Approaches to monitoring biological outcomes for HPV vaccination: challenges of early adopter countries

In this review, we describe plans to monitor the impact of human papillomavirus (HPV) vaccine on biologic outcomes in selected international areas (Australia, Canada, Mexico, the Nordic countries, Scotland, and the United States) that have adopted this vaccine. This summary of monitoring plans provides a background for discussing the challenges of vaccine monitoring in settings where resources and capacity may vary. A variety of approaches that depend on existing infrastructure and resources are planned or underway for monitoring HPV vaccine impact. Monitoring HPV vaccine impact on biologic outcomes is a complex and challenging task, but also plays an important role in documenting the benefit of vaccination, monitoring the progress of vaccination programs, and providing data to inform vaccination and disease prevention policies.     

AHI1 mutations cause both retinal dystrophy and renal cystic disease in Joubert syndrome

Background

Joubert syndrome (JS) is an autosomal recessive disorder characterised by hypotonia, ataxia, mental retardation, altered respiratory pattern, abnormal eye movements, and a brain malformation known as the molar tooth sign (MTS) on cranial MRI. Four genetic loci have been mapped, with two genes identified (AHI1 and NPHP1).

Methods

We screened a cohort of 117 JS subjects for AHI1 mutations by a combination of haplotype analysis and sequencing of the gene, and for the homozygous NPHP1 deletion by sequencing and marker analysis.

Results

We identified a total of 15 novel AHI1 mutations in 13 families, including nonsense, missense, splice site, and insertion mutations, with some clustering in the WD40 domains. Eight families were consanguineous, but no single founder mutation was apparent. In addition to the MTS, retinal dystrophy was present in 11 of 12 informative families; however, no subjects exhibited variable features of JS such as polydactyly, encephalocele, colobomas, or liver fibrosis. In contrast to previous reports, we identified two families with affected siblings who developed renal disease consistent with nephronophthisis (NPH) in their 20s. In addition, two individuals with classic NPH were found to have homozygous NPHP1 deletions.

Conclusions

Overall, 11% of subjects had AHI1 mutations, while ∼2% had the NPHP1 deletion, representing a total of less than 15% in a large JS cohort. Some preliminary genotype‐phenotype correlations are possible, notably the association of renal impairment, specifically NPH, in those with NPHP1 deletions. Subjects with AHI1 mutations may be at risk of developing both retinal dystrophy and progressive kidney disease.     

Periodontal assessment by right- and left-handed examiners: is there a difference?

BACKGROUND: Multiple factors that influence the precision of periodontal probing measurements have been identified. These factors can be categorized as being dependent upon host-related, probe-related, or examiner-related variables. However, the potential influence of examiner handedness (right or left) on the measurement of periodontal probing depths (PDs) has not been addressed. The purpose of this study was to determine whether the measurements of PDs in the right and left quadrants are influenced by the handedness of the examiner. METHODS: Eight systemically healthy adult subjects with varying degrees of attachment loss and a minimum of 20 teeth were examined by five right-handed and five left-handed clinicians. The 10 clinicians were trained and calibrated for reproducible probe placement and angulation. PDs were measured using a conventional periodontal probe at six sites per tooth. Mean PD measurements were compared between right- and left-handed examiners using analysis of variance (ANOVA) with a random patient effect to correlate participant data and a random effect for the examiner. RESULTS: There was no statistical difference in the measurement of PDs between right- and left-handed examiners at various locations in the mouth (P>0.17 in all cases). Only three individual sites showed a statistically significantly different mean PD between right- and left-handed examiners (unadjusted P<0.05; differences at or near 0.5 mm). Overall, right-handed examiners tended to record slightly higher PD measurements than left-handed examiners, but this difference did not reach statistical significance. CONCLUSIONS: The handedness of the periodontal examiner does not appear to influence the recorded measurement of probing depths. This finding is relevant to those conducting clinical research involving assessment of periodontal status.     

Cyclic loading of implant-supported prostheses: comparison of gaps at the prosthetic-abutment interface when cycled abutments are replaced with as-manufactured abutments

STATEMENT OF PROBLEM: Implant-supported prostheses are mechanically connected to implants. When this connection is a screw joint, it is likely that the fit will be imperfect. Previous studies demonstrate that deformation can occur at the interface between the prosthesis and implant following cyclic loading. This deformation alters the fit of components. If implant connection components, abutments, were to be reoriented or replaced, it is likely that deformed surfaces would no longer approximate each other. Likewise, it is possible that the deformation may deleteriously alter the fit to replacement components. PURPOSE: This study evaluated the changes in prosthesis-implant abutment fit when gold cylinders that have been cyclically loaded are mated to as-manufactured abutments. MATERIAL AND METHODS: Fifteen implant-supported frameworks were fabricated using conventional casting techniques and were cyclically loaded under 3 different loading conditions: anterior region, unilaterally on posterior cantilever, and bilaterally on posterior cantilever. A cyclical load of 200 N was applied to each framework for 200,000 cycles. The abutments and frameworks were returned to the definitive casts for measurements. Linear measurements (microm) of the gap between the prosthetic cylinder and the implant-supported abutment at 4 predetermined reference points were made. The cycled abutments were replaced with as-manufactured abutments, and the gaps were measured at the same reference points. The Mann-Whitney rank-sum test was applied to the 2 sets of data to determine whether significant changes in fit were observed following component replacement (alpha = .05). RESULTS: Although minor changes in component fit were seen, the data failed to show that gaps at the prosthetic-abutment interface of cycled abutments were significantly different from those of as-manufactured abutments. CONCLUSIONS: Within the limitations of this study, differences in the fit between the implant-supported prosthesis and the abutments were not significantly different when abutments worn through loading were replaced with new as-manufactured abutments.     

Retrospective multicenter cohort study of the clinical performance of 2-stage implants in South Korean populations

PURPOSE: To evaluate long-term follow-up clinical performance of dental implants in use in South Korean populations. MATERIALS AND METHODS: A retrospective multicenter cohort study design was used to collect long-term follow-up clinical data from dental records of 224 patients treated with 767 2-stage endosseous implants at Ajou University Medical Center and Bundang Jesaeng Hospital in South Korea from June 1996 through December 2003. Exposure variables such as gender, systemic disease, location, implant length, implant diameter, prosthesis type, opposing occlusion type, and date of implant placement were collected. Outcome variables such as date of implant failure were measured. RESULTS: Patient ages ranged from 17 to 71.7 years old (mean age, 45.6 years old). Implants were more frequently placed in men than in women (61% versus 39%, or 471 men versus 296 women). Systemic disease was described by 9% of the patients. All implants had hydroxyapatite-blasted surfaces. Most of the implants were 3.75 mm in diameter. Implant lengths 10 mm, 11.5 mm, 13 mm, and 15 mm were used most often. Differences of implant survival among different implant locations were observed. Implants were used to support fixed partial dentures for the majority of the restorations. The opposing dentition was natural teeth for about 50% of the implants. A survival rate of 97.9% (751 of 767) was observed after 4.5 years (mean, 1.95 +/- 1.2 years). CONCLUSION: Clinical performance of 2-stage dental implants demonstrated a high level of predictability. The results achieved with a South Korean population did not differ from results achieved with diverse ethnic groups.     

To modulate or not to modulate: differing results in uniquely shaped Williams syndrome brains

Voxel based morphometry (VBM) studies of Williams syndrome (WS) have demonstrated remarkably consistent findings of reduced posterior parietal gray matter compared to typical controls. Other WS VBM findings have been inconsistent, however. In particular, different findings have been reported for hypothalamus and orbitofrontal gray matter regions. We examined a sample of 8 WS and 9 control adults and show that the hypothalamus and orbitofrontal cortex results depend on whether the images undergo Jacobian modulation. Deformation based morphometry (DBM) analysis demonstrated that major brain shape differences between the groups accounted for the Jacobian modulated gray matter findings. These results indicate that cautious interpretations of modulated gray matter findings are warranted when there are gross shape and size differences between experimental groups. This study demonstrates the importance of methodological choices towards understanding a disorder like WS, but also highlights the consistency of parietal lobe, orbitofrontal, and midbrain findings for this disorder across methodologies, participants, and research groups.     

Cost-utility model of rasagiline in the treatment of advanced Parkinson's disease in Finland

BACKGROUND: The economic burden of Parkinson's disease (PD) is high, especially in patients experiencing motor fluctuations. Rasagiline has demonstrated efficacy against symptoms of PD in early and advanced stages of the disease. OBJECTIVE: To assess the cost-utility of rasagiline and entacapone as adjunctive therapies to levodopa versus standard levodopa care in PD patients with motor fluctuations in Finland. METHODS: A 2 year probabilistic Markov model with 3 health states: "25% or less off-time/day," "greater than 25% off-time/day," and "dead" was used. Off-time represents time awake with poor or absent motor function. Model inputs included transition probabilities from randomized clinical trials, utilities from a preference measurement study, and costs and resources from a Finnish cost-of-illness study. Effectiveness measures were quality-adjusted life years (QALYs) and number of months spent with 25% or less off-time/day. Uncertainty around parameters was taken into account by Monte Carlo simulations. RESULTS: Over 2 years from a societal perspective, rasagiline or entacapone as adjunctive therapies to levodopa showed greater effectiveness than levodopa alone at no additional costs. Benefits after 2 years were 0.13 (95% CI 0.08 to 0.17) additional QALYs and 5.2 (3.6 to 6.7) additional months for rasagiline and 0.12 (0.08 to 0.17) QALYs and 5.1 (3.5 to 6.6) months for entacapone, both in adjunct to levodopa compared with levodopa alone. CONCLUSIONS: The results of this study support the use of rasagiline and entacapone as adjunctive cost-effective alternatives to levodopa alone in PD patients with motor fluctuations in Finland. With a different mode of action, rasagiline is a valuable therapeutic alternative to entacapone at no additional charge to society.     

Apolipoprotein E epsilon 4 is associated with an increased vulnerability to cell death in Alzheimer’s disease

Summary. The presumption to suffer from Alzheimer’s disease (AD) accelerates with aging. One important risk factor seems to be the isoform epsilon 4 of the apolipoprotein E gene (Apo ɛ4), which increases the risk to develop AD at an earlier age. Furthermore, convincing evidence is provided that apoptotic cell death mechanisms play an important role in neuronal cell death in AD. In the present study, we investigated whether abnormalities in apoptosis and caspase-3 activity can be found at the level of lymphocytes and a T cell subtype, CD4 T cells, from AD patients compared to aged sex- and ApoE genotype-matched non-demented controls. Under different experimental conditions (at baseline or after in vitro incubation in the presence of proapoptotic stimuli) increased levels of apoptosis and enhanced caspase-3 activity were detected in lymphocytes from AD patients. This difference was most pronounced in the CD4⁺ T cell subtype. Notably, we found a significant increase of apoptotic cells and caspase-3 activity in lymphocytes from AD patients bearing one or two alleles of the ApoE4 compared to non-E4 carriers. Again, these effects were strongest in CD4⁺ T cells. Circulating amyloid-beta (Aβ) levels did not differ between AD patients bearing ApoE4 and non-ApoE4 and age-matched controls. Therefore, it is likely that circulating Aβ is not responsible for the observed effects, which might rather reflect an ongoing systemic response in AD, e.g. an increase in CD95 expression.