Site staff perspectives on communicating trial results to participants: Cost and feasibility results from the Show RESPECT cluster randomised, factorial, mixed-methods trial.

BACKGROUND/AIMS: Sharing trial results with participants is an ethical imperative but often does not happen. Show RESPECT (ISRCTN96189403) tested ways of sharing results with participants in an ovarian cancer trial (ISRCTN10356387). Sharing results via a printed summary improved patient satisfaction. Little is known about staff experience and the costs of communicating results with participants. We report the costs of communication approaches used in Show RESPECT and the views of site staff on these approaches. METHODS: We allocated 43 hospitals (sites) to share results with trial participants through one of eight intervention combinations (2 × 2 × 2 factorial; enhanced versus basic webpage, printed summary versus no printed summary, email list invitation versus no invitation). Questionnaires elicited data from staff involved in sharing results. Open- and closed-ended questions covered resources used to share results and site staff perspectives on the approaches used. Semi-structured interviews were conducted. Interview and free-text data were analysed thematically. The mean additional site costs per participant from each intervention were estimated jointly as main effects by linear regression. RESULTS: We received questionnaires from 68 staff from 41 sites and interviewed 11 site staff. Sites allocated to the printed summary had mean total site costs of sharing results £13.71/patient higher (95% confidence interval (CI): -3.19, 30.60; p = 0.108) than sites allocated no printed summary. Sites allocated to the enhanced webpage had mean total site costs £1.91/patient higher (95% CI: -14, 18.74; p = 0.819) than sites allocated to the basic webpage. Sites allocated to the email list had costs £2.87/patient lower (95% CI: -19.70, 13.95; p = 0.731) than sites allocated to no email list. Most of these costs were staff time for mailing information and handling patients' queries. Most site staff reported no concerns about how they had shared results (88%) and no challenges (76%). Most (83%) found it easy to answer queries from patients about the results and thought the way they were allocated to share results with participants would be an acceptable standard approach (76%), with 79% saying they would follow the same approach for future trials. There were no significant effects of the randomised interventions on these outcomes. Site staff emphasised the importance of preparing patients to receive the results, including giving opt-in/opt-out options, and the need to offer further support, particularly if the results could confuse or distress some patients. CONCLUSIONS: Adding a printed summary to a webpage (which significantly improved participant satisfaction) may increase costs to sites by ~£14/patient, which is modest in relation to the cost of trials. The Show RESPECT communication interventions were feasible to implement. This information could help future trials ensure they have sufficient resources to share results with participants.

A peer-led, school-based social network intervention for young people in the UK, promoting sexual health via social media and conversations with friends: intervention development and optimisation of STASH.

BACKGROUND: The quality of school-based sex and relationships education (SRE) is variable in the UK. Digitally-based interventions can usefully supplement teacher-delivered lessons and positively impact sexual health knowledge. Designed to address gaps in core SRE knowledge, STASH (Sexually Transmitted infections And Sexual Health) is a peer-led social network intervention adapted from the successful ASSIST (A Stop Smoking in Schools Trial) model, and based on Diffusion of Innovation theory. This paper describes how the STASH intervention was developed and refined. METHODS: Drawing on the Six Steps in Quality Intervention Development (6SQuID) framework, we tested a provisional programme theory through three iterative stages -: 1) evidence synthesis; 2) intervention co-production; and 3) adaptation - which incorporated evidence review, stakeholder consultation, and website co-development and piloting with young people, sexual health specialists, and educators. Multi-method results were analysed in a matrix of commonalities and differences. RESULTS: Over 21 months, intervention development comprised 20 activities within the three stages. 1) We identified gaps in SRE provision and online resources (e.g. around sexual consent, pleasure, digital literacy), and confirmed critical components including the core ASSIST peer nomination process, the support of schools, and alignment to the national curriculum. We reviewed candidate social media platforms, ruling out all except Facebook on basis of functionality restrictions which precluded their use for our purposes. 2) Drawing on these findings, as well as relevant behaviour change theories and core elements of the ASSIST model, we co-developed new content with young people and other stakeholders, tailored to sexual health and to delivery via closed Facebook groups, as well as face-to-face conversations. 3) A pilot in one school highlighted practical considerations, including around peer nomination, recruitment, awareness raising, and boundaries to message sharing. From this, a revised STASH intervention and programme theory were co-developed with stakeholders. CONCLUSIONS: STASH intervention development required extensive adaptation from the ASSIST model. Although labour intensive, our robust co-development approach ensured that an optimised intervention was taken forward for feasibility testing. Evidencing a rigorous approach to operationalising existing intervention development guidance, this paper also highlights the significance of balancing competing stakeholder concerns, resource availability, and an ever-changing landscape for implementation. TRIAL REGISTRATION: ISRCTN97369178.

Exploring the psychosexual impact and disclosure experiences of women testing positive for high-risk cervical human papillomavirus.

OBJECTIVES: To examine the psychosexual impact and disclosure experiences of women testing HPV-positive following cervical screening. DESIGN: In-depth semi-structured interviews. METHODS: Interviews were conducted with 21 women of screening age (i.e. those aged 24-65 years) in England who self-reported testing HPV-positive in the context of cervical screening in the last 12 months. Data were analysed using Framework Analysis. RESULTS: The sexually transmitted nature of HPV, and aspects relating to the transmission of HPV and where their HPV infection had come from, had an impact on women's current, past and future interpersonal and sexual relationships. Most women had disclosed their HPV infection to others, however the factors influencing their decision, and others' reactions to disclosure differed. The magnitude and extent of psychosexual impact was influenced by how women conceptualized HPV, their understanding of key aspects of the virus, concerns about transmitting HPV and having a persistent HPV infection. CONCLUSIONS: Increasing knowledge of key aspects of HPV, such as its high prevalence and spontaneous clearance, and the differences between HPV and other STIs, may increase women's understanding of their screening result and reduce any negative psychosexual consequences of testing HPV-positive. Referring to HPV as an infection that is passed on by skin-to-skin contact during sexual activity, rather than an STI, may help to lessen any psychosexual impact triggered by the STI label.

An interactive website for informed contraception choice: randomised evaluation of Contraception Choices.

OBJECTIVE: Improving use of effective contraception to prevent unintended pregnancy is a global priority, but misperceptions and concerns about contraception are common. Our objective was to evaluate an interactive website to aid informed choice of contraception. METHODS: The Contraception Choices website is an interactive digital intervention which offers tailored advice to aid contraception decision-making (www.contraceptionchoices.org). In a parallel single-blind trial, we randomised 927 women aged 15-30 years from six clinic settings to access the intervention website (n = 464) or to a waiting-list control group (n = 463). The study was initially a feasibility trial, evolving into an evaluation of efficacy, with two primary outcomes at six months: long-acting reversible contraception (LARC) use, and satisfaction with contraceptive method. Secondary outcomes included self-reported pregnancy and sexually transmitted infection diagnoses. Free-text comments on the 3 and 6 month outcome surveys were analysed thematically. FINDINGS: There was no significant difference between intervention and control groups in the proportion of women using LARC [30.4% intervention versus 31.0% control; adjusted odds ratio 0.87 (95% confidence interval 0.60 to 1.28)]; satisfaction with contraceptive method [82.6% versus 82.1%; adjusted ordinal odds ratio 0.93 (95% CI 0.69 to 1.25)]; self-reported pregnancy [3.3% versus 4.1%; adjusted odds ratio 0.90 (95% CI 0.45 to 1.79)] nor sexually transmitted infection [5.3% versus 4.7%; adjusted odds ratio 0.72 (95% CI 0.55 to 2.36)]. Highly positive free-text comments from intervention participants indicated that the website facilitates contraception choice and can help women feel better prepared before consultation with healthcare providers. INTERPRETATION: The Contraception Choices website was popular for its design, trustworthy information and decision aids but it was not associated with significant differences in use of LARC or satisfaction with contraceptive method. An interactive website can aid contraception choice, but interventions that address factors beyond women's control, such as access to services, and partner, family or community influences are needed to complement this approach. RESEARCH IN CONTEXT: Preventing unintended pregnancy through effective use of contraception is essential for women's health, but choosing between different contraceptive methods can be challenging, and the opportunity for adequate discussion during routine consultations is often constrained. EVIDENCE BEFORE THIS STUDY: We conducted two systematic literature reviews: 1) Factors influencing contraception choice, uptake and use: a meta-synthesis of systematic reviews; and 2) Effectiveness of interactive digital interventions (IDI) for contraception choice, uptake and use. For the first review we searched PubMed, CDSR, Epistemonikos, DoPHER, DARE, NHS Economic Evaluation Database, Campbell Library, NIHR Health Technology Assessment, and Health Evidence Canada databases for systematic reviews which addressed contraceptive choice, uptake or use, from 2000 to 2017. PROSPERO registration number: CRD42017081521 https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=81521. We synthesised the findings of 18 systematic reviews of mostly moderate or high quality. They highlighted the importance of women's knowledge, beliefs, perceptions of side effects and health risks, as well as relationship status, social network, economic and healthcare factors on contraception choice and use. For the second review, we searched 23 electronic databases, trials registers and reference lists for randomised controlled trials of IDI for contraception, including CENTRAL, MEDLINE, EMBASE, CINAHL, ERIC, ASSIA and PsycINFO, from start date to June 2017. PROSPERO registration number: CRD42017081636. We found only five randomised trials of IDI, all from the USA. Risk of bias prevented synthesis of results. www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=81636. ADDED VALUE OF THIS STUDY: Women's common concerns about contraception - fear of hormones, weight gain, cancer, infertility, mood changes, breaks from contraception and changes in bleeding patterns - underpinned development of a new interactive website (www.contraceptionchoices.org). Contraception Choices addresses women's concerns through succinct text; Q and A format (Frequently Asked Questions, Did you Know?; videos of women and health professionals); an effectiveness infographic, and an interactive decision aid (What's right for me?).In an online randomised trial with 927 women attending clinics, we found no association of the Contraception Choices intervention with the primary outcomes - satisfaction with contraceptive method and uptake of long-acting reversible methods at 6 months. Nor did we find an association with secondary adverse outcomes - sexually transmitted infections or pregnancy. Comments from women indicated that the website can meet young women's need for information on the benefits and drawbacks of contraception, help them to make informed decisions, and feel better prepared before healthcare consultations. Contraception Choices is now available on the NHS website: www.nhs.uk/conditions/contraception/which-method-suits-me. IMPLICATIONS OF ALL THE AVAILABLE EVIDENCE: Interactive digital interventions (websites) can aid contraception choice, but other intervention research is needed to address wider influences on unintended pregnancy, including partner views, friends, family, the media, wider society and experiences with healthcare professionals. Future research could examine the impact of the website in different settings, e.g. schools or different countries. We hypothesise that use of the website during contraceptive consultations might improve the efficiency or quality of consultation, for both patients and healthcare providers. Appropriate methodology and time-scale for evaluating digital health interventions remains a key question.

Concerns about disclosing a high-risk cervical human papillomavirus (HPV) infection to a sexual partner: a systematic review and thematic synthesis.

BACKGROUND: Human papillomavirus (HPV)-based cervical screening is now replacing cytology-based screening in several countries and many women in screening programmes will consequently receive HPV-positive results. Because of the sexually transmitted nature of HPV, receiving an HPV-positive result may raise questions about disclosing the infection to a sexual partner. OBJECTIVE: To review the quantitative and qualitative literature exploring women's concerns about disclosing a high-risk cervical HPV infection to a sexual partner. METHODS: We searched MEDLINE, PsycINFO, CINAHL Plus, Web of Science and EMBASE for studies reporting at least one disclosure-related outcome among women with high-risk HPV. We also searched the grey literature and carried out forward/backward citation searches. A narrative synthesis for quantitative studies and a thematic synthesis for qualitative studies were conducted. RESULTS: Thirteen articles met the inclusion criteria (12 qualitative, 1 quantitative). In the quantitative study, 60% of HPV-positive women felt disclosing an HPV result was 'risky'. Concerns about disclosing HPV to a sexual partner were influenced by the stigma that is associated with having an STI and uncertainty about how their partner would respond. Women questioned how, when and to whom they should disclose their HPV-positive status. CONCLUSIONS: The studies included in this review provide rich information about the range of concerns women have, the reasons for these concerns, and the questions women have about disclosing HPV to sexual partners. As studies were predominantly qualitative, the prevalence of concerns is unclear.

The psychosexual impact of testing positive for high-risk cervical human papillomavirus (HPV): A systematic review.

OBJECTIVES: Many countries are implementing human papillomavirus (HPV)-based cervical screening due to the higher sensitivity of the test compared with cytology. As HPV is sexually transmitted, there may be psychosexual consequences of testing positive for the virus. We aimed to review the literature exploring the psychosexual impact of testing positive for high-risk cervical HPV. METHODS: MEDLINE, PsycINFO, CINAHL Plus, Web of Science, and EMBASE were searched with no date limits. We also searched the grey literature, reference lists of included articles and carried out forward citation searching. Eligible studies reported at least one psychosexual outcome among HPV-positive women. Qualitative and quantitative papers were included. We extracted data using a standardised form and carried out a quality assessment for each article. We conducted a narrative synthesis for quantitative studies and a thematic synthesis for qualitative studies. RESULTS: Twenty-five articles were included. Quantitative study designs were diverse making it difficult to determine the impact that an HPV positive result would have in the context of routine screening. The qualitative literature suggested that psychosexual concerns cover a broad range of aspects relating to women's current and past relationships, both interpersonal and sexual. CONCLUSIONS: The psychosexual impact of testing positive for high-risk cervical HPV is unclear. This review highlights the need for further research in the context of HPV-based cervical screening. As primary HPV testing is introduced more widely, it is important to understand women's responses to testing HPV positive in the cancer screening context to minimise any adverse psychosexual impact.

Peer-led intervention to prevent and reduce STI transmission and improve sexual health in secondary schools (STASH): protocol for a feasibility study.

BACKGROUND: Young people in the UK are at highest risk of sexually transmitted infections and report higher levels of unsafe sex than any other age group. Involving peer supporters in intervention delivery is acceptable to students and effective in reducing risk behaviours via 'diffusion of innovation', particularly where peer supporters are influential in their networks. Informal peer-led interventions offer a useful alternative to peer-led didactic teaching, which has shown limited effects. Building on the successful ASSIST anti-smoking intervention, the 'STis And Sexual Health' (STASH) intervention involves identification and recruitment of the most influential students as peer supporters, training and support to these students by specialist trainers, positive sex and relationships messages, spread by peer supporters to their friendship groups in person and via social media. METHODS/DESIGN: This protocol describes a feasibility trial of the STASH intervention in six schools. It builds on an earlier study phase of intervention co-development using patient and public involvement (PPI) activities, followed by a pilot of intervention components and evaluation tools in one school. Participants are fourth year (S4) students (aged 14-16) in state-funded Scottish secondary schools who have received some level of teacher-led sex education. The previous cohort of S4 students (those completing S4 in the year prior to the intervention) will serve as controls. Data will be collected from controls (month 16), baseline (month 20-21) and follow-up (month 27-30) via a web-based questionnaire, which will measure (and test the reliability of) primary outcome measures for a phase III trial (delayed initiation of/abstinence from sex and consistent condom use), secondary outcomes and mediators of sexual behaviour (including school climate and social networks). The main feasibility outcome is whether the study meets pre-set progression criteria regarding feasibility and acceptability, measured largely via a process evaluation (basic measures in all 6 schools and in-depth in 2-4 schools). An economic evaluation reporting costs alongside consequences will be conducted. DISCUSSION: This study will inform decisions on the feasibility, design and sample size for a phase III effectiveness trial to assess whether the STASH intervention is effective in reducing the risk of sexually transmitted infections in young people. TRIAL REGISTRATION: ISRCTN97369178.

Variant Intestinal-Cell Kinase in Juvenile Myoclonic Epilepsy.

BACKGROUND: In juvenile myoclonic epilepsy, data are limited on the genetic basis of networks promoting convulsions with diffuse polyspikes on electroencephalography (EEG) and the subtle microscopic brain dysplasia called microdysgenesis. METHODS: Using Sanger sequencing, we sequenced the exomes of six members of a large family affected with juvenile myoclonic epilepsy and confirmed cosegregation in all 37 family members. We screened an additional 310 patients with this disorder for variants on DNA melting-curve analysis and targeted real-time DNA sequencing of the gene encoding intestinal-cell kinase ( ICK). We calculated Bayesian logarithm of the odds (LOD) scores for cosegregating variants, odds ratios in case-control associations, and allele frequencies in the Genome Aggregation Database. We performed functional tests of the effects of variants on mitosis, apoptosis, and radial neuroblast migration in vitro and conducted video-EEG studies in mice lacking a copy of Ick. RESULTS: A variant, K305T (c.914A→C), cosegregated with epilepsy or polyspikes on EEG in 12 members of the family affected with juvenile myoclonic epilepsy. We identified 21 pathogenic ICK variants in 22 of 310 additional patients (7%). Four strongly linked variants (K220E, K305T, A615T, and R632X) impaired mitosis, cell-cycle exit, and radial neuroblast migration while promoting apoptosis. Tonic-clonic convulsions and polyspikes on EEG resembling seizures in human juvenile myoclonic epilepsy occurred more often in knockout heterozygous mice than in wild-type mice (P=0.02) during light sleep with isoflurane anesthesia. CONCLUSIONS: Our data provide evidence that heterozygous variants in ICK caused juvenile myoclonic epilepsy in 7% of the patients included in our analysis. Variant ICK affects cell processes that help explain microdysgenesis and polyspike networks observed on EEG in juvenile myoclonic epilepsy. (Funded by the National Institutes of Health and others.).

Filtering genetic variants and placing informative priors based on putative biological function.

High-density genetic marker data, especially sequence data, imply an immense multiple testing burden. This can be ameliorated by filtering genetic variants, exploiting or accounting for correlations between variants, jointly testing variants, and by incorporating informative priors. Priors can be based on biological knowledge or predicted variant function, or even be used to integrate gene expression or other omics data. Based on Genetic Analysis Workshop (GAW) 19 data, this article discusses diversity and usefulness of functional variant scores provided, for example, by PolyPhen2, SIFT, or RegulomeDB annotations. Incorporating functional scores into variant filters or weights and adjusting the significance level for correlations between variants yielded significant associations with blood pressure traits in a large family study of Mexican Americans (GAW19 data set). Marker rs218966 in gene PHF14 and rs9836027 in MAP4 significantly associated with hypertension; additionally, rare variants in SNUPN significantly associated with systolic blood pressure. Variant weights strongly influenced the power of kernel methods and burden tests. Apart from variant weights in test statistics, prior weights may also be used when combining test statistics or to informatively weight p values while controlling false discovery rate (FDR). Indeed, power improved when gene expression data for FDR-controlled informative weighting of association test p values of genes was used. Finally, approaches exploiting variant correlations included identity-by-descent mapping and the optimal strategy for joint testing rare and common variants, which was observed to depend on linkage disequilibrium structure.

Hyperglycosylation and reduced GABA currents of mutated GABRB3 polypeptide in remitting childhood absence epilepsy.

Childhood absence epilepsy (CAE) accounts for 10% to 12% of epilepsy in children under 16 years of age. We screened for mutations in the GABA(A) receptor (GABAR) beta 3 subunit gene (GABRB3) in 48 probands and families with remitting CAE. We found that four out of 48 families (8%) had mutations in GABRB3. One heterozygous missense mutation (P11S) in exon 1a segregated with four CAE-affected persons in one multiplex, two-generation Mexican family. P11S was also found in a singleton from Mexico. Another heterozygous missense mutation (S15F) was present in a singleton from Honduras. An exon 2 heterozygous missense mutation (G32R) was present in two CAE-affected persons and two persons affected with EEG-recorded spike and/or sharp wave in a two-generation Honduran family. All mutations were absent in 630 controls. We studied functions and possible pathogenicity by expressing mutations in HeLa cells with the use of Western blots and an in vitro translation and translocation system. Expression levels did not differ from those of controls, but all mutations showed hyperglycosylation in the in vitro translation and translocation system with canine microsomes. Functional analysis of human GABA(A) receptors (alpha 1 beta 3-v2 gamma 2S, alpha 1 beta 3-v2[P11S]gamma 2S, alpha 1 beta 3-v2[S15F]gamma 2S, and alpha 1 beta 3-v2[G32R]gamma 2S) transiently expressed in HEK293T cells with the use of rapid agonist application showed that each amino acid transversion in the beta 3-v2 subunit (P11S, S15F, and G32R) reduced GABA-evoked current density from whole cells. Mutated beta 3 subunit protein could thus cause absence seizures through a gain in glycosylation of mutated exon 1a and exon 2, affecting maturation and trafficking of GABAR from endoplasmic reticulum to cell surface and resulting in reduced GABA-evoked currents.

Women who report having sex with women: British national probability data on prevalence, sexual behaviors, and health outcomes.

OBJECTIVES: We estimated the prevalence of same-sex experience among women and compared women reporting sex with women and men and women reporting sex exclusively with women with women reporting sex exclusively with men, in terms of sociodemographics and sexual, reproductive, and general health risk behaviors and outcomes. METHODS: We used a British probability survey (n=6399 women, aged 16 to 44 years) conducted from 1999 to 2001 with face-to-face interviewing and computer-assisted self-interviewing. RESULTS: We found that 4.9% of the women reported same-sex partner(s) ever; 2.8% reported sex with women in the past 5 years (n=178); 85.0% of these women also reported male partner(s) in this time. Compared with women who reported sex exclusively with men, women who reported sex with women and men reported significantly greater male partner numbers, unsafe sex, smoking, alcohol consumption, and intravenous drug use and had an increased likelihood of induced abortion and sexually transmitted infection diagnoses (age-adjusted odds ratios=3.07 and 4.41, respectively). CONCLUSIONS: For women, a history of sex with women may be a marker for increased risk of adverse sexual, reproductive, and general health outcomes compared with women who reported sex exclusively with men. A nonjudgmental review of female patients' sexual history should help practitioners discuss risks that women may face.

Bacterial vaginosis in lesbians and bisexual women.

OBJECTIVE: To determine whether bacterial vaginosis (BV) is associated with sexual activity between women. STUDY DESIGN: Cross-sectional survey of 708 new patients attending 2 sexual health clinics for lesbians and bisexual women in London, U.K. Questionnaire for demographic, sexual history, and sexual practice data linked with the results of genitourinary examination. RESULTS: BV was common (31.4%). The odds of BV was significantly associated with larger numbers of female sexual partners (odds ratio [OR], 1.6; confidence interval [CI], 1.05-2.44 for > or = 11 compared with 1-5 partners) and with smoking (OR, 1.43; CI, 1.01-2.03), but not with sex with men or vaginal douching. CONCLUSIONS: BV is common in women who have sex with women (WSW). The increasing odds of BV with larger numbers of female sexual partners suggest that BV may be sexually transmitted between women.