Plos medicine

  1. Correction: Discontinuation and tapering of prescribed opioids and risk of overdose among people on long-term opioid therapy for pain with and without opioid use disorder in British Columbia, Canada: A retrospective cohort study

    by The PLOS Medicine Staff

  2. Combined and progestagen-only hormonal contraceptives and breast cancer risk: A UK nested case–control study and meta-analysis

    by Danielle Fitzpatrick, Kirstin Pirie, Gillian Reeves, Jane Green, Valerie Beral

    Background

    Current or recent use of combined oral contraceptives (containing oestrogen+progestagen) has been associated with a small increase in breast cancer risk. Progestagen-only contraceptive use is increasing, but information on associated risks is limited. We aimed to assess breast cancer risk associated with current or recent use of different types of hormonal contraceptives in premenopausal women, with particular emphasis on progestagen-only preparations.

    Methods and findings

    Hormonal contraceptive prescriptions recorded prospectively in a UK primary care database (Clinical Practice Research Datalink [CPRD]) were compared in a nested case–control study for 9,498 women aged 50 years with incident invasive breast cancer diagnosed in 1996 to 2017, and for 18,171 closely matched controls. On average, 7.3 (standard deviation [SD] 4.6) years of clinical records were available for each case and their matched controls prior to the date of diagnosis. Conditional logistic regression yielded odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer by the hormonal contraceptive type last prescribed, controlled for age, GP practice, body mass index, number of recorded births, time since last birth, and alcohol intake. MEDLINE and Embase were searched for observational studies published between 01 January 1995 and 01 November 2022 that reported on the association between current or recent progestagen-only contraceptive use and breast cancer risk in premenopausal women. Fixed effects meta-analyses combined the CPRD results with previously published results from 12 observational studies for progestagen-only preparations.Overall, 44% (4,195/9,498) of women with breast cancer and 39% (7,092/18,171) of matched controls had a hormonal contraceptive prescription an average of 3.1 (SD 3.7) years before breast cancer diagnosis (or equivalent date for controls). About half the prescriptions were for progestagen-only preparations. Breast cancer ORs were similarly and significantly raised if the last hormonal contraceptive prescription was for oral combined, oral progestagen-only, injected progestagen, or progestagen-releasing intrauterine devices (IUDs): ORs = 1.23 (95% CI [1.14 to 1.32]; p 0.001), 1.26 (95% CI [1.16 to 1.37]; p 0.001), 1.25 (95% CI [1.07 to 1.45]; p = 0.004), and 1.32 (95% CI [1.17 to 1.49]; p 0.001), respectively. Our meta-analyses yielded significantly raised relative risks (RRs) for current or recent use of progestagen-only contraceptives: oral = 1.29 (95% CI [1.21 to 1.37]; heterogeneity χ25 = 6.7; p = 0.2), injected = 1.18 (95% CI [1.07 to 1.30]; heterogeneity χ28 = 22.5; p = 0.004), implanted = 1.28 (95% CI [1.08 to 1.51]; heterogeneity χ23 = 7.3; p = 0.06), and IUDs = 1.21 (95% CI [1.14 to 1.28]; heterogeneity χ24 = 7.9; p = 0.1). When the CPRD results were combined with those from previous published findings (which included women from a wider age range), the resulting 15-year absolute excess risk associated with 5 years use of oral combined or progestagen-only contraceptives in high-income countries was estimated at: 8 per 100,000 users from age 16 to 20 years and 265 per 100,000 users from age 35 to 39 years. The main limitation of the study design was that, due to the nature of the CPRD data and most other prescription databases, information on contraceptive use was recorded during a defined period only, with information before entry into the database generally being unavailable. This means that although our findings provide evidence about the short-term associations between hormonal contraceptives and breast cancer risk, they do not provide information regarding longer-term associations, or the impact of total duration of contraceptive use on breast cancer risk.

    Conclusions

    This study provides important new evidence that current or recent use of progestagen-only contraceptives is associated with a slight increase in breast cancer risk, which does not appear to vary by mode of delivery, and is similar in magnitude to that associated with combined hormonal contraceptives. Given that the underlying risk of breast cancer increases with advancing age, the absolute excess risk associated with use of either type of oral contraceptive is estimated to be smaller in women who use it at younger rather than at older ages. Such risks need be balanced against the benefits of using contraceptives during the childbearing years.

  3. Institutional dashboards on clinical trial transparency for University Medical Centers: A case study

    by Delwen L. Franzen, Benjamin Gregory Carlisle, Maia Salholz-Hillel, Nico Riedel, Daniel Strech

    Background

    University Medical Centers (UMCs) must do their part for clinical trial transparency by fostering practices such as prospective registration, timely results reporting, and open access. However, research institutions are often unaware of their performance on these practices. Baseline assessments of these practices would highlight where there is room for change and empower UMCs to support improvement. We performed a status quo analysis of established clinical trial registration and reporting practices at German UMCs and developed a dashboard to communicate these baseline assessments with UMC leadership and the wider research community.

    Methods and findings

    We developed and applied a semiautomated approach to assess adherence to established transparency practices in a cohort of interventional trials and associated results publications. Trials were registered in ClinicalTrials.gov or the German Clinical Trials Register (DRKS), led by a German UMC, and reported as complete between 2009 and 2017. To assess adherence to transparency practices, we identified results publications associated to trials and applied automated methods at the level of registry data (e.g., prospective registration) and publications (e.g., open access). We also obtained summary results reporting rates of due trials registered in the EU Clinical Trials Register (EUCTR) and conducted at German UMCs from the EU Trials Tracker. We developed an interactive dashboard to display these results across all UMCs and at the level of single UMCs. Our study included and assessed 2,895 interventional trials led by 35 German UMCs. Across all UMCs, prospective registration increased from 33% (n = 58/178) to 75% (n = 144/193) for trials registered in ClinicalTrials.gov and from 0% (n = 0/44) to 79% (n = 19/24) for trials registered in DRKS over the period considered. Of trials with a results publication, 38% (n = 714/1,895) reported the trial registration number in the publication abstract. In turn, 58% (n = 861/1,493) of trials registered in ClinicalTrials.gov and 23% (n = 111/474) of trials registered in DRKS linked the publication in the registration. In contrast to recent increases in summary results reporting of drug trials in the EUCTR, 8% (n = 191/2,253) and 3% (n = 20/642) of due trials registered in ClinicalTrials.gov and DRKS, respectively, had summary results in the registry. Across trial completion years, timely results reporting (within 2 years of trial completion) as a manuscript publication or as summary results was 41% (n = 1,198/2,892). The proportion of openly accessible trial publications steadily increased from 42% (n = 16/38) to 74% (n = 72/97) over the period considered. A limitation of this study is that some of the methods used to assess the transparency practices in this dashboard rely on registry data being accurate and up-to-date.

    Conclusions

    In this study, we observed that it is feasible to assess and inform individual UMCs on their performance on clinical trial transparency in a reproducible and publicly accessible way. Beyond helping institutions assess how they perform in relation to mandates or their institutional policy, the dashboard may inform interventions to increase the uptake of clinical transparency practices and serve to evaluate the impact of these interventions.

  4. Demand creation for HIV testing services: A systematic review and meta-analysis

    by Anjuli D. Wagner, Irene N. Njuguna, Jillian Neary, Kendall A. Lawley, Diana K. N. Louden, Ruchi Tiwari, Wenwen Jiang, Ngozi Kalu, Rachael M. Burke, Dorothy Mangale, Chris Obermeyer, Jaclyn N. Escudero, Michelle A. Bulterys, Chloe Waters, Bastien Mollo, Hannah Han, Magdalena Barr-DiChiara, Rachel Baggaley, Muhammad S. Jamil, Purvi Shah, Vincent J. Wong, Alison L. Drake, Cheryl C. Johnson

    Background

    HIV testing services (HTS) are the first steps in reaching the UNAIDS 95-95-95 goals to achieve and maintain low HIV incidence. Evaluating the effectiveness of different demand creation interventions to increase uptake of efficient and effective HTS is useful to prioritize limited programmatic resources. This review was undertaken to inform World Health Organization (WHO) 2019 HIV testing guidelines and assessed the research question, “Which demand creation strategies are effective for enhancing uptake of HTS?” focused on populations globally.

    Methods and findings

    The following electronic databases were searched through September 28, 2021: PubMed, PsycInfo, Cochrane CENTRAL, CINAHL Complete, Web of Science Core Collection, EMBASE, and Global Health Database; we searched IAS and AIDS conferences. We systematically searched for randomized controlled trials (RCTs) that compared any demand creation intervention (incentives, mobilization, counseling, tailoring, and digital interventions) to either a control or other demand creation intervention and reported HTS uptake. We pooled trials to evaluate categories of demand creation interventions using random-effects models for meta-analysis and assessed study quality with Cochrane’s risk of bias 1 tool. This study was funded by the WHO and registered in Prospero with ID CRD42022296947.We screened 10,583 records and 507 conference abstracts, reviewed 952 full texts, and included 124 RCTs for data extraction. The majority of studies were from the African (N = 53) and Americas (N = 54) regions. We found that mobilization (relative risk [RR]: 2.01, 95% confidence interval [CI]: [1.30, 3.09], p 0.05; risk difference [RD]: 0.29, 95% CI [0.16, 0.43], p 0.05, N = 4 RCTs), couple-oriented counseling (RR: 1.98, 95% CI [1.02, 3.86], p 0.05; RD: 0.12, 95% CI [0.03, 0.21], p 0.05, N = 4 RCTs), peer-led interventions (RR: 1.57, 95% CI [1.15, 2.15], p 0.05; RD: 0.18, 95% CI [0.06, 0.31], p 0.05, N = 10 RCTs), motivation-oriented counseling (RR: 1.53, 95% CI [1.07, 2.20], p 0.05; RD: 0.17, 95% CI [0.00, 0.34], p 0.05, N = 4 RCTs), short message service (SMS) (RR: 1.53, 95% CI [1.09, 2.16], p 0.05; RD: 0.11, 95% CI [0.03, 0.19], p 0.05, N = 5 RCTs), and conditional fixed value incentives (RR: 1.52, 95% CI [1.21, 1.91], p 0.05; RD: 0.15, 95% CI [0.07, 0.22], p 0.05, N = 11 RCTs) all significantly and importantly (≥50% relative increase) increased HTS uptake and had medium risk of bias.Lottery-based incentives and audio-based interventions less importantly (25% to 49% increase) but not significantly increased HTS uptake (medium risk of bias). Personal invitation letters and personalized message content significantly but not importantly (25% increase) increased HTS uptake (medium risk of bias). Reduced duration counseling had comparable performance to standard duration counseling (low risk of bias) and video-based interventions were comparable or better than in-person counseling (medium risk of bias). Heterogeneity of effect among pooled studies was high. This study was limited in that we restricted to randomized trials, which may be systematically less readily available for key populations; additionally, we compare only pooled estimates for interventions with multiple studies rather than single study estimates, and there was evidence of publication bias for several interventions.

    Conclusions

    Mobilization, couple- and motivation-oriented counseling, peer-led interventions, conditional fixed value incentives, and SMS are high-impact demand creation interventions and should be prioritized for programmatic consideration. Reduced duration counseling and video-based interventions are an efficient and effective alternative to address staffing shortages. Investment in demand creation activities should prioritize those with undiagnosed HIV or ongoing HIV exposure. Selection of demand creation interventions must consider risks and benefits, context-specific factors, feasibility and sustainability, country ownership, and universal health coverage across disease areas.

  5. Recording of intellectual disability in general hospitals in England 2006–2019: Cohort study using linked datasets

    by Rory Sheehan, Hassan Mansour, Matthew Broadbent, Angela Hassiotis, Christoph Mueller, Robert Stewart, Andre Strydom, Andrew Sommerlad

    Background

    Accurate recognition and recording of intellectual disability in those who are admitted to general hospitals is necessary for making reasonable adjustments, ensuring equitable access, and monitoring quality of care. In this study, we determined the rate of recording of intellectual disability in those with the condition who were admitted to hospital and factors associated with the condition being unrecorded.

    Methods and findings

    Retrospective cohort study using 2 linked datasets of routinely collected clinical data in England. We identified adults with diagnosed intellectual disability in a large secondary mental healthcare database and used general hospital records to investigate recording of intellectual disability when people were admitted to general hospitals between 2006 and 2019. Trends over time and factors associated with intellectual disability being unrecorded were investigated. We obtained data on 2,477 adults with intellectual disability who were admitted to a general hospital in England at least once during the study period (total number of admissions = 27,314; median number of admissions = 5). People with intellectual disability were accurately recorded as having the condition during 2.9% (95% CI 2.7% to 3.1%) of their admissions. Broadening the criteria to include a nonspecific code of learning difficulty increased recording to 27.7% (95% CI 27.2% to 28.3%) of all admissions. In analyses adjusted for age, sex, ethnicity, and socioeconomic deprivation, having a mild intellectual disability and being married were associated with increased odds of the intellectual disability being unrecorded in hospital records. We had no measure of quality of hospital care received and could not relate this to the presence or absence of a record of intellectual disability in the patient record.

    Conclusions

    Recognition and recording of intellectual disability in adults admitted to English general hospitals needs to be improved. Staff awareness training, screening at the point of admission, and data sharing between health and social care services could improve care for people with intellectual disability.

  6. Incidence, risk factors, and clinical outcomes of HBV reactivation in non-liver solid organ transplant recipients with resolved HBV infection: A systematic review and meta-analysis

    by Saifu Yin, Fan Zhang, Jiapei Wu, Tao Lin, Xianding Wang

    Background

    Current guidelines do not recommend routine antiviral prophylaxis to prevent hepatitis B virus (HBV) reactivation in non-liver solid organ transplant (SOT) recipients with resolved HBV infection, even in anti-hepatitis B surface antigen (anti-HBs)-negative recipients and those receiving intense immunosuppression. This systematic review and meta-analysis aimed to determine the incidence, risk factors, and clinical outcomes of HBV reactivation in non-liver SOT recipients.

    Methods and findings

    Three databases (PubMed, Embase, and Cochrane Library) were systematically searched up to December 31, 2022. Clinical studies reporting HBV reactivation in non-liver SOT recipients were included. Case reports, case series, and cohort studies with a sample size of less than 10 patients were excluded. Random-effects analysis was used for all meta-analyses. We included 2,913 non-liver SOT recipients with resolved HBV infection from 16 retrospective cohort studies in the analysis. The overall HBV reactivation rate was 2.5% (76/2,913; 95% confidence interval [95% CI 1.6%, 3.6%]; I2 = 55.0%). Higher rates of reactivation were observed in recipients with negative anti-HBs (34/421; 7.8%; 95% CI [5.2%, 10.9%]; I2 = 36.0%) by pooling 6 studies, experiencing acute rejection (13/266; 5.8%; 95% CI [2.3%, 14.5%]; I2 = 63.2%) by pooling 3 studies, receiving ABO blood type-incompatible transplantation (8/111; 7.0%; 95% CI [2.9%, 12.7%]; I2 = 0%) by pooling 3 studies, receiving rituximab (10/133; 7.3%; 95% CI [3.4%, 12.6%]; I2 = 0%) by pooling 3 studies, and receiving anti-thymocyte immunoglobulin (ATG, 25/504; 4.9%; 95% CI [2.5%, 8.1%]; I2 = 49.0%) by pooling 4 studies. Among recipients with post-transplant HBV reactivation, 11.0% (7/52; 95% CI [4.0%, 20.8%]; I2 = 0.3%) developed HBV-related hepatic failure, and 11.0% (7/52; 95% CI [4.0%, 20.8%]; I2 = 0.3%) had HBV-related death. Negative anti-HBs (crude odds ratio [OR] 5.05; 95% CI [2.83, 9.00]; p 0.001; I2 = 0%), ABO blood type-incompatible transplantation (crude OR 2.62; 95% CI [1.05, 6.04]; p = 0.040; I2 = 0%), history of acute rejection (crude OR 2.37; 95% CI [1.13, 4.97]; p = 0.022; I2 = 0%), ATG use (crude OR 3.19; 95% CI [1.48, 6.87]; p = 0.003; I2 = 0%), and rituximab use (crude OR 3.16; 95% CI [1.24, 8.06]; p = 0.016; I2 = 0%) increased the risk of reactivation. Adjusted analyses reported similar results. Limitations include moderate heterogeneity in the meta-analyses and that most studies were conducted in kidney transplant recipients.

    Conclusions

    Non-liver SOT recipients with resolved HBV infection have a high risk of HBV-related hepatic failure and HBV-related death if HBV reactivation occurs. Potential risk factors for HBV reactivation include rituximab use, anti-thymocyte immunoglobulin use, anti-HBs negative status, acute rejection history, and ABO blood type-incompatible transplantation. Further research on monitoring and routine antiviral prophylaxis of non-liver SOT recipients at higher risk of HBV reactivation is required.

  7. The future of HIV testing in eastern and southern Africa: Broader scope, targeted services

    by Anna Grimsrud, Lynne Wilkinson, Peter Ehrenkranz, Stephanie Behel, Thato Chidarikire, Tina Chisenga, Rachel Golin, Cheryl Case Johnson, Maureen Milanga, Obinna Onyekwena, Maaya Sundaram, Vincent Wong, Rachel Baggaley

    In this Policy Forum, Anna Grimsrud and colleagues discuss the future of HIV testing in eastern and southern Africa, using insights gleaned from a 2021 expert consultation.