Letter to the Editor on: "The Effects of Physical Exercise on Tumor Vasculature: Systematic Review and Meta-Analysis."

Dear Editor,We read with interest the recent article "The Effects of Physical Exercise on Tumor Vasculature: Systematic Review and Meta-analysis" 1 and after careful appraisal and consideration we feel that some aspects of the data and analysis warrant further review. The study reported some promising results, namely that both chronic and acute exercise appear to improve intratumoral vascularisation in animal models. This is an important finding given increased vascularisation through tumor modulation may have the potential to improve chemotherapy delivery and efficacy 2. However, after conducting further investigations, we query several details in the data extraction and analysis decision-making that we believe impact the conclusions of this article.

The effect of exercise on local and systemic adverse reactions after vaccinations - Outcomes of two randomized controlled trials.

INTRODUCTION: An adverse reaction associated with vaccination is considered to be a key barrier to vaccinate, yet little attention has been given to interventions to reduce their occurrence. Exercise is a behavioural adjuvant which may also influence adverse reactions. Here, two randomized controlled trials are reported, examining the effects of exercise on self-reported adverse reactions following vaccination in adolescents and young adults. METHODS: Study one; 116 adolescents receiving the HPV vaccine were randomly allocated to either Control (n = 56) or Pre-vaccine Exercise (n = 60) group (2015-2016). Exercise consisted of 15-minutes upper body exercise. Study two; 78 young adults receiving the influenza vaccine were randomly allocated to either Control (n = 19), or one of 3 exercise groups: Pre-vaccine Arm (n = 19), Pre-vaccine Leg (n = 20) or Post-vaccine Arm (n = 20) (2017). Exercise included 15-minutes of arm or leg exercises prior to or after vaccination. All participants in both studies completed an adverse events diary for seven-days post-vaccination. RESULTS: Study one; Reported days of tenderness in female adolescents that exercised were significantly lower than control (p = 0.032), with a similar trend in reported days of pain (p = 0.050). Furthermore, days of feeling ill (p = 0.070) and reduced appetite (p = 0.067) were found to be lower with exercise, although not significant. Overall, female adolescents reported significantly more days of pain (p = 0.003), tenderness (p < 0.001), swelling (p = 0.011), and feeling ill (p = 0.0040). Study two; Exercise groups reported reduced days of swelling (p = 0.018), fever (p = 0.013), and lowered appetite (p = 0.011) across both genders. Furthermore, females reported reduced days of medication use with exercise (p = 0.034), and a trend toward reduced days of swelling (p = 0.052). DISCUSSION: In two separate trials, a short bout of exercise reduced reported adverse reactions after vaccinations for local and systemic adverse reactions. Gender differences in reported local and systemic adverse reactions were more evident among adolescents than young adults. These findings support the need for further work to examine the potential benefit of exercise in improving vaccination procedures.

The effect of exercise on vaccine-related pain, anxiety and fear during HPV vaccinations in adolescents.

INTRODUCTION: With increased school-based vaccinations for improved coverage rates and practicality, the World Health Organization (WHO) recently endorsed research to identify possible interventions to reduce vaccine-related pain in mass clinical and school-based settings. In particular, the lack of research in adolescents indicate a particular need in this population. Acute exercise has analgesic effects and has been used as a behavioural adjuvant to vaccination. Here, we examine the effect of exercise on vaccine-related pain, anxiety and fear in adolescents, during a school-based program for HPV vaccinations. METHODS: 116 students (Female: 61, Male: 55) aged 11-13 years were randomly allocated to either an Exercise (n = 60) or Control (n = 56) group. All participants completed demographic and Trait-anxiety questionnaires prior to receiving the vaccine according to usual care. The Exercise group also performed upper body exercise for 15 min prior to receiving the vaccine. Immediately after the vaccine administration, all participants reported on pain, anxiety and fear at the time of receiving the vaccine. RESULTS: Female adolescents in the Exercise group reported significantly less pain (3.64; 95% CI, 2.98-4.30) than Controls (4.58; 95% CI, 3.96-5.19; p = 0.04). Further, females reported greater pain and anxiety than males in the Control group but not the Exercise group. CONCLUSION: This study supports the use of exercise prior to vaccine administration, especially in female adolescents who are particularly vulnerable to negative experiences during vaccination procedures. Furthermore, the ease of application, as well as the benefit of exercise, provides support for the use of simple exercise prior to vaccination in mass vaccination settings. Clinical trial registry: ANZCTR, ACTRN12614001185651.

Conveying campus sexual misconduct policy information to college and university students: Results from a 7-campus study.

OBJECTIVE: To examine the efficacy of different methods (ie, in-class policy reading; in-class policy reading and discussion; no reading or discussion) to deliver campus sexual misconduct policy information to students on 7 campuses. PARTICIPANTS: A total of 1,195 participants at 7 colleges and universities participated in the study from August to October 2014. Participants were randomly assigned at the class level and completed pretest and posttest surveys assessing knowledge of campus policy and resources and confidence to seek help for sexual assault. RESULTS: Students exposed to a larger dosage of material (in-class policy reading plus discussion) showed greater positive changes in attitudes and knowledge than students who did not receive information or were only read the policy. However, on some indices, students who were only read the policy showed positive outcomes compared with students receiving no intervention. CONCLUSION: Colleges and universities must use engaging methods to disseminate campus sexual misconduct policies to students.

Influenza vaccination in the organ transplant recipient: review and summary recommendations.

Influenza virus causes a spectrum of illness in transplant recipients with a high rate of lower respiratory disease. Seasonal influenza vaccination is an important public health measure recommended for transplant recipients and their close contacts. Vaccine has been shown to be safe and generally well tolerated in both adult and pediatric transplant recipients. However, responses to vaccine are variable and are dependent on various factors including time from transplantation and specific immunosuppressive medication. Seasonal influenza vaccine has demonstrated safety and no conclusive evidence exists for a link between vaccination and allograft dysfunction. Annually updated trivalent inactivated influenza vaccines have been available and routinely used for several decades, although newer influenza vaccination formulations including high-dose vaccine, adjuvanted vaccine, quadrivalent inactivated vaccine and vaccine by intradermal delivery system are now available or will be available in the near future. Safety and immunogenicity data of these new formulations in transplant recipients requires investigation. In this document, we review the current state of knowledge on influenza vaccines in transplant recipients and make recommendations on the use of vaccine in both adult and pediatric organ transplant recipients.

Effects on blood pressure and autonomic nervous system function of a 12-week exercise or exercise plus DASH-diet intervention in individuals with elevated blood pressure.

AIM: Hypertension is related to abnormalities in autonomic nervous system (ANS) function, with increased sympathetic output and decreased parasympathetic tone. Lifestyle interventions are the first line of treatment in hypertension, and decreased blood pressure (BP) effects may be related to changes in ANS function. Using heart rate recovery (HRR) from exercise as an index of parasympathetic tone and plasma noradrenaline as an index of sympathetic tone, we investigated the effects of lifestyle interventions on ANS function in patients with elevated BP. METHODS: Sedentary participants with elevated BP were randomly assigned to either an exercise only (N = 25), exercise plus dietary approaches to stop hypertension (DASH) diet (N = 12), or waitlist control (N = 15) 12-week intervention. Plasma noradrenaline was measured at rest and participants performed a peak exercise test before and after the intervention. HRR was calculated as peak heart rate (HR) minus HR at 1 min post-exercise. RESULTS: Heart rate recovery showed a significant group by time interaction; both intervention groups showed increases in HRR from pre- to post-intervention, while waitlist showed no change. Similarly, both exercise plus diet and exercise groups, but not waitlist, showed significant reductions in BP from pre- to post-intervention. Linear regression revealed that BP post-intervention was significantly predicted by change in HRR when controlling for pre-BP, age, gender and BMI. CONCLUSIONS: Lifestyle interventions induced training-reduced BP and altered autonomic tone, indexed by HRR. This study indicates the importance of behavioural modification in hypertension and that increased parasympathetic function is associated with success in reduction of BP.

Pertussis antibodies in postpartum women and their newborns.

OBJECTIVE: To (1) determine the proportion of mothers and infants who had levels of IgG antibody to pertussis antigens predicted to be potentially protective at delivery; (2) evaluate the efficiency of maternal-infant antibody transport; (3) extrapolate infant antibody titers at 6 weeks; and (4) identify maternal factors associated with potentially protective infant antibodies. STUDY DESIGN: Sera from mother-infant pairs from February 2006 through to April 2007 were tested for antibody to pertussis antigens by standardized ELISA (enzyme-linked immunosorbent assay). Potentially protective antibody levels were defined as >5 ELISA units (EU) for pertussis toxin (PT), and >10 EU for fimbriae (FIM) and pertactin (PRN). Serological evidence of previous maternal infection was defined from antibody to four antigens by k-means cluster analysis. RESULT: In total, 21% (17/81) of mothers and 26% (21/81) of infants had potentially protective antibody levels at delivery. Mean infant-maternal antibody ratios for PT, FIM and PRN were 1.26, 1.36 and 1.31, respectively. At 6 weeks, 11% (9/81) of infants were predicted to have potentially protective antibody levels. Using cluster analysis, 9% (7/81) of mothers had evidence of previous pertussis infection. Infants born to these mothers were predicted to be more likely to have potentially protective antibodies at 6 weeks (43%) than those born to mothers without previous infection (8%) (P=0.03). CONCLUSION: Approximately 75% of infants were born with pertussis antibody levels lower than the modest levels associated with potential protection. Despite effective antibody transfer, nearly 90% of infants were predicted to have little antibody by 6 weeks. Maternal immunization before or during pregnancy might simulate previous pertussis infection and help protect infants through the first months of life.

International Bordetella pertussis assay standardization and harmonization meeting report. Centers for Disease Control and Prevention, Atlanta, Georgia, United States, 19-20 July 2007.

An international meeting on Bordetella pertussis assay standardization and harmonization was held at the Centers for Disease Control and Prevention (CDC), Atlanta, GA, 19-20 July 2007. The goal of the meeting was to harmonize the immunoassays used for pertussis diagnostics and vaccine evaluation, as agreed upon by academic and government researchers, regulatory authorities, vaccine manufacturers, and the World Health Organization (WHO). The primary objectives were (1) to provide epidemiologic, laboratory, and statistical background for support of global harmonization; (2) to overview the current status of global epidemiology, pathogenesis and immunology of pertussis; (3) to develop a consensus opinion on existing gaps in understanding standardization of pertussis assays used for serodiagnosis and vaccine evaluation; and (4) to search for a multicenter process for addressing these priority gaps. Presentations and discussions by content experts addressed these objectives. A prioritized list of action items to improve standardization and harmonization of pertussis assays was identified during a group discussion at the end of the meeting. The major items included: (1) to identify a group that will organize, prepare, maintain, and distribute proficiency panels and key reagents such as reference and control sera; (2) to encourage the development and identification of one or more reference laboratories that can serve as an anchor and resource for other laboratories; (3) to define a performance-based assay method that can serve as a reference point for evaluating laboratory differences; (4) to develop guidance on quality of other reagents, e.g., pertussis toxin and other antigens, and methods to demonstrate their suitability; (5) to establish an international working group to harmonize the criteria to evaluate the results obtained on reference and proficiency panel sera; (6) to create an inventory to determine the amount of appropriate and well-characterized sera that are available globally to be used as bridging reagents for vaccine licensure; and (7) to seek specific guidance from regulatory authorities regarding the expectations and requirements for the licensure of new multicomponent pertussis vaccines.

Estimating the undetected burden of influenza hospitalizations in children.

During the 2004-2005 influenza season two independent influenza surveillance systems operated simultaneously in three United States counties. The New Vaccine Surveillance Network (NVSN) prospectively enrolled children hospitalized for respiratory symptoms/fever and tested them using culture and RT-PCR. The Emerging Infections Program (EIP) and a similar clinical-laboratory surveillance system identified hospitalized children who had positive influenza tests obtained as part of their usual medical care. Using data from these systems, we applied capture-recapture analyses to estimate the burden of influenza related-hospitalizations in children aged<5 years. During the 2004-2005 influenza season the influenza-related hospitalization rate estimated by capture-recapture analysis was 8.6/10,000 children aged<5 years. When compared to this estimate, the sensitivity of the prospective surveillance system was 69% and the sensitivity of the clinical-laboratory based system was 39%. In the face of limited resources and an increasing need for influenza surveillance, capture-recapture analysis provides better estimates than either system alone.

Predictors of influenza virus vaccination status in hospitalized children.

OBJECTIVE: To determine predictors of influenza virus vaccination status in children who are hospitalized during the influenza season. METHODS: A cross-sectional study was conducted among children who were hospitalized with fever between 6 months and 3 years of age or with respiratory symptoms between 6 months and 18 years of age. The 1999 to 2000 influenza vaccination status of hospitalized children and potential factors that influence decisions to vaccinate were obtained from a questionnaire administered to parents/guardians. RESULTS: Influenza vaccination rates for hospitalized children with and without high-risk medical conditions were 31% and 14%, respectively. For both groups of children, the vaccination status was strongly influenced by recommendations from physicians. More than 70% of children were vaccinated if a physician had recommended the influenza vaccine, whereas only 3% were vaccinated if a physician had not. Lack of awareness that children can receive the influenza vaccine was a commonly cited reason for nonvaccination. CONCLUSIONS: A minority of hospitalized children with high-risk conditions had received the influenza vaccine. However, parents' recalling that a clinician had recommended the vaccine had a positive impact on the vaccination status of children.

In vitro activity of ABT-773, telithromycin and eight other antimicrobials against erythromycin-resistant Streptococcus pneumoniae respiratory isolates of children.

The activity of the ketolide ABT-773 against 180 erythromycin-resistant Streptococcus pneumoniae obtained from children was compared with telithromycin, azithromycin, clarithromyin, roxithromycin, clindamycin, penicillin, levofloxacin and gatifloxacin. Ketolide MICs were all < or =1 mg/l, with ABT-773 being the most potent of all drugs tested. MIC(90)s for macrolides and azithromycin in mefE+ isolates were 16-32 compared with >128 mg/l for ermB+ isolates. ABT-773 and telithromycin MIC(90)s for mefE+ isolates were 0.125 and 0.5, compared with 0.032 and 0.016 mg/l for ermB+ isolates and 0.5 and 1 mg/l, respectively, for isolates containing both genes. Clindamycin was active against mefE+ but not ermB+ isolates. 155 isolates were resistant to penicillin. All fluoroquinolone MICs were < 1 mg/l. Further studies of ketolides for treatment of paediatric S. pneumoniae infections are warranted.

Development, acceptance, and use of immunologic correlates of protection in monitoring the effectiveness of combination vaccines.

The establishment of immunologic correlates of protection for all vaccine antigens is a worthwhile goal. It allows new vaccines to be licensed on the basis of attainment of defined immunologic benchmarks, without the need for large-scale efficacy trials for each new product. This is particularly important for the evaluation of new combination products. Efficacy trials of each new mixture would be unethical because routinely recommended vaccines would be denied children in the control group. The establishment of immunologic correlates of protection should be a defined goal of every efficacy trial. Additional ways to evaluate the immune responses-such as cell-mediated immunity, mucosal immunity, memory responses, and antibody avidity-should also be studied. Finally, ongoing surveillance efforts are also needed, to monitor the impact of new and combined vaccines on disease rates.

Iron-cofactored superoxide dismutase inhibits host responses to Mycobacterium tuberculosis.

Superoxide dismutase (SOD) is a ubiquitous metalloenzyme in aerobic organisms that catalyzes the conversion of superoxide anion to hydrogen peroxide. Mycobacterium tuberculosis is unusual in that it secretes large quantities of iron-cofactored SOD. To determine the role of SOD in pathogenesis, we constructed mutants of M. tuberculosis H37Rv with reduced SOD production. Compared with controls, SOD-diminished isolates were more susceptible to killing by hydrogen peroxide. The isolates were markedly attenuated, exhibiting nearly 100,000-fold fewer bacilli than virulent control strains in the lungs and spleens of C57BL/6 mice 4 wk after intravenous inoculation. In the lung, SOD-attenuated M. tuberculosis induced robust interstitial mononuclear cell infiltration within 24 h and many cells were apoptotic by TUNEL staining, whereas virulent H37Rv exhibited minimal early inflammatory response and only rare interstitial mononuclear cell apoptosis. During prolonged infections, C57BL/6 mice tolerated SOD-attenuated M. tuberculosis better than BCG, exhibiting 68% greater weight gain, quicker eradication of bacilli from the spleen, and less alveolar lung infiltration. These results establish the importance of SOD in the pathogenesis of tuberculosis. Its effect appears to be mediated in part by inhibiting innate host immune responses, including early mononuclear cell infiltration of infected tissues and apoptosis.

Efficacy of inactivated and cold-adapted vaccines against influenza A infection, 1985 to 1990: the pediatric experience.

BACKGROUND: Influenza is a common and potentially serious infection in children. Although there is interest in broadening the use of influenza vaccine in healthy children, there are few large, randomized, controlled trials that evaluate the safety and efficacy of inactivated vaccine in the pediatric population. METHODS: From 1985 through 1990 a randomized, controlled trial of cold-adapted and inactivated vaccines for the prevention of influenza A disease was conducted at Vanderbilt University, and the cumulative results from this trial in patients of all ages have been previously published. We reanalyzed the data from this trial in the subset of patients who were younger than 16 years at the time of their participation. We determined vaccine safety, immunogenicity and efficacy, based on culture-positive illness and seroconversion, in this subset of patients. RESULTS: During the 5 years of the study, 791 children younger than 16 years received 1809 doses of either inactivated or cold-adapted vaccine or placebo. The vaccines were well-tolerated, and there were no serious reactions. Inactivated trivalent influenza vaccines were 91.4 and 77.3% efficacious in preventing symptomatic, culture-positive influenza A H1N1 and H3N2 illness, respectively. The efficacy of the inactivated vaccine based on hemagglutination inhibition assay seroconversion was 67.1 and 65.5%, respectively, for H1N1 and H3N2 serotypes. CONCLUSIONS: Inactivated trivalent influenza A vaccines are well-tolerated and efficacious in the prevention of influenza A disease in children 1 to 16 years old.

Varicella in a pediatric heart transplant population on nonsteroid maintenance immunosuppression.

OBJECTIVE: Varicella-zoster virus has been reported to produce serious, often life-threatening, disease in immunosuppressed patients with a variety of diagnoses. The impact of this virus on the young child after heart transplantation has not been reported. METHODS: We reviewed the charts of 28 children who were <10 years of age at heart transplantation and had at least 1 year of follow-up. The median follow-up period was 7 years (1.4-13.0 years). All were seronegative for varicella-zoster virus before transplantation. Fourteen (50%) developed varicella at a median time posttransplantation of 3.3 years. The first 7 were admitted for intravenous acyclovir for 3 days followed by oral acyclovir for 7 days. The last 7 were treated as outpatients with oral valacyclovir for 7 days (n = 6) or with oral acyclovir for 10 days (n = 1). RESULTS: Intravenous and oral regimens both were well tolerated and were without complications. No patient was receiving steroids at the time that they developed their initial episode of varicella. One patient was receiving steroids for therapy of posttransplantation lymphoproliferative disease when she developed recurrent varicella or generalized zoster. No episodes of rejection were attributed to the varicella-zoster virus infection. There were no episodes of localized zoster. All patients experienced seroconversion from undetectable to detectable antibody titers early after varicella, and 12 of the 14 patients continued to have persistent detectable titers in late follow-up. Two of the 14 who received chemotherapy or enhanced immunosuppression after retransplantation transiently lost detectable varicella-zoster virus antibodies but currently have detectable titers. CONCLUSIONS: Primary varicella-zoster infection was well tolerated in our young pediatric heart transplant recipients, with no serious complications. We now reserve inpatient/intravenous therapy for those who are unable to tolerate oral medications or those who are receiving enhanced immunosuppression.

Fifth vaccination with dipthteria, tetanus and acellular pertussis is beneficial in four- to six-year-olds.

OBJECTIVE: Diphtheria, tetanus and pertussis serum antibody titers were assessed before a fifth dose of diphtheria-tetanus-acellular pertussis (DTaP) or diphtheria-tetanus-whole cell pertussis (DTwP) vaccination at age 4 to 6 years. METHODS: Healthy children who had participated in a series of National Institutes of Health-sponsored trials assessing DTwP and DTaP vaccines provided prevaccination sera before a fifth dose of DTwP or DTaP. The trial design was prospective, randomized and double blind. Diphtheria, tetanus and pertussis antibody titers were measured by enzyme-linked immunosorbent assay. Pertussis results are expressed in enzyme-linked immunosorbent assay units/ml based on US Food and Drug Administration reference sera. Tetanus and diphtheria toxin concentrations are expressed in IU/ml with a WHO international reference sera as a standard. RESULTS: For diphtheria 100% of the children had antibody titers above the minimum protective level of 0.01 IU/ml and 86 to 100% (depending on prior vaccine product) had titers >0.1 IU/ml. However, only 0 to 40% of the children had antibody titers > or =1.0 IU/ml, a titer associated with more certain durable protection. For tetanus none of the children had an antibody titer below 0.01 IU/ml, and 93 to 100% had titers > or =0.1 IU/ml, a titer associated with more certain, durable protection. For pertussis the geometric mean concentrations of antibody before booster were uniformly very low, and the percentage of children exceeding the minimum detectable titer of antibody by 4-fold was also low. CONCLUSION: Before a 4- to 6-year-old booster, a large proportion of children have titers of antibody to diphtheria below the certain, durable protective level. Because serologic correlates and minimum protective titers of antibody to pertussis antigens have not been established, the relevance of the low titers determined in the current study is unknown but a potential concern.

Linezolid for the treatment of community-acquired pneumonia in hospitalized children. Linezolid Pediatric Pneumonia Study Group.

OBJECTIVE: To determine the safety, tolerance, pharmacokinetics and efficacy of linezolid, a new oxazolidinone antibiotic in the treatment of community-acquired pneumonia in hospitalized children. DESIGN: A Phase II, open label multicenter study of intravenous linezolid followed by oral linezolid suspension, both at a dose of 10 mg/kg every 12 h. Efficacy was assessed at 7 to 14 days after the last dose of linezolid. PATIENTS: Children 12 months to 17 years old with community-acquired pneumonia admitted to the hospital of 14 participating centers. RESULTS: From July 21, 1998, through May 14, 1999, 79 children were enrolled and 78 received linezolid. Sixty-six children completed treatment and follow-up and were evaluable for clinical outcome. The median age of the evaluable patients was 3 years (range, 1 to 12 years); 47 were 2 to 6 years old. Pathogens were isolated from blood or pleural fluid cultures in 8 children: Streptococcus pneumoniae, 6 (2 penicillin-resistant); Group A Streptococcus, 1; methicillin-resistant Staphylococcus aureus, 1. Chest tubes were placed in 9 patients. The mean total duration of intravenous and oral administration was 12.2 +/- 6.2 days (range, 6 to 41 days). The mean peak and trough plasma concentrations of linezolid were 9.5 +/- 4.8 and 0.8 +/- 1.2 microg/ml, respectively. At the follow-up visit 7 to 14 days after the last dose of linezolid, 61 patients (92.4%) were considered cured including all the patients with proven pneumococcal pneumonia, one failed (methicillin-resistant Staphylococcus aureus) and 4 were considered indeterminate. The most common adverse effects in the intent to treat group were diarrhea (10.3%), neutropenia (6.4%) and elevation in alanine aminotransferase (6.4%). CONCLUSIONS: Linezolid was well-tolerated and could be considered an alternative to vancomycin for treating serious infections caused by antibiotic-resistant Gram-positive cocci in children pending results of additional studies.