Jesper Mehlsen

A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women.

BACKGROUNDnThe investigational 9-valent viruslike particle vaccine against human papillomavirus (HPV) includes the HPV types in the quadrivalent HPV (qHPV) vaccine (6, 11, 16, and 18) and five additional oncogenic types (31, 33, 45, 52, and 58). Here we present the results of a study of the efficacy and immunogenicity of the 9vHPV vaccine in women 16 to 26 years of age.nnnMETHODSnWe performed a randomized, international, double-blind, phase 2b-3 study of the 9vHPV vaccine in 14,215 women. Participants received the 9vHPV vaccine or the qHPV vaccine in a series of three intramuscular injections on day 1 and at months 2 and 6. Serum was collected for analysis of antibody responses. Swabs of labial, vulvar, perineal, perianal, endocervical, and ectocervical tissue were obtained and used for HPV DNA testing, and liquid-based cytologic testing (Papanicolaou testing) was performed regularly. Tissue obtained by means of biopsy or as part of definitive therapy (including a loop electrosurgical excision procedure and conization) was tested for HPV.nnnRESULTSnThe rate of high-grade cervical, vulvar, or vaginal disease irrespective of HPV type (i.e., disease caused by HPV types included in the 9vHPV vaccine and those not included) in the modified intention-to-treat population (which included participants with and those without prevalent infection or disease) was 14.0 per 1000 person-years in both vaccine groups. The rate of high-grade cervical, vulvar, or vaginal disease related to HPV-31, 33, 45, 52, and 58 in a prespecified per-protocol efficacy population (susceptible population) was 0.1 per 1000 person-years in the 9vHPV group and 1.6 per 1000 person-years in the qHPV group (efficacy of the 9vHPV vaccine, 96.7%; 95% confidence interval, 80.9 to 99.8). Antibody responses to HPV-6, 11, 16, and 18 were noninferior to those generated by the qHPV vaccine. Adverse events related to injection site were more common in the 9vHPV group than in the qHPV group.nnnCONCLUSIONSnThe 9vHPV vaccine prevented infection and disease related to HPV-31, 33, 45, 52, and 58 in a susceptible population and generated an antibody response to HPV-6, 11, 16, and 18 that was noninferior to that generated by the qHPV vaccine. The 9vHPV vaccine did not prevent infection and disease related to HPV types beyond the nine types covered by the vaccine. (Funded by Merck; ClinicalTrials.gov number, NCT00543543).

Effects of a Ginkgo biloba extract on forearm haemodynamics in healthy volunteers.

The aim was to validate possible vasodilating effects of a Ginkgo biloba extract with a secondary aim of finding a pharmacodynamic signal relating to the active component of these extracts. We studied the effect of G. biloba extract on forearm haemodynamics in 16 healthy subjects (nine females, seven males) with a median age of 32 years (range: 21–47). The study was conducted as a randomized, double‐blinded cross‐over design using oral treatment with G. biloba extract (Gibidyl Forte® t.i.d. or placebo for 6 weeks. Forearm blood flow and venous capacity were measured by strain‐gauge plethysmography. Blood pressure was measured by standard sphygmomanometry, and forearm vascular resistance (FVR) was derived. Measurements were made at baseline and after 3, 6, 9 and 12 weeks of treatment. Forearm blood flow was significantly higher during active treatment after 3 and 6 weeks as compared with placebo treatment for 3 and 6 weeks (P<0·05). Mean arterial blood pressure was unchanged, making the calculated FVR significantly lower during active treatment (P<0·02). It is concluded that oral treatment with a G. biloba extract (Gibidyl Forte®) is able to dilate forearm blood vessels causing increments in regional blood flow without changing blood pressure levels in healthy subjects. The increments in blood flow may be used as a biological signal for pharmacokinetic studies.

Blood-retinal barrier permeability versus diabetes duration and retinal morphology in insulin dependent diabetic patients

Abstract The blood‐retinal barrier permeability to fluorescein was quantitated in 54 patients (22 females and 32 males) with insulin dependent diabetes mellitus (IDDM) of different duration. Correlation was demonstrated between permeability and diabetes duration. A normal permeability was measured in patients with up to ten years diabetes duration. A pathologically increased permeability was measured with ten to 15 years diabetes duration and during the next decade the permeability increased rapidly to 5–10 times the normal value. Onset of diabetes in the decade before and after puberty did not change the pattern. However, the pathologically increased permeability after ten years duration of the disease could not be demonstrated in diabetics with onset of the disease after the age of 30 years. The permeability of the blood‐retinal barrier correlated well with changes in retinal morphology as seen by ophthalmoscopy and fluorescein angiography. However, there was an overlap in permeability between groups with different retinal appearance. A significant factor was the presence of macular edema, which also apparently indicated a preproliferative state.

The blood‐retinal barrier permeability to fluorescein in normal subjects and in juvenile diabetics without retinopathy

Abstract The blood‐retinal barrier permeability to fluorescein was determined in 20 eyes from 17 normal volunteers (mean age 31 years) and in 20 eyes from 19 juvenile diabetics without apparent retinopathy (mean age 35 years – mean duration of diabetes 6 years). The permeability was in normal subjects (1.1 ± 0.4) · 10‐7 cm/sec (mean ± 2 · SD) and in juvenile diabetics (1.1 ± 0.7) · 10‐7 cm/sec (mean ± 2 · SD). Thus a break‐down of the blood‐retinal barrier cannot be demonstrated as a very early and general phenomenon in the early course of the diabetic disease. The fluorescein diffusion coefficient in the vitreous body was determined and juvenile diabetics without apparent retinopathy showed a diffusion coefficient of (0.80 ± 0.25) · 10‐5 cm2/sec (mean ± 2 · SD), which was the same as in normals where the diffusion coefficient was (0.69 ± 0.46) · 10‐5 cm2/sec (mean ± 2 · SD).

An open-label, randomized study of a 9-valent human papillomavirus vaccine given concomitantly with diphtheria, tetanus, pertussis and poliomyelitis vaccines to healthy adolescents 11-15 years of age.

Background: A 9-valent human papillomavirus (9vHPV) vaccine has recently been reported to be safe and highly efficacious against infection and disease related to HPV6/11/16/18/31/33/45/52/58. We evaluated the immunogenicity and safety of the 9vHPV vaccine administered concomitantly with REPEVAX (diphtheria, tetanus, acellular pertussis and inactivated poliomyelitis vaccine). Methods: This open-label, randomized, multicenter study enrolled 1054 males and females ages 11–15 years. Subjects were randomly assigned to each group in a 1:1 ratio. Subjects received a 0.5 mL dose of 9vHPV vaccine intramuscularly at day 1, months 2 and 6 and a 0.5 mL dose of REPEVAX either on day 1 (concomitant vaccination group; n = 526) or at month 1 (nonconcomitant vaccination group, n = 528). Serologic responses for each vaccine component were tested by 1-sided tests of noninferiority between groups. Systemic and injection-site adverse experiences (AEs) and serious AEs were monitored. Results: Noninferiority of anti-HPV geometric mean titers and seroconversion rates for all 9vHPV antigens were demonstrated for the concomitant group compared with the nonconcomitant group. Seroconversion rates for the 9vHPV vaccine types were ≥99.8% in both groups at month 7. For REPEVAX, noninferiority of immune response was established for diphtheria, tetanus, all polio and pertussis antigens for both groups. There were no vaccine-related serious AEs. Conclusion: Overall, concomitant administration of 9vHPV vaccine and REPEVAX was generally well tolerated and did not interfere with the immune response to either vaccine. This strategy would minimize the number of visits required to deliver each vaccine individually.

Differential effects of endurance training and weight loss on plasma adiponectin multimers and adipose tissue macrophages in younger, moderately overweight men

Obese individuals are characterized by low circulating adiponectin concentrations and an increased number of macrophages in adipose tissue, which is believed to be causally associated with chronic low-grade inflammation and insulin resistance. Regular physical exercise decreases overall morbidity in obese subjects, which may be due to modulations of inflammatory pathways. In this randomized clinical trial we investigated the separate effects of endurance training-induced weight loss, diet-induced weight loss, and endurance training per se (without weight loss) on plasma adiponectin multimer composition (Western blotting) and adipose tissue macrophage content (immunohistochemistry) in young, moderately overweight men. Weight loss and endurance training per se decreased whole body fat percentage in an additive manner. No intervention-induced changes were observed for plasma total adiponectin. Surprisingly, endurance training, irrespectively of any associated weight loss, shifted the adiponectin multimer distribution toward a lower molecular weight (21% decrease in HMW/LMW, P = 0.015), whereas diet-induced weight loss shifted the distribution toward a higher molecular weight (42% increase in HMW/MMW, P < 0.001). Furthermore, endurance training per se increased the number of anti-inflammatory CD163⁺ macrophages [from 12.7 ± 2.1 (means ± SE) to 16.1 ± 3.1 CD163⁺ cells/100 adipocytes, P = 0.013], whereas diet-induced weight loss tended to decrease CD68⁺ macrophages in subcutaneous abdominal adipose tissue. Thus regular physical exercise influences systemic and adipose tissue inflammatory pathways differently than diet-induced weight loss in younger, moderately overweight men. Our data suggest that some of the health benefits of a physically active lifestyle may occur through modulations of anti- rather than pro-inflammatory pathways in young, overweight men.

Reduced sympathetic activity in idiopathic rapid-eye-movement sleep behavior disorder and Parkinson's disease

BACKGROUNDnMore than 50% of patients with idiopathic REM sleep behavior disorder (iRBD) will develop Parkinsons disease or Lewy body dementia. In a previous study, we found attenuated heart rate responses in iRBD and Parkinsons disease patients during sleep. The current study aimed to evaluate heart rate variability further in order to identify possible changes in these components during wakefulness and sleep in patients with iRBD and Parkinsons disease.nnnMETHODSnWe evaluated heart rate variability in 5-minute electrocardiography segments from wakefulness, and non-REM and REM sleep in 11 iRBD patients and 23 Parkinsons disease patients, and compared these with 10 control subjects.nnnRESULTS AND CONCLUSIONSnPatients with iRBD had attenuated sympathetic nervous system activity compared with controls and this was more pronounced in patients with Parkinsons disease. The cardiac parasympathetic nervous system seems to be relatively well preserved in patients with iRBD and Parkinsons disease. The progressive reduction of sympathetic nervous activity is in line with the postganglionic sympathetic nervous dysfunction seen in early Parkinsons disease.

The prognosis of impaired left ventricular systolic function and heart failure in a middle‐aged and elderly population in an urban population segment of Copenhagen

To determine the prognosis, total mortality and cardiac morbidity, of patients with left ventricular systolic dysfunction and heart failure (HF) in a general population sample.

Blunted autonomic response in cluster headache patients

Background Cluster headache (CH) is a disabling headache disorder with chronobiological features. The posterior hypothalamus is involved in CH pathophysiology and is a hub for autonomic control. We studied autonomic response to the head-up tilt table test (HUT) including heart rate variability (HRV) in CH patients and compared results to healthy controls. Methods and materials Twenty-seven episodic and chronic CH patients and an equal number of age-, sex- and BMI-matched controls were included. We analyzed responses to HUT in the time and frequency domain and by non-linear analysis. Results CH patients have normal cardiovascular responses compared to controls but increased blood pressure. In the frequency analysis CH patients had a smaller change in the normalized low- (LF) (2.89 vs. 13.38, pu2009<u20090.05) and high-frequency (HF) (–2.86 vs. –13.38, pu2009<u20090.05) components as well as the LF/HF ratio (0.81 vs. 2.62, pu2009<u20090.05) in response to tilt. In the Poincaré plot, the change in ratio between long- and short-term variation was lower in patients (SD1/SD2, –0.05 vs. –0.17, pu2009<u20090.05). Conclusions CH patients show decreased autonomic response to HUT compared to healthy controls. This can be interpreted as dysregulation in the posterior hypothalamus and supports a theory of central autonomic mechanisms involvement in CH.

4-valent human papillomavirus (4vHPV) vaccine in preadolescents and adolescents after 10 years

This report summarizes the immunogenicity, effectiveness, and safety of the 4vHPV vaccine in adolescent and preadolescent subjects after 10 years. OBJECTIVES: We describe the final 10-year data for the long-term follow-up study of the 4-valent human papillomavirus (4vHPV) vaccine in preadolescents and adolescents. METHODS: In the base study (V501-018), 1661 sexually inactive boys and girls received the 4vHPV vaccine (early vaccination group [EVG], managed for 9.9 years) or a placebo at day 1, month 2, and month 6. Thereafter, at month 30, the placebo group (catch-up vaccination group [CVG], managed for 7.4 years) received the 4vHPV vaccine by using the same dosing schedule. Long-term anti-HPV type 6, 11, 16, and 18 immune responses were assessed. Effectiveness was estimated by calculating the incidence rate of the primary endpoints (HPV types 6, 11, 16, and 18–related disease or persistent infection). RESULTS: For HPV types 6, 11, and 16, 89% to 96% of subjects remained seropositive through 10-years postvaccination. The preadolescents had 38% to 65% higher geometric mean titers at month 7, which remained 16% to 42% higher at 10 years compared with adolescents. No cases of HPV type 6, 11, 16, and 18–related diseases were observed. Ten subjects had a persistent infection of ≥6 months duration with vaccine-type HPV and 2 subjects had persistent infection for ≥12 months. No new serious adverse events were reported through 10 years. CONCLUSIONS: A 3-dose regimen of the 4vHPV vaccine was immunogenic, clinically effective, and generally well tolerated in preadolescents and adolescents during 10 years of follow-up. These long-term findings support efforts to vaccinate this population against HPV before exposure.