment.P<.05, 2-sided. Data missing at random will be handled by multiple imputations. For continuous secondary outcomes, linear mixed models (LMM) [2 peak, NT-proBNP, hsCRP, and the SHFM.This trial will use a 2 parallel-group design with 3 repeated assessments at baseline, 4-, and 12-months. A generalized mixed model (GMM) will evaluate the primary outcome, which is a binary code of whether the 12-month KCCQ  increasels (LMM)  for repeSubanalyses will explore whether therapeutic changes in primary or secondary outcomes following e-Counseling differ significantly within subgroups–sex, age, and income level. We will use GMM to evaluate the dose-response relationship between e-Counseling and improvement in our primary outcome; and LMM to evaluate this dose-response relationship for prognostic measures of CHF at the 12-month outcome using a ratio of adherence to treatment (number of emails sent/number of emails opened).Three committees will be established for quality control and quality assurance purposes. The Steering Committee will hold teleconference meetings every 3 months to review trial progress, overall outcome rates, issues related to evaluation of primary or secondary outcomes, and response of research staff to any adverse incidents. This group will recommend whether our trial should continue without protocol modification, with modification, or whether it should be terminated. The Outcome Adjudication Committee will meet every 6 months by teleconference to adjudicate issues related to primary outcome status of subjects. The Safety and Monitoring Committee will meet annually with the option of expedited meetings in the event of an urgent issue or unexpected “serious adverse event.”It is critical for preventive eHealth care in Canada to establish a foundation upon which a pan-Canadian e-platform can be built for patients with CHF in order to improve the quality of life and adherence to self-care behaviors. It is reasonable to expect that CHF-CePPORT will provide data that is indispensible in helping investigators in Canada to develop a compelling Phase 3 trial where the independent benefit of e-Counseling for CHF can be evaluated with regard to decreasing HF hospitalizations and mortality-as has been shown for telehealth ,70,95.Findings from CHF-CePPORT will also help guide the development of CHF e-Counseling services provided by the Heart and Stroke Foundation of Canada. Their Consumer eHealth platform offers visibility and accessibility for disseminating information and resources developed by CHF-CePPORT through its website. In 2011, this e-platform accommodated 395,044 users who searched for heart health information, while 160,600 users completed structured risk assessments. Second, our results will be submitted for presentation at national meetings and peer-reviewed publications. Third, the Heart and Stroke Clinical Update is an annual continuing medical education conference hosted by the Heart and Stroke Foundation of Canada for primary care physicians. Pending the results of this study, there is interest to develop a workshop for Canadian physicians and health professionals on the use of our e-platform to promote self-care in patients with CHF. As results become available, our team will develop a knowledge translation supplement grant.The proposed e-platform in CHF-CePPORT is designed to complement (rather than compete with) e-programs that are housed in collaborating institutions. Following our trial, our aim is to build supplementary e-links to specialized programs in participating CHF clinics within Canada. At the same time, we expect that the e-platform in CHF-CePPORT will evolve as an e-Counseling resource for CHF clinics through collaborations with other investigators. To that end, members of our research team are affiliated with societies that are engaged in knowledge dissemination and application. These affiliations will permit direct dissemination of study outcomes to key opinion leaders and facilitate uptake of new knowledge to a broader audience.


Hyperglycemia represents an independent prognostic factor in critically ill non-diabetic patients but not in those with diabetes. In this context, there is an ongoing debate on the benefit of an intensive insulin therapy, particularly in diabetic patients. We tested the hypothesis that expression of the receptor for advanced glycation end-products (RAGE), an important signal transduction receptor that elicits long-lasting nuclear factor kappa B (NF-κB) activation, may underlie this difference. RAGE expression is regulated by multiple ligands, including high mobility group box-1 (HMGB-1), and is reflected by its released soluble form (sRAGE).A predesigned analysis was conducted of prospectively collected samples from 76 hyperglycemic critically ill patients  aged ≥18 years with blood glucose of > 6.1 mmol/L enrolled in a randomized controlled trial comparing intensive insulin therapy with conventional insulin therapy. sRAGE and its ligand HMGB-1 together with IL-6, and soluble thrombomodulin  were evaluated in ICU, at Days 1, 3, 5 and 7. Plasma samples from 18 healthy subjects were used as controls.Both diabetic and non-diabetic hyperglycemic patients showed increased plasma sRAGE, HMGB-1 and soluble thrombomodulin levels at the time of admission to ICU. Plasma IL-6 concentration was only increased in non-diabetic patients. Plasma levels of sRAGE were higher in diabetic compared with non-diabetic patients. Intensive insulin therapy resulted in a significant decrease of sRAGE and thrombomodulin at Day 7, in diabetic but not in non-diabetic patients. Circulating sRAGE levels correlated positively with IL-6 and soluble thrombomodulin levels and inversely with HMGB-1. Multivariate regression analysis demonstrated that sRAGE remains independently correlated with HMGB-1 only in diabetic patients. Neither sRAGE nor any inflammatory markers are associated with mortality.These findings support the hypothesis that sRAGE release, time-course and response to intensive insulin therapy differ between hyperglycemic diabetic and non-diabetic critically ill patients. Whether this difference underlies the dissimilarity in clinical outcome of hyperglycemia in these two conditions warrants further studies. Hyperglycemia represents an important independent risk factor for morbidity and mortality in critically ill patients admitted to ICU ,2. AccorHyperglycemia in the presence of oxidant stress promotes glycoxidation of intra- and extracellular proteins and an accumulation of advanced glycation end-products (AGE) . EngagemRAGE is activated by a large number of ligands including AGE, amyloid β-peptides, S-100 proteins and HMGB-1 . PreventRAGE has several soluble receptor isoforms resulting from alternative splicing of the full length mRNA or proteolysis of the cell-surface receptor ,21. An iThe present investigation included 76 hyperglycemic critically ill  consecutive patients who stayed at least three days in the ICU. Diagnosis of diabetes was based on the history as established by the patient primary team prior to hospital admission. The study population was part of a randomized controlled study that evaluated the effects of IIT versus CIT on the outcome of 523 critically ill patients. Informed consent was obtained from all patients included in the study before randomization. Insulin therapy was titrated to maintain blood glucose concentrations between 4.4 and 6.1 mmol/L in the IIT group and 10 and 11.1 mmol/L in the CIT group [Blood samples were collected in EDTA-treated tubes on the day of admission to ICU, then on Days 3, 5 and 7. The samples were immediately centrifuged at 4°C for 20 minutes at 1,600 g. Plasma samples were stored at -80°C until assayed.Plasma concentrations of sRAGE, HMGB-1, thrombomodulin and IL-6 were measured in accordance with the manufacturers' instructions using commercial ELISA kits from R&D Systems ), Diagnostica Stago ) and Shino-test Corporation ). Eighteen plasma samples from healthy individuals were included in the sRAGE, HMGB-1, thrombomodulin and IL-6 assays.P < 0.05. The statistical analysis of data was done by using the statistical software package SAS version 9.1.3 .Descriptive variables are given as the mean ± SE. Skewed data are presented as median and interquartile ranges (IQR 25th to 75th percentile). Comparisons were performed using Wilcoxon and Kruskal-Wallis tests. The mixed linear model was used to compare the groups over time. Pearson correlation coefficients were used to determine the degree of the linear relationship between the continuous variables. Linear and logistic regression analyses were performed to determine the associations between outcome, inflammatory markers and clinical and biochemical variables. A multivariate linear regression model was used to test the interaction between renal function assessed by the calculated creatinine clearance and diabetes on plasma sRAGE levels. Differences were considered significant at Table On the day of admission to ICU, plasma sRAGE, HMGB-1 and thrombomodulin levels are significantly higher in all critically ill patients with or without diabetes as compared with healthy control subjects  and (61 (27 to 124) vs. 159 (59 to 224 pg/ml); P = 0.02), respectively. No differences in HMGB-1 and soluble thrombomodulin is found between these two groups of patients. Plasma sRAGE levels correlate positively with plasma IL-6 and soluble thrombomodulin levels and inversely with those of HMGB-1  and thrombomodulin (61 (35 to 81) vs. 104 ng/ml, P = 0.03) at day 7 post-admission, while creatinine clearance did not significantly change over time , the plasma levels of sRAGE, HMGB-1, thrombomodulin and IL-6 are similar between IIT and CIT in diabetic and non-diabetic patients Figure . CompareP = 0.08).Multivariate regression analysis demonstrates that sRAGE remains independently correlated with HMGB-1 only in diabetic patients Table . NeitherUni- and multivariate logistic regression analyses demonstrate that hyperglycemia is an independent predictor of mortality in non-diabetic patients but not in patients with diabetes. Neither sRAGE nor any inflammatory markers are associated with mortality Table . HoweverFindings from this study reveal that on admission to ICU, critically ill patients with hyperglycemia display elevated circulating levels of sRAGE, HMGB-1 and soluble thrombomodulin. Circulating plasma IL-6 levels were increased only in non-diabetic patients. This suggest that sRAGE is a component of the host's systemic inflammatory response to hyperglycemic critical illness.More important, the results show that diabetic and non-diabetic patients display distinct sRAGE release and time course pattern to acute illness as well as response to IIT. The plasma sRAGE concentration is significantly higher in diabetic patients than in those without diabetes. Administration of IIT attenuates significantly the levels of sRAGE at ICU day 7 only in diabetic patients. These findings suggest albeit indirectly that RAGE pathway activation and response to IIT differ between hyperglycemic diabetic and non-diabetic critically ill patients. Whether this accounts for the difference in clinical course and outcome observed between these two conditions could not be ascertained because of the discrepancy in baseline characteristics between the two study groups. Nonetheless, the findings warrant further investigations because of their potential clinical and therapeutic implications. Indeed, if different mechanistic pathways of inflammation are at play in hyperglycemic diabetic and non-diabetic critically ill patients, the use of a uniform therapeutic approach for all patients may not be physiologically sound.RAGE is a pattern recognition receptor that has been shown to contribute to both initiation and perpetuation of inflammation in experimental sepsis ,12,14,16Several studies have examined the association between sRAGE levels and renal function, and revealed that sRAGE is independently associated with decreased glomerular filtration rate -29, althPrevious study demonstrated that IIT protects the endothelium of critically ill patients by down-regulating iNOS gene expression; however, diabetic and non-diabetic patients were not segregated . Indeed,Some limitations of this study merit consideration. First, the 76 patients studied comprise a small subgroup from a total sample of 523 in the medial-surgical ICU. Considering the inclusion and exclusion criteria of the RCT, the results may not be extended to all hyperglycemic critically ill patients whether they are diabetic or not. Second, the immunoassay used in this study discriminates neither the RAGE that results from cleavage of the cell-surface receptor nor the different sRAGE splice variants . Indeed,Despite the limitations, the current study has revealed that sRAGE release, time-course and response to IIT differ between hyperglycemic diabetic and non-diabetic critically ill patients. Whether this difference underlies in part the dissimilarity in the immune response and outcome to critical illness in these two conditions warrants further studies.• Both diabetic and non-diabetic hyperglycemic patients display increased plasma sRAGE, HMGB-1 and soluble thrombomodulin levels at the time of ICU admission• Plasma levels of sRAGE are higher in critically ill diabetic patients compared with hyperglycemic non-diabetic patients• Intensive insulin therapy significantly decreases plasma sRAGE and soluble thrombomodulin in diabetic patients, but not in those without diabetes• RAGE pathway activation and response to IIT differ between hyperglycemic diabetic and non-diabetic critically ill patientsAGE: advanced glycation end-products; APACHE II: Acute Physiology and Chronic Health Evaluation; BMI: body mass index; CIT: conventional insulin therapy; EDTA: ethylene diamine tetra acetic acid; HMGB-1: high mobility group box-1; IIT: intensive insulin therapy; IL-6: interleukin-6; iNOS: inducible form of nitric oxide synthase; IQR: interquartile range; LOS: length of stay; LPS: lipopolysaccharide; mRNA: messenger RNA; NF-κB: nuclear factor kappa B; RAGE: receptor for advanced glycation end-products; RCT: randomized controlled trial; SAS: Statistical Analysis System; SOFA: Sequential Organ Failure Assessment; TNF: tumor necrosis factor.The authors declare that they have no competing interests.The PI (YMA) had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. YMA, AHR and AB were responsible for the conception and design. YMA, AHR, EB, SHK, RJB and BN took part in the acquisition of data. EB, SHK, RJB and BN were involved in blood sample collection. AB, EB, SHK, RJB and BN were involved in laboratory work. YMA, MD and AB were responsible for analysis and interpretation of data. YMA, MD and AB were responsible for drafting the manuscript. YMA, AHR, EB and AB were in charge for the critical revision of the manuscript. YMA, MD and AB were responsible for statistical analysis. YMA, AHR and AB were in charge for the general supervision.


Profound alterations in immune responses associated with uremia and exacerbated by dialysis increase the risk of active tuberculosis (TB). Evidence of the long-term risk and outcome of active TB after acute kidney injury (AKI) is limited.This population-based-cohort study used claim records retrieved from the Taiwan National Health Insurance database. We retrieved records of all hospitalized patients, more than 18 years, who underwent dialysis for acute kidney injury (AKI) during 1999–2008 and validated using the NSARF data. Time-dependent Cox proportional hazards model to adjust for the ongoing effect of end-stage renal disease (ESRD) was conducted to predict long-term de novo active TB after discharge from index hospitalization.p<0.001) and did not  recover from AKI requiring dialysis had significantly higher incidence of TB than patients without AKI. The external validated data also showed nonrecovery subgroup  had high risk of developing active TB compared with non-AKI. Additionally, active TB was associated with long-term all-cause mortality after AKI requiring dialysis .Out of 2,909 AKI dialysis patients surviving 90 days after index discharge, 686 did not require dialysis after hospital discharge. The control group included 11,636 hospital patients without AKI, dialysis, or history of TB. The relative risk of active TB in AKI dialysis patients, relative to the general population, after a mean follow-up period of 3.6 years was 7.71. Patients who did (hazard ratio [HR], 3.84; AKI requiring dialysis seems to independently increase the long-term risk of active TB, even among those who weaned from dialysis at discharge. These results raise concerns that the increasing global burden of AKI will in turn increase the incidence of active TB. Tuberculosis (TB) accounts for a significant proportion of all deaths caused by infectious diseases. Controlling TB is a major public health issue, especially in developing countries. The relative risk (RR) of developing active TB is 10–25times for patients with chronic kidney disease (CKD) or those on hemodialysis, and 37times for renal transplant recipients than general population Profound alterations in immune responses associated with uremia and exacerbated by dialysis increase the risk of active TB The current study used a population-based and record-based case-control design to evaluate the association between AKI requiring dialysis and long-term risk of active TB using the National Health Insurance Research Database of Taiwan.The Taiwan National Health Insurance (NHI) database is a nationwide insurance program covering outpatient visits, hospital admissions, prescriptions, intervention procedures, and disease profiles for over 99% of the population in Taiwan (23.12 million in 2009) In cooperation with the Bureau of NHI, the NHRI of Taiwan used a systematic, random sampling method to build a representative database of 1,000,000 NHI enrollees Because the identification numbers of all subjects in the NHRI databases were encrypted to protect the privacy of the individuals, this study was exempted from full review by the Institution Review Board of the National Taiwan University Hospital and informed consents were waived.th revision, Clinical Modification (ICD-9-CM) and procedure codes (including Taiwan Classification of Procedures). We excluded patients requiring prolonged hospitalization and those who underwent kidney transplantation. All patients, aged >18 years, and who had a first-time admission diagnosis of AKI requiring dialysis were identified. Those who survived for >90 days after discharge without re-hospitalization  were selected for further analysis. Patients were analyzed from January 2000 through December 2008 to confirm that there was no diagnosis of AKI, dialysis, or TB within 1 year prior to index admission. Comorbidities were defined according to the International Classification of Disease, 9Patients in the AKI–dialysis group were further divided into 2 sub-groups, based on whether they continued dialysis (recovery and nonrecovery sub-groups). As in our previously report Charlson comorbidity index scores were based on pre-existing conditions identified from a patient's medical records Demographic and clinical characteristics of study subjects and hospitals at index hospital admission were examined, including age, sex, year of admission, and prevalence of selected comorbidities. Data representing the hospitalization period included diagnosis codes; the categories of major operations; resource use, including hemodialysis; mechanical ventilation (MV); intensive care unit (ICU) admission; and outcomes. To determine pre-existing comorbidities, we used a relatively strict criterion: at least 1 admission or at least 3 outpatient visits for treatment of a certain disease during the year prior to the index admission.The government of Taiwan monitors active TB, and anti-TB drugs are controlled by a central government health institute. Doctors must report every new case to the Taiwan center of disease control (CDC) within 1 week after the commencement of TB treatment. We defined active TB as an ICD-9 code in the range 010–018 on at least 3 ambulatory visits or admission, and insurance claims for at least 2 TB drugs  for more than 90 days, because it takes 2 months to obtain a TB culture report in clinical practice The main outcome of developing long-term active TB and selection criteria for identifying patients with AKI-dialysis were validated by analysis of another prospectively collected data of the National Taiwan University Hospital Study Group on Acute Renal Failure (NSARF) p values<0.05 were considered statistically significant. Analyses with Cox proportional hazards regression model and propensity score model were conducted separately within each stratum to evaluate the risk of the outcomes after adjustments for all variables. For outcomes measurements, an individual was censored at active TB identification or at the end of the measurement period.Continuous variables were reported as mean ± standard deviations; discrete variables were presented as counts or percentages. All data were analyzed using R software, version 2.14.1 . Two-sided Due to the strong correlation between ESRD and TB, we used a Cox proportional hazards model with time-dependent covariates to evaluate the impact of ESRD on the risk of active TB In specificity testing, we constructed a propensity score using a non-parsimonious multi-variable logistic regression model in an attempt to make an unbiased estimate of the confounders predicting dialysis during index admission, a binary dependent variable, under a set of covariates , more than 18 years of age, who had a first-time diagnosis of AKI requiring dialysis and who survived for >90 days after index discharge . Each AKI–dialysis patient was matched to 4 hospital patients without AKI or dialysis, for a control group of 1,1636 patients  Table 1.p<0.001) (p<0.001).During a mean follow-up period of 3.6 years, a significantly greater proportion of AKI patients developed end-stage renal disease (ESRD), compared to the non-AKI group  Table 1.p<0.001) for the nonrecovery sub-group and 3.84  for the recovery sub-group. Other risk factors predicting the development of active TB were age >45 years , male sex , and chronic obstructive pulmonary disease . This model had good validity (C-index = 0.79). However, ESRD after AKI, the time-dependent explanatory variable, was not associated with development of active TB according to our Cox proportional hazards model . Additionally, in the AKI–dialysis group, active TB was associated with increased all-cause mortality .The incidence of TB was 590, 650, and 83 per 100,000 person-years in the recovery sub-group, nonrecovery sub-group, and non-AKI group, respectively. The risk of TB infection in AKI–dialysis patients relative to the general population was 7.71. The hazard ratio for developing active TB, relative to non-AKI patients, was 6.39 . AKI-recovery groups had higher ratio of TB than non-AKI group in spite of subsequent CKD.Sensitivity analysis was consistent with our main finding that the AKI–dialysis group had a higher incidence of active TB than the non-AKI group Fig. 3. We validated our main findings using prospective critical care data from the multi-centers , NSARF, to guide us in conducting more broad-based research on AKI from nationally representative sources. Among 234 AKI-dialysis patients survival to discharge, 180 (76.9%) recovered from dialysis within 90 days after discharge from index admission. In the NSARF cohort, 8788 patients without AKI and survival to 90 days after hospital discharge were enrolled as controls. There were 70 (0.8%), 5 (2.8%) and 2 (3.7%) in non-AKI, recovery and non-recovery groups respectively had active TB after a mean follow-up of 3.3 years. (1.01–5.13 years). Consistent with our previous findings, the results obtained using the Cox proportional hazard model showed that recovery group  and nonrecovery subgroup  had high risk of developing long-term active tuberculosis compared with non-AKI.inR2 = 0.819; Hosmer–Lemeshow goodness-of-fit [GOF] test, p<0.001).The risk factors predicting dialysis during index hospitalization were components of propensity scores and are listed in Table S1 To restore the interval validity of subsequent group comparisons and reduce the influence of observations on the overall results, we weight-trimmed 888 patients by estimated propensity scores. After careful matching, there were 526 patients in the recovery sub-group, 1,935 in the nonrecovery sub-group, and 11.196 in the non-AKI group.p<0.001) (C-index = 0.79) . After adjustment according to weight-trimmed propensity scores, patients in the nonrecovery sub-group had a greater long-term risk of active TB   for active TB, independent of possible confounders. These findings are noteworthy from the perspective of a clinician providing long-term care to an individual with AKI requiring dialysis. Our study is the first to elucidate nationwide epidemiological characteristics of de novo AKI requiring dialysis in hospitalized patients and to compare the long-term risk of active TB among those continuing and not continuing dialysis and those without AKI or dialysis. The result is true in our native critical cohort; that is, patients survival from dialysis -requiring AKI, even recovery from dialysis, had higher risk of developing active TB than patients without AKI or dialysis.Taiwan has an intermediate burden of TB. The annual incidence of TB in Taiwanese dialysis patients was 490 per 100,000 in 1997, which was 6.9 times greater than that of the general population The kidneys are uniquely positioned to serve as immunomodulatory organs 26 While the time-dependent ESRD episode after AKI was neither related to long-term TB disease, the strong impacts of AKI-dialysis attenuated other's impacts on incident TB, ex. DM, ESRD.In a large cohort study of the risk of active TB, the hazard ratio for patients with chronic obstructive pulmonary disease (COPD) was 3 times greater than that of the general population TB patients with greater frailty were expected to have higher mortality and higher adjusted HRs for death, compared with non-TB patients, especially patients who recovered from AKI requiring dialysis. This phenomenon underlines the importance of evaluating the inherent frailty of research study subjects when comparing outcomes in patients with and without TB. Nonetheless, in all scenarios, patients who recovered from AKI still fared more poorly than patients without AKI or dialysis. Further studies are needed to disentangle the underlying factors contributing to this finding.Major strengths of our study are the large sample and the nature of the cohort, which was based on the general population. AKI–dialysis cases in this study were presumably more severe by reason of the stringent definition that was set to avoid miss-classification of patients. Because of the retrospective nature of the claims data, the standard procedure for diagnosing TB infection, for example, acid-fast staining and culturing, was not identified. Additionally, some data had to be inferred indirectly from administrative records, including smoking status and nutritional status, because they were not available from the National Health Research Institute (NHRI). Nonetheless, we do the external data validation using the well designed, prospective collecting, native critical data, and the results were consisted with the finding from nationwide data. Some future perspectives in AKI research are highlighted with respect to novel therapeutic strategies in the prevention and control of TB.Our findings suggest that the occurrence of TB could be associated with AKI episode. New AKI therapeutic and caring strategies are needed for improved outcomes in AKI patients, targeting not only renal dysfunction alone, but also long-term frailty, which is expected to be associated with greater risk of active TB. Accordingly, the high incidence of TB after recovery from AKI requiring dialysis will correspond to high mortality. Our results raise concerns that the increasing global burden of AKI will include increased incidence of active TB.File S1Table S1. Demographics and comorbidities added into a non-parsimonious propensity model to predict dialysis during index hospitalization in the AKI-dialysis and non-AKI groups. Table S2. Characteristics of patients in the AKI-dialysis and non-AKI groups at index hospitalization matched by weight trimmed logistic regression estimated propensity scores. Figure S1. Cox proportional hazards model for long-term active TB events, stratified by AKI–dialysis status at index hospitalization and adjusted by weight-trimmed logistic regression estimated propensity scores.(DOC)Click here for additional data file.