Phase 1 Safety and Tolerability Study of BMP-7 in Symptomatic Knee Osteoarthritis

BACKGROUND: There are no proven therapies that modify the structural changes associated with osteoarthritis (OA). Preclinical data suggests that intra-articular recombinant human BMP-7 (bone morphogenetic protein-7) has reparative effects on cartilage, as well as on symptoms of joint pain. The objective of this study was to determine the safety and tolerability as well as dose-limiting toxicity and maximal tolerated dose of intra-articular BMP-7. The secondary objectives were to determine the effect on symptomatic responses through 24 weeks. METHODS: This was a Phase 1, double-blind, randomized, multi-center, placebo-controlled, single-dose escalation safety study consisting of 4 dosing cohorts in participants with knee OA. Each cohort was to consist of 8 treated participants, with treatment allocation in a 3:1 active (intra-articular BMP-7) to placebo ratio. Eligible participants were persons with symptomatic radiographic knee OA over the age of 40. The primary objective of this study was to determine the safety and tolerability of BMP-7 including laboratory assessments, immunogenicity data and radiographic assessments. Secondary objectives were to determine the proportion of participants with a 20%, 50%, and 70% improvement in the WOMAC pain and function subscales at 4, 8, 12, and 24 weeks. Other secondary outcomes included the change from baseline to 4, 8, 12, and 24 weeks for the OARSI responder criteria. RESULTS: The mean age of participants was 60 years and 73% were female. All 33 participants who were enrolled completed the study and most adverse events were mild or moderate and were similar in placebo and BMP-7 groups. The 1 mg BMP-7 group showed a higher frequency of injection site pain and there was no ectopic bone formation seen on plain x-rays. By week 12, most participants in both the BMP-7 and placebo groups experienced a 20% improvement in pain and overall the BMP-7 group was similar to placebo with regard to this measurement. In the participants who received 0.1 mg and 0.3 mg BMP-7, there was a trend toward greater symptomatic improvement than placebo. The other secondary endpoints showed similar trends including the OARSI responder criteria for which the BMP-7 groups had more responders than placebo. CONCLUSIONS: There was no dose limiting toxicity identified in this study. The suggestion of a symptom response, together with the lack of dose limiting toxicity provide further support for the continued development of this product for the treatment of osteoarthritis.ARC Future Fellowship; Stryker Biotec

Patient characteristics but not virulence factors discriminate between asymptomatic and symptomatic E. coli bacteriuria in the hospital

Abstract Background Escherichia coli is a common cause of asymptomatic and symptomatic bacteriuria in hospitalized patients. Asymptomatic bacteriuria (ASB) is frequently treated with antibiotics without a clear indication. Our goal was to determine patient and pathogen factors suggestive of ASB. Methods We conducted a 12-month prospective cohort study of adult inpatients with E. coli bacteriuria seen at a tertiary care hospital in St. Louis, Missouri, USA. Urine cultures were taken at the discretion of treating physicians. Bacterial isolates were tested for 14 putative virulence genes using high-throughput dot-blot hybridization. Results The median age of the 287 study patients was 65 (19–101) years; 78% were female. Seventy percent had community-acquired bacteriuria. One-hundred ten (38.3%) patients had ASB and 177 (61.7%) had symptomatic urinary tract infection (sUTI). Asymptomatic patients were more likely than symptomatic patients to have congestive heart failure (p = 0.03), a history of myocardial infarction (p = 0.01), chronic pulmonary disease (p = 0.045), peripheral vascular disease (p = 0.04), and dementia (p = 0.03). Patients with sUTI were more likely to be neutropenic at the time of bacteriuria (p = 0.046). Chronic pulmonary disease [OR 2.1 (95% CI 1.04, 4.1)] and dementia [OR 2.4 (95% CI 1.02, 5.8)] were independent predictors for asymptomatic bacteriuria. Absence of pyuria was not predictive of ASB. None of the individual virulence genes tested were associated with ASB nor was the total number of genes. Conclusions Asymptomatic E. coli bacteriuria in hospitalized patients was frequent and more common in patients with dementia and chronic pulmonary disease. Bacterial virulence factors could not discriminate symptomatic from asymptomatic bacteriurias. Asymptomatic E. coli bacteriuria cannot be predicted by virulence screening.http://deepblue.lib.umich.edu/bitstream/2027.42/112675/1/12879_2013_Article_2423.pd

The Daily Association Between Affect and Alcohol Use: A Meta-Analysis of Individual Participant Data

Influential psychological theories hypothesize that people consume alcohol in response to the experience of both negative and positive emotions. Despite two decades of daily diary and ecological momentary assessment research, it remains unclear whether people consume more alcohol on days they experience higher negative and positive affect in everyday life. In this preregistered meta-analysis, we synthesized the evidence for these daily associations between affect and alcohol use. We included individual participant data from 69 studies (N = 12,394), which used daily and momentary surveys to assess affect and the number of alcoholic drinks consumed. Results indicate that people are not more likely to drink on days they experience high negative affect, but are more likely to drink and drink heavily on days high in positive affect. People self-reporting a motivational tendency to drink-to-cope and drink-to-enhance consumed more alcohol, but not on days they experienced higher negative and positive affect. Results were robust across different operationalizations of affect, study designs, study populations, and individual characteristics. These findings challenge the long-held belief that people drink more alcohol following increases in negative affect. Integrating these findings under different theoretical models and limitations of this field of research, we collectively propose an agenda for future research to explore open questions surrounding affect and alcohol use

The risk of developing a second cancer after receiving craniospinal proton irradiation

The purpose of this work was to compare the risk of developing a second cancer after craniospinal irradiation using photon versus proton radiotherapy by means of simulation studies designed to account for the effects of neutron exposures. Craniospinal irradiation of a male phantom was calculated for passively-scattered and scanned-beam proton treatment units. Organ doses were estimated from treatment plans; for the proton treatments, the amount of stray radiation was calculated separately using the Monte Carlo method. The organ doses were converted to risk of cancer incidence using a standard formalism developed for radiation protection purposes. The total lifetime risk of second cancer due exclusively to stray radiation was 1.5% for the passively scattered treatment versus 0.8% for the scanned proton beam treatment. Taking into account the therapeutic and stray radiation fields, the risk of second cancer from intensity-modulated radiation therapy and conventional radiotherapy photon treatments were 7 and 12 times higher than the risk associated with scanned-beam proton therapy, respectively, and 6 and 11 times higher than with passively scattered proton therapy, respectively. Simulations revealed that both passively scattered and scanned-beam proton therapies confer significantly lower risks of second cancers than 6 MV conventional and intensity-modulated photon therapies. © 2009 Institute of Physics and Engineering in Medicine

Transcranial, noninvasive evaluation of the potential misery perfusion during hyperventilation therapy of traumatic brain injury patients

Hyperventilation (HV) therapy uses vasoconstriction to reduce intracranial pressure (ICP) by reducing cerebral blood volume. However, as HV also lowers cerebral blood flow (CBF), it may provoke misery perfusion (MP) where the decrease in CBF is coupled with increased oxygen extraction fraction (OEF). MP may rapidly lead to the exhaustion of brain energy metabolites, making it vulnerable to ischemia. MP is difficult to detect at the bedside, which is where transcranial hybrid, near-infrared spectroscopies are promising since they noninvasively measure OEF and CBF.Peer ReviewedPostprint (author's final draft

Catheter removal versus retention in the management of catheter-associated enterococcal bloodstream infections

It is unclear whether CVC removal is necessary to successfully manage enterococcal CA-BSI. MEthoDs: A 12-month retrospective cohort study of adults with enterococcal CA-BSI was conducted at a tertiary care hospital; clinical, microbiological and outcome data were collected. rEsuLts: A total of 111 patients had an enterococcal CA-BSI. [37.9]; P=0.03), but similar rates of recurrent bacteremia (nine [11.0%] versus two (7.0%); P=0.7) and a similar post-BSI length of hospital stay (median days [range]) (11.1 [1.7 to 63.1 days] versus 9.3 [1.9 to 31.8 days]; P=0.3). Catheter retention was an independent predictor of mortality (OR 3.34 [95% CI 1.21 to 9.26]). ConCLusIons: To the authors' knowledge, the present article describes the largest enterococcal CA-BSI series to date. Mortality was increased among patients who had their catheter retained. Additional prospective studies are necessary to determine the optimal management of enterococcal CA-BSI. [37, Catheter removal versus retention in the management of catheter-associated enterococcal bloodstream infections The aim of the present study was to examine the epidemiology, treatment and subsequent outcomes of patients with enterococcal CA-BSI, comparing patients with retained versus removed catheters. Our hypothesis was that catheter management does not affect patient outcomes. MEthoDs setting Barnes-Jewish Hospital (BJH), a 1250-bed teaching hospital, is the largest hospital in Missouri (USA), and has a referral base that includes the St Louis Metropolitan area, eastern Missouri and western Illinois. It houses all medical specialties, including a stem cell transplantation unit. BJH is affiliated with the Washington University School of Medicine (St Louis, Missiouri, USA). study design A retrospective cohort study of patients with enterococcal CA-BSIs during their hospital stay was performed. CA-BSI was defined as enterococcal bacteremia in a patient with a central venous catheter (CVC) in place for at least 48 h and no alternative source of infection. The hospital's medical informatics database was queried for blood cultures positive for any Enterococcus species; this dataset was merged with a manually collected dataset of CVC usage in the hospital, which is part of the hospital infection control database. Inclusion and exclusion criteria Adult patients admitted to BJH between January 1, 2006 and December 31, 2006, who presented with, or developed, an enterococcal bloodstream infection and had a CVC present at the time of detection of this infection were included. All types and locations of CVCs were included. Blood cultures were obtained during routine care either peripherally and/or from the CVC. Patients who presented to the hospital with a CVC already in place were included. Patient history and physical examination as well as admitting diagnosis and microbiology results were reviewed to determine whether the catheter was the primary focus of the bacteremia. Patients with a primary focus of bacteremia other than the catheter, patients with a CVC in place for <48 h, and patients who died on the day of the positive blood culture were excluded. Polymicrobial infections were included except concurrent Staphylococcus aureus bacteremia or candidemia within ±3 days of the enterococcal bacteremia (n=20) because both entities are established indications for catheter removal. Data collection Demographic characteristics, medical history, clinical presentation, diagnostic and therapeutic procedures, antibiotic treatment and key markers of outcome (recurrence of bloodstream infection, length of hospital stay after the bloodstream infection, crude mortality) were abstracted from the medical records. Admission Charlson comorbidity and McCabe severity of illness scores were determined. Duration of catheter retention time after the bacteremia was recorded. Information on antibiotic lock therapy was collected; however, this treatment modality was not used in patients from this cohort. Postdischarge mortality at both 30 days and three months after bacteremia was obtained from the Social Security Death Index (www. ssdi-search.com). Definitions Renal insufficiency was defined by a serum creatinine level >132.6 μmol/L. Sepsis and sepsis-induced hypotension were defined using established criteria (13). Appropriate therapy was defined as pathogen-directed treatment with antibiotics matching susceptibilities. A catheter was considered to be retained if it was present for the duration of the hospitalization after the first positive blood culture. Recurrence of bacteremia (used here synonymously with intermittent bacteremia) was defined as a second positive blood culture after ≥1 negative blood culture and an interval of ≥1 day during their hospitalization. Community-onset enterococcal bloodstream infection was defined as having the first positive blood culture drawn within 48 h of hospital admission. Data analysis and statistical methods Data entry was performed using Access and Excel (Microsoft Corporation, USA). Data analysis was performed using SPSS 17 (IBM Corporation, USA). Univariate comparisons among categorical variables and outcome measures were performed using the χ 2 test or Fisher's exact test. A two-sided P <0.05 was considered to be statistically significant. Also calculated was the absolute difference in proportion (∆ p ) of rates of outcome measures including the 95% CI of this difference to describe the precision of this point estimate. Analysis of the difference in proportions and 95% CI enabled the interpretation of statistical significance (if the 95% CI did not cross zero) as well as clinical significance (if the upper limit of the 95% CI exceeded a predefined difference). An absolute difference in recurrence of bacteremia and mortality rates of 15% was considered to represent a clinically significant difference; this estimate was chosen based on previous literature regarding catheter management and clinical experience (14,15). Comparisons among continuous independent variables were performed using the Student's t test or Mann-Whitney U test as appropriate. Variables found to have P<0.1 in univariate testing were considered for entry into a forward, stepwise multivariate logistic regression model. The study was approved by the Washington University Human Research Protection Office (#07-0690). rEsuLts Demographics, comorbidities and clinical presentation There were 111 patients with enterococcal CA-BSI who met inclusion criteria. The mean (± SD) age was 58.2±15.3 years; 56 (50.5%) patients were male; and 77 (69.4%) were white. There were 36 (32%) patients admitted to the oncology/bone marrow transplant service. The most frequent comorbidities were malignancies (n=62 [55.9%]), diabetes (n=35 [31.5%]) and renal insufficiency (n=31 [27.9%]). Twenty-five (22.5%) patients had metastatic solid tumours, 28 (25.2%) had leukemia, six (5.4%) had lymphomas and three (2.7%) had nonmetastatic solid tumours. There were 20 (18%) patients who were neutropenic at the time of bloodstream infection. Of all bloodstream infections, 90 (81%) were hospital-acquired. None of the patients were diagnosed with infective endocarditis during the admission. Microbiology Of the enterococcal bloodstream infections, 45 (40.5%) were caused by E faecalis and 61 (55.0%) by E faecium. Of the bacteremias caused by E faecalis, 10 (22.2%) were due to vancomycin-resistant isolates while 57 (93.4%) of the bacteremias caused by E faecium were vancomycin resistant. An additional five (4.5%) infections were caused by other Enterococcus species. A total of 37 patients (33.3%) had polymicrobial infections in which the most common polymicrobial organism was coagulase-negative Staphylococcus (n=26 [23.4%]). There were 24 (34.9%) polymicrobial E faecalis bacteremias and 10 (27.0%) polymicrobial E faecium bacteremias. Additionally, there was no difference in polymicrobial bacteremias among patients who had their catheter removed versus retained (28 [34.1%] versus nine [31.0%]; P=0.8). Vancomycin-susceptible E faecalis caused 30 (36.6%) of 82 infections in which catheters were removed during the hospitalization and five (17.2%) of 29 infections in which they were retained (P=0.09). Vancomycin-resistant E faecium (VRE) caused 42 (51.2%) of infections in which catheters were removed and 15 (51.7%) in which they were retained (P=0.9). Overall, there was no difference in the number of vancomycin-resistant isolates regardless of whether a catheter was removed Catheter management The CVC was retained during the hospitalization in 29 (26.1%) patients. In univariate analysis, patients with removed CVCs were similar to patients whose CVC was retained DIsCussIon Removal of an intravascular catheter is, with few exceptions, considered to be an essential part of managing CA-BSI. However, robust data to support this approach are only available for a limited number of pathogens responsible for these infections. Despite the lack of sufficient data to provide an evidence-based recommendation with regard to CA-BSI caused by Enterococcus species, national guidelines recommend removing the involved catheters (9). To our knowledge, the present study represents the largest investigation into catheter management and outcomes of enterococcal bloodstream infections. The main finding of the present study was increased mortality in patients whose catheters were retained during the hospitalization. Our findings suggest that catheter removal should be considered to improve patient survival. Also, the difference in the two outcome proportions exceeded the predetermined clinically meaningful difference of 15%, which gives us a quantitative estimate of the impact of catheter removal. The patient groups were very similar with respect to demographic characteristics and comorbidities, including adjunctive antibiotic treatment with the aminoglycoside gentamicin. These findings are congruent with the single study encountered in the scientific literature that scrutinized outcomes of enterococcal CA-BSI and specifically investigated catheter management, albeit in a smaller number of patients (11). There, the authors retrospectively examined 61 enterococcal CA-BSI, with 82% of the episodes due to E faecalis and polymicrobial infections found in 18% of the study population. Of note, they did not exclude patients with concurrent Staphylococcus aureus or yeast bloodstream infections, although these infections likely guided catheter management significantly more than the detection of enterococci. Sandoe et al (11) evaluated whether successful treatment of a bloodstream infection was possible without removal of the catheter, which was achieved in five of 13 cases (38%). If the catheter was removed, the chance for cure was higher (40 of 48 [83%]). They found a combination of a cell wall-active agent with an aminoglycoside to be significantly more effective than monotherapy when the catheter was retained. The authors concluded that, although the removal of the catheter was performed in the majority of cases, it did not appear to be a necessary part of the management as long as antimicrobial treatment was optimized. In our study, even though we did not set cure as an end point, 67 (81.7%) of 82 patients with catheters removed survived the hospital admission and 61 (74.4%) survived at 30 days postbacteremia. These rates were much lower for patients with retained catheters. In summary, these data suggest that although enterococcal CA-BSI are not an absolute indication for catheter removal, removal should be favoured over catheter retention. Reasons for catheter retention may have been that the treating physicians of patients who were severely ill at the time of enterococcal bloodstream infection were reluctant to remove the catheter because it was essential for nonantibiotic medications; that the patients had limited options for alternative intravenous access; or that their comorbidities increased the risk of catheter removal and replacement. Catheter management may have been driven by reasons other than the infection alone, and removing the catheter could have been a lower priority or higher risk in the patients' overall medical management. Because we collected crude mortality data, it is also conceivable that patients died from causes not related to the CA-BSI. Of note, we did not observe a difference in recurrence of infection depending on catheter management; it is possible that the size of the cohort prevented us from noting a statistically significant difference. Our patients are notable for a high percentage of comorbid conditions, including metastatic solid tumours (23%) and leukemia (25%); accordingly, the crude in-hospital mortality rate was high in our study population. An independent factor associated with death was the detection of VRE in the stool, which may be a marker for frequent health care exposure. Despite this finding, CA-BSIs with vancomycinresistant E faecium did not result in increased mortality compared with non-VRE infections. This is different from an earlier prospective study and a more recent meta-analysis, in which vancomycin resistance was found to be associated with increased mortality Limitations of the present study include its retrospective design, the fact that the diagnosis of recurrent infection depended on the treating physician ordering blood cultures and that postdischarge outcomes, including completion of planned antibiotic therapy, follow-up blood cultures, and catheter removal postdischarge, were not studied. In addition, catheter management is potentially influenced by other reasons for retention (difficulty of finding alternative access, bleeding diathesis) and we did not report outcomes for different catheter types. Finally, changes in the usage of daptomycin and linezolid have occurred since the time of the study. Although this was the largest study of enterococcal CA-BSI to date, it is still a relatively small sample to detect rare outcomes. ConCLusIons Based on our study findings, catheter removal is preferable to retention in patients with enterococcal CA-BSI. A large prospective or multicentre study should be performed to identify patients at highest risk for mortality and to add strength to our results. DECLArAtIons: None of the following authors has a conflict of interest to declare: J Marschall, ML Piccirillo, J Doherty

In vitro test of external Qigong

BACKGROUND: Practitioners of the alternative medical practice 'external Qigong' generally claim the ability to emit or direct "healing energy" to treat patients. We investigated the ability of experienced Qigong practitioners to enhance the healthy growth of cultured human cells in a series of studies, each following a rigorously designed protocol with randomization, blinding and controls for variability. METHODS: Qigong practitioners directed healing intentionality toward normal brain cell cultures in a basic science laboratory. Qigong treatments were delivered for 20 minutes from a minimum distance of 10 centimeters. Cell proliferation was measured by a standard colony-forming efficiency (CFE) assay and a CFE ratio (CFE for treated samples/CFE for sham samples) was the dependent measure for each experiment. RESULTS: During a pilot study (8 experiments), a trend of increased cell proliferation in Qigong-treated samples (CFE Qigong/sham ratios > 1.0) was observed (P = 0.162). In a formal study (28 experiments), a similar trend was observed, with Qigong-treated samples showing on average more colony formation than sham samples (P = 0.036). In a replication study (60 experiments), no significant difference between Qigong-treated samples and sham samples was observed (P = 0.465). CONCLUSION: We observed an apparent increase in the proliferation of cultured cells following external Qigong treatment by practitioners under strictly controlled conditions, but we did not observe this effect in a replication study. These results suggest the need for more controlled and thorough investigation of external Qigong before scientific validation is claimed