HPV16/18 vaccination in the Netherlands: Monitoring long-term effects on HPV infections and immunogenicity

Human papillomavirus is one of the most common sexually transmittable infections. An infection with a hr HPV type can persist and cause the development of malignancies on the anogenital site and in the head and neck region. To strongly reduce the transmission of HPV and development of (cervical) cancer, prophylactic, bivalent HPV vaccination was introduced into the Dutch NIP in 2009 as a girls-only vaccine, preventing the most oncogenic HPV types 16 and 18. The current thesis describes monitoring of the routine HPV vaccination program within the Netherlands using intermediate endpoints, given the large gap between occurrence of HPV infection and development of cancer. Serological measurements are important in vaccination research and evaluation, since they can provide information on the responsiveness to a vaccine. Therefore, in chapter 2, the populationbased changes in seroprevalence of unvaccinated individuals were evaluated over a ten-year time period, during which HPV vaccination was implemented in the Netherlands. IgG antibody levels to seven hr HPV types as induced by natural infection showed that seroprevalence increased over the past decade among unvaccinated women, while it was stable among men. A lower seroprevalence among young women or herd effects among men, which may follow from the recent introduction of the HPV vaccination program among teenage girls in the Netherlands, was not yet observed. In chapter 3, the focus was on vaccine derived immune responses. Antibody levels remained high up till nine years past vaccination (three doses), both for vaccine types and to some extent for cross protective types. Immune responses from vaccinated women who presented with an HPV infection were compared to immune responses from women without infection, but the difference was not significant in the year before infection. This indicates that an immune correlate of protection, i.e. a threshold that should be reached in order to be protected, cannot be easily determined. This was also described in chapter 4, where we provided a review of the currently available information about immunological responses following vaccination with three different HPV vaccines, with special attention to long-term effects and dosing schedules. In chapter 5 we used data from sexual health clinic visitors (Passyon study) to assess trends of type-specific HPV prevalence over time since the introduction of HPV vaccination. Both among vaccinated women, heterosexual men, and unvaccinated women, declining trends of vaccine HPV types 16 and 18 were observed. This indicates that the population-level impact of a girls-only HPV vaccination program extends beyond the targeted group, inducing first- and secondorder herd effects. Chapter 6 focused on the vaccine effectiveness of two doses of routinely provided HPV vaccination. Genital infections among vaccinated (two doses) and unvaccinated participants from the HAVANA2 cohort were compared and indicated high, significant vaccine effectiveness against vaccine type infections (HPV16/18) and cross protective type infections (HPV31/33/45) up to four years after vaccination. In chapter 7, methodological challenges regarding vaccine effectiveness estimates were described, specifically the selection of the right method. Different statistical methods as identified in the literature were described, compared, and applied to the HAVANA data in order to identify the most robust method for VE estimates from observational cohort data. Although deviations in the calculated VE against persistent HPV16/18/31/33/45 infections were limited, the PWP-TT approach was selected as preferable for the current data. The method of choice was applied in chapter 8, where we studied the long-term protection from the three-dose schedule up to 10 years after vaccination using HAVANA data. No indication of waning protecting over time was observed, as the VE against persistent vaccine type infections remained very high. This was also the case for cross protective HPV types

In vivo metabolism of ibuprofen in growing conventional pigs : a pharmacokinetic approach

The juvenile conventional pig has been suggested as a preclinical animal model to evaluate pharmacokinetic (PK), pharmacodynamic (PD), and safety parameters in children. However, a lot of developmental changes in pig physiology still need to be unraveled. While the in vitro ontogeny of pig biotransformation enzymes is getting more attention in literature, the in vivo developmental changes have not yet been investigated. Therefore, the aim of the current study was to evaluate the biotransformation of ibuprofen (IBU) in conventional pigs aged 1 week, 4 weeks, 8 weeks, and 6-7 months after a single intravenous and oral administration of 5 mg/kg body weight (BVV) of IBU, using a PK approach in a crossover design for each age group. An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to determine 2-hydroxyibuprofen (2OH-IBU), carboxyibuprofen (COOH-IBU), and ibuprofen glucuronide (IBU-GICA) in pig plasma. All three metabolites could be quantified in plasma and the following PK parameters were determined: C-max, T-max, AUC(0 -> 6h), area under plasma concentration-time curve (AUC) ratio between parent drug and metabolite, and the absolute oral bioavailability of the parent drug IBU. The plasma concentrations of the metabolites were always lower than those of IBU. The bioavailability was high, indicating limited pre-systemic biotransformation. The AUC ratio of 2OH-IBU and COOH-IBU/IBU showed a significant increase at 4 weeks of age compared to the 1-week-old and 6- to 7-month-old pigs. Interestingly, the IBUGIcA/IBU AUC ratio did not change with age. The present study demonstrated that the main metabolites of IBU in human are also present in growing pigs. The oxidative phase I metabolism of IBU in growing conventional pigs did change with age. In contrast, age did not seem to affect the glucuronidation capacity of IBU in conventional pigs, although more studies with other substrate drugs are needed to confirm this

Patient Evaluation of Emotional Comfort Experienced (PEECE): Developing and testing a measurement instrument

Objectives: The Patient Evaluation of Emotional Comfort Experienced (PEECE) is a 12-item questionnaire which measures the mental well-being state of emotional comfort in patients. The instrument was developed using previous qualitative work and published literature. Design: Instrument development. Setting: Acute Care Public Hospital, Western Australia. Participants: Sample of 374 patients. Interventions: A multidisciplinary expert panel assessed the face and content validity of the instrument and following a pilot study, the psychometric properties of the instrument were explored. Main outcome measures: Exploratory and confirmatory factor analysis assessed the underlying dimensions of the PEECE instrument; Cronbach’s α was used to determine the reliability; κ was used for test–retest reliability of the ordinal items. Results: 2 factors were identified in the instrument and named ‘positive emotions’ and ‘perceived meaning’. A greater proportion of male patients were found to report positive emotions compared with female patients. The instrument was found to be feasible, reliable and valid for use with inpatients and outpatients. Conclusions: PEECE was found to be a feasible instrument for use with inpatient and outpatients, being easily understood and completed

Characterization of porcine hepatic and intestinal drug metabolizing CYP450 : comparison with human orthologues from a quantitative, activity and selectivity perspective

Over the past two decades, the pig has gained attention as a potential model for human drug metabolism. Cytochrome P450 enzymes (CYP450), a superfamily of biotransformation enzymes, are pivotal in drug metabolism. Porcine CYP450 has been demonstrated to convert typical substrates of human CYP450. Nevertheless, knowledge and insight into porcine CYP450 quantity and substrate selectivity is scant, especially regarding intestinal CYP450. The current study aimed to map the quantities of hepatic and intestinal CYP450 in the conventional pig by using a proteomic approach. Moreover, the selectivity of the six most common used probe substrates (phenacetin, coumarin, midazolam, tolbutamide, dextromethorphan, and chlorzoxazone) for drug metabolizing enzyme subfamilies (CYP1A, CYP2A, CYP3A, CYP2C, CYP2D and CYP2E respectively), was investigated. Hepatic relative quantities were 4% (CYP1A), 31% (CYP2A), 14% (CYP3A), 10% (CYP2C), 28% (CYP2D) and 13% (CYP2E), whereas for the intestine only duodenal CYP450 could be determined with 88% for CYP3A and 12% for CYP2C. Furthermore, the results indicate that coumarin (CYP2A), midazolam (CYP3A), tolbutamide (CYP2C), and dextromethorphan (CYP2D) are as selective for porcine as for human CYP450. However, phenacetin (CYP1A2) and chlorzoxazone (CYP2E1) are less selective for the specific enzyme, despite similarities in selectivity towards the different enzymes involved compared to humans

Living with multiple myeloma: A focus group study of unmet needs and preferences for survivorship care

Purpose: To describe the unmet informational, psychological, emotional, social, practical, and physical needs and preferences for posttreatment survivorship care of individuals living with multiple myeloma to inform the development of relevant, personcentered, survivorship services. Methods: An exploratory, descriptive study using 2 focus groups with 14 participants, 6 to 49 months postdiagnosis. Results: Thematic analysis revealed 7 key themes: information needs, experience with health-care professionals, coping with side effects, communicating with family and friends, dealing with emotions, support needs, and living with the chronicity of myeloma. Participants described key characteristics of survivorship care relevant to their needs and indicated they would like a more whole of person approach to follow-up when the main treatment phases had completed. Conclusion: Participants in this study described unmet needs across a breadth of domains that varied over time. The development of flexible, person-centered approaches to comprehensive survivorship care is needed to address the considerable quality-of-life issues experienced by people living with multiple myeloma. Nurse-led care may offer 1 viable model to deliver enhanced patient experience—providing the vital “link” that people described as missing from their survivorship care

Postnatal maturation of the glomerular filtration rate in conventional growing piglets as potential juvenile animal model for preclinical pharmaceutical research

Adequate animal models are required to study the preclinical pharmacokinetics (PK), pharmacodynamics (PD) and safety of drugs in the pediatric subpopulation. Over the years, pigs were presented as a potential animal model, since they display a high degree of anatomical and physiological similarities with humans. To assess the suitability of piglets as a preclinical animal model for children, the ontogeny and maturation processes of several organ systems have to be unraveled and compared between both species. The kidneys play a pivotal role in the PK and PD of various drugs, therefore, the glomerular filtration rate (GFR) measured as clearance of endogenous creatinine (Jaffe and enzymatic assay) and exo-iohexol was determined in conventional piglets aging 8 days (n = 16), 4 weeks (n = 8) and 7 weeks (n = 16). The GFR data were normalized to bodyweight (BW), body surface area (BSA) and kidney weight (KW). Normalization to BSA and KW showed an increase in GFR from 46.57 to 100.92 mL/min/m2 and 0.49 to 1.51 mL/min/g KW from 8 days to 7 weeks of age, respectively. Normalization to BW showed a less pronounced increase from 3.55 to 4.31 mL/min/kg. The postnatal development of the GFR was comparable with humans, rendering the piglet a convenient juvenile animal model for studying the PK, PD and safety of drugs in the pediatric subpopulation. Moreover, to facilitate the assessment of the GFR in growing piglets in subsequent studies, a formula was elaborated to estimate the GFR based on plasma creatinine and BW, namely eGFR =1.879 × BW^1.092/Pcr^0.600