The impact of childhood varicella vaccination on the incidence of herpes zoster in the general population: modelling the effect of exogenous and endogenous varicella-zoster virus immunity boosting.

BACKGROUND: A controversy exists about the potential effect of childhood varicella vaccination on Herpes Zoster (HZ) incidence. Mathematical models projected temporary HZ incidence increase after vaccine introduction that was not confirmed by real-world evidence. These models assume that absence of contacts with infected children would prevent exogenous boosting of Varicella-Zoster-Virus (VZV) immunity and they do not include an endogenous VZV immunity-boosting mechanism following asymptomatic VZV reactivation. This study aims to explore the effect of various assumptions on exogenous and endogenous VZV immunity-boosting on HZ incidence in the general population after introduction of routine childhood varicella vaccination. METHODS: An age-structured dynamic transmission model was adapted and fitted to the seroprevalence of varicella in France in absence of vaccination using the empirical contact matrix. A two-dose childhood varicella vaccination schedule was introduced at 12 and 18 months. Vaccine efficacy was assumed at 65%/95% (dose 1/dose 2), and coverage at 90%/80% (dose 1/dose 2). Exogenous boosting intensity was based on assumptions regarding HZ-immunity duration, age-dependent boosting effect, and HZ reactivation rates fitted to observed HZ incidence. Endogenous boosting was the same as pre-vaccination exogenous boosting but constant over time, whilst exogenous boosting depended on the force of infection. Five scenarios were tested with different weightings of exogenous (Exo) - endogenous (Endo) boosting: 100%Exo-0%Endo, 75%Exo-25%Endo, 50%Exo-50%Endo, 25%Exo-75%Endo, 0%Exo-100%Endo. RESULTS: HZ incidence before varicella vaccination, all ages combined, was estimated at 3.96 per 1000 person-years; it decreased by 64% by year 80 post vaccine introduction, for all boosting assumptions. The 100%Exo-0%Endo boosting scenario, predicted an increase in HZ incidence for the first 21 years post vaccine introduction with a maximum increase of 3.7% (4.1/1000) at year 9. However, with 0%Exo-100%Endo boosting scenario an immediate HZ decline was projected. The maximum HZ incidence increases at 10, 3, and 2 years post vaccination were 1.8% (75%Exo-25%Endo), 0.8% (50%Exo-50%Endo) and 0.2% (25%Exo-75%Endo), respectively. CONCLUSIONS: Assuming modest levels of endogenous boosting, the increase in HZ incidence following childhood varicella vaccination was smaller and lasted for a shorter period compared with 100%Exo-0%Endo boosting assumption. Endogenous boosting mechanism could partly explain the divergence between previous HZ-incidence projections and real-world evidence.

Coverage, efficacy or dosing interval: which factor predominantly influences the impact of routine childhood vaccination for the prevention of varicella? A model-based study for Italy.

BACKGROUND: Varicella is a highly infectious disease with a significant public health and economic burden, which can be prevented with childhood routine varicella vaccination. Vaccination strategies differ by country. Some factors are known to play an important role (number of doses, coverage, dosing interval, efficacy and catch-up programmes), however, their relative impact on the reduction of varicella in the population remains unclear. This paper aims to help policy makers prioritise the critical factors to achieve the most successful vaccination programme with the available budget. METHODS: Scenarios assessed the impact of different vaccination strategies on reduction of varicella disease in the population. A dynamic transmission model was used and adapted to fit Italian demographics and population mixing patterns. Inputs included coverage, number of doses, dosing intervals, first-dose efficacy and availability of catch-up programmes, based on strategies currently used or likely to be used in different countries. The time horizon was 30 years. RESULTS: Both one- and two-dose routine varicella vaccination strategies prevented a comparable number of varicella cases with complications, but two-doses provided broader protection due to prevention of a higher number of milder varicella cases. A catch-up programme in susceptible adolescents aged 10-14 years old reduced varicella cases by 27-43 % in older children, which are often more severe than in younger children. Coverage, for all strategies, sustained at high levels achieved the largest reduction in varicella. In general, a 20 % increase in coverage resulted in a further 27-31 % reduction in varicella cases. When high coverage is reached, the impact of dosing interval and first-dose vaccine efficacy had a relatively lower impact on disease prevention in the population. Compared to the long (11 years) dosing interval, the short (5 months) and medium (5 years) interval schedules reduced varicella cases by a further 5-13 % and 2-5 %, respectively. Similarly, a 10 % increase in first-dose efficacy (from 65 to 75 % efficacy) prevented 2-5 % more varicella cases, suggesting it is the least influential factor when considering routine varicella vaccination. CONCLUSIONS: Vaccination strategies can be implemented differently in each country depending on their needs, infrastructure and healthcare budget. However, ensuring high coverage remains the critical success factor for significant prevention of varicella when introducing varicella vaccination in the national immunisation programme.

Incidence of acute otitis media in children below 6 years of age seen in medical practices in five East European countries.

BACKGROUND: Although acute otitis media (AOM) remains a major public health problem worldwide and brings economic burden on health care system and caregivers, little information is available about its epidemiology in Eastern Europe. METHODS: We conducted an epidemiological, prospective, observational, multi-centre cohort study (NCT01365390) in five East European countries (Estonia, Lithuania, Poland, Romania and Slovenia) between June 2011 and January 2013 to determine the incidence and clinical characteristics of AOM among children aged < 6 years during 1 year. RESULTS: AOM incidence was 160.7 cases (95 % confidence interval [CI]: 144.7-177.9) per 1000 person-years (PY) being the lowest in the < 1 year age group (92.3 cases [95 % CI: 59.7-136.2] per 1000 PY) and the highest in the 3- < 4 years age group (208.9 cases [95 % CI: 165.1-260.7] per 1000 PY). AOM incidence was similar across the countries, with the exception of Slovenia (340.3 cases [95 % CI: 278.3-412.0] per 1000 PY). There was a lower risk in breastfed children and a higher risk in those attending school/childcare or with allergies. AOM required 521 visits to the doctor. Antibiotics were prescribed for 276 (74.8 %) episodes with the lowest prescription rate in Estonia (51.4 %) and the highest in Romania (83.7 %). Complications were rare and hospitalisations occurred in 2 % of the cases. CONCLUSIONS: The disease burden of AOM in Eastern Europe is relevant and public health initiatives to reduce it should be considered. TRIAL REGISTRATION: ClinicalTrial.gov NCT01365390 .

Human papillomavirus prevalence and type-distribution in cervical glandular neoplasias: Results from a European multinational epidemiological study.

Cervical glandular neoplasias (CGN) present a challenge for cervical cancer prevention due to their complex histopathology and difficulties in detecting preinvasive stages with current screening practices. Reports of human papillomavirus (HPV) prevalence and type-distribution in CGN vary, providing uncertain evidence to support prophylactic vaccination and HPV screening. This study [108288/108290] assessed HPV prevalence and type-distribution in women diagnosed with cervical adenocarcinoma in situ (AIS, N = 49), adenosquamous carcinoma (ASC, N = 104), and various adenocarcinoma subtypes (ADC, N = 461) from 17 European countries, using centralised pathology review and sensitive HPV testing. The highest HPV-positivity rates were observed in AIS (93.9%), ASC (85.6%), and usual-type ADC (90.4%), with much lower rates in rarer ADC subtypes (clear-cell: 27.6%; serous: 30.4%; endometrioid: 12.9%; gastric-type: 0%). The most common HPV types were restricted to HPV16/18/45, accounting for 98.3% of all HPV-positive ADC. There were variations in HPV prevalence and ADC type-distribution by country. Age at diagnosis differed by ADC subtype, with usual-type diagnosed in younger women (median: 43 years) compared to rarer subtypes (medians between 57 and 66 years). Moreover, HPV-positive ADC cases were younger than HPV-negative ADC. The six years difference in median age for women with AIS compared to those with usual-type ADC suggests that cytological screening for AIS may be suboptimal. Since the great majority of CGN are HPV16/18/45-positive, the incorporation of prophylactic vaccination and HPV testing in cervical cancer screening are important prevention strategies. Our results suggest that special attention should be given to certain rarer ADC subtypes as most appear to be unrelated to HPV.

Post-marketing monitoring of intussusception after rotavirus vaccination in Japan.

PURPOSE: Rotarix(TM) was launched in November 2011 in Japan to prevent rotavirus gastroenteritis. Some studies suggest that Rotarix(TM) may have a temporal association with a risk of intussusception (IS). We assessed a possible association between IS and Rotarix(TM) vaccination in Japan. METHODS: All IS cases spontaneously reported post-vaccination (Brighton collaboration levels 1, 2, and 3) were extracted from the GlaxoSmithKline spontaneous report database on the 11th of January 2013. Expected numbers of IS cases were estimated using the number of vaccine doses distributed and the Japanese incidence rate of IS stratified by month of age. The observed versus expected analysis considered the IS cases for each risk period (7 and 30 days post-vaccination) and for each vaccine dose (two doses). RESULTS: Before January 2013, approximately 601 000 Rotarix(TM) doses were distributed in Japan. For a risk period of 7 days post-dose 1 and post-dose 2, 10 and five IS cases were observed, whereas 3.4 and 7.6 were expected, providing an observed-to-expected ratio of 2.96 (95% confidence interval [CI]: 1.42; 5.45) and 0.66 (95% CI: 0.21; 1.53), respectively. For a risk period of 30 days post-dose 1 and post-dose 2, 14 and eight cases were observed, whereas 14.5 and 32.7 were expected, providing an observed-to-expected ratio of 0.97 (95% CI: 0.53; 1.62) and 0.24 (95% CI: 0.11; 0.48), respectively. CONCLUSION: A statistically significant excess of IS cases was observed within 7 days post-dose 1, but not post-dose 2. These results are consistent with previous observations in large post-marketing safety studies in other world regions.

Vericiguat Use in Patients with Heart Failure in Real-World Settings during the First Year after the Drug Authorization in Japan.

Background: Vericiguat was developed to treat patients with heart failure (HF). Currently, limited data are available to characterize vericiguat-treated patients in real-world clinical settings. Methods: This retrospective cohort study was done using a Japanese hospital administrative database to describe the use of vericiguat in patients with HF in real-world settings. Adult patients diagnosed with HF prescribed vericiguat between 1 July 2021 and 30 September 2022 were included. Patient characteristics at the initiation of vericiguat treatment, patterns of HF medication use, and vericiguat dose titrations were assessed within the first 90 days of treatment. Results: The study included 829 patients who were initiated on vericiguat therapy. The mean age was 75.5 years and 69.0% were male. Hypertension, coronary artery disease, and diabetes mellitus were present in 91.7, 71.3, and 60.1% of patients, respectively. Most patients had previously received HF medications, with high percentages using angiotensin-receptor blocker neprilysin inhibitors (ARNI; 43.9%) and sodium-glucose cotransporter-2 inhibitors (54.4%). During the first 90 days of vericiguat treatment, 65.8% of the patients were uptitrated from their starting dose, and 32.3% had reached the maximal daily dose. The median time to reach the maximal daily dose was 34 days. The multivariable model identified that initiating vericiguat treatment in an outpatient setting and using ARNI before initiating vericiguat treatment were factors significantly associated with reaching the maximal daily dose of vericiguat at any given time, whereas older age, chronic kidney disease, hyperkalemia, and anemia were not associated. Conclusions: These findings provide early insights into the use of vericiguat, which aid in optimizing the combinations and/or sequences of HF treatment incorporating vericiguat therapy.

Differences in human papillomavirus type distribution in high-grade cervical intraepithelial neoplasia and invasive cervical cancer in Europe.

Knowledge of differences in human papillomavirus (HPV)-type prevalence between high-grade cervical intraepithelial neoplasia (HG-CIN) and invasive cervical cancer (ICC) is crucial for understanding the natural history of HPV-infected cervical lesions and the potential impact of HPV vaccination on cervical cancer prevention. More than 6,000 women diagnosed with HG-CIN or ICC from 17 European countries were enrolled in two parallel cross-sectional studies (108288/108290). Centralised histopathology review and standardised HPV-DNA typing were applied to formalin-fixed paraffin-embedded cervical specimens dated 2001-2008. The pooled prevalence of individual HPV types was estimated using meta-analytic methods. A total of 3,103 women were diagnosed with HG-CIN and a total of 3,162 with ICC (median ages: 34 and 49 years, respectively), of which 98.5 and 91.8% were HPV-positive, respectively. The most common HPV types in women with HG-CIN were HPV16/33/31 (59.9/10.5/9.0%) and in ICC were HPV16/18/45 (63.3/15.2/5.3%). In squamous cell carcinomas, HPV16/18/33 were most frequent (66.2/10.8/5.3%), and in adenocarcinomas, HPV16/18/45 (54.2/40.4/8.3%). The prevalence of HPV16/18/45 was 1.1/3.5/2.5 times higher in ICC than in HG-CIN. The difference in age at diagnosis between CIN3 and squamous cervical cancer for HPV18 (9 years) was significantly less compared to HPV31/33/'other' (23/20/17 years), and for HPV45 (1 year) than HPV16/31/33/'other' (15/23/20/17 years). In Europe, HPV16 predominates in both HG-CIN and ICC, whereas HPV18/45 are associated with a low median age of ICC. HPV18/45 are more frequent in ICC than HG-CIN and associated with a high median age of HG-CIN, with a narrow age interval between HG-CIN and ICC detection. These findings support the need for primary prevention of HPV16/18/45-related cervical lesions.

HPV-genotypes in high-grade intraepithelial cervical lesions in Danish women.

OBJECTIVE: A study was undertaken to assess the distribution of high-risk HPV-genotypes in high-grade cervical intraepithelial neoplastic lesions in Danish women. DESIGN: Observational, cross-sectional. SETTING: Danish data from a multi-centre study undertaken in 13 European countries. POPULATION: 290 archived fixed biopsies with high-grade cervical lesions from the Departments of Pathology at the University Hospitals in Hvidovre and Odense, Denmark. METHODS: Relevant histological samples were anonymized and shipped to a central laboratory for histopathology review and PCR-testing for HPV-DNA. A standardised HPV-test methodology was utilised to enable comparison of HPV-genotype distribution. RESULTS: Of 290 Danish cervical samples, 276 were evaluated as histologically adequate and all of these were HPV-positive (HPV⁺). Of the HPV⁺ samples 77.9% were diagnosed with a single HPV-type, with cervical intraepithelial neoplasia (CIN)3 diagnosed in 82.3% and CIN2, CIN2/3, adenocarcinoma in situ (AIS) and AIS⁺ other high-grade lesion diagnosed in the remaining 17.7%. The most prevalent HPV-types were: HPV16 (54.0%), HPV33 (13.5%), HPV31 (10.7%), HPV18 (7.9%) and HPV52 (4.7%). Of the HPV⁺ samples, 21.4% were diagnosed with multiple HPV-types, with CIN3 diagnosed in 79.6% and CIN2, CIN2/3, AIS and AIS⁺ other high-grade lesion diagnosed in the remaining 20.4%. The most prevalent HPV-types were: HPV16 (49.2%), HPV31 (30.5%), HPV52 (27.1%), HPV51 (20.3%), HPV18 (16.9%), HPV33 (13.6%), HPV45 (11.9%), with 0.7% unknown types. CONCLUSIONS: HPV16 and HPV18 were detected in approximately 75% of high-grade intraepithelial cervical lesions in a Danish population (single or multiple infections); these two genotypes are considered causative in at least 61.9% of the high-grade intraepithelial lesions (single infection).

HPV genotypes in invasive cervical cancer in Danish women.

OBJECTIVE: Human papillomavirus (HPV) genotype distribution in invasive cervical cancers may differ by geographic region. The primary objective of this study was to estimate HPV-genotype distribution in Danish women with a diagnosis of invasive cervical cancer. DESIGN: Observational, cross-sectional. POPULATION: Danish data from a multi-center study undertaken in 12 European countries. METHODS: A total of 342 archived fixed tissue samples with diagnosis of invasive cervical cancer from the Departments of Pathology in the University Hospitals in Hvidovre and Odense, Denmark, were anonymized and shipped to a central laboratory for histopathology review and PCR testing for HPV DNA. A standardized HPV-test methodology was used to enable comparison of HPV-type distribution. MAIN OUTCOME MEASURES: Occurrence of HPV genotypes in Danish women with cervical cancer. RESULTS: There were 261 samples evaluated as histologically adequate and 251 (96%) of these were HPV-positive (HPV+). The most frequent diagnosis was squamous cell carcinoma (78.9% of histological adequate and 79.3% of HPV+). Adenocarcinoma, adenosquamous carcinoma and other types were found in 14.9, 3.4 and 2.7% of the histologically adequate group and 14.7, 3.6 and 2.4% of the HPV+ group, respectively. In 92.8% of HPV+ women only a single HPV type was diagnosed. HPV-type distribution in the latter population was as follows: HPV-16: 62.2%; HPV-18: 14.6%; HPV-33: 6.9%; HPV-45: 6.4% and HPV-31: 3.4%. Of the HPV+ women, 6.4% were diagnosed with multiple HPV types and 0.8% had unknown HPV types. CONCLUSION: HPV-16 and -18 are detected in 74.3% of Danish women with diagnosis of invasive cervical cancer, while HPV-16, -18, -31, -33, -45 and 58 are detected in 90.0% of women with invasive cervical disease.

The burden of rotavirus gastroenteritis and hospital-acquired rotavirus gastroenteritis among children aged less than 6 years in Japan: a retrospective, multicenter epidemiological survey.

BACKGROUND: Rotavirus is a leading worldwide cause of acute gastroenteritis in young children. This retrospective hospital-based study assessed the burden of rotavirus gastroenteritis in children younger than 6 years in Japan. METHODS: Children admitted to eight hospitals for acute gastroenteritis between 2008 and 2009 were identified from hospital admission databases. Diagnosis of acute gastroenteritis/rotavirus gastroenteritis and hospital-acquired rotavirus gastroenteritis was confirmed based on either the International Classification of Diseases and Related Health Problems 10th revision (ICD10) codes (intestinal infectious diseases [AA00-AA09] and rotavirus gastroenteritis [A08.0]) or from rapid rotavirus diagnostic test results. RESULTS: Of 13,767 hospitalized children, 11.9% (1,644), 4.8% (665) and 0.6% (81) were diagnosed with acute gastroenteritis, rotavirus gastroenteritis and hospital-acquired rotavirus gastroenteritis, respectively. Among acute gastroenteritis hospitalizations, 40.5% (665/1,644; ICD10 and rapid test) and 57.7% (645/1,118; rapid test only) were confirmed as rotavirus positive. Of 1,563 children with community-acquired acute gastroenteritis, 584 (37.4%) cases were confirmed as rotavirus positive. The median durations of hospitalization for all and community-acquired rotavirus gastroenteritis were 5.0 days (range: 2.0-133.0 days) and 5.0 days (range: 2.0-34.0 days), respectively. Among rotavirus gastroenteritis hospitalizations, 12.2% (81/665) of cases were hospital-acquired and the median duration of hospitalization was 10.0 days (range: 2.0-133.0 days). The median duration of additional hospitalization due to hospital-acquired rotavirus gastroenteritis was 3.0 days (range: 0-14 days). The overall incidence rate of hospital-acquired rotavirus gastroenteritis was 1.0 per 1,000 children hospital-days. The number of rotavirus gastroenteritis cases peaked between February and May in both 2008 and 2009, and the highest number of cases was reported in March 2008 (21.8%; 145/665). The highest number of rotavirus gastroenteritis hospitalizations (24.1%; 160/665) was observed in children aged 12-18 months. The proportion of hospital-acquired rotavirus gastroenteritis was higher in children aged below 18 months as compared to children at least 18 months of age (0.94 [95% CI: 0.71-1.21] vs. 0.39 [95% CI: 0.25-0.58]) and for children hospitalized for at least 5 days compared to those hospitalized for less than 5 days (0.91 [95% CI: 0.72-1.14] vs. 0.15 [95% CI: 0.05-0.32]). CONCLUSIONS: Both community- and hospital-acquired rotavirus gastroenteritis are significant public health problems in Japan. Data from this study justify the need for the introduction and implementation of rotavirus vaccination in the Japanese national immunization program. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01202201.

The impact of childhood acute rotavirus gastroenteritis on the parents' quality of life: prospective observational study in European primary care medical practices.

BACKGROUND: Rotavirus (RV) is the commonest cause of acute gastroenteritis in infants and young children worldwide. A Quality of Life study was conducted in primary care in three European countries as part of a larger epidemiological study (SPRIK) to investigate the impact of paediatric rotavirus gastroenteritis (RVGE) on affected children and their parents. METHODS: A self-administered questionnaire was linguistically validated in Spanish, Italian and Polish. The questionnaire was included in an observational multicentre prospective study of 302 children aged <5 years presenting to a general practitioner or paediatrician for RVGE at centres in Spain, Italy or Poland. RV infection was confirmed by polymerase chain reaction (PCR) testing (n = 264). The questionnaire was validated and used to assess the emotional impact of paediatric RVGE on the parents. RESULTS: Questionnaire responses showed that acute RVGE in a child adversely affects the parents' daily life as well as the child. Parents of children with RVGE experience worry, distress and impact on their daily activities. RVGE of greater clinical severity (assessed by the Vesikari scale) was associated with higher parental worries due to symptoms and greater changes in the child's behaviour, and a trend to higher impact on parents' daily activities and higher parental distress, together with a higher score on the symptom severity scale of the questionnaire. CONCLUSIONS: Parents of a child with acute RVGE presenting to primary care experience worry, distress and disruptions to daily life as a result of the child's illness. Prevention of this disease through prophylactic vaccination will improve the daily lives of parents and children.

Burden of Male Hypogonadism and Major Comorbidities, and the Clinical, Economic, and Humanistic Benefits of Testosterone Therapy: A Narrative Review.

Male hypogonadism and major comorbidities such as type 2 diabetes mellitus, obesity, cardiovascular disease, and osteoporosis appear closely connected, forming a vicious cycle that leads to further hypogonadism. This narrative review provides a comprehensive overview of the current literature on the overall burden of male hypogonadism alongside related comorbidities, and how this may be alleviated through testosterone therapy. Observational and clinical data demonstrate that the interaction of male hypogonadism and its related comorbidities is associated with increased mortality, cardiovascular event risk and reduced quality of life. Evidence from epidemiological and registry-based studies shows that this clinical and humanistic burden translates to increased economic burden on health-care systems, through increased physician visits, medical claims, and drug costs. Male hypogonadism can be managed with testosterone therapy, which is intended to normalize testosterone concentrations and thereby reduce both hypogonadism symptoms and risk of comorbidities. Clinical and observational data suggest that in males with hypogonadism, testosterone therapy rapidly and sustainably improves glycemia, reduces risk of progression to diabetes, leads to significantly reduced waist circumference and fat mass, while providing significant positive effects on cardiovascular event risk and bone density. Significant and sustained improvement in patient-reported erectile function, urinary function, and aging male symptoms have also been shown. Economic evaluations have estimated that reduced comorbidity risk following testosterone therapy may lead to cost-savings, with one study estimating yearly inpatient savings of £3732 for treating comorbidities after intervention. A major unmet need exists in the area of male hypogonadism, particularly related to common comorbidities. Options for treatment include testosterone therapy, which has been shown to alleviate the clinical, economic, and humanistic burden associated with these conditions. As the prevalence of male hypogonadism is likely to increase globally, and this condition may be currently underdiagnosed, cost-saving testosterone therapies should be increasingly considered to manage hypogonadism.

Real-World Assessment of Interferon-ß-1b and Interferon-ß-1a Adherence Before and After the Introduction of the BETACONNECT® Autoinjector: A Retrospective Cohort Study.

BACKGROUND: Both interferon beta-1b (IFN-ß-1b) and interferon beta-1a (IFN-ß-1a) are immunomodulators that require regular subcutaneous self-administration by patients with multiple sclerosis (MS). However, no electronic autoinjector is available for IFN-ß-1a in the US. OBJECTIVE: This retrospective cohort study investigated adherence to two subcutaneous disease-modifying therapies, IFN-ß-1b and IFN-ß-1a, during two periods (before and after the introduction of the BETACONNECT® autoinjector for IFN-ß-1b). PATIENTS AND METHODS: Data were evaluated from the MarketScan database for adults in the US with an MS diagnosis and a medical claim for subcutaneous IFN-ß-1b or IFN-ß-1a, either before (October 2013-September 2015) or after the introduction of BETACONNECT (October 2016-September 2018). Patient populations were propensity-score matched by demographic and clinical characteristics. Persistence was recorded, and adherence was evaluated by medication possession ratio (MPR). RESULTS: The study included 196 IFN-ß-1b and 365 IFN-ß-1a people with MS (PwMS) (pre-BETACONNECT period), and 126 IFN-ß-1b and 223 IFN-ß-1a PwMS (post-BETACONNECT period). In the pre-BETACONNECT period, the proportion with at least 80% MPR was higher for IFN-ß-1a (90%) than for IFN-ß-1b (83%), but in the post-BETACONNECT period the proportion with ≥ 80% MPR was higher for IFN-ß-1b (92%) than for IFN-ß-1a (86%). In the pre-BETACONNECT period, median persistence (in days) was higher for IFN-ß-1a (199) than for IFN-ß-1b (152), while in post-BETACONNECT period persistence was higher for IFN-ß-1b (327) than for IFN-ß-1a (229). CONCLUSIONS: Following the introduction of BETACONNECT, this exploratory study suggested that PwMS taking IFN-ß-1b were more adherent compared with those taking IFN-ß-1a, with higher persistence, and more than 90% reached 80% MPR, a threshold commonly used to define good adherence.

Longitudinal changes in risk status in pulmonary arterial hypertension.

AIMS: Low-risk status in pulmonary arterial hypertension (PAH) predicts better survival. The present study aimed to describe changes in risk status and treatment approaches over multiple clinical assessments in PAH, taking age and comorbidity burden into consideration. METHODS AND RESULTS: The study included incident patients from the Swedish PAH registry, diagnosed with PAH in 2008-2019. Group A (n = 340) were ≤75 years old with <3 comorbidities. Group B (n = 163) were >75 years old with ≥3 comorbidities. Assessments occurred at baseline, first-year (Y1) and third-year (Y3) follow-ups. The study used an explorative and descriptive approach. Group A: median age was 65 years, 70% were female, and 46% had no comorbidities at baseline. Baseline risk assessment yielded low (23%), intermediate (66%), and high risk (11%). Among patients at low, intermediate, or high risk at baseline, 51%, 18%, and 13%, respectively, were at low risk at Y3. At baseline, monotherapy was the most common therapy among low (68%) and intermediate groups (60%), while dual therapy was the most common among high risk (69%). In patients assessed as low, intermediate, or high risk at Y1, 66%, 12%, and 0% were at low risk at Y3, respectively. Of patients at intermediate or high risk at Y1, 35% received monotherapy and 13% received triple therapy. In low-risk patients at Y1, monotherapy (40%) and dual therapy (43%) were evenly distributed. Group B: median age was 77 years, 50% were female, and 44% had ≥3 comorbidities at baseline. At baseline, 8% were at low, 80% at intermediate, and 12% at high risk. Monotherapy was the most common therapy (62%) in Group B at baseline. Few patients maintained or reached low risk at follow-ups. CONCLUSIONS: Most patients with PAH did not meet low-risk criteria during the 3 year follow-up. The first year from diagnosis seems important in defining the longitudinal risk status.

The effects of storage time and sampling season on the stability of serum 25-hydroxy vitamin D and androstenedione.

Knowledge of the stability of serum samples stored in large biobanks is pivotal for reliable assessment of hormone-dependent disease risks. We studied the effects of sample storage time and season of serum sampling on the stability of 25-hydroxy vitamin D (25-OHD) and androstenedione in a stratified random sample of 402 women, using paired sera from the Finnish Maternity Cohort. Serum samples selected were donated between 6 and 24 yr ago. The storage time did not affect serum 25-OHD and androstenedione levels. However, there was a significant mean difference in the 25-OHD levels of sera withdrawn during winter (first sample) vs. during summer (second sample; -18.4 nmol/l, P

Poor outcome of patients with pulmonary arterial hypertension with insufficient response to phosphodiesterase-5 inhibitors alone or in combination with other specific therapy: a registry-based study.

Phosphodiesterase-5 inhibitors are commonly used in pulmonary arterial hypertension but, as suggested by the RESPITE study, phosphodiesterase-5 inhibitor therapy (mono-/combination) does not always have a satisfactory treatment effect. This study aimed to investigate the clinical course of pulmonary arterial hypertension patients not at treatment goal after at least 90 days of treatment with phosphodiesterase-5 inhibitors, alone or in combination with other pulmonary arterial hypertension therapies. The study included 106 incident patients from the Swedish Pulmonary Arterial Hypertension Registry, treated with phosphodiesterase-5 inhibitors for ≥90 days, who were not at a pre-specified treatment goal, i.e. in World Health Organisation functional class III, with 6-min walking distance 165-440 m, and N-terminal prohormone of brain natriuretic peptide >300 ng/L. Changes in World Health Organisation functional class, 6-min walking distance, N-terminal prohormone of brain natriuretic peptide, and risk group between index and follow-up were assessed. Of patients with complete follow-up data, (n = 53) 77% were on combination therapy and risk assessment yielded 98% at intermediate risk at index. At follow-up, 11 patients transitioned from World Health Organisation functional class III to World Health Organisation functional class II, the median (Q1; Q3) change in 6-min walking distance was 6 (-30; 42) meters and in N-terminal prohormone of brain natriuretic peptide 47 (-410; 603) ng/L, while 89% remained at an intermediate risk. Of those without complete follow-up data, 11 patients died and 2 underwent lung transplantation. In conclusion, pulmonary arterial hypertension patients treated with phosphodiesterase-5 inhibitors, as single or combination therapy and not achieving the pre-specified treatment goals after ≥90 days have an unfavourable clinical course.

Endogenous steroid hormone levels in early pregnancy and risk of testicular cancer in the offspring: a nested case-referent study.

According to the leading hypothesis on testicular cancer (TC) etiology exposure to a specific pattern of steroid hormones in utero, in particular, to high levels of estrogens and low levels of androgens is the major determinant of TC risk in the offspring. We performed a case-referent study nested within Finnish, Swedish and Icelandic maternity cohorts exploiting early pregnancy serum samples to evaluate the role of maternal endogenous steroid hormones with regard to the risk of TC. TC cases and referents were aged between 0 and 25 years. For each case-index mother pair, three or four matched referent-referent mother pairs were identified using national population registries. First trimester or early second trimester sera were retrieved from the index mothers of 73 TC cases and 286 matched referent mothers, and were tested for dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone, estradiol, estrone, and sex hormone binding globulin (SHBG). Offspring of mothers with high DHEAS levels had a significantly decreased risk of TC (OR for highest vs. lowest DHEAS quartile, 0.18 (95% CI 0.06-0.58). In contrast, offspring of mothers with high androstenedione levels had an increased risk of TC (OR 4.1; 95% CI 1.2-12.0). High maternal total estradiol level also tended to be associated with an increased risk of TC in the offspring (OR 32; 95% CI 0.98-1,090). We report the first direct evidence that interplay of maternal steroid hormones in the early pregnancy is important in the etiology of TC in the offspring.

Burden of Herpes Zoster in the Japanese Population with Immunocompromised/Chronic Disease Conditions: Results from a Cohort Study Claims Database from 2005-2014.

INTRODUCTION: The aim of this study is to describe the disease burden and costs of herpes zoster (HZ) in the general adult Japanese population or patients with immunocompromised (IC) conditions or chronic disorders. METHODS: A retrospective cohort study of individuals aged 18-74 years was conducted using January 2005 to December 2014 records from the Japan Medical Data Center claims database. Twenty-eight IC conditions and chronic disorders were defined by diagnosis codes and/or procedures/treatments. HZ and its related complications were identified. Incidence rates (IR), frequency of HZ-related complications, healthcare resource utilization (HRU), and direct medical costs were estimated. HRU and costs were estimated on a subcohort of HZ cases occurring April 2012-January 2014. RESULTS: The overall IR of HZ in the total cohort of 2,778,476 adults was 4.92/1000 person-years (PY) [95% confidence interval (CI): 4.86-4.98] and increased with age. The IR in the IC cohort (51,818 subjects) was 8.87/1000 PY (95% CI: 8.29-9.48), ranging from 5.55/1000 PY (95% CI: 4.26-7.09) in psoriasis to 151.68/1000 PY (95% CI: 111.45-201.71) in hematopoietic stem cell transplant recipients; most IRs were in the range 6-10/1000 PY. The IRs in individuals with chronic disorders were also relatively high, in the range 5.40-12.90/1000 PY. The frequency of postherpetic neuralgia was 4.01% (95% CI: 3.72-4.33) in the total cohort and 11.73% (95% CI: 9.01-14.93) in the IC cohort. The mean [standard deviation (SD)] number of outpatient visits was 3.4 (4.9) and 5.0 (5.7), respectively, and the proportion of HZ patients hospitalized was 2.20% and 6.70%, respectively. The mean (SD) direct medical cost per HZ episode was ¥34,664 (¥54,433) and ¥55,201 (¥92,642) in the total and IC cohort, respectively. CONCLUSIONS: The elevated burden of HZ in Japanese individuals harboring IC conditions and chronic disorders documented in our study underlines the need for prevention of HZ in people with these conditions. FUNDING: GlaxoSmithKline Biologicals SA.

Maternal Epstein-Barr virus and cytomegalovirus infections and risk of testicular cancer in the offspring: a nested case-control study.

During recent decades the incidence of testicular cancer (TC) has increased rapidly around the world. Associated exogenous etiological factors might therefore be identifiable. We performed a case-control study nested within Finnish, Swedish and Icelandic maternity cohorts exploiting early pregnancy serum samples to evaluate the role of congenital or neonatal infections with Epstein-Barr virus (EBV) and cytomegalovirus (CMV) as risk factors of TC in the offspring. For each case-index mother pair, three or four matched control-control mother pairs were identified using national population registries. First trimester sera were retrieved from the index mothers of 66 TC cases and 258 matched control mothers, and were tested for antibodies to EBV and CMV. High level of maternal EBV IgG antibodies was associated with significantly increased risk of TC in the offspring (odds ratio (OR), 2.50; 95% confidence interval (CI), 1.15, 5.40), especially with risk of non-seminoma TC (OR, 2.73; 950% CI, 1.25, 5.99) and non-seminoma TC diagnosed under 8 years of age (OR, 2.72; 95% CI, 1.05, 7.04). In contrast, offspring of CMV IgG-seropositive mothers had a decreased risk of TC diagnosed under 8 years of age (OR, 0.35; 95% CI, 0.14, 0.89). Our results suggest that EBV and CMV infections may be associated with TC.

Effect of long-term storage on hormone measurements in samples from pregnant women: the experience of the Finnish Maternity Cohort.

Validity of biobank studies on hormone associated cancers depend on the extent the sample preservation is affecting the hormone measurements. We investigated the effect of long-term storage (up to 22 years) on immunoassay measurements of three groups of hormones and associated proteins: sex-steroids [estradiol, progesterone, testosterone, dihydroepiandrosterone sulphate (DHEAS), sex hormone-binding globulin (SHBG)], pregnancy-specific hormones [human chorionic gonadotropin (hCG), placental growth hormone (pGH), alpha-fetoprotein (AFP)], and insulin-like growth factor (IGF) family hormones exploiting the world largest serum bank, the Finnish Maternity Cohort (FMC). Hormones of interest were analyzed in a random sample of 154 Finnish women in the median age (29.5 years, range 25 to 34 years) of their first pregnancy with serum samples drawn during the first trimester. All hormone measurements were performed using commercial enzyme-linked- or radio-immunoassays. Storage time did not correlate with serum levels of testosterone, DHEAS, hCG, pGH and total IGFBP-1. It had a weak or moderate negative correlation with serum levels of progesterone (Spearman's ranked correlation coefficient (r(s))=- 0.36), IGF-I (r(s)=-0.23) and IGF binding protein (BP)-3 (r(s)=-0.38), and weak positive correlation with estradiol (r(s)=0.23), SHBG (r(s)=0.16), AFP (r(s)=0.20) and non-phosphorylated IGF binding protein (BP)-1 (r(s)=0.27). The variation of all hormone levels studied followed the kinetics reported for early pregnancy. Bench-lag time (the time between sample collection and freezing for storage) did not materially affect the serum hormone levels. In conclusion, the stored FMC serum samples can be used to study hormone-disease associations, but close matching for storage time and gestational day are necessary design components of all related biobank studies.