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Introduction The Salford Lung Studies (SLS) were real-world randomised controlled trials set within UK primary care that assessed the effectiveness and safety of initiating once-daily fluticasone furoate/vilanterol versus continuing usual care in patients with chronic obstructive pulmonary disease or asthma. Data were collected for a relatively short period, limiting the study of long-term outcomes. To broaden the capture of SLS patients’ data, we undertook the Extended SLS (Ext-SLS), aiming to better understand the patient disease journey and the effects of treatment in a real-world setting, through collection of patient-level data. Here, we present study design information and the challenges and learnings gathered in creating the Ext-SLS. Methods The Ext-SLS was intended to augment the SLS by collecting retrospective and prospective (up to 10 years from consent) primary and secondary care electronic health record (EHR) data and patient questionnaires. After ethics approval, general practitioners (GPs) obtained consent from SLS patients remotely (mean 3.2 years post-SLS completion). To facilitate GPs identifying eligible patients, a novel EHR-based approach flagged SLS patients who were alive and registered with their original GP. An automated system sent consent forms/questionnaires to patients. Medical data were collected via EHRs; primary care data were extracted from GPs’ systems whilst secondary care data were sourced from the UK NHS. Results Of the 75 GP sites from the SLS, 35 (47%) declined Ext-SLS participation leaving 4158 potentially eligible patients; 1169 (28%) patients were excluded as GPs could not confirm them as SLS participants or due to incapacity. Of 2989 patients invited, 1189 (40%) consented. Conclusions Developing an EHR-based trial extension was achieved, with reasonable consent rates amongst invited patients. The resulting Ext-SLS is a unique and valuable research resource. Leveraging EHRs and technology reduced GP burden, facilitating participation. Initiation of extension studies prior to study close-out may help increase GP and patient participation. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01827-2.

Belimumab is approved for active, autoantibody-positive systemic lupus erythematosus (SLE) and lupus nephritis, but limited data exist regarding its use in pregnancy. The Belimumab Pregnancy Registry (BPR, GSK Study BEL114256; NCT01532310) was created to evaluate pregnancy and infant outcomes following belimumab exposure.Individuals with SLE exposed to belimumab from 4 months before and/or during pregnancy can enroll into the BPR. The primary outcome is major birth defects; secondary outcomes include miscarriages, stillbirths, elective termination, pre-term birth, neonatal death, small for gestational age, and adverse infant outcomes during the first year of life. Belimumab exposure timing, concomitant medications, and other potential confounding factors are also collected. Data up to March 8, 2021, are reported descriptively.From an expected sample size target of 500 prospective pregnancies with a known outcome, only 55 were enrolled in the study. Among these, two pregnancy losses and 53 pregnancies with a live birth outcome were reported. Ten of the 53 live birth pregnancies resulted in a major birth defect. Ten pregnancies were enrolled after the pregnancy outcome occurred and were examined retrospectively (four live births with no defects, four miscarriages, and two elective terminations). There was no indication or pattern of birth defects associated with belimumab.Low recruitment numbers for the BPR and incomplete information limit the conclusions regarding belimumab exposure during pregnancy. There was no pattern or common mechanism of birth defects associated with belimumab within the BPR data.

Purpose To assess the feasibility of using Clinical Practice Research Datalink (CPRD) data for identifying populations of patients with chronic obstructive pulmonary disease (COPD) eligible for a hypothetical pragmatic trial. Methods A retrospective multidatabase cohort study using CPRD primary care and linked secondary care data to describe the characteristics of populations of patients with COPD. Patients' demographic and lifestyle factors, comorbidity profile, spirometry measurements and treatment changes were evaluated, as was the distribution of follow‐up time and types of losses during follow‐up. Characteristics were evaluated using descriptive statistics. Results A total of 322 991 patients from 1148 primary care practices in the United Kingdom across two CPRD primary care databases, CPRD GOLD and CPRD Aurum, were potentially eligible to participate in a hypothetical trial using CPRD, starting on 31 December 2017. Patients with COPD in CPRD GOLD and CPRD Aurum were comparable in terms of age (median age 70 vs. 68 years), gender (50% vs. 52% male), disease severity (e.g., 25% vs. 24% Medical Research Council [MRC] dyspnoea score grades 3–5) and history of respiratory conditions (e.g., 43% vs. 38% asthma). High proportions of patients with COPD in CPRD GOLD and CPRD Aurum were available on 31 December 2012 for follow‐up at 1, 2, and 5 years (92%, 85% and 67%, respectively). Conclusions Patients and data from CPRD GOLD and CPRD Aurum were comparable across key aspects relevant to COPD trials. A pragmatic trial using CPRD to recruit patients with COPD is scientifically feasible.

Background Estimates for lung function decline in chronic obstructive pulmonary disease (COPD) have differed by study setting and have not been described in a UK primary care population. Purpose To describe rates of FEV1 and FVC decline in COPD and investigate characteristics associated with accelerated decline. Patients and Methods Current/ex-smoking COPD patients (35 years+) who had at least 2 FEV1 or FVC measurements ≥6 months apart were included using Clinical Practice Research Datalink. Patients were followed up for a maximum of 13 years. Accelerated rate of lung function decline was defined as the fastest quartile of decline using mixed linear regression, and association with baseline characteristics was investigated using logistic regression. Results A total of 72,683 and 50,649 COPD patients had at least 2 FEV1 or FVC measurements, respectively. Median rates of FEV1 and FVC changes or decline were −18.1mL/year (IQR: −31.6 to −6.0) and −22.7mL/year (IQR: −39.9 to −6.7), respectively. Older age, high socioeconomic status, being underweight, high mMRC dyspnoea and frequent AECOPD or severe AECOPD were associated with an accelerated rate of FEV1 and FVC decline. Current smoking, mild airflow obstruction and inhaled corticosteroid treatment were additionally associated with accelerated FEV1 decline whilst women, sputum production and severe airflow obstruction were associated with accelerated FVC decline. Conclusion Rate of FEV1 and FVC decline was similar and showed similar heterogeneity. Whilst FEV1 and FVC shared associations with baseline characteristics, a few differences highlighted the importance of both lung function measures in COPD progression. We identified important characteristics that should be monitored for disease progression.

ObjectiveDescribe available data on birth defects and pregnancy loss in women with systemic lupus erythematosus (SLE) exposed to belimumab.MethodsData collected from belimumab clinical trials, the Belimumab Pregnancy Registry (BPR), and postmarketing/spontaneous reports up to 8 March 2020 were described. Belimumab exposure timing, concomitant medications and potential confounding factors were summarised descriptively.ResultsAmong 319 pregnancies with known outcomes (excluding elective terminations), 223 ended in live births from which birth defects were identified in 4/72 (5.6%) in belimumab-exposed pregnancies and 0/9 placebo-exposed pregnancies across 18 clinical trials, 10/46 (21.7%) belimumab-exposed pregnancies in the BPR prospective cohort (enrolled prior to pregnancy outcome) and 0/4 belimumab-exposed pregnancies in the BPR retrospective cohort (enrolled after pregnancy outcome), and 1/92 (1.1%) in belimumab-exposed pregnancies from postmarketing/spontaneous reports. There was no consistent pattern of birth defects across datasets. Out of pregnancies with known outcomes (excluding elective terminations), pregnancy loss occurred in 31.8% (35/110) of belimumab-exposed women and 43.8% (7/16) of placebo-exposed women in clinical trials; 4.2% (2/48) of women in the BPR prospective cohort and 50% (4/8) in the BPR retrospective cohort; and 31.4% (43/137) of belimumab-exposed women from postmarketing/spontaneous reports. All belimumab-exposed women in clinical trials and the BPR received concomitant medications and had confounding factors and/or missing data.ConclusionsObservations reported here add to limited data published on pregnancy outcomes following belimumab exposure. Low numbers of exposed pregnancies, presence of confounding factors/other biases, and incomplete information preclude informed recommendations regarding risk of birth defects and pregnancy loss with belimumab use.

Retosiban, an oxytocin receptor antagonist, was developed for treating spontaneous preterm labor (sPTL) in women with intact membranes. This ARIOS follow-up study aimed to characterize clinical safety, morbidity, and mortality of infants exposed to retosiban or comparator over 2 years. ARIOS prospectively assessed outcomes in infants whose mothers received at least one dose of retosiban or comparator (placebo/atosiban) in two Phase 3 sPTL trials. Both trials were terminated prematurely owing to poor enrolment. Infants could be enrolled into ARIOS from 28 days after estimated due date until hospital discharge or up to 9 months (corrected age). An internally developed questionnaire detailing medical conditions, mortality and resource use (Child Health Inventory; CHI), Ages and Stages Questionnaire-3 (ASQ-3), Modified Checklist for Autism in Toddlers-Revised with Follow-Up, and Child Behavior Checklist for Ages 1.5 to 5 were completed remotely by parents or legal guardians at prespecified intervals. Serious adverse events (SAEs) were primarily captured via CHI. No comparative statistical analysis was conducted between treatment arms. A total of 49 (86%) infants who had received retosiban and 49 (78%) infants who had received a comparator were enrolled in ARIOS. No deaths occurred during the study. Nine infants experienced SAEs: 6/49 (12.2%) infants in the comparators group and 3/49 (6.1%) in the retosiban group. Of the nine SAEs, seven were due to infections, three, and four in the retosiban and comparators groups, respectively. Based on ASQ-3 score, the incidence of neurodevelopmental delay at 18 and 24 months were 0/18 (0%) and 2/25 (8%) with retosiban and 7/22 (31.8%) and 3/21 (14.3%) with comparator, respectively. The current study showed no unexpected adverse outcome or impairment with retosiban based on safety monitoring and neurodevelopment assessments. No further follow-up is intended owing to the discontinuation of clinical development of retosiban.· There is a need for an effective and safe treatment for sPTL.. · ARIOS was a follow-up study of two Phase 3 trials in sPTL.. · There were no safety concerns with retosiban treatment.. · Slow recruitment led to termination of the Phase 3 trials..

To analyze the impact of ≥1 major congenital anomaly (CA) on risk and hospitalization for common neonatal morbidities. Retrospective infant cohort: 241,033 preterm and 3,446,156 term singletons in the US Premier Healthcare database (2006–2013) with up to 1-year follow-up. Discharge records were searched for ≥1 CA and neonatal morbidities. Five morbidities demonstrated strong increasing rates as GA decreased. RRs in preterm infants with CAs relative to those without CAs were: RDS (2.17, 95% CI 2.14–2.21), sepsis (2.42, 95% CI 2.37–2.46), apnea (2.04, 95% CI 2.01–2.07), infectious diseases (2.37, 95% CI 2.34–2.41), and hyperbilirubinemia (1.25, 95% CI 1.24–1.26). Median length of NICU stay (days) was consistently longer in infants with ≥1 CA relative to infants without CA during each GA period. Preterm infants with ≥1 major CA have increased risk of hospitalization for common morbidities, implying compromised neonatal health regardless of CA type.

PURPOSE: To validate an algorithm for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) episodes derived in an electronic health record (EHR) database, against AECOPD episodes collected in a randomized clinical trial using an electronic case report form (eCRF).METHODS: We analyzed two data sources from the Salford Lung Study in COPD: trial eCRF and the Salford Integrated Record, a linked primary-secondary routine care EHR database of all patients in Salford. For trial participants, AECOPD episodes reported in eCRF were compared with algorithmically derived moderate/severe AECOPD episodes identified in EHR. Episode characteristics (frequency, duration), sensitivity, and positive predictive value (PPV) were calculated. A match between eCRF and EHR episodes was defined as at least 1-day overlap.RESULTS: In the primary effectiveness analysis population (n = 2269), 3791 EHR episodes (mean [SD] length: 15.1 [3.59] days; range: 14-54) and 4403 moderate/severe AECOPD eCRF episodes (mean length: 13.8 [16.20] days; range: 1-372) were identified. eCRF episodes exceeding 28 days were usually broken up into shorter episodes in the EHR. Sensitivity was 63.6% and PPV 71.1%, where concordance was defined as at least 1-day overlap.CONCLUSIONS: The EHR algorithm performance was acceptable, indicating that EHR-derived AECOPD episodes may provide an efficient, valid method of data collection. Comparing EHR-derived AECOPD episodes with those collected by eCRF resulted in slightly fewer episodes, and eCRF episodes of extreme lengths were poorly captured in EHR. Analysis of routinely collected EHR data may be reasonable when relative, rather than absolute, rates of AECOPD are relevant for stakeholders' decision making.

Achondroplasia (ACH) is a rare, genetic condition and is the most common skeletal dysplasia resulting in disproportionate short stature and numerous multi-systemic comorbidities. As we enter an era of new treatment options which may impact comorbidities, it is important to understand the background rates of these events to aid evaluation of potential treatment effects. Thus, the aim of this literature review was to provide a comprehensive quantification of prevalence estimates of comorbidities in achondroplasia by age for use as a compiled reference to assist in quantifying the risk/benefit of new treatment options and informing timely management of ACH.PubMed and Embase databases were searched, complemented by manual bibliography searching, for peer-reviewed articles published between 1975 and 2021, guided by PRISMA principles. Number of patients and the prevalence of specific comorbidities by age were extracted. We calculated exact 95 %-confidence limits for the proportion of affected patients (prevalence) and data were presented visually using forest plots. An a priori decision was made not to utilise meta-analytic techniques to pool estimates as we intended to understand the variability in comorbidities by displaying each estimate separately.The literature search identified 206 articles of which 73 were eligible for inclusion. The majority of studies (n = 34) had been conducted in the USA or in Europe (n = 20). Study designs were mostly retrospective chart reviews (n = 33) or small cohort studies (n = 19). The availability of literature on particular conditions varied but trended towards a focus on assessment and prevention of severe conditions, such as respiratory conditions in children (21 studies), neurological manifestations (16 studies) and upper spine compression (15 studies). There was substantial heterogeneity in study design, type of clinical setting, populations and use of definitions in reporting comorbidities which need to be considered when interpreting study results. Despite the variability of the studies, comorbidity patterns by age were recognizable. In infants, a high prevalence (20 %) was found for kyphosis, a range of neurological manifestations and sleep apnea. There was also an excess mortality in infancy (4-7.8/100 person-years). Conditions identified in infancy continued to prevail in childhood. Genu varum was highly prevalent from the age children started to walk (9-75 %). Other conditions started to emerge in children; those with a high prevalence (20 %) were hearing loss and pain. In adolescence, neurological manifestations in the arm, neck or leg were reported (~15 %), consistent with symptomatic spinal stenosis or spinal compression. Fewer studies were available in older populations, especially in adults; however limited data suggest that pain and cardiovascular conditions, particularly excess weight and obesity, became more prevalent into adulthood. Mortality rates increased again in older age-groups.This review provides a reference base of current knowledge of the type and frequency of comorbidities in ACH. This not only allows future contextualisation of new treatment options but supports clinical decision-making on the timely medical management and intervention of ACH. This review also reflects the current medical priorities in the management of ACH, indicating a focus on pediatric care and the complex needs of individuals with ACH involving many different disciplines. Further studies into the natural history of this rare disease using more consistent definitions of comorbidities, especially into adulthood, are needed to elucidate the multi-systemic nature of this condition.

BACKGROUND Enrollment in pregnancy registries is challenging despite substantial awareness-raising activities, generally resulting in low recruitment owing to limited safety data. Understanding patient and physician awareness of and attitudes toward pregnancy registries is needed to facilitate enrollment. Crowdsourcing, in which services, ideas, or content are obtained by soliciting contributions from a large group of people using web-based platforms, has shown promise for improving patient engagement and obtaining patient insights. OBJECTIVE This study aimed to use web-based crowdsourcing platforms to evaluate Belimumab Pregnancy Registry (BPR) awareness among patients and physicians and to identify potential barriers to pregnancy registry enrollment with the BPR as a case study. METHODS We conducted 2 surveys using separate web-based crowdsourcing platforms: Amazon Mechanical Turk (a 14-question patient survey) and Sermo RealTime (a 11-question rheumatologist survey). Eligible patients were women, aged 18-55 years; diagnosed with systemic lupus erythematosus (SLE); and pregnant, recently pregnant (within 2 years), or planning pregnancy. Eligible rheumatologists had prescribed belimumab and treated pregnant women. Responses were descriptively analyzed. RESULTS Of 151 patient respondents over a 3-month period (n=88, 58.3% aged 26-35 years; n=149, 98.7% with mild or moderate SLE; and n=148, 98% from the United States), 51% (77/151) were currently or recently pregnant. Overall, 169 rheumatologists completed the survey within 48 hours, and 59.2% (100/169) were based in the United States. Belimumab exposure was reported by 41.7% (63/151) patients, whereas 51.7% (75/145) rheumatologists had prescribed belimumab to 10 patients who were pregnant or trying to conceive. Of the patients exposed to belimumab, 51% (32/63) were BPR-aware, and 45.5% (77/169) of the rheumatologists were BPR-aware. Overall, 60% (38/63) of patients reported belimumab discontinuation because of pregnancy or planned pregnancy. Among the 77 BPR-aware rheumatologists, 70 (91%) referred patients to the registry. Concerns among rheumatologists who did not prescribe belimumab during pregnancy included unknown pregnancy safety profile (119/169, 70.4%), and 61.5% (104/169) reported their patients’ concerns about the unknown pregnancy safety profile. Belimumab exposure during or recently after pregnancy or while trying to conceive was reported in patients with mild (6/64, 9%), moderate (22/85, 26%), or severe (1/2, 50%) SLE. Rheumatologists more commonly recommended belimumab for moderate (84/169, 49.7%) and severe (123/169, 72.8%) SLE than for mild SLE (36/169, 21.3%) for patients trying to conceive recently or currently pregnant. Overall, 81.6% (138/169) of the rheumatologists suggested a belimumab washout period before pregnancy of 0-30 days (44/138, 31.9%), 30-60 days (64/138, 46.4%), or >60 days (30/138, 21.7%). CONCLUSIONS In this case, crowdsourcing efficiently obtained patient and rheumatologist input, with some patients with SLE continuing to use belimumab during or while planning a pregnancy. There was moderate awareness of the BPR among patients and physicians.

Pragmatic or real-world trials typically incorporate many elements of pragmatism, including a generalizable target patient population for recruitment and collection of data through the process of routine care. However, in some instances critical data will need to be collected outside of usual practice to meet the research objective. This chapter will highlight some pragmatic trials that incorporated bespoke primary data collection into the protocol. These examples illustrate the range of specific study objectives, settings, and the choices made by investigators to maintain a pragmatic approach while still optimizing the validity of the study.

The Salford Lung Studies (SLS) were real-world effectiveness RCTs of initiating FF/VI vs. usual care (1:1) in asthma and COPD. Data were only collected in SLS for a relatively short period, limiting study of long-term outcomes. The Extended-SLS aims to augment the SLS, collecting 1° and 2° care electronic health record (EHR) data and patient questionnaires. After receiving Ethics approval, GPs remotely consented SLS subjects (mean 3.2 yrs post-completion). To facilitate GPs in identifying eligible patients, a novel EHR-based approach was used to flag subjects who completed the SLS, were still alive and registered with the same GP. An automated system (Docmail) was used to send consent forms/questionnaires direct to patients. Medical data were collected solely via EHRs; a trusted 3rd party extracted 1°-care data from GPs systems and NHS Digital provided linked 2°-care data. Of the 75 GP sites from the original SLS, 35 did not participate, resulting in 4,158 potentially eligible subjects from 40 practices; 18% were excluded as could not be confirmed as SLS subjects or incapacity. Of 2,989 invited, 39% consented to the study (see Figure). We demonstrate that developing an EHR-based, trial extension is achievable with good consent rates. Leveraging of EHRs and technology reduced GP burden, facilitating participation. Initiation of extension studies prior to study close out may help in reducing patient attrition.

Background Preterm labour and birth (PTL/PTB) is characterised by major health and developmental risks for children, life–changing consequences for their families, and substantial healthcare and economic challenges for wider society. While it is known that PTL/PTB impacts infant healthcare costs in the short and long term in Germany, maternal costs have not been described in detail. The aim of this study was to comprehensively describe costs and resource use among PTL/PTB mothers during pregnancy, at hospitalisation for delivery, and up to three years after delivery—overall and according to gestational age (GA) at delivery. Methods This study used data from the Statutory Health Insurance (SHI) sample of the AOK Hessen database in Germany. Mothers aged 12–44 years with deliveries between 2009 and 2013 and > 9 months of medical history prior to delivery were included. PTL/PTB mothers were defined by an International Classification of Diseases, 10th Revision (ICD-10) code for PTL during pregnancy, a diagnosis-related group (DRG) code indicating birthweight

Purpose A composite end point (CE) measuring neonatal benefit was created for use in tocolytic randomized controlled trials with rates assessed using data from one referral hospital. The goal of this study was to assess wider generalizability of the CE, using data from multiple integrated delivery networks, creating a cohort of linked mother-neonate pairs to understand neonatal outcomes in a broad population. Methods Retrospective data on births (2001-2012) were collected from 4 US integrated delivery networks in the COMparative effectiveness PAtient Safety and Surveillance (COMPASS) Research Network, and linked mother-neonate pairs were identified. The CE was analyzed for all in-hospital singleton neonates at ≥24 weeks of gestational age (GA) born to mothers aged ≤45 years at a referral hospital or hospital with >2000 annual births. Results The CE analyses included 56 485 eligible mother-neonate pairs; frequency of the CE decreased from 89% to 66% between GA weeks 24 and 29 and further decreased to 34 weeks of GA. Composite end point rates were 20% to 30% lower at 24 to 30 weeks of GA in COMPASS compared with Medical University of South Carolina but were similar by 31 weeks. Conclusions The COMPASS Network enabled evaluation of the CE across a large population demonstrating that the CE findings could be replicated beyond a single hospital and the potential for lower CE frequency. Based on this, an adaptive design was adopted for randomized controlled trials, specifically sample size reestimation to mitigate against the risk of lower outcome rates, highlighting the use of real-world data in drug development.

Safety and tolerability evaluation of adapted dose regimens containing fosamprenavir/ritonavir (FPV/r) in HIV-infected subjects with viral hepatitis co-infection.A retrospective multicohort analysis was conducted. Subjects from three European cohorts who started FPV/r or lopinavir/ritonavir (LPV/r) as a comparator contributed data to a centralized database. Subjects were divided into five groups by treatment regimen and level of hepatic impairment (aspartate aminotransferase [AST] platelet ratio index [APRI] scoreor ≥2). Multivariable Cox regression analyses controlling for demographic factors, baseline CD4 count, FIB-4 score, use of antiretroviral therapy, and laboratory markers (bilirubin and platelet count) were performed to identify factors independently associated with risk of developing adverse events or safety events (eg, drug discontinuation, alanine aminotransferase (ALT) elevation, hepatic decompensation/death).A total of 1096 patients contributed data to the study. Fosamprenavir/ritonavir (except in subjects with APRI ≥2 receiving standard dose) was associated with a higher two-year risk of drug discontinuation compared with LPV/r. Restricting the analysis to discontinuations due to adverse events (AEs), only subjects who received the reduced dose were more likely to discontinue ≥1 drug in the FPV/r regimen. There were no statistical differences in ALT elevation between groups. Incidence of hepatic decompensation events was similar among groups except for subjects who received non standard doses of FPV, though the number of events was small.Fosamprenavir/ritonavir discontinuation rate due to AEs or ALT elevation was similar across all European-approved FPV/r doses and to that of LPV/r subjects. Although liver tolerated antiretrovirals, such as integrase inhibitor and entry inhibitor, the use of FPV/r is acceptable in HIV infected patients with viral hepatitis.

AIM Recent evidence is emerging indicating long-term effects in infants born after an episode of preterm labour (PTL), even if birth is at term. This population-based study compared long-term rates of outcomes and health-care utilisation (HCU) in children born following spontaneous preterm labour, irrespective of gestational age at delivery or of an uncomplicated pregnancy (SPTLu), with children born following full-term labour (FTL), overall stratified by comorbidity status and assessed using a composite morbidity measure (CM). METHODS Retrospective data on mother-neonate pairs were collected from a patient-linked dataset from the Netherlands Perinatal Registry and the PHARMO Database Network. Children born between 2000 and 2010 were followed until 2012. RESULTS Of pregnancies in 134 006 mother-neonate pairs, 122 894 (92%) pregnancies resulted in FTL, and 11 112 (8%) resulted in PTL. Of the PTL pregnancies, 6599 (59%) were SPTLu. Mean follow-up after birth was 6.6-6.7 years. Children from SPTLu pregnancies were at increased risk of neurodevelopmental and respiratory conditions compared with those from FTL pregnancies. In children from SPTLu pregnancies, the presence of the CM was associated with an increased risk of respiratory conditions and failure to thrive. Post-natal hospitalisations (incidence rate (IR) per 100 patient-years: 18.1 vs. 11.7) and specialist referrals (IR per 1000 patient-years: 290.6 vs. 184.5) occurred significantly more frequently in children from SPTLu versus FTL pregnancies. CONCLUSION The increased risk of morbidities and HCU in children born following SPTLu pregnancy in this population-based setting reinforces the need for safe interventions that can effectively halt labour and lead to an improvement in childhood outcomes.

IntroductionTraditional phase IIIb randomised trials may not reflect routine clinical practice. The Salford Lung Study in chronic obstructive pulmonary disease (SLS COPD) allowed broad inclusion criteria and followed patients in routine practice. We assessed whether SLS COPD approximated the England COPD population and evidence for a Hawthorne effect.MethodsThis observational cohort study compared patients with COPD in the usual care arm of SLS COPD (2012–2014) with matched non-trial patients with COPD in England from the Clinical Practice Research Datalink database. Generalisability was explored with baseline demographics, clinical and treatment variables; outcomes included COPD exacerbations in adjusted models and pretrial versus peritrial comparisons.ResultsTrial participants were younger (mean, 66.7 vs 71.1 years), more deprived (most deprived quintile, 51.5% vs 21.4%), more current smokers (47.5% vs 32.1%), with more severe Global initiative for chronic Obstructive Lung Disease stages but less comorbidity than non-trial patients. There were no material differences in other characteristics. Acute COPD exacerbation rates were high in the trial population (98.37th percentile).ConclusionThe trial population was similar to the non-trial COPD population. We observed some evidence of a Hawthorne effect, with more exacerbations recorded in trial patients; however, the largest effect was observed through behavioural changes in patients and general practitioner coding practices.

Background: Preterm labor (PTL)/preterm birth (PTB) impose significant burden on health-care systems. Women with uncomplicated pregnancies at risk of PTL/PTB have not been widely investigated, and published evidence on the costs of these women and their infants in Italy is absent. We aimed to describe women with uncomplicated pregnancies and associated costs for these women and their infants. Methods: Data on women aged 12–44 years with uncomplicated pregnancies who delivered between 1 September 2009 and 31 December 2014 with PTL diagnosis alone or PTL and PTB were included from four Italian databases. Costs were examined during pregnancy, delivery, and 3 years after delivery for mothers and infants, overall and by gestational age (GA). Results: A total of 3058 mothers linked to 3333 infants were included. Costs during pregnancy were €1777. Costs during delivery for PTL/PTB mothers and their infants ranged from €3174 (GA ≥37) to €21007 (GA Conclusions: In Italy, PTL/PTB mothers with uncomplicated pregnancies with infants at lower GAs appeared to incur higher medical costs compared to mothers with infants at higher GAs in all three time periods, with particularly marked differences found when considering mother and infant combined costs.

Objective To propose and assess a composite endpoint (CE) of neonatal benefit based on neonatal mortality and morbidities by gestational age (GA) for use in preterm labor clinical trials. Study Design A descriptive, retrospective analysis of the Medical University of South Carolina Perinatal Information System database was conducted. Neonatal morbidities were assessed for inclusion in the CE based on clinical significance/risk of childhood neurodevelopmental impairment, frequency, and association with GA in a mother–neonate linked cohort, comprising women with uncomplicated singleton pregnancies delivered at ≥24 weeks' GA. Results Among 17,912 mother–neonate pairs, neonates were at a risk of numerous severe but infrequent morbidities. Clinically important, predominantly rare events were combined into a CE comprising neonatal mortality and morbidities, which decreased in frequency with increasing GA. The highest CE frequency occurred at Conclusions Descriptive epidemiological assessment and clinical input were used to develop a CE to measure neonatal benefit, comprising clinically meaningful outcomes. These empirical data and CE allowed trials investigating tocolytics to be sized appropriately.

Objective: We examined the association between blood eosinophil levels and subsequent rate of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in a population-based cohort of COPD patients managed in primary care. Methods: This retrospective cohort study included COPD patients from the UK Clinical Practice Research Datalink linked to the Hospital Episodes Statistics. Patients had ≥1 blood eosinophil count that was not performed within ±30 days of an AECOPD episode. Blood eosinophil counts were modelled as a continuous exposure variable using a fractional polynomial model; the best fitting model was plotted against the incidence rate (IR) of moderate or severe AECOPD per person-year (PY), stratified by AECOPD history and inhaled corticosteroid (ICS) use. Results: A total of 17,495 patients were included. In the overall cohort, the adjusted IRs of moderate or severe AECOPD increased modestly with increasing eosinophil counts, from 0.80/PY for blood eosinophil levels

Purpose: Fosamprenavir, combined with low-dose ritonavir (FPV/r), is indicated for treatment of HIV-infected children aged ≥6years in Europe. Our purpose was to assess the safety of licensed use of FPV/r in HIV-infected children reported to six cohorts in the European Pregnancy and Paediatric HIV Cohort Collaboration. Methods: Retrospective analysis of individual patient data for all children aged 6-18years taking the licensed dose of FPV up to 31/12/10. Adverse events (clinical events and absolute neutrophil counts, total cholesterol and triglycerides, and alanine transaminase) were summarised and DAIDS gradings characterised severity. Results: Ninety-two HIV-infected children aged 6-18years took the licensed dose, comprising 3% of the total number of children in follow-up in participating cohorts. Median age at antiretroviral therapy initiation was 6years (interquartile range 1-11years), and median age at start of FPV/r was 15years (12-17years). Estimated median time on an FPV-containing regimen was 52months, with a total of 266.9 patient years of exposure overall. Half (54%) were on an FPV-containing regimen at last follow-up. Rates of grade 3/4 events were generally low for all biochemical toxicity markers, and no serious adverse events considered to be causally related to FPV/r were reported. Conclusions: Results suggest that long-term licensed dose FPV-containing regimens appear to be generally well tolerated with few reported toxicities in HIV-infected children in Europe, although relatively infrequently prescribed. No serious events were reported. © 2013 The Authors.

Persistent high-risk human papillomavirus (HR-HPV) infection is the strongest risk factor for high-grade cervical precancer. We performed a systematic review and meta-analysis of HPV persistence patterns worldwide. Medline and ISI Web of Science were searched through January 1, 2010 for articles estimating HPV persistence or duration of detection. Descriptive and meta-regression techniques were used to summarize variability and the influence of study definitions and characteristics on duration and persistence of cervical HPV infections in women. Among 86 studies providing data on over 100,000 women, 73% defined persistence as HPV positivity at a minimum of two time points. Persistence varied notably across studies and was largely mediated by study region and HPV type, with HPV-16, 31, 33 and 52 being most persistent. Weighted median duration of any-HPV detection was 9.8 months. HR-HPV (9.3 months) persisted longer than low-risk HPV (8.4 months), and HPV-16 (12.4 months) persisted longer than HPV-18 (9.8 months). Among populations of HPV-positive women with normal cytology, the median duration of any-HPV detection was 11.5 and HR-HPV detection was 10.9 months. In conclusion, we estimated that approximately half of HPV infections persist past 6 to 12 months. Repeat HPV testing at 12-month intervals could identify women at increased risk of high-grade cervical precancer due to persistent HPV infections.

Purpose Global data on age-specific prevalence of human papillomavirus (HPV) infection in males, especially for oncogenic HPV types 16 and 18, are essential for future efforts to prevent HPV-related diseases, including expanded access to HPV prophylactic vaccines for boys and young men. Methods A systematic review of peer-reviewed publications was conducted to summarize worldwide data on genital HPV-DNA prevalence in men. Studies using polymerase chain reaction or hybrid capture detection assays were included. Results Approximately 6,600 abstracts were identified. Of them, 64 reported age-specific HPV prevalence and were included in the review. Of these, 38 were from populations at high risk of HPV infections, such as sexually transmitted infection clinic attendees, human immunodeficiency virus-positive males, and male partners of women with HPV infection or abnormal cytology. The largest proportions of studies were from Europe (38%) and North America (25%), with smaller proportions from Central and South America (19%), Asia (11%), and Africa (5%). Across all regions, data on HPV prevalence were generally limited to men >18 years of age. HPV prevalence was high among sexually active men in all regions but with considerable variation, from 1% to 84% among low-risk men and from 2% to 93% among high-risk men. Peak HPV prevalence spanned a wide range of ages and was generally not concentrated in the younger age groups. Age-specific prevalence curves were relatively flat or declined only slightly following peak prevalence. Conclusions Genital HPV infection in men varies widely, both between and within high- and low-risk groups and by geographic region. Compared with that in women, HPV prevalence in men seems to peak at slightly older ages and remains constant or decreases slightly with increasing age, suggesting persistent HPV infection or a higher rate of reinfection.

Objective To determine herpes simplex virus (HSV)-2 and HSV-1 seroprevalence in women and men in Romania. Methods A cross-sectional seroprevalence survey was conducted between 2004 and 2005 on a total of 1058 women and men representative of the population of Bucharest. All participants were aged 15–44 years and completed a structured questionnaire. A blood sample was collected to detect IgG anti-HSV-1 and HSV-2 serum antibodies using the HerpeSelect ELISA (Focus Diagnostics). Results A total of 761 women (median age 29 years) and 297 men (median age 29 years) were included. Overall, HSV-2 seroprevalence (15.2%) increased with age. Among women, HSV-2 seroprevalence increased from 11.0% in 15–19-year-olds to 38.3% in 40–44-year-olds. Among men, seroprevalence increased from 4.0% in 20–24-year-olds to 27.1% in 40–44-year-olds. HSV-2 seroprevalence was significantly higher among women than men (17.0% vs. 10.8%). HSV-1 seropositivity was high (87.2%) in all age groups, with no clear trend by age or by sex. In addition to older age and female sex, risk factors for HSV-2 included greater number of lifetime sexual partners, lower educational attainment, and history of genital vesicles. Lower educational level and rural residence were associated with a higher risk of HSV-1 seropositivity. Conclusions In Romania, HSV-2 seroprevalence was higher in women than men, and was within European limits and lower than that in Africa and the USA. In contrast, HSV-1 seroprevalence was generally higher than that previously recorded in similarly aged populations in Western Europe.

Thrombocytopenia (TCP) is a haematological condition known to occur in chronically infected hepatitis C (HCV) patients and may interfere with diagnostic procedures, such as liver biopsy, because of risk of bleeding. It may also exclude patients from effective antiviral treatment. We conducted a systematic literature review of articles and conference abstracts, to assess the prevalence of TCP among those with HCV and to describe demographics, liver disease stage and treatment characteristics of these patients. Studies of individuals with confirmed chronic HCV infection were included in the review if the study had a clear definition of thrombocytopenia and a sample size of at least 50 subjects. The final selection included 27 studies (21 articles and six abstracts). The definitions of thrombocytopenia varied between studies and were based either on platelet counts, with threshold levels ranging between ≤ 100 × 10(9) and ≤ 180 × 10(9) /L, or on criteria set in haematological guidelines. The prevalence of TCP ranged from 0.16% to 45.4% and more than half of the studies reported a TCP prevalence of 24% or more. Because of the different TCP definitions, heterogeneity in study design and insufficient data on study characteristics such as age, gender, HCV treatment rates and disease severity an overall summary estimate of TCP prevalence among patients with HCV was not feasible. However, the relatively large prevalence in the majority of the studies suggests that there may be a substantial number of HCV patients at risk of bleeding complications and reduced likelihood of successful HCV antiviral treatment.

Type-specific prevalence data of human papillomavirus (HPV) DNA in penile carcinoma are needed to determine the potential impact of HPV prophylactic vaccines, assuming demonstrated efficacy in men. A review was conducted using search terms including HPV and penile cancer. Studies using polymerase chain reaction (PCR) assays for HPV DNA detection in invasive penile carcinoma were included. A total of 1,266 squamous cell carcinoma (SCC) cases contributed data from 30 studies. The number of SCC was similar in Europe (28.2%), North America (27.6%), South America (23.9%) and Asia (20.4%). All SCC were histologically confirmed with biopsies for DNA detection. Most commonly used PCR primers were type-specific (35.2%), and combination PCR (18.2%). HPV prevalence was 47.9%, ranging from 22.4% in verrucous SCC to 66.3% for the basaloid/warty subtypes. HPV16 (30.8%), HPV6 (6.7%) and HPV18 (6.6%) were the most prevalent types. HPV16 and/or HPV 18 prevalence was 36.7%. HPV DNA was detected in half of SCC, with HPV16 being the most common type. If proven efficacious in men, prophylactic vaccines targeting carcinogenic types HPV16 and 18 could potentially reduce approximately one-third of incident SCC.

We thank Dr. Castle for his constructive and contributory commentary (1) on our meta-analysis of human papillomavirus (HPV) persistence and cervical neoplasia. We agree that ascertaining HPV persistence may have clinical utility and that several issues must be addressed before persistence can be effectively implemented in cervical screening programs. As Dr. Castle mentioned a single HPV test is more sensitive but less specific than a single Papanicolaou test for the detection of cervical precancer and cancer. In fact HPV testing at a single time point has approximately 20-40 percent higher sensitivity than Papanicolaou testing and 5-10 percent lower specificity. Incorporating HPV persistence into routine cervical cancer screening may help to improve specificity without unduly reducing sensitivity by distinguishing women with short-term infections and therefore lower risk of cervical precancer and cancer from women with long-term infections and therefore higher risk. (excerpt)

Although antiretroviral therapy (ART) is critical for preventing mother-to-child transmission of HIV, concern has been raised about the possibility that it may cause mitochondrial dysfunction in infants. There is adequate evidence for a mechanism by which exposure to nucleoside reverse transcriptase inhibitors (NRTIs) could lead to mitochondrial dysfunction; animal studies have shown evidence of mitochondrial dysfunction in the offspring of animals treated with NRTIs and mitochondrial disorders occur in adults treated with NRTIs. This systematic review synthesises the published research on mitochondrial dysfunction and disorders in infants exposed to HIV and antiretrovirals. We found conflicting evidence regarding the possible association of in utero ART exposure with mortality and morbidity due to mitochondrial dysfunction. ART exposure in utero or postpartum was associated with persistent decreases in lymphocytes, neutrophils and platelets as well as an increased risk of transient lactic acidaemia, anaemia and mitochondrial DNA depletion, although these laboratory findings were generally not associated with clinical symptoms. We conclude that large, prospective studies of HIV-exposed infants are needed to resolve the discrepant results regarding morbidity and mortality related to mitochondrial disorders, to ascertain the clinical significance of effects on laboratory values, to determine whether or not the incidence of mitochondrial disorders differs by regimen and to develop predictive models that might identify which infants are at the greatest risk. The challenges that remain to be addressed include the development of a sensitive but affordable screening algorithm in combination with specific diagnostic criteria; consistent collection of data on ART exposure and other risk factors, long-term follow-up of HIV-exposed but uninfected children and implementation in resource-limited settings.

Summary Background The prevalence of infections with herpes viruses 1 and 2 (HSV1 and HSV2) have significantly changed in the developed countries during the last three decades. This study provides up-to-date estimates of HSV-1 and HSV-2 seroprevalence and information on the correlates of infection in a representative sample of the Israeli population. Methods Three thousand eight hundred and eighty-one sera collected in 2000–2001 from an age-stratified general population sample were tested using an indirect IgG ELISA for type-specific HSV-1 and HSV-2 antibodies. Results Unadjusted HSV-1 seroprevalence was 59.8% (95% confidence interval: 58.2–61.4) and increased with age in both genders. Multivariate analysis revealed that HSV-1 seroprevalence rates were significantly higher in females, non-Jews, subjects who were not born in Israel, inhabitants of Jerusalem and Southern Israel and among subjects also seropositive for HSV-2. Unadjusted HSV-2 seroprevalence among adults was 9.2% (95% confidence interval: 7.9–10.2), and was higher in females, peaking at 20.5% in females aged 40–49. In a multivariate model, females, subjects who were not born in Israel and residents of Jerusalem and Southern Israel were significantly associated with HSV-2 seropositivity. Conclusions HSV-1 seroepidemiology in Israel resembles the trends in industrialized countries. HSV-2 seroprevalence rates is in the lower range reported across Europe.

Objective: To examine the type specific seroprevalence of herpes simplex virus (HSV) types 1 and 2 infections, stratified by age and gender, and associated risk factors for HSV-2 seropositivity in Poland. Methods: 2257 serum samples of individuals from 15–65 years were randomly selected from serum banks in four different geographical regions of Poland, including the Zachodnio-pomorskie, Warminsko-mazurskie, Lubelskie, and Mazowieckie districts. Type specific serum antibodies to HSV-1 and HSV-2 were detected using HerpeSelect IgG ELISA tests. Results: Overall prevalences of type specific HSV-1 and HSV-2 serum antibodies were 90.4% and 9.3%, respectively. Age standardised HSV-2 seroprevalence was higher in women (9.7%) than men (8.8%) (p = 0.06), and increased notably with age from 4% in 15–24 year olds to 12% in those aged 50–65 years. HSV-1 seroprevalence was consistently higher than HSV-2 seroprevalence in each specific age group, ranging from 74.5% in 15–24 year olds to 98.8% in 50–65 year olds. HSV-2 seroprevalence varied significantly by geographical region, with the highest prevalence in the Zachodnio-pomorskie district (12%). Significant multivariate risk factors for HSV-2 seropositivity included older age, female gender, and geographical place of residence. Conclusion: This large survey found a notably high seroprevalence of HSV-1, even among young female adolescents 15–19 years of age (80%). HSV-2 seropositivity was under 12% in all age groups surveyed in Poland, tending to be among the lowest overall HSV-2 seropositivity rates reported thus far in Europe.

This study describes the differences in sexual behaviour in individuals with genital herpes (GH) during "symptomatic" and "asymptomatic" periods of the disease.A cross sectional questionnaire was undertaken by 1193 individuals attending clinics between 1998 and 2001. All participants in this analysis were in heterosexual, monogamous partnerships, self identified with a history of symptomatic GH and with confirmed HSV-2 infection.Sexual activity reported during asymptomatic v symptomatic periods of GH was 98% v 40% (p0.001), 76% v 29% (p0.001), and 25% v 11% (p0.001) for vaginal, oral, and anal intercourse, respectively, while "always" condom use during asymptomatic and symptomatic periods was 20% v 35% (p0.001), 2% v 7% (p0.001), and 10% v 15% (p = 0.131), respectively. The proportion of individuals who either abstained from vaginal intercourse or "always" used condoms was 21% v 74% (p0.001), for asymptomatic v symptomatic periods. Multivariable analyses indicated that factors associated with engaging in intercourse during symptomatic periods of GH included current intrauterine device use (adjusted odds ratio (aOR) = 2.96, 95% confidence interval (CI) = 1.46 to 6.02); living in Latin America (aOR = 2.16, CI = 1.19 to 3.91) or Europe (aOR = 1.67, CI = 1.21 to 2.28), compared with North America; previous sexually transmitted disease (aOR = 1.42, CI = 1.08 to 1.89); a higher number of sexual acts per month (aOR = 1.09, CI = 1.06 to 1.11); and a higher number of GH recurrences per year (aOR = 1.08, CI = 1.03 to 1.12).These data indicate that the majority of people with GH either abstained from intercourse or "always" used condoms during symptomatic periods of GH. However, condom use was relatively low during asymptomatic periods in comparison with symptomatic periods. These results highlight that further education on GH prevention is warranted, particularly for symptomatic periods.

Countries in the the Asia-Pacific region and Africa tend to have the highest prevalence of hepatitis B infection worldwide. Hepatitis B infection progresses from an asymptomatic persistently infected status to chronic hepatitis B, cirrhosis, decompensated liver disease and/or hepatocellular carcinoma. The aim of this review was to summarize rates and risk factors for progression between disease states in the Asia-Pacific region and Africa. A literature search was conducted employing MEDLINE and EMBASE (1975-2003) using the following key words: hepatitis B, natural history, disease progression, cirrhosis, hepatocellular carcinoma, mortality, Africa and the Asia-Pacific region. Bibliographies of articles reviewed were also searched. Ranges for annual progression rates were: (i) asymptomatic persistent infection to chronic hepatitis B, 0.84-2.7%; (ii) chronic hepatitis B to cirrhosis, 1.0-2.4%; and (iii) cirrhosis to hepatocellular carcinoma, 3.0-6.6%. Patients with asymptomatic persistent infection and chronic hepatitis B had relatively low 5-year mortality rates ( 50%) were much higher in patients with decompensated liver disease and hepatocellular carcinoma. No data were found for progression rates in African populations. Hepatitis B e antigen was a risk factor for chronic hepatitis B, and bridging hepatic necrosis in chronic hepatitis B increased the risk of cirrhosis. Risk factors for hepatocellular carcinoma included cirrhosis, co-infection with hepatitis C virus, and genetic and environmental factors. In this review, wide ranges of disease progression estimates are documented, emphasizing the need for further studies, particularly in Africa, where progression rates are largely not available. Summarizing information on factors associated with disease progression should assist in focusing efforts to arrest the disease process in those at most risk.

Low-grade squamous intraepithelial lesions (LSIL) associated with certain human papillomavirus (HPV) genotypes may preferentially progress to cervical cancer. HPV genotyping may thus have the potential to improve the effectiveness of screening programs and to reduce overtreatment. LSIL cases (n = 8,308) from 55 published studies were included in a meta-analysis. HPV genotype distribution was assessed by geographic region and in comparison with published data on cervical squamous cell carcinoma (SCC). HPV detection in LSIL was 80% in North America but less than 70% in other regions, most likely reflecting regional differences in LSIL diagnosis. Among 5,910 HPV-positive LSILs, HPV16 was the most common genotype (26.3%) followed by HPV31 (11.5%), HPV51 (10.6%), and HPV53 (10.2%). HPV-positive LSILs from Africa were 2-fold less likely to be infected with HPV16 than those in Europe, and HPV-positive LSILs from North America were more likely to be infected with HPV18 than those from Europe or South/Central America. Interpretation for rarer genotypes was hampered by variation in HPV testing methodology. SCC/LSIL prevalence ratios indicated that HPV16 was 2-fold and HPV18 was 1.5-fold more common in SCC than in HPV-positive LSIL, thus appearing more likely to progress than other high-risk genotypes (SCC/LSIL prevalence ratios between 0.05 and 0.85). HPV53 and HPV66 showed SCC/LSIL ratios of 0.02 and 0.01, respectively. HPV genotype distribution in LSIL differs from that in cervical cancer, highlighting the importance of HPV genotype in the risk of progression from LSIL to malignancy. Some regional differences in the relative importance of HPV genotypes in LSIL were noted.

Background: Little non-clinic-based data are available on incident genital warts rates and related healthcare use. Goal: The goal of this study was to describe the incidence and predictors of genital warts and associated healthcare utilization patterns among a group of privately insured patients in the United States. Study: Health claims were evaluated prospectively from 5,914,107 privately insured individuals. Results: The rate of new genital warts claims per 100,000 person-years at risk, age-standardized to the 2001 U.S. privately insured population, increased from 117.8 in 1998 to 205.0 in 2001. The highest rates were among 20- to 29-year-olds. The majority of claims came from dermatology and obstetrics/gynecology. Conclusions: The incidence of genital warts, as measured by the rate of new claims, appears to be rising. Age associations with the rate of new genital warts claims differed by gender; these associations may be influenced by changes in health-seeking behavior, potentially driven by health awareness.

OBJECTIVES: To estimate the average cost per screening offer, cost per testing episode and cost per chlamydia positive episode for an opportunistic chlamydia screening programme (including partner management), and to explore the uncertainty of parameter assumptions, based on the costs to the healthcare system. METHODS: A decision tree was constructed and parameterised using empirical data from a chlamydia screening pilot study and other sources. The model was run using baseline data from the pilot, and univariate and multivariate sensitivity analyses were conducted. RESULTS: The total estimated cost for offering screening over 12 months to 33,215 females aged 16-24 was 493,412 pounds . The average cost (with partner management) was 14.88 pounds per screening offer (90% credibility interval (CI) 10.34 to 18.56), 21.83 pounds per testing episode (90% CI 18.16 to 24.20), and 38.36 pounds per positive episode (90% CI 33.97 to 42.25). The proportion of individuals accepting screening, the clinician (general practitioner/nurse) time and their relative involvement in discussing screening, the test cost, the time to notify patients of their results, and the receptionist time recruiting patients had the greatest impact on the outcomes in both the univariate and multivariate sensitivity analyses. CONCLUSIONS: Results from this costing study may be used to inform resource allocation for current and future chlamydia screening programme implementation.

Objectives: There have been few recent population-based herpes simplex virus type 2 (HSV-2) seroprevalence studies in England, but reports from the United States have indicated a 30% rise in HSV-2 seroprevalence between 1976 and 1994. This study aimed to ascertain trends in HSV-2 infection in England between 1991 and 2000. Study Design: Anonymized serum residues collected through public health laboratories across England from individuals aged 16 to 64 years seeking health care through the National Health Service in 1991 (n = 2259) and 2000 (n = 3646) were tested for anti-HSV-2 IgG using the HerpeSelect 2 enzyme-linked immunosorbent assay IgG (Focus). Results: In 9 sites across England, the age- and sex-standardized HSV-2 seroprevalence was 9.7% (95% confidence interval, 8.4-11.0%). Data from 4 sites common to both study years indicated no change in HSV-2 seroprevalence between 1991 and 2000. Conclusions: After adjustment for age, sex, and geographic location, there was no evidence of a change in seroprevalence between 1991 and 2000.

Objectives: To determine the prevalence and treatment outcomes among young women screened opportunistically for genital Chlamydia trachomatis and to evaluate the impact of screening in those participating. Design: An opportunistic screening programme (1 September 1999 to 31 August 2000) using urine samples, tested by ligase chain reaction (LCR). In-depth interviews were used for programme evaluation. Setting: Screening was offered in two health authorities at general practice, family planning, genitourinary medicine (GUM), adolescent sexual health, termination of pregnancy clinics and women’s services in hospitals (antenatal, colposcopy, gynaecology and infertility clinics). Main participants: Sexually active women (16–24 years) attending for any reason. Main outcome measures: Screening data: prevalence of infection by age and healthcare setting; proportion of positive patients attending for treatment. Evaluation data: participants’ attitudes and views towards screening and follow up. Results: In total, 16 930 women (16–24 years) were screened. Prevalence was higher in younger women (16–20) than those aged 21–24 years and was highly variable at different healthcare settings (range 3.4%–17.6%). Prevalence was approximately 9% in general practice. The role of the project health advisers in managing results and coordinating treatment of positive individuals was essential; the vast majority of all positives were known to be treated. Women felt that screening was beneficial. Improving awareness and education about sexually transmitted infections is required to alleviate negative reactions associated with testing positive for infection. Conclusions: Prevalence of infection outside GUM clinics is substantial and opportunistic screening using urine samples is an acceptable method of reaching individuals with infection who do not normally present at specialist clinics.

A pilot study has been carried up in the United Kingdom to assess the feasibility of a national screening programme of genital chlamydial infections. The preliminary results show a high acceptance rate (70% of the candidates) and a significant coverage of the target population (40% over a six months period). Several other studies are ongoing in order to specify the more appropriate screening processes and partner notification strategies, as well as the cost effectiveness of a national programme.

Objective Data on human papillomavirus (HPV) prevalence in vulvar and vaginal cancers are limited. These data are important to predict the potential future effect of prophylactic HPV vaccines. Our aim was to conduct a systematic review of HPV type distribution in vulvar and vaginal invasive carcinomas, vulvar intraepithelial neoplasia (VIN), and vaginal intraepithelial neoplasia. Data sources A MEDLINE search was conducted using the terms vulvar/vaginal cancer, intraepithelial neoplasia, and HPV/human papillomavirus through September 2007 with no specified start date or language restrictions. Methods of study selection A total of 725 abstracts (564 vulvar, 161 vaginal) were reviewed, of which 67 studies (56 vulvar, 11 vaginal) met the inclusion criteria of using polymerase chain reaction (PCR) or hybrid capture assays for HPV DNA detection and having more than one case with HPV data available. Tabulation, integration and results This review identified 2,790 vulvar (1,379 invasive, 1,340 VIN2/3, 71 VIN1) and 315 vaginal cases (83 invasive, 166 vaginal intraepithelial neoplasia 2/3, 66 vaginal intraepithelial neoplasia 1). Most cases were from North America and Europe (87.2%), with few from Asia (5.5%) and South America (7.3%). Human papillomavirus prevalence in vulvar cancer, VIN2/3, and VIN1 was 40.1%, 80.4%, and 77.5%, respectively. HPV prevalence in vaginal cancer, vaginal intraepithelial neoplasia (VAIN)2/3, and VAIN1 was relatively higher at 65.5%, 92.6%, and 98.5%, respectively. HPV16 was the most common type in vulvar (29.3%) and vaginal (55.4%) cancers, VIN2/3 (71.2%) and VAIN2/3 (65.8%). Conclusion Human papillomavirus prevalence was higher among vaginal than vulvar cases, and HPV16 accounted for most HPV-positive cases for both cancers. Although the potential effect of HPV vaccines on these gynecologic cancers may not be as high as for cervical cancer due to their more diverse causes, vaccinating young women against HPV16/18 may help to reduce the incidence of HPV-related cases.

A systematic review was conducted of HPV type distribution in anal cancer and anal high-grade and low-grade squamous intraepithelial lesions (HSIL and LSIL). A Medline search of studies using PCR or hybrid capture for HPV DNA detection was completed. A total of 1,824 cases were included: 992 invasive anal cancers, 472 HSIL cases and 360 LSIL cases. Crude HPV prevalence in anal cancer, HSIL, and LSIL was 71, 91 and 88%, respectively. HPV16/18 prevalence was 72% in invasive anal cancer, 69% in HSIL and 27% in LSIL. The HPV 16 and/or 18 prevalence in invasive anal cancer cases was similar to that reported in invasive cervical cancer. If ongoing clinical trials show efficacy in preventing anal HPV infection and associated anal lesions, prophylactic HPV vaccines may play an important role for the primary prevention of these cancers in both genders.

Detection of persistent cervical carcinogenic human papillomavirus (HPV) DNA is used as a marker for cervical cancer risk in clinical trials. The authors performed a systematic review and meta-analysis of the association between persistent HPV DNA and high-grade cervical intraepithelial neoplasia (CIN2-3), high-grade squamous intraepithelial lesions (HSIL), and invasive cervical cancer (together designated CIN2-3/HSIL+) to evaluate the robustness of HPV persistence for clinical use. MEDLINE and Current Contents were searched through January 30, 2006. Relative risks (RRs) were stratified by HPV comparison group. Of 2,035 abstracts, 41 studies were eligible for inclusion in the meta-analysis. Over 22,500 women were included in calculation of RRs for persistent HPV DNA detection and cervical neoplasia. RRs ranged from 1.3 (95% confidence interval: 1.1, 1.5) to 813.0 (95% confidence interval: 168.2, 3,229.2) for CIN2-3/HSIL+ versus 12 months), wider testing intervals, CIN2-3/HSIL+, and use of an HPV-negative reference group were consistently associated with higher RRs. Thus, HPV persistence was consistently and strongly associated with CIN2-3/HSIL+, despite wide variation in definitions and study methods. The magnitude of association varied by duration of persistence and testing interval. Precise definition and standardization of HPV testing, sampling procedure, and test interval are needed for reliable clinical testing. These findings validate HPV persistence as a clinical marker and endpoint.

The aim was to study the type-specific seroprevalence of Herpes simplex virus (HSV)-1 and HSV-2 infections and the associated risk factors in children, adolescents and adults in Greece. A total of 1867 serum samples from children, adolescents and adults of both genders aged from 0 to 60 years were collected from three large hospital-referral centres in Athens. All sera were tested for type-specific antibodies to HSV-1 and HSV-2 using HerpeSelect IgG ELISA tests (Focus Diagnostics Cypress, Cal, USA). Overall age-adjusted seroprevalence of HSV-1 and HSV-2 was 72.0% and 10.2%, respectively. HSV-1 seropositivity was low in children up to nine years of age, increased sharply in adolescence, and was higher in females than males in each group surveyed. HSV-2 seropositivity was low (0.8%) below 20 years of age and increased to a maximum prevalence of 18.7% in men and 22.7% in women. Multivariate risk factor analyses indicated that HSV-1 seropositivity was associated with socioeconomic indicators (e.g. lower educational level, residency outside greater Athens), whereas HSV-2 was associated with sexual behavioural factors (e.g. being divorced, greater number of lifetime sexual partners). HSV-2 risk factor profiles were similar in women and in men. This first large seroprevalence study in Greece showed a high age-standardized HSV-1 seropositivity after adolescence and a relatively low age-standardized HSV-2 seroprevalence from birth to 60 years of age. Dual seropositivity to HSV-1 and HSV-2 was low (0.6%) in females under 20 years of age, suggesting that the potential use of an HSV-2 prophylactic vaccine in adolescents could reduce the spread of HSV-2 infection.

Global data on age-specific prevalence of human papillomavirus (HPV) infection overall, and for high-risk HPV types 16 and 18, are essential for the future implementation of HPV prophylactic vaccines for cervical cancer prevention.A systematic review of peer-reviewed publications was conducted to summarize worldwide data on genital HPV-DNA prevalence in women. Studies with clear descriptions of polymerase chain reaction or hybrid capture detection assays were included.A total of 346,160 women were included in 375 studies. Of 134 studies with age-stratified HPV prevalence data (116 low sexual risk populations, 18 high sexual risk populations), over 50% were from Europe and the Middle East (38%) and North America (19%), with smaller proportions from Asia and Australia (21%), Central and South America (11%), and Africa (10%). Across all geographical regions, data on HPV prevalence were generally limited to women over 18 years of age. Consistently across studies, HPV infection prevalence decreased with increasing age from a peak prevalence in younger women (or =25 years of age). In middle-aged women (35-50 years), maximum HPV prevalence differed across geographical regions: Africa (approximately 20%), Asia/Australia (approximately 15%), Central and South America (approximately 20%), North America (approximately 20%), Southern Europe/Middle East (approximately 15%), and Northern Europe (approximately 15%). Inconsistent trends in HPV prevalence by age were noted in older women, with a decrease or plateau of HPV prevalence in older ages in most studies, whereas others showed an increase of HPV prevalence in older ages. Similar trends of HPV 16 and/or 18 prevalence by age were noted among 12 populations with available data.Genital HPV infection in women is predominantly acquired in adolescence, and peak prevalence in middle-aged women appears to differ across geographical regions. Worldwide variations in HPV prevalence across age appear to largely reflect differences in sexual behavior across geographical regions. Further studies of HPV prevalence in adolescents are needed for all geographic regions.